A Phase II, Randomised, Adaptive, Open-Label Platform Trial To Evaluate Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B
Phase: PHASE2
Conditions: Hepatitis B, Chronic
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase II, Randomised, Adaptive, Open-Label Platform Trial to 
Evaluate Efficacy and Safety of Multiple Combination Therapies in 
Participants with Chronic Hepatitis B 
NCT Number: 
NCT04225715 
Document Date: 
Protocol Amendment Version 7: 18-July-2022 
 
 
 

CONFIDENTIAL 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
Protocol WV41073, Version 7.0 
 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMISED, ADAPTIVE, OPEN-LABEL 
PLATFORM TRIAL TO EVALUATE EFFICACY AND 
SAFETY OF MULTIPLE COMBINATION THERAPIES IN 
PARTICIPANTS WITH CHRONIC HEPATITIS B 
PROTOCOL NUMBER: 
WV41073 
VERSION: 
7.0  
EUDRACT NUMBER: 
2019-002086-35 
IND NUMBER: 
141485 
TEST PRODUCT: 
RO7049389, RO7020531, RO7445482, RO7191863 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic signature and date stamp on the final page of this 
document 
DATE AMENDED: 
Version 1: 13 June 2019 
 
Version 2: 25 November 2019 
 
Version 3: 20 July 2020 
 
Version 4: 14 October 2020 
 
Version 5: 25 August 2021 
 
Version 6: 16 December 2021 
 
Version 7: See electronic signature and date stamp on the 
final page of this document. 
 
 

Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
2/Protocol WV41073, Version 7.0 
 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE II, RANDOMISED, ADAPTIVE, OPEN-LABEL 
PLATFORM TRIAL TO EVALUATE EFFICACY AND 
SAFETY OF MULTIPLE COMBINATION THERAPIES IN 
PARTICIPANTS WITH CHRONIC HEPATITIS B 
PROTOCOL NUMBER: 
WV41073 
VERSION NUMBER: 
7.0 
EUDRACT NUMBER: 
2019-002086-35 
IND NUMBER: 
141485 
TEST PRODUCT: 
RO7049389, RO7020531, RO7445482, RO7191863 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files, and return a copy to your local 
Study Monitor. 
 

Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
3/Protocol WV41073, Version 7.0 
PROTOCOL AMENDMENT, VERSION 7 
RATIONALE 
Protocol WV41073 Version 7 has been amended with the following changes to the 
global protocol. The key changes in WV41073 protocol along with a rationale for the 
changes have been summarized below:  
 
Section 4.1 has been updated to justify additional recruitment of participants in each 
treatment arm due to significant number of participants with consecutive missing 
visits as a result of COVID-19 lockdown and restrictions, with potential impact on the 
evaluation of the primary endpoint due to incomplete data.  
 
Section 6.8, the nucleoside analogue (NUC) stopping criteria have been amended 
to take into account participants with very low HBsAg levels at baseline and to 
prevent participants from stopping NUCs who have not demonstrated more than 
1 log10 IU/mL decline in HBsAg after the end of treatment. 
 
 Section 8.3.8.2 was amended to ensure patients who have discontinued NMEs 
and/or NUC therapy are monitored closely, to enable early detection and prompt 
management of virological relapse to prevent participants potentially developing 
liver decompensation. NUC re-starting criteria were amended as a precautionary 
measure based on feedback received from study Investigators, the publication of a 
case report from a non-Roche clinical trial in a similar patient population, and 
feedback received from liver and HBV experts and not based on any safety findings 
from this study. 
 
Section 8.3.8.3, for elevated ALT management where twice weekly laboratory tests 
are recommended, local laboratory tests may be performed in addition to central 
laboratory for participant’s ALT monitoring and management and decision-making 
may be based on local laboratory results   
 
Section 9.2 and Section 9.4.2 has been updated accordingly due to the additional 
recruitment of participant  
 
Section 4.2.3, 8.7.3 and Section 3, Table 1 and all Appendices tables for Screening 
and Treatment Periods, footnote ‘h’ was clarified for HBV genotyping by alternative 
methodologies.    
 
Appendix 7-Table 2, Appendix 9-Table 4, Appendix 10-Table 4, Appendix 12-Table 
5 and Appendix 13-Table 9, the 24-week primary endpoint follow-up visit window is 
extended to accommodate individual participants encountering extreme 
circumstances such as pandemic, natural disasters etc. without compromising the 
scientific integrity of the analysis. 
 
Appendix 7-Table 2, Appendix 9-Table 4, Appendix 10-Table 4, Appendix 12-
Table 5 and Appendix 13-Table 9, footnote added to the HBV DNA quantitative 
assessment for close monitoring to enable early detection and prompt management 
of virological relapse 
 
Appendix 12-Table 4, Footnote ‘x’ added to provide further guidance regarding 
24 hour pooled urine collection for siRNA PK.  

Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
4/Protocol WV41073, Version 7.0 
 
Appendix 13 has been updated to confirm dose selected and provide dose 
justification for 
, including preliminary pre-clinical 
AAV-HBV data supporting the rationale for combining PD-L1 LNA and siRNA.  
 
Appendix 13-Table 7 and Table 8 have been amended to remove PD-L1 LNA 
dosing regimens that are no longer applicable. 
 
Appendix 13-Table 7, hematology panel has been added at Week 20, Week 22, and 
Week 24, and urinalysis at Week 14 and Week 16, which was omitted in error. 
 
Appendix 13-Table 8 has been amended so that laboratory assessments are 
performed weekly and not every other week i.e., laboratory assessments performed 
at Weeks 26, 28, 30, 32, 34, and 36 to be consistent with 24-week treatment arm 
(Appendix 13-Table 7) and the selection of a weekly dosing regimen. This is not 
related to any new safety concerns or any new safety data.  
 
Appendix 13 – Section 13.4 has been amended to address inconsistency and to 
avoid repetition the text in Section 13.6 has been removed and updated to refer the 
reader to Appendix 13 - Section 13.4.  
 
Appendix 13 – Section 13.10.1 has been updated to align discrepant text with the 
timepoints outlined in Table 7 and Table 8. 
 
Appendix 13 – Section 13.11.1 has been updated to remove text regarding the 
collection of exploratory kidney biomarkers which were not included in Table 7 and 
Table 8. 
 
Appendix 13-Table 9, added the note regarding frequency of visits for those 
participants who discontinue NUC therapy later in follow up which was omitted in 
error. 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol. 
 

Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
5/Protocol WV41073, Version 7.0 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM………………………………………………….2 
1. 
PROTOCOL SUMMARY ............................................................... 14 
1.1 
Synopsis .................................................................................. 14 
1.2 
Schematic of Study Design ...................................................... 20 
1.3 
Schedule of Activities ............................................................... 22 
2. 
INTRODUCTION ........................................................................... 22 
2.1 
Study Rationale ....................................................................... 22 
2.2 
Background.............................................................................. 23 
2.2.1 
Chronic Hepatitis B .................................................................. 23 
2.2.2 
Currently Available Therapies .................................................. 23 
2.3 
Benefit/Risk Assessment ......................................................... 24 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 24 
4. 
STUDY DESIGN ........................................................................... 26 
4.1 
Overall Design ......................................................................... 26 
4.1.1 
Length of the Study .................................................................. 27 
4.2 
Scientific Rationale for Study Design ....................................... 27 
4.2.1 
Rationale for Study Population ................................................ 28 
4.2.2 
Rationale for Control Treatment arm ....................................... 28 
4.2.3 
Rationale for Biomarker Assessments ..................................... 28 
4.3 
Justification for Dose ............................................................... 30 
4.4 
End-of-study Definition ............................................................ 30 
5. 
STUDY POPULATION .................................................................. 30 
5.1 
Inclusion Criteria ...................................................................... 30 
5.2 
Exclusion Criteria ..................................................................... 32 
5.3 
Lifestyle Considerations ........................................................... 34 
5.4 
Screen Failures ........................................................................ 34 
6. 
STUDY TREATMENTS ................................................................. 35 
6.1 
Treatments Administered ......................................................... 35 
6.2 
Preparation/Handling/Storage/Accountability........................... 35 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....... 36 

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6.4 
Treatment Compliance ............................................................ 36 
6.4.1 
Method of Treatment Assignment ............................................ 36 
6.5 
Concomitant Therapy .............................................................. 37 
6.5.1 
Permitted Therapy ................................................................... 38 
6.5.2 
Administrative Structure ........................................................... 38 
6.5.3 
Prohibited Therapy .................................................................. 38 
6.6 
Dose Modification .................................................................... 38 
6.7 
Treatment after the End of the Study ....................................... 38 
6.8 
CRITERIA FOR STOPPING NUCLEOSIDE ANALOGUE ....... 39 
7. 
DISCONTINUATION OF STUDY TREATMENT, 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
THE STUDY AND LOST TO FOLLOW-UP ................................... 39 
7.1 
Discontinuation/Interruption of Study Treatment ...................... 39 
7.2 
Participant Discontinuation/Withdrawal from the Study ........... 41 
7.3 
Lost to Follow-Up ..................................................................... 41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 42 
8.1 
Efficacy Assessments .............................................................. 43 
8.2 
Safety Assessments ................................................................ 43 
8.2.1 
Physical Examinations ............................................................. 43 
8.2.2 
Vital Signs ................................................................................ 44 
8.2.3 
Electrocardiograms .................................................................. 44 
8.2.4 
Liver Imaging Assessments ..................................................... 45 
8.2.5 
Clinical Safety Laboratory Assessments .................................. 46 
8.2.6 
Medical History and Demographic Data .................................. 47 
8.3 
Adverse Events and Serious Adverse Events ......................... 47 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 47 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 48 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 48 
8.3.3.1 
Investigator Follow-Up ............................................................. 48 
8.3.3.2 
Sponsor Follow-Up .................................................................. 49 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 49 

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8.3.4.1 
Emergency Medical Contacts .................................................. 49 
8.3.5 
Pregnancy................................................................................ 49 
8.3.6 
Adverse Events of Special Interest .......................................... 50 
8.3.7 
Disease-Related Events Not Qualifying as Adverse Events .... 50 
8.3.8 
Management of Specific Adverse Events ................................ 51 
8.3.8.1 
Management of Virological Breakthrough ................................ 51 
8.3.8.2 
Management of Virological Relapse ........................................ 51 
8.3.8.3 
Management of Elevated Alanine Aminotransferase (ALT) 
Levels ...................................................................................... 52 
8.3.8.4 
Management of NME-Related AEs .......................................... 54 
8.4 
Treatment of Overdose ............................................................ 54 
8.5 
Pharmacokinetics .................................................................... 54 
8.6 
Immunogenicity Assessments ................................................. 54 
8.7 
Pharmacodynamics and Biomarkers Assessments ................. 55 
8.7.1 
HBV Dynamic Biomarker Assessments ................................... 55 
8.7.2 
HBV DNA Monitoring ............................................................... 55 
8.7.3 
HBV Genome Sequencing ....................................................... 55 
8.7.4 
Genetic and Genomic Analyses ............................................... 56 
8.7.4.1 
Clinical Genotyping .................................................................. 56 
8.7.4.2 
Transcriptome Analysis ........................................................... 56 
8.8 
Pharmacodynamics and Biomarker Samples .......................... 56 
8.8.1 
Mandatory Samples ................................................................. 57 
8.8.1.1 
Blood Sampling ........................................................................ 57 
8.8.1.2 
Urine Sampling ........................................................................ 57 
8.9 
Samples for Research Biosample Repository.......................... 57 
8.9.1 
Overview of the Research Biosample Repository .................... 57 
8.9.2 
Sample Collection .................................................................... 58 
8.10 
Health Economics .................................................................... 58 
8.11 
Timing of Study Assessments .................................................. 58 
8.11.1 
Screening and Pre-treatment Assessments............................. 58 
8.11.2 
Assessments during Treatment ............................................... 59 
8.11.3 
Assessments at Study Completion .......................................... 59 
8.11.4 
Follow-up Assessments ........................................................... 59 

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8.11.5 
Assessments at Unscheduled Visits/Early termination Visit .... 59 
9. 
STATISTICAL CONSIDERATIONS .............................................. 59 
9.1 
Statistical Hypotheses ............................................................. 60 
9.2 
Sample Size Determination ..................................................... 60 
9.3 
Populations for Analyses ......................................................... 61 
9.4 
Statistical Analyses .................................................................. 61 
9.4.1 
Demographics and Baseline Characteristics ........................... 61 
9.4.2 
Efficacy Analyses ..................................................................... 61 
9.4.3 
Safety Analyses ....................................................................... 62 
9.4.4 
Pharmacokinetic Analyses ....................................................... 63 
9.4.5 
Immunogenicity Analyses ........................................................ 64 
9.4.6 
Pharmacodynamic Analyses .................................................... 64 
9.4.7 
Pharmacokinetic/ Pharmacodynamic Relationships ................ 64 
9.5 
Interim Analyses ...................................................................... 64 
9.6 
Summaries of Conduct of Study .............................................. 66 
10. 
REFERENCES.............................................................................. 67 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................... 72 
 
 
LIST OF TABLES 
Table 1 
Objectives and Endpoints ........................................................... 25 
Table 2 
All Combination Arms: General Criteria for Dose 
Interruptions/Discontinuations for All New Molecular Entities ..... 40 
Table 3 
Analysis Populations ................................................................... 61 
Table 4 
Efficacy Statistical Analysis Methods .......................................... 62 
Table 5 
Safety Statistical Analysis Methods ............................................ 63 
 
 
LIST OF FIGURES 
Figure 1 
Principle Elements of the Planned Platform Study Design .......... 21 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........... 73 

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Appendix 2 
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up, and Reporting ............................................................ 83 
Appendix 3 
Procedures for Recording Adverse Events ................................. 93 
Appendix 4 
Clinical Laboratory Tests ............................................................ 98 
Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................ 101 
Appendix 6 
Planned, Ongoing, and Terminated Treatment Arms And 
Terminated Arm Safety Follow Up ............................................ 106 
Appendix 7 
Study Details Specific to NUC Control Arm............................... 109 
Appendix 8 
Study Details Specific to CpAM (RO7049389) + TLR7 
(RO7020531) + NUC Arm ......................................................... 115 
Appendix 9 
Study Details Specific to siRNA (RO7445482) + NUC Arms .... 140 
Appendix 10 Study Details Specific to siRNA (RO7445482) + PEG-IFN + 
NUC Arm................................................................................... 155 
Appendix 11 Study Details Specific to siRNA (RO7445482) + CpAM 
(RO7049389) + NUC Arm ......................................................... 173 
Appendix 12 Study Details Specific to siRNA (RO7445482) + TLR7 
(RO7020531) + NUC Arm ......................................................... 188 
Appendix 13 Study Details Specific to siRNA (RO7445482) + PD-L1 LNA 
(RO7191863) + NUC Arms ....................................................... 211 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AAV-HBV 
Recombinant adeno-associated virus carrying hepatitis 
B virus genome 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibodies 
ANA 
Antinuclear antibody 
ASGPR 
asialoglycoprotein receptor 
ASMA 
Anti–smooth muscle antibody 
ARFI 
Acoustic radiation force impulse 
AST 
Aspartate aminotransferase 
a-TPO 
Anti-thyroperoxidase antibodies 
AUC 
Area under the curve 
BID 
Twice daily 
CAP 
Controlled attenuation parameter 
cccDNA 
Covalently closed circular deoxyribonucleic acid 
CHB 
Chronic hepatitis B 
CL 
Clearance 
CM 
Composite measure 
Cmax 
Peak concentration 
CpAM 
Core protein allosteric modulator 
CRS 
cytokine release syndrome 
CSR 
Clinical study report 
CYP 
Cytochrome P450  
DAA 
Direct-acting antiviral 
DDI 
Drug-drug interaction 
DAIDs 
Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIH 
Entry-into-human 

 
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11/Protocol WV41073, Version 7.0 
EOT 
End-of-treatment 
ETV 
Entecavir 
EU 
European Commission 
EV 
Extracellular vesicle 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GalNAc 
N-acetyl-D-galactosamine 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
HA 
Health Authority 
HAP 
Heteroaryldihydropyrimidine 
HAV 
Hepatitis A 
HBcrAg 
Hepatitis B core-related antigen 
HBeAg 
Hepatitis B early antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDV 
Hepatitis D virus 
HDL 
High-density lipoproteins 
HEV 
Hepatitis E virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HV 
Healthy volunteers 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IM 
Immunomodulatory agent 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IP-10 
Interferon gamma-induced protein 10 
IRB 
Institutional Review Board 
IR 
Injection reaction 

 
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ISG 
Interferon-stimulated genes 
ISR 
Injection site reaction 
IVRS/IWRS 
Interactive Voice/Web Response System 
LDL 
Low-density lipoproteins 
LFT 
Liver function test 
LLN 
Lower limits of normal 
LLOQ 
Lower limit of quantification 
LNA 
Locked nucleic acid 
LPLV 
Last participant, last visit 
MDRD 
Modification of Diet in Renal Disease 
mISR 
Modified injection site reaction 
MN 
Mobile nursing 
MR 
Magnetic resonance 
NIMP 
Non-investigational medicinal product 
NK 
Natural killer 
NME 
New molecular entity 
NPLC 
non-parenchymal liver cells 
NUC 
Nucleos(t)ide  
OATP 
Organic anion transporter polypeptide 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
pDC 
Plasmacytoid dendritic cells 
PD-L1 
Programmed Death Ligand-1  
PEG IFN-α 
Pegylated interferon-alpha 
pgRNA 
Pre-genomic ribonucleic acid 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
QD 
Once a day 
QOD 
Once every other day 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate using the Bazett’s 
correction factor 
QTcF 
QT corrected for heart rate using the Fridericia’s 
correction factor 
QW 
Once a week 
Q4W 
Every 4 weeks 

 
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RBC 
Red blood cell 
RBR 
Research biosample repository 
RISC 
RNA-induced silencing complex 
RGT 
Response-guided therapy 
RNA 
Ribonucleic acid 
RO7049389 
CpAM 
RO7020531 
TLR7 
RO7445482 
siRNA 
RUO 
Research-use only 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous 
siRNA 
Short interfering RNA 
SoA 
Schedule of activities 
SOC 
Scientific Oversight Committee 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TAF 
Tenofovir alafenamide 
TBD 
To be determined 
TDF 
Tenofovir disoproxil fumarate 
TLR7 
Toll-like receptor 7 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-childbearing potential 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
14/Protocol WV41073, Version 7.0 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II, RANDOMISED, ADAPTIVE, OPEN-LABEL 
PLATFORM TRIAL TO EVALUATE EFFICACY AND SAFETY OF 
MULTIPLE COMBINATION THERAPIES IN PARTICIPANTS WITH 
CHRONIC HEPATITIS B 
SHORT TITLE 
COMBINATION THERAPIES FOR CHB 
PROTOCOL NUMBER: 
WV41073 
VERSION: 
7.0 
TEST PRODUCT: 
RO7049389, RO7020531, RO7445482, RO7191863 
PHASE: 
II  
 
STUDY RATIONALE 
Chronic hepatitis B (CHB) virus infection is a major global healthcare problem, with an estimated 
prevalence of 257 million people. Current treatments reduce the risk of CHB sequelae but are 
associated with very low rates of functional cure (hepatitis B surface antigen [HBsAg] loss rates 
generally not exceeding 3% after one year of therapy).  
Multi-drug therapies with compounds targeting different steps in viral replication or combinations 
with drugs that restore the innate and/or adaptive host immune responses are presumably more 
likely to be efficacious than monotherapy. New treatment regimens may be more likely to achieve 
functional cure by a combination of multiple direct antiviral mechanisms or through the 
augmentation of anti-hepatitis B virus (HBV) immune responses.  
The Sponsor intends to identify finite-duration combination therapies including one or more new 
molecular entities (NMEs), that are associated with high rates of sustained loss of HBsAg 
( 0.05 IU/mL; functional cure) using the present platform Phase 2 study. 
Platform studies have the objective to study multiple therapies in the context of a single disease, 
with therapies allowed to enter or leave the platform based on availability and emerging data. 
Thus, the Sponsor plans to study combination therapies employing a master protocol, where 
combination therapies can enter the study in a dynamic manner after obtaining Health Authority 
(HA)/Ethics Committee (EC) approval of subsequent protocol amendments. 

 
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OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To estimate the effect of NME 
combination therapies on inducing a 
functional cure over the control arm. 
 
% participants with HBsAg loss at 
24 weeks post-EOT.  
Secondary a 
 
To characterize the efficacy profile of 
NME combination therapies. 
 
% participants with HBsAg loss.  
 
% participants with HBsAg 
seroconversion.  
 
% participants with HBeAg loss 
(baseline HBeAg-positive participants). 
 
% participants with HBeAg 
seroconversion (baseline 
HBeAg-positive participants). 
 
% participants with HBV DNA < lower 
limit of quantification (LLOQ),  200 
IU/mL and  2,000 IU/mL. 
 
To characterize the PD profile of NME 
combination therapies. 
 
Including but not limited to: change 
from baseline in quantitative HBsAg, 
anti-HBs, HBeAg, anti-HBe, anti-HBc, 
HBcrAg, HBV RNA, and HBV DNA 
levels over time. 
 
To characterize the plasma PK profiles 
of NMEs.  
 
Estimated PK parameters from sparse 
sampling and population PK models. 
 
To assess the safety and tolerability of 
NME combination therapies. 
 
Incidence, nature, and severity of AEs 
and laboratory abnormalities. 
 
To identify presence of PK/PD 
relationship.  
 
Analyses of PK/PD data. 
 
To explore potential effects of ADA on 
NMEs and/or IMP, as applicable. 
 
Relationship between ADA status, PK, 
safety, PD, and efficacy. 
Abbreviations:  %=percent; AE=adverse event; DNA=deoxyribonucleic acid; EOT=end-of-
treatment; HBcrAg=hepatitis B core-related antigen; HBeAg=hepatitis B e antigen; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; LLOQ=lower limit of quantification; 
NME=new molecular entity; NUC=nucleos(t)ides; PD=pharmacodynamic; 
PK=pharmacokinetic; RNA=ribonucleic acid. 
a Efficacy and PD endpoints are assessed at every 12-week time point. 
 
 

 
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OVERALL DESIGN 
STUDY DESIGN 
This is a Phase II, randomized, adaptive, open-label, multi-arm, multi-center, international, 
platform study designed to evaluate safety, tolerability, and efficacy of new combination therapies 
including one or more NMEs in CHB participants with preserved liver function and without 
significant fibrosis/cirrhosis. The platform design allows comparison of multiple new combination 
therapies against a common control, and introduction of additional treatment arms at later study 
time points.  
This study is designed to be adaptive to open additional shorter duration treatment arms or to 
expand existing treatment arms for NME combination therapies that show promising efficacy 
outcomes. The platform design also has the flexibility to open new treatment arms to explore 
different combination regimens or different patient populations pending new submission and 
HA/EC approval. Based on emerging data and/or company prioritization of assets, treatment 
arms may be terminated early or not opened for randomization or certain NMEs in the 
combination treatment arm might be terminated while therapy is maintained with the remaining 
NMEs. The Sponsor will notify the Investigator and HA/EC if the study or certain treatment arms 
or certain NMEs are placed on hold, or if the Sponsor decides to discontinue certain treatment 
arms or certain NMEs. 
For the first combination, participants will be randomized on Day 1 to an NME combination arm 
(N=30) or the control arm (N=30) using an adaptive stratified sampling method, stratified at 
screening HBsAg level ( 1,000 IU/mL,  1000 IU/mL), with a minimum of 12 participants per arm 
with a screening HBsAg level of  1000 IU/mL. For NME combination arms that will be introduced 
later into the platform study, the allocation ratio of participants to the control arm, will depend on 
the number of actively enrolling arms with the stipulation that no more than 17% of participants 
will be randomly allocated to a control arm. Additionally, for subsequent arms the proportion of 
patients with HBsAg level  1000 IU/mL,  1000 IU/mL within each treatment arm, will be 
maintained as closely as possible to the first combination treatment arm. 
Due to strict lockdowns and restrictions in China in March - May 2022, as of 31 May 2022 approximately 
30-53% of participants in each treatment arm have missed study visits and siRNA drug administration at 
the site.  As a result, a number of participants have consecutive visits missed with potential impact on the 
evaluation of the primary endpoint due to incomplete data. To preserve the viability of the study, if 
COVID-19 restrictions continue, or any future COVID-19 outbreaks or any force majeure (e.g. natural 
disasters, supply chain disruption, outbreak of hostilities etc.) impacting participants, will lead to 
additional participants being recruited to the study to ensure that the number of participants per treatment 
arm with the full dose as per the randomized dose regimen remains approximately 30. The maximum 
number of additional participants to be recruited will be approximately 30 for each treatment arm. 
The treatment period duration will be a maximum of 48 weeks, after which participants will enter a 
48-week follow-up period. Treatment duration may be shortened (12 or 24 weeks) for 48 week 
NME combination arms, and/or a response-guided therapy (RGT) arm may be added following 
planned interim analyses; up to four planned interim analyses will be conducted for each 
treatment arm. Treatment arms that achieve 30% difference, compared to NUC control arm, for 
HBsAg loss at EOT or follow-up Weeks 12 and 24 (primary endpoint) may be expanded to accrue 
additional efficacy and safety data and to contribute to Phase 3 design planning as guided by the 
emerging data, for example, enrichment for HBeAg-positive or HBeAg-negative participant 
populations. An expansion may also be triggered prior to EOT, for a treatment arm that gives an 
early indication of efficacy. The decision criteria to trigger an expansion arm in this case, will be 
documented as an appendix to the IMC/Scientific Oversight Committee (SOC) charter. 
 
 
 

 
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LENGTH OF STUDY 
The total length of the study, from screening of the first participant to the end-of-study, is 
expected to be approximately 3 to 5 years, depending on the number and timing of additional 
treatments arms that are added to the study.  
The study duration for each participant will be approximately 2 years divided as follows: 
 
Screening period: up to 8 weeks. 
 
Treatment period: up to 48 weeks. 
 
Safety follow-up period: 48 weeks. 
 
END-OF-STUDY 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last study visit. The end-of-study is defined as the date when the last 
participant completes the last visit (LPLV). 
 
DATA MONITORING COMMITTEE: YES  
An Internal Monitoring Committee and a Scientific Oversite Committee will be utilized in this study. 
 
PARTICIPANT POPULATION 
The study will enroll CHB participants with preserved liver function and without significant 
fibrosis/cirrhosis.  
The initial study population will consist of virologically suppressed CHB participants on 
established NUC therapy between 18 and 65 years of age, inclusive. Additional participant 
populations (e.g., treatment naïve CHB participants) may be explored within the study in 
treatment arms to be added at a later date pending new submission and HA/EC approval. 
 
INCLUSION/EXCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following inclusion criteria 
apply: 
Informed Consent 
1. Able and willing to provide written informed consent and to comply with the study 
protocol according to International Council for Harmonization (ICH) and local 
regulations. 
 
Age 
2. Participants must be between 18 and 65 years of age, inclusive, at the time of signing 
the informed consent. 
 
Weight 
3. Body mass index between 18 and 32 kg/m2 inclusive. 
 
Type of Participants and Disease Characteristics 
4. Participants with CHB infection (HBsAg positive for  6 months) who are on NUC 
(entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy for 2 months, 
having received the same NUC therapy for 3 months prior to screening.  
5. HBV DNA below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and 
confirmed at screening.  
6. Alanine transaminase (ALT)  1.5 x upper limit of normal (ULN) for > 6 months prior to 
screening, and confirmed at screening  
7. Screening laboratory values (hematology, chemistry, urinalysis) within normal range, or 
judged not clinically significant by the Investigator. 
 
 
 

 
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Sex 
8. Male and female participants:  
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of preventing fetal/embryonic drug exposure.  
The following contraception requirements must be followed unless otherwise stated in 
the respective appendix of each treatment arm. 
a) 
Female Participants:  
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies: 
• 
Woman of non-childbearing potential (WONCBP). 
• 
Woman of childbearing potential (WOCBP), who: 
– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or use 
highly effective contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 6 months after the final dose 
of study treatment. Examples of contraceptive methods with a failure rate of 
< 1% per year include bilateral tubal occlusion, male sterilization, established 
proper use of hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices, and copper intrauterine devices.  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
WOCBP must be willing to undergo a urine pregnancy test every three 
months until the end of study.  
b) 
Male Participants:  
During the treatment period and for at least 6 months after the final dose of study 
treatment, agree to:  
• 
Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that together 
result in a failure rate of < 1% per year, with a partner who is a woman of 
childbearing potential (WOCBP). 
• 
With pregnant female partner, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid exposing 
the embryo. 
• 
Refrain from donating sperm. 
 
Participants are excluded from the study if any of the following exclusion criteria apply: 
Medical Conditions 
1. Pregnant (positive pregnancy test) or lactating women. 
2. Co-infection with other pathogens such as hepatitis A (HAV), hepatitis C (HCV), hepatitis 
D (HDV), hepatitis E (HEV), or human immunodeficiency virus (HIV). 
3. History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis (F3 or 
above on liver biopsy, ≥7.4 kPa on transient elastography, > 1.32 m/s on acoustic 
radiation force impulse [ARFI] elastography, or > 3.13 kPa on magnetic resonance [MR] 
elastography), or > 7.1 kPa on 2D-shear wave elastography [2D-SWE]), or 
decompensated liver disease (e.g., ascites, hepatic encephalopathy). Liver biopsy or 
transient elastography/ARFI/MR result must be obtained within 6 months prior to 
randomization. 
4. History of or suspicion of hepatocellular carcinoma (HCC) (e.g., elevated -fetoprotein 
[AFP] levels, or suggestive lesions on abdominal ultrasound or other imaging, etc.). 

 
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5. Thyroid disease poorly controlled on prescribed medications or clinically relevant 
abnormal thyroid function tests (thyroid-stimulating hormone [TSH], free triiodothyronine 
[FT3], free thyroxin [FT4]) at screening, as judged by the Investigator. 
6. Clinically significant disease other than CHB that, in the opinion of the Investigator, 
makes the participant unsuitable for the study. 
7. Pre-existing cardiac disease that in the opinion of the investigator would increase the 
risk for the participant to participate in the study.  
8. History of alcohol abuse and/or drug abuse within one year of randomization.  
9. History of having received (in the last 6 months) or currently receiving any systemic 
anti-neoplastic (including radiation) or immunosuppressive including biologic 
immunosuppressors) or immune modulating treatment (including non-biological oral 
immune modulating drugs e.g., methotrexate > 25 mg per week, 
azathioprine > 3.0 mg/kg/day or 6-mercaptopurine > 1.5mg/kg/day) for malignant or 
non-malignant disorders.  
10. Currently taking, or have received within 3 months of Day 1, systemic corticosteroids at 
a high-dose (e.g., 40 mg prednisolone per day for) > 7 days, or a low-dose (e.g., 20 mg 
prednisolone per day) for > 14 days.  
 
Diagnostic Assessments 
11. Electrocardiogram (ECG) with clinically significant abnormalities, including QTcF interval 
(QT corrected using Fridericia’s formula) 450 msec for males and 470 msec for 
females at screening. 
12. Laboratory parameters at screening: 
a. Hemoglobin < lower limit of normal (LLN); platelets < LLN; international normalized 
ratio (INR) > 1.1 × ULN.  
b. Albumin < 3 g/dL; total bilirubin > ULN (exception: Gilbert’s disease). 
c. Positive results for anti-mitochondrial antibodies (AMA > 1:80), antinuclear antibody 
(ANA > 1:80), anti–smooth muscle antibody (ASMA > 1:40), or anti-thyroperoxidase 
antibodies (a-TPO ≥ ULN). 
d. White blood cell count < 2500 cells/mm3; neutrophil count < 1500 cells/mm3 
(< 1000 cells/mm3 if considered a physiological variant in a participant of African 
descent). 
e. Glomerular filtration rate (GFR; using Modification of Diet in Renal Disease [MDRD]) 
< 60 mL/min. 
f. 
Positive test for drugs of abuse (including recreational drugs) and/or positive alcohol 
test at screening. For positive cannabinoids test, the eligibility is at the investigator’s 
discretion.  
 
Prior/Concurrent Clinical Study Experience 
13. Previous treatment with an investigational agent for HBV within 6 months prior to 
screening. 
14. Unable to comply with any drugs or nutrients listed in prohibited medications and 
prohibited food sections in the respective treatment arm appendix. 
15. Known hypersensitivity to any excipients of the study drug. 
 
NUMBER OF PARTICIPANTS 
Approximately 30 participants will be randomized in each treatment arm. The overall number of 
participants in this study will depend on the number of treatment arms that are included, which is 
not known at present.  
 
 
 

 
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CONCOMITANT MEDICATIONS 
In general, the following concomitant medication are prohibited during the study: 
• 
Systemic immunosuppressive drugs, immunomodulators, cytotoxic or chemotherapeutic 
agents, radiation therapy. 
• 
Systemic high-dose corticosteroids (e.g., > 40 mg prednisolone per day) > 7 days or low-
dose corticosteroids (e.g., > 20 mg prednisolone per day) for > 14 days. 
Unless otherwise stated in the respective appendix of each treatment arm, prescribed 
concomitant medication is not prohibited during the study. Participants should refrain from taking 
non-prescription medication, unless it is considered necessary by the Investigator. 
1.2 
SCHEMATIC OF STUDY DESIGN 
An overview of the principal elements for the platform study design, including the initial treatment 
arms, is provided in Figure 1.  

 
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Figure 1 
Principle Elements of the Planned Platform Study Design 
 
 
Abbreviations: EOT = end-of-treatment; HBsAg = Hepatitis B surface antigen; NME = new molecular entity; NUC = nucleos(t)ide; TBD = to be 
determined; wk = week.  
*Initially 30 participants. Up to five additional participants per future treatment arm may be randomized to the NUC control arm. 
NOTE: This schematic is for illustrative purposes only and demonstrates that treatment duration may be up to 48 weeks, i.e. some arms may have 
shorter durations of treatment. Treatment duration for each combination arm is detailed in the respective appendix.  
  

 
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1.3 
 
SCHEDULE OF ACTIVITIES 
The SoA(s) for each treatment arm is provided in the respective appendix as listed in 
Appendix 6. 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Chronic hepatitis B (CHB) virus infection is a major global healthcare problem, with an 
estimated prevalence of 257 million people (WHO 2018). Nearly 25% of all CHB patients 
develop serious liver diseases such as cirrhosis and primary hepatocellular carcinoma 
(HCC). More than 887,000 people die every year due to the consequences of CHB 
(WHO 2018). 
Current treatments reduce the risk of CHB sequelae but are associated with very low 
rates of functional cure (generally not exceeding 3% after one year of therapy). Due to 
the therapeutic limitations of the currently available drugs for CHB treatment, there is a 
need for new treatments of a finite duration that can also yield higher rates of functional 
cure (Wang and Chen 2014).  
Multi-drug therapies with compounds targeting different steps in viral replication or 
combinations with drugs that restore the innate and/or adaptive host immune responses 
are presumably more likely to be efficacious than monotherapy. New treatment regimens 
may be more likely to achieve functional cure by a combination of multiple direct antiviral 
mechanisms or through the augmentation of anti-hepatitis B virus (HBV) immune 
responses (Liu et al 2017; Durantel and Zoulim 2016; Lok et al 2017; HBV Forum Nov 
15th 2016). Additional strategies to restore anti-HBV T-cell function and further improve 
the magnitude and durability of the anti-HBV immune response may be required to 
achieve high rates of functional CHB cure.  
The Sponsor intends to identify finite-duration combination therapies including one or 
more new molecular entities (NMEs) that are associated with high rates of sustained 
loss of hepatitis B surface antigen (HBsAg < 0.05 IU/mL; functional cure) using the 
present platform Phase 2 study.  
Platform studies have the objective to study multiple therapies in the context of a single 
disease, with therapies allowed to enter or leave the platform based on availability and 
emerging data (Woodcock and LaVange 2017). Thus, the Sponsor plans to study 
combination therapies employing a master protocol, where combination therapies can 
enter the study in a dynamic manner after obtaining Health Authority (HA)/Ethics 
Committee (EC) approval of subsequent protocol amendments.  
The scientific rationale for the study design is provided in Section 4.2. 

 
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2.2 
BACKGROUND 
2.2.1 
Chronic Hepatitis B 
Chronic HBV infection (defined as persistent detection of serum HBsAg, the hallmarks of 
which are high levels of circulating HBV DNA and HBsAg) is a consequence of the 
presence of a viral reservoir, i.e., episomal covalently closed circular deoxyribonucleic 
acid (cccDNA) in the nucleus of an infected hepatocyte. Despite advancements in the 
understanding of HBV disease biology, complete cure, i.e., eradication of cccDNA is not 
currently possible by available treatments. Nevertheless, the sustained clearance of 
HBsAg has been shown to protect against disease progression and development of HBV 
complications including cirrhosis, liver failure, and HCC. Accordingly, functional cure is 
defined as sustained, undetectable HBsAg in serum and HBV DNA in circulation, with or 
without seroconversion to anti-HBs, after completion of a finite course of treatment 
(Lok et al 2017). Partial cure will demonstrate sustained plasma HBV DNA suppression 
after completion of treatment, but with persistently detectable circulating HBsAg.  
Other clinically meaningful endpoints include HBV DNA suppression and alanine 
aminotransferase (ALT) normalization, which indicate virologic and biochemical 
responses to therapies, respectively. For hepatitis B e antigen (HBeAg)-positive patients, 
HBeAg seroconversion is indicative of a better prognosis, including lower rates of 
cirrhosis and slower disease progression. Sustained suppression of HBV replication, 
regardless of HBeAg status, is associated with biochemical remission, histological 
improvement, and reduced risk of disease progression. 
2.2.2 
Currently Available Therapies  
Currently, there are two therapeutic classes available for the treatment of CHB:  
subcutaneously administered interferon (IFN) preparations (conventional or pegylated 
interferon-alpha [PEG-IFN-α]) and orally administered nucleos (t)ide analogues (NUCs; 
tenofovir, entecavir, adefovir, telbivudine, and lamivudine). After 1 year of treatment, 
both types of treatment can suppress circulating HBV DNA levels (virologic response, 
7%-94%), normalize serum liver transaminase enzymes (biochemical response, 32%-
83%), and induce HBeAg seroconversion in HBeAg-positive patients (serological 
response, 10%-32%). Although these treatments reduce the risk of CHB sequelae, they 
are associated with very low rates of functional cure (HBsAg loss rates generally not 
exceeding 3% after one year of therapy) (European Association for the Study of the 
Liver [EASL] 2017).  
Furthermore, the existing standard-of-care therapies have important limitations. For 
example, virologic relapse after treatment discontinuation is a major limitation of 
currently approved therapies, which rarely result in functional cure. IFN-based therapies 
have common adverse events of flu-like symptoms and can be associated with 
treatment-limiting adverse effects (e.g., neutropenia, thrombocytopenia), while NUCs 
require long-term and possibly lifelong therapy in the majority of treated patients. Given 
these limitations, there is an unmet need for novel treatments of a finite duration that 

 
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yield higher functional cure rates (Liu et al 2017; Durantel and Zoulim 2016; Lok et al 
2017; Wang and Chen 2014).  
2.3 
BENEFIT/RISK ASSESSMENT 
This Phase II, platform study is designed to accelerate the development of novel 
combination regimens by establishing proof-of-concept clinical data in participants with 
CHB. Enrolment of multiple experimental arms within a single study, rather than one or 
two experimental arms within multiple studies, will result in an overall reduction in the 
number of participants receiving control treatment.  
The NME combination regimens aim to result in therapeutic benefit for participants, 
represented by higher functional cure rates than observed with current standard-of-care 
therapies. For every combination regimen tested, the individual NME has shown 
acceptable safety/tolerability in Phase I studies, and non-clinical toxicology and safety 
pharmacology are supportive of its use within a combination regimen. For specific 
details, refer to the Investigator Brochure of the individual NMEs.  
Only participants with preserved liver function and without significant fibrosis/cirrhosis 
will be enrolled, thus reducing the risk of severe liver-related adverse events. The initial 
study population will consist of virologically suppressed CHB participants on established 
NUC therapy. Given NUC therapy is generally administered indefinitely and associated 
with low rates of functional cure, this population is considered appropriate for studies of 
novel CHB therapeutic regimens, as highlighted in current guidelines (FDA 2018).  
The target and proposed mechanism of action classification for the presently studied 
investigational medicinal products (IMP) are summarized in Table 2 in Appendix 6. 
Background information for each treatment arm, including a benefit-risk assessment, is 
provided in the respective appendix.  
3. 
OBJECTIVES AND ENDPOINTS 
This randomized controlled platform study in CHB participants will compare the efficacy 
and safety of novel combination regimens against a control arm. The primary objective is 
to compare the functional cure rates assessed at 24 weeks post end-of-treatment (EOT). 
The objectives and corresponding endpoints are provided in Table 1. 
 
 

 
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Table 1 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To estimate the effect of NME 
combination therapies on inducing a 
functional cure over the control arm. 
 
% participants with HBsAg loss at 
24 weeks post-EOT.  
Secondary a 
 
To characterize the efficacy profile of 
NME combination therapies. 
 
% participants with HBsAg loss  
 
% participants with HBsAg 
seroconversion.  
 
% participants with HBeAg loss 
(baseline HBeAg-positive participants). 
 
% participants with HBeAg 
seroconversion (baseline HBeAg-
positive participants). 
 
% participants with HBV DNA < lower 
limit of quantification (LLOQ), 
< 200 IU/mL and < 2,000 IU/mL. 
 
To characterize the PD profile of NME 
combination therapies. 
 
Including but not limited to: change 
from baseline in quantitative HBsAg, 
anti-HBs, HBeAg, anti-HBe, anti-HBc, 
HBcrAg, HBV RNA, and HBV DNA 
levels over time. 
 
To characterize the plasma PK profiles 
of NMEs. 
 
Estimated PK parameters from sparse 
sampling and population PK models. 
 
To assess the safety and tolerability of 
NME combination therapies. 
 
Incidence, nature, and severity of AEs 
and laboratory abnormalities. 
 
To identify presence of PK/PD 
relationship.  
 
Analyses of PK/PD data. 
 
To explore potential effects of ADA on 
NMEs and/or IMP, as applicable. 
 
Relationship between ADA status, PK, 
safety, PD, and efficacy. 
Exploratory 
 
To characterize the profile of novel 
viral response markers. 
 
Profiles and changes from baseline of 
total HBsAg post-dissociation of 
HBsAg/HBsAb complexes/components 
of HBsAg. 
 
To assess the relationship between 
baseline disease characteristics and 
efficacy/safety responses. 
 
Association between primary and 
secondary outcomes and HBV 
genotype (obtained using HBV RNA or 
DNA sequencing and/or any alternative 
methodology, and/or from medical 
records prior to study entry). 
 
To assess the association of genetic 
polymorphisms with the PK profiles of 
NMEs and/or efficacy/safety primary 
and secondary endpoints. 
 
Genetic association with PK 
parameters and/or primary and 
secondary endpoints by clinical 
genotyping. 
a Efficacy and PD endpoints are assessed at every 12-week time point. 
 

 
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4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a Phase II, randomized, adaptive, open-label, multi-arm, multi-center, 
international, platform study (Woodcock et al 2017) designed to evaluate safety, 
tolerability, and efficacy of new combination therapies including one or more NMEs in 
CHB participants with preserved liver function and without significant fibrosis/cirrhosis. 
The platform design allows comparison of multiple new combination therapies against a 
common control, and introduction of additional treatment arms at later study time points.  
This study is designed to be adaptive to open additional shorter duration treatment arms 
or to expand existing treatment arms for NME combination therapies that show 
promising efficacy outcomes. The platform design also has the flexibility to open new 
treatment arms to explore different combination regimens or different participant 
populations pending new submission and HA/EC approval. Based on emerging data 
and/or company prioritization of assets, treatment arms may be terminated early or not 
opened for randomization or certain NMEs in the combination treatment arm might be 
terminated while therapy is maintained with the remaining NMEs. The Sponsor will notify 
the Investigator and HA/EC if the study or certain treatment arms or certain NMEs are 
placed on hold, or if the Sponsor decides to discontinue certain treatment arms or 
certain NMEs.  
Treatment arms may be staggered relative to other treatment arms in order to increase 
study efficiency with regards to timely interim data readouts or to reduce the complexity 
of study conduct. 
For the first combination, participants will be randomized on Day 1 to an NME 
combination arm (N=30) or the control arm (N=30) using an adaptive stratified sampling 
method, stratified at screening HBsAg level ( 1,000 IU/mL,  1000 IU/mL), with a 
minimum of 12 participants per arm with a screening HBsAg level of  1000 IU/mL. For 
NME combination arms that will be introduced later into the platform study, the allocation 
ratio of participants to the control arm, will depend on the number of actively enrolling 
arms with the stipulation that no more than 17% of participants will be randomly 
allocated to a control arm. Additionally, for subsequent arms the proportion of patients 
with HBsAg level  1000 IU/mL,  1000 IU/mL within each treatment arm, will be 
maintained as closely as possible to the first combination treatment arm. 
Due to strict lockdowns and restrictions in China in March - May 2022, as of 31 May 2022 
approximately 30-53% of participants in each treatment arm have missed study visits and siRNA 
drug administration at the site.  As a result, a number of participants have consecutive visits missed 
with potential impact on the evaluation of the primary endpoint due to incomplete data. To preserve 
the viability of the study, if COVID-19 restrictions continue, or any future COVID-19 outbreaks 
or any force majeure (e.g. natural disasters, supply chain disruption, outbreak of hostilities etc.) 
impacting participants, will lead to additional participants being recruited to the study to ensure 

 
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that the number of participants per treatment arm with the full dose as per the randomized dose 
regimen remains approximately 30 (see Section 9.2). The maximum number of additional 
participants to be recruited will be approximately 30 for each treatment arm (see Section 9.2). 
Randomization will also take into account arm-specific exclusion criteria of actively 
enrolling arms. Participants will be ineligible for a specific arm if they meet any of the 
exclusion criteria outlined for that arm (please see arm specific appendix). Details on 
treatment assignment and randomization are provided in Section 6.4.1  
The primary endpoint is the proportion of participants with HBsAg loss at 24 weeks post-
EOT as defined in Section 4.4. 
The treatment period duration will be a maximum of 48 weeks, after which participants 
will enter a 48-week follow-up period. Treatment duration may be shortened (12 or 24 
weeks) for 48 week NME combination arms, and/or a response-guided therapy (RGT) 
arm may be added following planned interim analyses; up to four planned interim 
analyses will be conducted for each treatment arm (see Section 9.5). Treatment arms 
that achieve 30% difference, compared to NUC control arm, for HBsAg loss at EOT or 
follow-up Weeks 12 and 24 (primary endpoint) may be expanded to accrue additional 
efficacy and safety data and to contribute to Phase 3 design planning as guided by the 
emerging data, for example, enrichment for HBeAg positive or HBeAg negative 
participant populations. An expansion may also be triggered prior to EOT, for a 
treatment arm that gives an early indication of efficacy. The decision criteria to trigger an 
expansion arm in this case, will be documented as an appendix to the IMC/Scientific 
Oversight Committee (SOC) charter.  
An overview of the study design is provided in Section 1.2. Details on the planned 
treatment arms are provided in Appendix 6. 
4.1.1 
Length of the Study 
The total length of the study, from screening of the first participant to the end-of-study 
(see Section 4.4), is expected to be approximately 3 to 5 years, depending on the 
number and timing of additional treatments arms that are added to the study.  
The study duration for each participant will be approximately 2 years divided as follows: 
 
Screening period: up to 8 weeks. 
 
Treatment period: up to 48 weeks. 
 
Safety follow-up period: 48 weeks. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study design rationale is provided in Section 4.1. 

 
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4.2.1 
Rationale for Study Population 
The study will enroll CHB participants with preserved liver function and without 
significant fibrosis/cirrhosis, thus reducing the risk of liver-related adverse events.  
The initial participant population consists of virologically suppressed adult CHB 
participants on established NUC therapy, which current guidelines recommended as an 
appropriate study population for early phase clinical studies for CHB (FDA 2018).  
4.2.2 
Rationale for Control Treatment arm  
The control arm is considered necessary to generate a within-study comparator dataset 
in order to evaluate the magnitude of treatment effects within the combination treatment 
arms.  
4.2.3 
Rationale for Biomarker Assessments 
HBV Dynamic Biomarkers 
Functional CHB cure is defined as the sustained, undetectable serum HBsAg (defined 
as < 0.05 IU/mL) and HBV DNA in plasma, with or without seroconversion to anti-HBs, 
after completion of a finite course of treatment (Lok et al 2017). Therefore, the main 
virological endpoint in this study relies on measuring HBsAg and HBV DNA at time 
points defined in the SoAs (the SoA(s) for each treatment arm is provided in the 
respective appendix as listed in Appendix 6).  
Additional well-established HBV dynamic biomarkers for the assessment of HBV 
treatment outcomes will include the time course of anti-HBs levels and the evolution of 
HBeAg and anti-HBe status. In participants that are HBeAg positive at study entry, a 
validated research-use-only (RUO) semi-quantitative assay may be used to follow the 
time course of serum HBeAg levels over time. In order to avoid a potential loss of 
sensitivity of HBsAg detection due to the formation of HBsAg/anti-HBs complexes, an 
assay is being developed by the Sponsor that may be used in some participants to 
measure HBsAg independently of the putative formation of complexes, i.e. total HBsAg 
post-dissociation of HBsAg/HBsAb complexes/components of HBsAg, as appropriate.  
Several HBV biomarkers have recently emerged in the field that may further support the 
demonstration of improved virus control and the achievement of HBV cure. Results from 
these novel biomarkers will not have an impact on any clinical decisions or other 
endpoint evaluation. 
Among these, pregenomic HBV RNA that bypasses reverse transcription and is released 
in plasma may provide a direct measure of the transcriptional activity of cccDNA. 
Consistent with this view, in NUC-treated participants with suppressed HBV DNA, the 
presence of detectable circulating HBV RNA signals an increased probability of HBV 
DNA rebound upon NUC cessation (Wang et al 2016; Fan et al 2020; Seto et al 2020; 
Kaewdech et al 2020). In the course of this study, a validated real-time polymerase 

 
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chain reaction-based RUO assay may be used to quantify the ability of NME 
combinations to affect HBV RNA. 
Circulating hepatitis B core-related antigen (HBcrAg) levels provide one additional 
biomarker that could support demonstration of the achievement of HBV cure. HBcrAg is 
a composite circulating biomarker comprising HBcAg (core antigen, which is part of HBV 
virions), HBeAg (which arises from the same open reading frame as HBcAg and is 
secreted), and p22cr (precore protein). Emerging data correlate HBcrAg measurements 
with cccDNA levels and activity and HBV treatment outcomes (Mak et al 2018; Chen et 
al 2017; Inoue and Tanaka 2020; Li et al 2020). In the course of this study, a validated 
RUO method based on a quantitative enzyme-linked immunosorbent assay may be used 
to quantify HBcrAg in serum. 
Antibodies against HBcAg (anti-HBc) are the first to appear during the acute phase of 
infection. The IgM anti-HBc levels will gradually disappear and be followed by the 
production of IgG anti-HBc. Novel assays for the quantification of IgG or total anti-HBc 
have been developed. The levels of this biomarker have been shown to vary through the 
different phases of the cHBV infection. They are higher during the immune clearance 
and reactivation phases than during the immune tolerance and inactive carrier phases. 
Moreover, high levels of IgG or total anti-HBc correlated with a higher rate of HBeAg 
seroconversion in HBeAg-positive patients treated with NUCs. In the course of this 
study, a validated RUO method may be used to quantify total anti-HBc in serum (Jia et al 
2014; Yuan et al 2013; Fan et al 2016). 
The initial participant population recruited in this study will be established on effective 
NUC therapy at study entry and will have circulating HBV DNA levels below the assay 
lower limit of quantification (defined as below 20 IU/mL) for at least 6 months, confirmed 
at screening. Response to therapy aiming at functional cure could potentially be 
modulated by HBV genotype. To determine HBV genotype in participants with 
undetectable HBV DNA, Sanger or deep sequencing may be attempted in some 
participants using amplified HBV RNA from a plasma sample collected at Day 1 or at 
any follow-up time point, as appropriate. The HBV genotype may also be inferred using 
alternative approaches, such as serovariant determination. 
HBV DNA Monitoring  
During the course of the study, participants will be monitored to ensure that HBV DNA 
suppression is maintained. Participants who experience HBV DNA breakthrough while 
having NUC therapy, with or without administration of a combination of NMEs, will need 
to attend a clinic visit for repeat testing. If the HBV DNA level is confirmed to be more 
than 100 IU/mL or 1-log above nadir, the participants will be assessed for evidence of 
drug resistance using sequencing and potentially phenotyping. The sample will also be 

 
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used to determine the HBV genotype and a pharmacokinetic (PK) sample will be 
collected. 
Finally, participants who have been taken off the combination of NMEs and the NUC 
therapy will have their HBV DNA monitored every 2 weeks for the first 3 months and 
monthly thereafter until 48 weeks post-EOT. If the HBV DNA level rises, participants will be 
monitored and managed in case of virological relapse as per Section 8.3.8.2  and an 
unscheduled blood sample will be collected for potential characterization of the HBV 
genome and where feasible phenotyping (see Sections 8.7.2 and 8.7.3). 
4.3 
JUSTIFICATION FOR DOSE 
Refer to the respective appendix of each treatment arm for details. 
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last study visit. The end-of-study is defined as the date 
when the last participant completes the last visit (LPLV).  
5. 
STUDY POPULATION 
The study population rationale is provided in Section 4.2.1. 
The study will enroll CHB participants with preserved liver function and without 
significant fibrosis/cirrhosis.  
The initial study population will consist of virologically suppressed CHB participants on 
NUC therapy between 18 and 65 years of age, inclusive, who fulfil all of the study 
eligibility criteria. Additional participant populations (e.g., treatment naïve CHB 
participants) may be explored within the study in treatment arms to be added at a later 
date pending new submission and HA/EC approval. 
Prospective approval of protocol deviations from eligibility inclusion/exclusion criteria, 
also known as protocol waivers or exemptions are not permitted.  
Any treatment arm-specific inclusion/exclusion criteria defined in the corresponding 
appendix (of actively recruiting arms), takes precedence over the inclusion/exclusion 
criteria defined in Section 5.1 and Section 5.2. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 

 
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Informed Consent 
1. 
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Council for Harmonization (ICH) and local 
regulations. 
Age 
2. 
Participants must be between 18 and 65 years of age, inclusive, at the time of 
signing the informed consent. 
Weight 
3. 
Body mass index between 18 and 32 kg/m2 inclusive.  
Type of Participants and Disease Characteristics 
4. 
Participants with CHB infection (HBsAg positive for 6 months) who are on NUC 
(entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy 
for 12 months, having received the same NUC therapy for 3 months prior to 
screening.  
5. 
HBV DNA below the LLOQ or < 20 IU/mL for > 6 months prior to screening and 
confirmed at screening.  
6. 
Alanine transaminase (ALT) 1.5 x upper limit of normal (ULN) for > 6 months prior 
to screening, and confirmed at screening  
7. 
Screening laboratory values (hematology, chemistry, urinalysis) within normal 
range, or judged not clinically significant by the Investigator. 
Sex 
8. 
Male and female participants: 
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of preventing fetal/embryonic drug exposure.  
The following contraception requirements must be followed unless otherwise stated in 
the respective appendix of each treatment arm. 
a) Female Participants:  
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies: 
 
Woman of non-childbearing potential (WONCBP), as defined in Appendix 5. 
 
Woman of childbearing potential (WOCBP), who: 

 
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– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or use 
highly effective contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 6 months after the final dose of 
study treatment. Examples of contraceptive methods with a failure rate of < 1% 
per year include bilateral tubal occlusion, male sterilization, established proper 
use of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices (see Appendix 5).  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
WOCBP must be willing to undergo a urine pregnancy test every 3 months until 
the end of study.  
b) Male Participants:  
During the treatment period and for at least 6 months after the final dose of study 
treatment, agree to:  
 
Remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures such as a condom plus an additional contraceptive 
method that together result in a failure rate of < 1% per year, with a partner 
who is a woman of childbearing potential (WOCBP, as defined in Section 1 
in Appendix 5). 
 
With pregnant female partner, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo. 
 
Refrain from donating sperm. 
 
Please refer to the respective appendix of each treatment arm for additional or more 
stringent treatment-related inclusion criteria that must be checked in all participants 
before randomization if any arm requiring additional inclusion criteria is open for 
recruitment. See Table 3 in Appendix 6 for the list of applicable exclusion criteria. 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. 
Pregnant (positive pregnancy test) or lactating women. 
2. 
Co-infection with other pathogens such as hepatitis A (HAV), hepatitis C (HCV), 
hepatitis D (HDV), hepatitis E (HEV), or human immunodeficiency virus (HIV). 
3. 
History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis (F3 or 
above on liver biopsy, ≥ 7.4 kPa on transient elastography, > 1.32 m/s on acoustic 
radiation force impulse [ARFI] elastography, or > 3.13 kPa on magnetic resonance 
[MR] elastography or > 7.1 kPa on 2D-shear wave elastography [2D-SWE]), or 
decompensated liver disease (e.g., ascites, hepatic encephalopathy). Liver biopsy 
or transient elastography/ARFI/MR result must be obtained within 6 months prior to 
randomization. 

 
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4. 
History of or suspicion of hepatocellular carcinoma (HCC) (e.g., elevated -
fetoprotein [AFP] levels, suggestive lesions on abdominal ultrasound or other 
imaging, etc.). 
5. 
Thyroid disease poorly controlled on prescribed medications or clinically relevant 
abnormal thyroid function tests (thyroid-stimulating hormone [TSH], free 
triiodothyronine [FT3], free thyroxin [FT4]) at screening, as judged by the 
Investigator. 
6. 
Clinically significant disease other than CHB that, in the opinion of the Investigator, 
makes the participant unsuitable for the study. 
7. 
Pre-existing cardiac disease that in the opinion of the investigator would increase 
the risk for the patient to participate to the study. 
8. 
History of alcohol abuse and/or drug abuse within one year of randomization. 
9. 
History of having received (in the last 6 months) or currently receiving any systemic 
anti-neoplastic (including radiation) or immunosuppressive (including biologic 
immunosuppressors) or immune modulating treatment (including non-biological oral 
immune modulating drugs; e.g., methotrexate > 25 mg per week, 
azathioprine > 3.0 mg/kg/day or 6-mercaptopurine > 1.5 mg/kg/day) for malignant or 
non-malignant disorders.  
10. Currently taking, or have received within 3 months of Day 1, systemic 
corticosteroids at a high-dose (e.g., 40 mg prednisolone per day for) > 7 days, or a 
low-dose (e.g., 20 mg prednisolone per day) for > 14 days.  
Diagnostic Assessments 
11. Electrocardiogram (ECG) with clinically significant abnormalities, including QTcF 
interval (QT corrected using Fridericia’s formula) ≥450 msec for males and ≥470 
msec for females at screening. 
12. Laboratory parameters at screening: 
a) Hemoglobin < lower limit of normal (LLN); platelets < LLN; international 
normalized ratio (INR) > 1.1 × ULN.  
b) Albumin < 3 g/dL; total bilirubin > ULN (exception: Gilbert’s disease). 
c) Positive results for anti-mitochondrial antibodies (AMA > 1:80), antinuclear 
antibody (ANA > 1:80), anti–smooth muscle antibody (ASMA > 1:40), or anti-
thyroperoxidase antibodies (a-TPO ≥ ULN). 
d) White blood cell count < 2500 cells/mm3; neutrophil count < 1500 cells/mm3 
(< 1000 cells/mm3 if considered a physiological variant in a participant of African 
descent). 
e) Glomerular filtration rate (GFR; using Modification of Diet in Renal Disease 
[MDRD])  60 mL/min.  
f) Positive test for drugs of abuse (including recreational drugs) and/or positive 
alcohol test at screening. For positive cannabinoids test, the eligibility is at the 
Investigator’s discretion. 
 

 
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Prior/Concurrent Clinical Study Experience 
13. Previous treatment with an investigational agent for HBV within 6 months prior to 
screening. 
14. Unable to comply with any drugs or nutrients listed in prohibited medications and 
prohibited food sections in the respective treatment arm appendix. 
15. Known hypersensitivity to any excipients of the study drug.  
 
Please refer to Table 3 in Appendix 6 for the list of applicable inclusion/exclusion criteria 
and check the respective appendix of each treatment arm for additional treatment-
related inclusion/exclusion criteria that must be checked in all participants before 
randomization if any arm requiring additional exclusion criteria is open for recruitment. 
All eligibility decisions are made by the Investigator. The Medical Monitor is available to 
the Investigator to answer any medical questions. 
5.3 
LIFESTYLE CONSIDERATIONS  
Alcohol intake should be strongly discouraged, but limited intake is allowed, when in 
agreement with the Investigator. Refer to the respective appendix of each treatment arm 
for treatment-related details. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study.  
If a subject fails an inclusion/exclusion criterion due to a transient and non-clinically 
significant condition at screening, the Investigator may repeat the relevant 
assessment(s) within the screening period. If the subject fails a second time, they will be 
classified as a screen failure. 
Re-screening is allowed for participants who were screened in the study and met all 
study inclusion/exclusion criteria within both screening visits (Day -56 to -7 and Day -14 
to -7) but failed to be subsequently randomized within the screening period. In order to 
re-screen such a subject, all inclusion and exclusion criteria should be re-evaluated and 
all applicable screening assessments repeated. With the exception of the eye 
examination if randomization will occur within 6 months from the last examination.  
In some instances, participants who did not meet the inclusion/exclusion criteria during 
the screening period (including those following re-testing) and were registered as screen 
failures in the IxRS system, can be re-screened and will be treated as new participants 
provided the new screening informed consent form (ICF) signature date is at least 6 
months after the previous screen failure date. In order to re-screen such a subject, all 

 
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inclusion and exclusion criteria should be re-evaluated and all applicable screening 
assessments repeated.  
Re-screened participants are required to sign a new ICF and will be assigned a new 
screening number. 
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. 
6. 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), or 
medical device(s) intended to be administered to a study participant according to the 
study protocol. 
All IMPs required for completion of this study will be provided by the Sponsor. All non-
investigational medicinal products (NIMPs) required for completion of this study will be 
either provided or reimbursed by the Sponsor. 
6.1 
TREATMENTS ADMINISTERED 
Refer to the respective appendix of each treatment arm for details. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and will bear a label with the identification required by local law, the protocol number, 
drug identification, and dosage. 
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations. 
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and contents. Any damaged shipments will be replaced. 
Upon arrival of the IMPs at the site, site personnel will complete the following: 
 
Check the IMPs for damage. 
 
Verify proper identity, quantity, integrity of seals, and temperature conditions. 
 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The Investigator or delegate must confirm that appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 

 
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in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
The Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
6.4 
TREATMENT COMPLIANCE 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct study treatment according to the randomization schedule. This individual will 
write the date dispensed and participant number on the study treatment vial/bottle label 
and on the Drug Accountability Record. This individual will also record the study 
treatment number received by each participant during the study. 
Each participant will be provided with a paper and/or an electronic medication diary. It is 
mandatory that each treatment which is self-administered is recorded in the diary, 
including any modified/missed doses and their reason. Participants must bring 
completed drug diaries to each visit during the treatment period to be reviewed by the 
investigator. Each modified/missed dose must be recorded on the eCRF. 
6.4.1 
Method of Treatment Assignment 
This is an open-label study; however, the specific treatment to be taken by a participant 
will be assigned using an Interactive Voice/Web Response System (IVRS/IWRS). 
Potential selection bias due to the open-label status of this study will be reduced by the 
use of central randomization. The site will contact the IVRS/IWRS prior to the start of 
study treatment administration for each participant. The site will record the treatment 
assignment on the applicable electronic case report form (eCRF), if required.  
This study will use an adaptive stratified sampling method, minimization, for 
randomization. The first participant will be allocated a treatment at random; the treatment 
allocated to the next participant will be dependent on the characteristics of those 

 
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participants already enrolled with the aim of minimizing the imbalance within each 
stratification level (screening HBsAg level  1000 IU/mL vs.  1000 IU/mL). A minimum of 
12 participants per arm with a screening HBsAg level of  1000 IU/mL is required.  
For treatment arms starting at later study time points, the ongoing central randomization 
to the control arm ensures any potential selection bias is minimized, specifically, if there 
is only one treatment arm recruiting. The subsequent randomization ratio will depend on 
the number of experimental treatment arms that are open for recruitment with the 
condition that no more than 1/6th (0%-17%) of the participants will be randomly allocated 
to the control arm at a given time. Additionally, for subsequent arms the proportion of 
HBsAg level   1000 IU/mL or  1000 IU/mL within each treatment arm will be 
maintained as closely as possible to the first combination treatment arm.  
Randomization will also take into account arm-specific exclusion criteria of actively 
enrolling arms. Participants will be ineligible for a specific arm if they meet any of the 
exclusion criteria outlined for that arm (please see arm specific appendix). The 
arm-specific exclusion criteria will specifically relate to safety due to the molecule’s 
Mechanism of Action (MOA); therefore, it is not expected to introduce any bias in the 
efficacy outcome. However, a flexible cap will be added to the other recruiting arm(s) to 
control the number of participants being randomized to these arms, in order to maintain 
the element of randomization to the end of the randomization period.  
Expansion arm/s (of a treatment arm that shows promising efficacy outcomes): If only 
one expansion arm is open at the time, eligible participants will be enrolled in that arm. If 
two or more expansion arms are enrolling at one time, a fixed permuted block 
randomization will be used to allocate participants to arms. 
As an additional step to minimize bias, on-treatment and off-treatment virology data 
(HBV DNA excluded) will not be routinely available to sites, and they will be stored in a 
restricted data repository for access by the IMC Biometricians. During study conduct, 
aggregated summaries of data will only be available to the IMC and SOC. However, 
other members of the Sponsor may have access to aggregated summaries/virology data 
to assist with decision making, as considered necessary by the IMC. 
6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) and any non-
medication interventions (e.g., individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, rehabilitative therapy) used by a participant from 30 days 
prior to screening until the follow-up visit must be recorded in eCRF along with reason 
for use, dates of administration (including start and end dates), and dosage information 
(including dose and frequency).  

 
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The Medical Monitor should be contacted for advice if there are any questions regarding 
concomitant or prior therapy. All concomitant medications should be reported to the 
Investigator and recorded on the Concomitant Medications eCRF. All therapy and/or 
medication administered to manage adverse events should be recorded on the Adverse 
Event eCRF. 
6.5.1 
Permitted Therapy 
Participants who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. Paracetamol/acetaminophen, at doses 
of up to 2 g/day, is permitted for use any time during the study. 
6.5.2 
Administrative Structure 
For information on the Internal Monitoring Committee (IMC) and Scientific Oversite 
Committee (SOC), please refer to Appendix 1.  
6.5.3 
Prohibited Therapy 
In general, the following concomitant medication are prohibited during the study: 
 
Systemic immunosuppressive drugs, immunomodulators, cytotoxic or 
chemotherapeutic agents, radiation therapy. 
 
Systemic high-dose corticosteroids (e.g., > 40 mg prednisolone per day) > 7 days 
or low-dose corticosteroids (e.g., > 20 mg prednisolone per day) for > 14 days. 
 
Unless otherwise stated in the respective appendix of each treatment arm, prescribed 
concomitant medication is not prohibited during the study. Participants should refrain 
from taking non-prescription medication, unless it is considered necessary by the 
Investigator. 
6.6 
DOSE MODIFICATION 
Please refer to the respective appendix for each treatment arm for dose modification or 
interruption guidelines. 
6.7 
TREATMENT AFTER THE END OF THE STUDY 
The Sponsor does not intend to provide study treatment or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal.  
 
 

 
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6.8 
CRITERIA FOR STOPPING NUCLEOSIDE ANALOGUE  
Participants who complete the treatment period will stop NUC therapy if laboratory results 
on samples taken at end-of-treatment or at any of the follow-up visits show:  
 
ALT 1.25  baseline values, AND 
 
HBV DNA  LLOQ or 20 IU/mL, AND 
 
negative HBeAg, AND 
 
HBsAg 100 IU/mL and ≥1 log10 IU/mL decline from baseline or HBsAg loss. 
 
These criteria for stopping NUCs do not apply to any patients who have discontinued 
study drug prematurely for any reason. 
7. 
DISCONTINUATION OF STUDY TREATMENT, PARTICIPANT 
DISCONTINUATION/WITHDRAWAL FROM THE STUDY AND 
LOST TO FOLLOW-UP 
Participants have the right to voluntarily discontinue study treatment or withdraw from 
the study at any time for any reason.  
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study-specific procedures as outlined in this 
protocol. 
Details on study and site closures are provided in Appendix 1. 
7.1 
DISCONTINUATION/INTERRUPTION OF STUDY TREATMENT 
Reasons for discontinuation or interruption of study treatment (or withdrawal from the 
study) may include, but are not limited to, the following: 
 
Participant withdrawal of consent at any time 
 
Participant non-compliance with study requirements 
 
Any medical condition or AE/laboratory abnormalities that the Investigator or 
Sponsor determines may jeopardize the participant’s safety if he or she continues in the 
study 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
 
Pregnancy 

 
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 
CHB disease progression (e.g., development of liver cirrhosis or liver 
decompensation) 
 
Confirmed virological breakthrough 
For management of virological breakthrough see Section 8.3.8.1; for ALT elevations see 
Section 8.3.8.3, and for NME-related adverse events refer to the respective appendix of 
each treatment arm for details.  
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator, or the Sponsor), an interruption should be considered. 
Unless otherwise stated in the respective appendix of each treatment arm, participants 
who have temporarily interrupted study treatment should be considered to restart as 
soon as medically justified in the opinion of the Investigator. The Medical Monitor is 
available to the Investigator to answer any medical questions. 
Table 2 below serves as a reference guide for the reasons of study treatment 
discontinuation/interruption which may occur in the study. 
 
Table 2 All Combination Arms: General Criteria for Dose 
Interruptions/Discontinuations for All New Molecular Entities  
 
 
Every effort should be made to obtain information on participants who withdraw from the 
treatment but have not withdrawn from the study. Participants who permanently 
discontinue study treatment will be asked to return to the clinic for an unscheduled/early 

 
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termination visit and will undergo follow-up assessments. The primary reason for 
premature study treatment discontinuation should be documented on the appropriate 
eCRF.  
Participants, who permanently discontinue study treatment as part of an early 
termination of a treatment arm due to Sponsor’s decision, will undergo safety follow-up 
assessments as described in Appendix 6. For participants who are in treatment arms 
NOT terminated by the sponsor, will proceed as planned and undergo follow up as per 
the SOA of the respective treatment arm.  
Participants who discontinue study treatment due to non-safety reasons may be 
replaced.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason. 
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determines may jeopardize the 
participant’s safety if he/she continues in the study. 
If possible, information on the reason for withdrawal from the study should be obtained. 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. Participants will not be followed for any reason after consent has 
been withdrawn. 
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR). 
See the SoA (the SoA for each treatment arm is provided in the respective appendix as 
listed in Appendix 6) for data to be collected at the time of study discontinuation, at 
safety and follow-up visits, and for any further evaluations that need to be completed. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 

 
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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
 
Discontinuation of sites or of study as a whole is described in Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their time points are summarized in the SoA (the SoA(s) for each 
treatment arm is provided in the respective appendix as listed in Appendix 6). Protocol 
waivers or exemptions are not allowed. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for screening 
or baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time-frame defined in the SoA. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Mobile nursing (MN) services (e.g., home visits, study drug administration, vital signs, 
laboratory sample collection, etc.) may be offered to sites and patients who express 
interest in these services and which may benefit the study conduct, as per local 
regulations. The Sponsor will select a healthcare company that will be responsible for 
providing MN services for the participating sites (MN vendor), and details regarding the 
services provided will be described in the MN Manual. Patient participation with MN 
services will be optional and will require signing of an additional MN ICF that will detail 
the specifics of these mobile services. 
All residual laboratory samples (e.g., safety laboratory, PK, PK/PD, biomarker, 
immunogenicity, etc.) may be used to repeat laboratory tests in the event of a problem 
with the original sample as outlined in the SoA. Additionally, the residual samples may 
be used for HBV biomarker analyses to further understand disease biology and 
treatment impact, where country regulations allow it. This may include, but is not limited 

 
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to, analysis of viral and host response factors (DNA and/or non-DNA) to infection and 
treatment, development/validation of HBV assays, and immunogenicity analyses. 
Unless otherwise specified below, all residual samples (including blood, slides, extracts, 
etc.) will be destroyed within 5 years after the date of final CSR. For participants who 
provide additional consent to the optional RBR, and where country regulations allow it, 
leftover samples will be transferred to RBR (see Section 8.9). 
8.1 
EFFICACY ASSESSMENTS  
Efficacy assessment endpoints are measured through markers of antiviral activity in the 
study. Blood samples will be taken at defined time points (the SoA[s] for each treatment 
arm is provided in the respective appendix as listed in Appendix 6) to monitor viral 
markers and study their correlation with administered doses and PK data.  
The primary efficacy parameter is the incidence of HBsAg loss (i.e., defined as HBsAg 
< 0.05 IU/mL) at 24 weeks post-EOT. Additional parameters include the change in 
HBsAg and anti-HBs over time, incidence, and timing of HBsAg and anti-HBs 
seroconversion, changes in HBeAg and anti-HBe status in the course of the study. Other 
efficacy biomarkers including changes in HBV DNA, HBcrAg, anti-HBc, total HBsAg 
(post-dissociation of HBsAg/HBsAb complexes/components of HBsAg), and HBV RNA 
levels may be measured, as appropriate. 
The efficacy assessments will include all participants in the efficacy analysis population 
analyzed according to the treatment arm and dose schedule to which they are 
randomized (see Section 9.3). 
8.2 
SAFETY ASSESSMENTS 
Planned time points for all safety assessments are provided in the SoA (the SoA[s] for 
each treatment arm is provided in the respective appendix as listed in Appendix 6). 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; ECGs; and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study.  
Refer to arm-specific appendices for combination specific safety assessments. 
8.2.1 
Physical Examinations 
A complete physical examination will be conducted at screening and at the end-of-
treatment period, and will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, dermatological, neurological, and musculoskeletal systems.  

 
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Further examination of other body systems may be performed in case of evocative 
symptoms at the Investigator’s discretion. Any abnormality identified at screening should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
At other visits, limited, symptom-directed physical examinations should be performed 
when clinically indicated. Changes from baseline abnormalities should be recorded in 
participants’ notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. Investigators should pay 
special attention to clinical signs related to previous serious illnesses. 
Height will be recorded at screening. Weight will be recorded at screening, Day 1, and 
every 12 weeks thereafter during the treatment period (or as outlined in the treatment arm 
specific appendix).  
8.2.2 
Vital Signs 
Vital signs (temperature, pulse rate, respiratory rate, and blood pressure) will be 
assessed after the participant has been resting in a supine or sitting position for a period 
of at least 5 minutes prior to a blood draw or at least 10 minutes following a blood draw. 
Blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature 
(oral or tympanic) will be recorded at the time points specified in the SoA tables within 
the respective appendix of each treatment arm. 
Blood pressure and pulse measurements will be assessed with a well-calibrated 
automatic instrument with a digital readout in triplicate. The mean of the triplicate 
recordings will be used for the time point result. Manual techniques will be used only if 
an automated device is not available. When measuring blood pressure, the participant's 
arm should be unconstrained by clothing or other material and the individual should be 
comfortably seated, with the legs uncrossed, and the back and arm supported, such that 
the middle of the cuff on the upper arm is at the level of the right atrium (the mid-point of 
the sternum). The ideal cuff should have a bladder length that is 80% and a width that is 
at least 40% of arm circumference (a length-to-width ratio of 2:1). 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (the SoA[s] for each 
treatment arm is provided in the respective appendix as listed in Appendix 6) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. To minimize variability, it is important that participants be in a resting 
position for at least 10 minutes prior to each ECG evaluation. Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate. 
Environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. ECGs should be 
performed prior to any scheduled vital sign measurements and blood draws. In case of 
an absolute QTc of > 500 msec, and/or an increase from baseline QTc > 60 msec, a 
triplicate ECG must be recorded within the next 5 minutes. It may be appropriate to 

 
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repeat abnormal ECGs to rule out improper lead placement potentially contributing to the 
ECG abnormality.  
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory. 
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcF (Fridericia’s correction) and RR will be 
calculated/recorded on the eCRF. Changes in T-wave and U-wave morphology and 
overall ECG interpretation will be documented. T-wave information will be captured as 
normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal. 
8.2.4 
Liver Imaging Assessments 
Abdominal hepatic ultrasound will be conducted at screening and during the study as 
outlined in the SoA (the SoA(s) for each treatment arm is provided in the respective 
appendix as listed in Appendix 6) for HCC surveillance, as participants with CHB are at 
risk of disease progression to liver cirrhosis and/or developing HCC. 
Staging of liver fibrosis will be conducted at screening in order to exclude participants 
with significant fibrosis/cirrhosis (Metavir F3/F4). Liver biopsy or transient 
elastography/ARFI/MR results obtained within 6 months prior to randomization are also 
acceptable. Acceptable non-invasive assessments for staging degree of fibrosis for this 
study includes transient elastography (Fibroscan) (Li et al 2018), acoustic radiation force 
impulse (ARFI) elastography (Dong et al 2015), and magnetic resonance (MR) 
elastography (Huwart et al 2008).  
Of the above, liver stiffness measurement using transient elastography has been widely 
accepted in the assessment and staging of liver fibrosis. Transient elastography should 
be performed on a participant lying supine with the right arm elevated to facilitate access 
to the right liver lobe. A participant has to be in fasted state. At each assessment, at 
least 10 valid measurements should be taken and the following results recorded: 
 
No. of readings taken & reading success rate (n, %) 
 
Median stiffness (kPa) 
 
Interquartile range / IQR (kPa)  
 
Controlled attenuation parameter (CAP), if available 
 
The final result of a transient electrography assessment can be regarded as valid if the 
number of valid readings is ≥10, the success rate (ratio of valid readings to total number 

 
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of readings) is > 60%, and the IQR (reflecting variability of measurements) is less than 
30% of the median liver stiffness measurements (EASL-ALEH 2015). 
8.2.5 
Clinical Safety Laboratory Assessments 
A list of clinical laboratory tests to be performed is provided in Appendix 4 and these 
assessments must be conducted in accordance with the separate laboratory manual and 
the SoA (the SoA(s) for each treatment arm is provided in the respective appendix as 
listed in Appendix 6). Normal ranges for the laboratory parameters must be supplied to 
the Sponsor if local laboratory is used. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. 
 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
 
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory. 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety. 
Where the clinical significance of abnormal lab results at screening is considered 
uncertain, screening lab tests may be repeated before randomization to confirm 
eligibility. 
If there is an alternative explanation for a positive urine or blood test for drugs of abuse, 
e.g., previous occasional intake of a medication or food containing for example, codeine, 
benzodiazepines, or opiates, the test could be repeated to confirm washout. 
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information. 

 
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8.2.6 
Medical History and Demographic Data 
Medical history includes clinically significant diseases (e.g., cancer), history of surgery, 
reproductive status, smoking habits, use of alcohol and drugs of abuse, and all 
prescribed or OTC medications used by the participant within 30 days prior to the 
screening visit. 
For all participants, the detailed HBV history will be documented including date of HBV 
diagnosis, any previous assessment of liver fibrosis (including date and outcome of any 
liver biopsy), HBV genotype (if documented), and all previous HBV treatment and 
outcomes of treatment including occurrence of any NUC resistance. 
Demographic data will include age, sex, and self‑reported race/ethnicity. The 
information about race/ethnicity of CHB participants is important because host genetics 
may modulate responses to study treatments. In addition, the information can be used to 
infer the likely HBV genotype where genotype information has not been obtained in 
routine clinical care, which is a common circumstance. There are different HBV variants 
with geographical distribution (Tanwar et al 2012; Sunbul et al 2014) that show different 
transmission modalities (e.g., vertical, in childhood, in adulthood), disease course, and 
response to treatment. The relevance of HBV genotypes is that HBV genotypes have a 
distinct geographical distribution and are known to influence clinical and virological 
parameters to treatment responses to IFN (Rajoriya et al 2017). 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 2. 
The adverse events of special interest and disease-related events and/or disease-
related outcomes not qualifying as AEs or SAEs are discussed in Section 8.3.6 and 
Section 8.3.7. 
The Investigator and any qualified designees are responsible for ensuring that all 
adverse events (including assessment of seriousness, severity and causality (see 
Appendix 2) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Appendix 2. Procedures 
used for recording adverse events are provided in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 

 
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Investigators will seek information on adverse events at each participant’s contact. All 
adverse events, whether reported by the participant or noted by study personnel, will be 
recorded in the participant’s medical record and on the Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (e.g., serious adverse events related to invasive procedures such as biopsies). 
Any other adverse event should not be reported. 
After initiation of study treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until the last follow-up visit.  
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after their last follow-up visit.  
However, if the Investigator learns of any SAE (including a death) or other adverse 
events of concern that are believed to be related to prior treatment with study treatment, 
at any time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation time points. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
8.3.3.1 
Investigator Follow-Up 
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the event is 
otherwise explained, the participant is lost to follow-up (see Section 7.3), or the 
participant withdraws consent. Every effort should be made to follow all serious adverse 
events considered to be related to study treatment or study-related procedures until a 
final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant’s medical record to facilitate source 
data verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 

 
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All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5. 
8.3.3.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow-up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the Investigator to the Sponsor of a SAE is essential (i.e., no more 
than 24 hours after learning of the event) so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.  
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.  
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure (IB) and will notify the 
IRB/IEC, if appropriate according to local requirements. 
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB, and EC, see Appendix 2. 
8.3.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitor is available 
24 hours a day 7 days a week. Medical Monitor contact details will be available on a 
separate list generated by the study management team. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study.  

 
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Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
6 months after the final dose of study treatment. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Adverse Events of Special Interest  
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Appendix 2 for reporting instructions). 
Adverse events of special interest for this study include the following: 
 
Cases of elevated ALT or AST (> 3 × ULN and > 3 × baseline) in combination with 
either an elevated total bilirubin (> 2 × ULN) or clinical jaundice (Potential Hy’s law) 
 
ALT or aspartate aminotransferase (AST) elevations ≥ 10 × ULN 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
- 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product. This term applies only 
when a contamination of the study treatment is suspected. 
 
Grade ≥3 hematology lab abnormalities (e.g., lymphopenia, neutropenia, 
leukopenia) 
 
Severe/serious injection site reactions and/or injection reactions  
 
8.3.7 
Disease-Related Events Not Qualifying as Adverse Events 
The following disease-related events (DREs) can be observed in participants with CHB: 
 
ALT or AST increase < 10 × ULN with preserved hepatic function 
 
Because these events may be associated with the disease under study, they should not 
be reported according to the standard process for AEs. ALT increase > 3 × ULN should 
be managed according to Section 8.3.8.3. 

 
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8.3.8 
Management of Specific Adverse Events 
8.3.8.1 
Management of Virological Breakthrough 
Participants with suspected virological breakthrough (HBV DNA > 100 IU/mL or > 1-log 
increase from nadir) during treatment will attend a study visit (scheduled or 
unscheduled) within 2 weeks for: 
 
a confirmatory test of HBV DNA and plasma drug levels 
 
thorough evaluation of adherence and factors that may be affecting treatment 
compliance 
 
If virological breakthrough is confirmed:  
 
the sample will be further tested for HBV genome characterization through HBV 
DNA sequencing and where feasible phenotyping 
 
NMEs will be discontinued  
 
The investigator will manage the CHB participant’s NUC treatment, according to 
current guidelines and local regulations (guided by participant's treatment history, 
assessment of adherence, HBV DNA levels, and any available result of drug 
resistance testing). 
 
8.3.8.2 
Management of Virological Relapse 
Participants who have discontinued all study treatments (NME combinations) including NUC 
therapy should be followed up every 2 weeks for first 12 weeks, thereafter monthly up to week 48 
of the follow up period to enable early detection of HBV DNA rebound and appropriate 
management of virological relapse. 
In addition, participants with HBV DNA > 20 IU/mL but < 2,000 IU/mL in follow-up, should 
undergo monitoring every two weeks.  
Participants who discontinue all study treatment (NME combination and NUC therapy for 
the treatment arms or NUC therapy for the NUC control arm) and subsequently experience 
virological relapse (HBV DNA > 2,000 IU/mL) during the follow-up period will undergo 
weekly monitoring: an unscheduled blood sample will be collected for potential HBV 
genome characterization and where feasible phenotyping.  
NUC therapy should be restarted in the following scenarios:  
 
HBV DNA > 20,000 IU/mL (regardless of other biochemical parameters or ALT values)  
 
HBV DNA > 2,000 IU/mL and ALT >1.5 x ULN 

 
HBV DNA > 2,000 IU/mL and ALT ≤ 1.5 x ULN and if the retest (central or local 
laboratory) of HBV DNA performed within 1 week after availability of the initial results 
from the central laboratory confirms HBV DNA > 2,000 IU/mL (regardless of ALT values 
or other biochemical parameters) 
 
Immediately restart treatment in participants with clinically significant signs of decreasing 
liver function based on laboratory findings (e.g., INR, direct bilirubin) or clinical 
assessments (e.g., ascites, hepatic encephalopathy) regardless of HBV DNA or ALT levels. 
 

 
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For these additional unscheduled monitoring visits, the following laboratory assessments should 
be performed using the unscheduled lab kit: hematology, chemistry, coagulation, GLDH, 
urinalysis, HBV serology, HBV DNA quantitative, Total HBsAg, HBcrAg, and HBV RNA 
quantitative.  
Note: The guidance for the management of virological relapse (frequency of monitoring, 
laboratory assessments, NUC restarting rules) described in this section should be followed in 
conjunction with the guidance for the management of elevated ALT levels described in 
Section 8.3.8.3. 
8.3.8.3 
Management of Elevated Alanine Aminotransferase (ALT) 
Levels 
The initial study population consists of CHB participants who are virally suppressed 
following > 12 months of NUC treatment. The majority of these participants (90%) have 
normal ALT levels, while approximately 10% have ALT levels within 1–2  ULN at 
baseline (Marcellin et al 2019).  
For this study, close monitoring will be initiated if ALT elevations exceed > 3  ULN. 
ALT elevations during treatment 
 
ALT elevation with preserved hepatic function (e.g., no significant changes in 
bilirubin, International Normalized Ratio [INR]/prothrombin time [PT], albumin, 
and/or alkaline phosphatase [ALP]):  
- 
ALT 3–10  ULN: *Repeat ALT, LFTs (including total bilirubin, direct bilirubin, 
AST, ALP, albumin), coagulation (INR, PT), and PD parameters (HBV DNA, 
HBsAg, quantitative HBeAg) every week until ALT< 3  ULN. 
- 
ALT > 10  ULN: Immediately interrupt NMEs and continue NUC treatment. 
*Repeat ALT, LFTs, coagulation, and PD parameters #twice weekly until ALT 
level  10  ULN, then weekly until ALT < 3  ULN. Consider re-introducing 
NME therapy on a case-by-case basis based on subsequent lab results. The 
Medical Monitor is available to the Investigator to answer any medical questions. 
 
ALT elevation accompanied by declining liver synthetic and excretory functions 
(total bilirubin > 2  ULN, or albumin  3.0 g/dL, or INR  1.5) or other signs of 
hepatic impairment (severe fatigue, vomiting): 
- 
Immediately discontinue NMEs and continue NUC treatment. 
- 
*Repeat ALT, LFTs, Coagulation, and PD parameters #twice weekly until levels 
return towards baseline levels or normal range 
o Investigate the participant for potential etiologies of the laboratory changes. 
o If alternative reasons/diagnoses cannot explain the laboratory changes, 
potential drug-induced liver injury (DILI) will be considered. 
*Frequency of monitoring may need to be adjusted based upon clinical scenario and 
severity of injury. # As the central laboratory results generation and reporting will take time, for 

 
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participant safety monitoring an additional local laboratory tests may be performed at the same 
time as the central laboratory test, and decision-making may be based on local laboratory results. 
For marked and/or persistent ALT elevations, collect a spare serum sample (to allow 
retrospective evaluation of potential etiologies) and consider liver biopsy on a case-by-
case basis (if deemed clinically relevant).  
If ALT elevations are associated with increased HBV DNA levels, virological 
breakthrough will be suspected and managed as described in Section 8.3.8.3. 
ALT elevations during follow-up 
 
ALT elevation with preserved hepatic function:  
- 
ALT 3–10  ULN: *Repeat ALT, LFTs, Coagulation (INR, PT) and PD 
parameters every week until ALT< 3  ULN. 
- 
ALT > 10  ULN: *Repeat ALT, LFTs, Coagulation (INR, PT) and PD parameters 
#twice weekly until ALT< 10  ULN; then weekly until ALT < 3  ULN.  
 
ALT elevation accompanied by declining liver synthetic and excretory functions or 
other signs of hepatic impairment: 
- 
Continue/restart NUC treatment. 
- 
*Repeat ALT, LFTs, Coagulation, and PD parameters #twice weekly until levels 
return towards baseline levels or normal range. 
- 
Investigate the participant for potential etiologies of the laboratory changes. 
- 
If alternative reasons/diagnoses cannot explain the laboratory changes, potential 
drug-induced liver injury (DILI) will be considered.  
- 
Further management according to local standard clinical practice.  
*Frequency of monitoring may need to be adjusted based upon clinical scenario and 
severity of injury. # As the central laboratory results generation and reporting will take time, for 
participant safety monitoring an additional local laboratory tests may be performed at the same 
time as the central laboratory test, and decision-making may be based on local laboratory results. 
For marked and/or persistent ALT elevations, collect a spare serum sample (to allow 
retrospective evaluation of potential etiologies) and consider liver biopsy on a case-by-
case basis (if deemed clinically relevant).  
In participants who have discontinued NUC therapy,  NUC treatment should be restarted 
if the criteria outlined in Section 8.3.8.2 are met. Note: The guidance for the management of 
ALT elevations (frequency of monitoring, laboratory assessments, NUC restarting rules) described 
in this section should be followed in conjunction with the guidance for the management of 
virological relapse described in Section 8.3.8.2.  

 
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In participants who have not discontinued NUC therapy (e.g., NUC control arm), if ALT 
elevations are associated with increased HBV DNA levels, virological breakthrough will 
be suspected and managed as described in Section 8.3.8.1. 
8.3.8.4 
Management of NME-Related AEs 
Refer to the respective appendix of each treatment arm for details. 
8.4 
TREATMENT OF OVERDOSE 
Any dose above that planned will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. Refer to the local 
prescribing information or NME Investigator Brochure’s for more details. 
8.5 
PHARMACOKINETICS 
Pharmacokinetic analyses that are specific to a treatment arm are stated in each 
respective appendix. Pharmacokinetic that are applicable to all treatment arms are 
described below. 
Blood and/or urine samples to evaluate concentrations of the standard-of-care drugs, 
the NMEs, and their metabolites when applicable will be collected as outlined specifically 
in the SoA tables in the respective appendix of each treatment arm.  
In general, PK sampling will be represented by sparse sampling throughout the duration 
of the study. During the course of the study, PK sampling time points may be modified 
based on emerging data, to ensure the PK of all standards-of-care and NMEs can be 
adequately characterized. Additional PK samples may be taken at the time of treatment 
discontinuation, if the participant experiences an unexpected adverse event or if the 
participant experiences an adverse event leading to dose-reduction or delayed treatment 
administration. The date and time of each sample collection will be recorded on the 
eCRF. All treatment drug levels and their metabolites as appropriate will be analyzed 
using validated assays. NUC control participants will not be analyzed in the first 
instance, but retained for subsequent analysis if appropriate. Details on sampling 
procedures, sample storage and shipment are given in the sample documentation.  
8.6 
IMMUNOGENICITY ASSESSMENTS  
NMEs or IMPs included in combination therapies in this study that are human antibodies, 
oligopeptides, or oligonucleotides can present a risk that anti-drug antibodies (ADAs) 
against them could develop, potentially reducing their efficacy and/or potentially resulting 
in symptomatic hypersensitivity reactions, including immune-complex reactions. 
When a particular combination will include such type of molecules (human antibodies, 
oligopeptides, or oligonucleotides), antibodies against them may be evaluated in blood 
samples collected from all participants according to their corresponding SoA. 

 
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Validated screening, confirmatory, and titer assays will be employed to detect ADAs 
against these molecules. The date and time of each sample will be recorded in the 
eCRF. 
Details on sampling procedures, sample storage, and shipment are given in the sample 
documentation. 
8.7 
PHARMACODYNAMICS AND BIOMARKERS ASSESSMENTS 
Pharmacodynamic and biomarker analyses that are specific to a treatment arm are 
stated in each respective appendix. Pharmacodynamic and biomarker analyses that are 
applicable to all treatment arms are described below. 
8.7.1 
HBV Dynamic Biomarker Assessments  
The following well-established HBV laboratory tests will be measured using serum 
samples: quantitative and qualitative HBsAg, quantitative anti-HBs, qualitative HBeAg, 
semi-quantitative HBeAg (calculated), and qualitative anti-HBe. 
Additional HBV dynamic biomarkers may be measured in all or some participants, as 
appropriate. This may include, but not be limited to, quantitative HBV RNA, quantitative 
HBcrAg, quantitative total anti-HBc, and quantitative total HBsAg (post-dissociation of 
HBsAg/HBsAb complexes/components of HBsAg) using plasma or serum samples. 
8.7.2 
HBV DNA Monitoring 
The emergence of a virological breakthrough while on NUC therapy, or the emergence 
of a virological relapse in participants taken off NME combination and NUC therapy 
during the follow-up period, will be monitored through the quantification of HBV DNA in 
plasma. In the event that the HBV DNA level is above the defined thresholds for 
potential virological breakthrough (HBV DNA > 100 IU/mL or 1-log above nadir during 
treatment) or relapse (> 2,000 IU/mL for participants off NUC therapy) (as defined in 
Section 8.3.8), a plasma sample will be collected for a confirmatory quantification of HBV 
DNA at an unscheduled visit or at the next visit of the participant. 
8.7.3 
HBV Genome Sequencing 
In some participants, HBV genome (DNA and/or RNA) sequencing may be done as 
appropriate.  
HBV RNA sequencing: HBV RNA will be extracted and amplified using the plasma 
sample collected at Day 1. If this sample is missed, it can be collected at any other 
scheduled visit. If the amplification yields enough HBV RNA material, RNA-based 
sequencing will be attempted to determine the HBV genotype. The HBV genotype may also 
be inferred using alternative approaches, such as serovariant determination. 
HBV DNA sequencing: In the event of a confirmed HBV DNA breakthrough, as defined 
in Section 8.3.8.1, HBV DNA will be extracted and amplified using the plasma sample 

 
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collected for the confirmatory HBV DNA quantification. If the amplification yields enough 
HBV DNA material, DNA sequencing of either the whole HBV genome or selected 
regions of interest will be attempted to determine genotype and mutations with potential 
to be associated with drug resistance and where feasible phenotyping. If this process 
fails, extraction, amplification, and sequencing may be attempted at a later time point. 
In the event of an HBV DNA virological relapse, as defined in Section 8.3.8.2, the 
plasma sample collected for the confirmatory HBV DNA quantification will be stored for 
potential HBV genome characterization and where feasible phenotyping. 
8.7.4 
Genetic and Genomic Analyses 
8.7.4.1 
Clinical Genotyping 
A whole blood sample for germline DNA analysis will be taken once, at baseline or 
before study treatment administration (the SoA(s) for each treatment arm is provided in 
the respective appendix as listed in Appendix 6). If this sample is missed, it can be 
collected at any other scheduled visit. DNA will be used to determine if alleles at genes 
associated with transport, metabolism, and/or mode of action of NMEs, tested in 
combination in this study, affect the PK, pharmacodynamic (PD), activity, or safety of the 
study treatment. Known candidate genes of interest specific to NME combinations are 
listed in the respective appendices. These assessments may be performed if safety or 
activity rationales develop and if considered appropriate by local regulations. 
8.7.4.2 
Transcriptome Analysis 
RNA extraction and subsequent gene expression profiling may be performed from 
leftover samples to identify biomarker signatures predictive or associated with treatment 
response/safety. These assessments may be performed in some of the participants if 
safety or activity rationales develop, pending approval from country health authorities 
and local ethic committees as appropriate. 
Given the complexity and nature of these analyses, genetic and genomic data and 
analyses will not be shared with investigators or study participants unless required by 
law. Participants will not be identified by name or any other personally identifying 
information. Data arising from all biosamples including samples for analyses of inherited 
DNA will be subject to the confidentiality standards described in the sample 
documentation. 
8.8 
PHARMACODYNAMICS AND BIOMARKER SAMPLES 
Samples should be collected as specified in the SoA (the SoA(s) for each treatment arm 
is provided in the respective appendix as listed in Appendix 6).  
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered to be critical for safety or for measuring the primary 
outcome may be only tested in some of the participants and/or some of the scheduled 
visits. 

 
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Details on sampling procedures, sample storage, and shipment are given in the sample 
documentation. 
8.8.1 
Mandatory Samples 
Unless otherwise stated, the following samples for pharmacodynamics and biomarker 
research are required and will be collected from all participants in this study: 
8.8.1.1 
Blood Sampling 
Mandatory whole blood samples will be collected according to the SoA (the SoA(s) for 
each treatment arm is provided in the respective appendix as listed in Appendix 6) for 
quantitative and/or qualitative measurement of the HBV dynamic markers, the HBV DNA 
monitoring, and the HBV genome sequencing (see Section 8.7.1, Section 8.7.2, and 
Section 8.7.3).  
A mandatory whole blood sample will also be taken for germline DNA extraction and 
clinical genotyping from every participant. If the sample is missed on Day 1, it can be 
collected at any other scheduled visit (see Section 8.7.4.1). The sample for clinical 
genotyping will be destroyed immediately after the analysis is performed and the results 
are checked for accuracy. 
8.8.1.2 
Urine Sampling 
Urine samples will be collected according to the SoA (the SoA(s) for each treatment arm 
is provided in the respective appendix as listed in Appendix 6) for renal standard safety 
biomarkers (see Appendix 4). 
8.9 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY 
8.9.1 
Overview of the Research Biosample Repository 
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic samples, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage and analysis of the RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for participants in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional Research Biosample Repository, in countries where 
regulations allow this collection. Collected RBR samples will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy or progressive disease. 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation. 
 
To increase knowledge and understanding of disease biology and drug safety. 

 
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 
To study treatment response, including drug effects and the processes of drug 
absorption and disposition.  
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
8.9.2 
Sample Collection 
Leftover plasma, serum, urine, solid tissues, and blood samples collected through the 
duration of the study will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to the NMEs administered in 
combinations in this study, CHB, or drug safety. 
Participants will not be identified by name or any other personally identifying information. 
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies. The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.  
For all samples, dates of consent and sample collection should be recorded on the 
associated RBR page of the eCRF. Details on processes for collection and shipment of 
these samples can be found in separate sample documentation. 
RBR samples will be stored and used until they are exhausted or no longer needed. The 
RBR storage period will be in accordance with the IRB/EC‑approved Informed Consent 
Form and applicable laws (e.g., Health Authority requirements). 
The repository samples will be subject to the confidentiality standards as described 
under Confidentiality and in Appendix 1. 
8.10 
HEALTH ECONOMICS 
Health Economics parameters are not evaluated in this study. 
8.11 
TIMING OF STUDY ASSESSMENTS 
8.11.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site. 
All screening, and all pre-treatment assessments (related to entry criteria), must be 
completed and reviewed to confirm that participants meet all eligibility criteria. The 
Investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure. 

 
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An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 
Screening and pre-treatment assessments will be performed within 56 days prior to 
Day 1, unless otherwise specified.  
8.11.2 
Assessments during Treatment 
All assessments must be performed according to the SoA (the SoA(s) for each treatment 
arm is provided in the respective appendix as listed in Appendix 6). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment. The following sequence should be followed unless 
otherwise specified in the SoA. 
 
Urine collection 
 
ECG recordings 
 
Vital signs 
 
PK, viral dynamic, safety blood sampling 
 
Study drug administration 
 
8.11.3 
Assessments at Study Completion 
Participants who prematurely discontinue study treatment but remain in the study, 
should continue to attend the follow-up visits including the 48 weeks, after the EOT visit. 
Participants who prematurely discontinue the study should attend an early termination 
visit. 
8.11.4 
Follow-up Assessments 
After the study completion, adverse events should be followed as outlined in 
Section 8.3.1 and Section 8.3.3. 
8.11.5 
Assessments at Unscheduled Visits/Early termination Visit 
Please see the SoA(s) for each treatment arm as provided in the respective appendix as 
listed in Appendix 6 for activities that are required to be performed in case of an 
unscheduled visit/early termination visit. 
9. 
STATISTICAL CONSIDERATIONS 
For each treatment arm, the analysis of complete data will be performed when all 
participants have either completed the follow-up period or have discontinued early from 
the arm, all data from the arm are in the database and have been cleaned and verified, 
and the database is locked.  

 
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The final analysis for safety efficacy and pharmacodynamic endpoints for each treatment 
arm will be based on participant data collected for that arm. No adjustment for multiplicity 
will be made as each investigational treatment arm will be compared separately to NUC 
control and is therefore independent. The study is not powered to compare 
investigational treatment arms against each other. 
Continuous variables will be summarized using descriptive statistics including means, 
standard deviations, medians, and minimum and maximum values. Categorical variables 
will be summarized through use of counts and percentages. Listings will be used in 
place of tables in the event of small sample sizes. 
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP). 
9.1 
STATISTICAL HYPOTHESES 
As this is an exploratory study, no formal hypothesis testing will be performed.  
9.2 
SAMPLE SIZE DETERMINATION 
Approximately 30 participants will be randomized in each treatment arm. Approximately 
five participants per arm may be replaced if participants have a dose regimen change or 
discontinue due to non-safety reasons, this is to ensure that the number of participants 
per arm of the randomized dose regimen remains close to 30. Participants may be 
replaced at the Sponsor’s discretion. In the event of COVID-19 or force majeure events that 
significantly impact compliance with the randomized dosing regimen, up to 30 additional 
participants may be enrolled per treatment arm to ensure that the randomized dose regimen 
remains close to 30. Criteria and the decision to enroll additional participants will be at the 
Sponsor’s discretion. Please refer to specific combo arms in the appendix for additional 
information about participants. The overall number of participants in this study will 
depend on the number of treatment arms that are included, which is not known at 
present.  
The primary endpoint is the proportion of participants with HBsAg loss at 24 weeks post-
EOT. Assuming a 3% NUC response rate (EASL 2017), a sample size of 30 participants 
per arm provides 78% power to detect a pairwise 30% difference between a combination 
treatment arm and the NUC control arm. This is based on two-treatment arm continuity 
corrected, two-sided, chi-squared test of equal proportions at a significance level of 5 %.  
The sample size of combination treatment arms that achieve 30% delta for HBsAg loss 
at Week 48 (EOT) or follow-up Week 12 or 24 may be expanded up to approximately 
100 participants. An expansion may also be triggered prior to EOT, for a treatment arm 
that gives an early indication of efficacy. The decision criteria to trigger an expansion 
arm in this case, will be documented as an appendix to the IMC/SOC charter. The 
expansion arm may be utilized to increase the precision of the efficacy treatment 

 
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estimates; exploration of participant subgroups (e.g., baseline HBeAg status) and/or gain 
more additional safety data prior to Phase 3 clinical trials. 
9.3 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined in Table 3. 
Table 3 
Analysis Populations 
Population 
Description 
Safety 
All participants randomized to a treatment regimen who 
received at least one dose of any drug for their assigned 
treatment regimen, whether prematurely withdrawn from the 
study or not, will be included in the safety analysis.  
Modified ITT 
All participants who were randomized and received at least 
one dose of each drug for their assigned treatment regimen. 
Participants will be analyzed according to the treatment arm to 
which they were randomized. 
Pharmacokinetic 
Participants will be excluded from the PK analysis population if 
they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol, or if data are 
unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the 
reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure. 
Immunogenicity (when 
applicable) 
Participants who had at least one pre-dose (baseline) or at 
least one post-dose ADA assessment will be included and 
analyzed according to the treatment they actually received or 
were allocated to receive.  
 
9.4 
STATISTICAL ANALYSES 
9.4.1 
Demographics and Baseline Characteristics 
Descriptive statistics will be generated for demographic and baseline disease 
characteristics including sex, race, ethnicity, origin (for Asian participants only), age, 
weight, height, body mass index, HBV DNA and HBsAg levels, and HBV history 
including but not limited to duration of HBV disease, likely route of transmission, HBV 
genotype, HBeAg status, previous HBV treatments, and length of time on NUCs. 
9.4.2 
Efficacy Analyses 
All efficacy analyses will be based on the efficacy analysis population.  
For the treatment arms where additional patients have been recruited to proactively mitigate any 
impact of COVID-19 or force majeure events, the primary analysis will be performed when 
approximately 30 patients considered evaluable for the primary analysis reach the primary 
endpoint of Week 24 post EOT. The criteria to assess evaluability will be described in the SAP. If 
the primary analysis is positive for an experimental treatment arm, any additional patients that 
have been recruited to that treatment arm, will continue and be included in the final CSR.  

 
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Any sensitivity analyses including patients considered ‘unevaluable’ for the primary analysis 
will be specified in the SAP. 
For the primary endpoint (% participants with HBsAg loss at 24 weeks post-EOT), the 
estimated treatment difference adjusted for baseline HBsAg level, along with the 
associated 95% Confidence Interval in the proportion of participants with HBsAg loss at 
24 weeks post-EOT between the experimental and the associated control arm will be 
provided.  
Confidence Intervals will be estimated using Cochran-Mantel-Haenszel (CMH) weighting 
method with continuity correction (Lu 2008). Participants with missing or no response 
assessments will be classified as non-responders. 
Summary statistics will be produced by treatment arm for each of the endpoints defined 
Table 4. In addition, graphical displays will be produced of mean and individual 
participant data as appropriate. 
Table 4 
Efficacy Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Primary 
Treatment effect with associated binomial CI 
Secondary 
Descriptive statistics 
 
9.4.3 
Safety Analyses 
All safety analyses will be based on the safety analysis population grouped according to 
the treatment assigned at randomization. 
All safety analyses will be based on the entire safety analysis population (Table 5). The 
safety data, including AEs, reasons for withdrawal from study, laboratory data, ECGs, 
concomitant medications, vital signs, and physical examination results will be listed and 
summarized descriptively. Marked abnormalities will be flagged for laboratory data. As 
appropriate, listings, summary tables and graphs (participant plot and/or mean plots) will 
be provided for safety and tolerability assessments. 
 
 

 
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Table 5 
Safety Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Adverse events 
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor. 
Adverse events will be summarized by mapped term and appropriate 
thesaurus level. 
Clinical laboratory 
tests 
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
tabular summaries, individual listings with flagging of abnormal results.  
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events AE grading will be used to present shifts from 
baseline to the worst grade observed during treatment  
See Appendix 4 for details on standard reference ranges and data 
transformation and the definition of laboratory abnormalities. 
Vital signs 
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate. 
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate. 
Concomitant 
medications 
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level. 
Concomitant medications will be presented in summary tables and listings. 
 
9.4.4 
Pharmacokinetic Analyses 
Analyses will be carried out on the PK analysis population (see Table 3). 
Plasma concentrations of the NMEs and/or their metabolites when applicable, and 
standard-of-care drugs (where applicable) will be plotted and reported as individual 
values and summarized (mean, standard deviation, coefficient of variation, median, 
range, geometric mean, and geometric mean coefficient of variation) by treatment arm, 
over time when appropriate and as data allow. PK parameters including volume of 
distribution [Vd], clearance [CL]) may be estimated using population PK models 
developed for each asset from the literature or from the Phase 1 studies conducted with 
each NME. Based on these models secondary PK parameters including area under the 
curve (AUC) and peak concentration (Cmax) may be estimated. 
 
 

 
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9.4.5 
Immunogenicity Analyses 
The analyses will be carried out on the immunogenicity analysis population, irrespective 
of whether or not a participant receives any treatment (Shankar et al 2014, see Table 3). 
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence during both the treatment and follow-up periods) will be summarized.  
 
Participants are considered to be ADA positive if they are ADA negative at baseline 
but develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and the 
titer of one or more post-baseline samples is greater than the titer of the baseline 
sample by a scientifically reasonable margin such as at least 4-fold 
(treatment-enhanced ADA response).  
 
Participants are considered to be ADA negative if they are ADA negative at baseline 
and all post-baseline samples are negative, or if they are ADA positive at baseline 
but do not have any post-baseline samples with a titer that is greater than the titer of 
the baseline sample by a scientifically reasonable margin such as at least 4-fold 
(treatment unaffected). 
9.4.6 
Pharmacodynamic Analyses 
Analyses will be carried out on the efficacy analysis population (see Table 3). 
All pharmacodynamic parameters will be presented by listings and descriptive summary 
statistics separately by treatment arm or treatment arms.  
9.4.7 
Pharmacokinetic/ Pharmacodynamic Relationships 
Relationship between study drug(s) and/or metabolites exposure and any PD 
parameters and/or outcome (e.g., safety-related marker, adverse events, safety 
biomarkers, viral dynamic markers, and viral response) may be presented by graphical 
analysis and used for further development of a model. 
9.5 
INTERIM ANALYSES  
There will be up to four planned interim analyses for each treatment arm. The exact 
number of planned interim analyses will depend on the overall duration of the treatment 
arm as well as the sequencing of the drugs in the treatment arm.  
The first three interim analyses will occur, depending on the overall duration of the 
treatment arm as well as the sequencing of the drugs in the treatment arm, once all 
participants within a treatment arm have been randomized and have reached 12 weeks, 
24 weeks, and EOT respectively after the start of therapy (or have discontinued from the 
study). The fourth interim analyses will be performed when all participants within a 

 
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treatment arm have completed the follow-up Week 12 visit (or have discontinued from 
the study).  
Additional design considerations are provided. The below timing of planned interim 
analyses and RGT are illustrated based on a 48-week treatment duration arm; for arms 
with shorter treatment duration, the number of the interim analyses as well as the RGT 
early treatment discontinuations will be adjusted accordingly. 
 
First interim analysis at 12 weeks for a treatment arm: if the observed on-treatment 
HBsAg loss rate of a combination is at least 30% greater than that of control, the 
Sponsor will take into consideration the available safety and pharmacodynamic data 
and may commence a new treatment arm of sample size of approximately 30 
participants with 12-weeks’ treatment duration. In addition, the Sponsor may start a 
new arm of sample size of approximately 30 participants with a RGT, whereby 
participants will discontinue treatment early at Weeks 12, 24, or 36 if HBsAg loss is 
observed.  
 
Second interim analysis at 24 weeks for a treatment arm: if the observed on-
treatment HBsAg loss rate of a combination is at least 30% greater than that of 
control, the Sponsor will take into consideration the available safety and 
pharmacodynamic data and may commence a new treatment arm of sample size of 
approximately 30 participants with 24-weeks treatment duration. In addition, the 
Sponsor may start a new arm of sample size of approximately 30 participants with a 
RGT approach, whereby participants will discontinue treatment early at Week 12, 24, 
or 36 if HBsAg loss is observed. 
 
Third and fourth interim analyses at Week 48 and follow-up Week 12: for safety and 
internal decision-making purposes (e.g., front-loading Ph3 activities), and if the 
observed HBsAg loss rate of a combination is at least 30% greater than that of 
control, the Sponsor may decide to expand the treatment arm up to approximately 
100 participants. An expansion may also be triggered prior to EOT, for a treatment 
arm that gives an early indication of efficacy. The decision criteria to trigger an 
expansion arm in this case, will be documented as an appendix to the IMC/SOC 
charter.  
 
Above pre-specified study adaptations allow for NME combination therapies that show 
promising efficacy outcomes to be further evaluated promptly, based on emerging data, 
without delays that would be otherwise incurred through protocol amendments. These 
decision criteria assume that the on-treatment HBsAg loss rate is predictive of the 24-
week post-EOT HBsAg loss rate.  
The Statistical Analysis Plan will describe the planned interim analyses in detail. 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim analyses not specified above. The decision to conduct an 
optional interim analysis and the timing of the analysis will be documented in the 

 
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Sponsor’s trial master file prior to the conduct of the interim analysis. The interim 
analysis will be performed and interpreted by Sponsor study team personnel. 
9.6 
SUMMARIES OF CONDUCT OF STUDY 
The number of participants who were randomized, discontinued treatment, completed 
treatment, discontinued study and completed the study (including follow-up period) will 
be summarized. Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by each treatment arm. 
For safety-evaluable participants, study drug administration data will be tabulated or 
listed by treatment arm within each stage, and any dose modifications will be flagged. 
Means and standard deviations will be used to summarize the total dose and dose 
intensity for each study drug. Reasons for discontinuation of study drugs will also be 
tabulated. 

 
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10. 
REFERENCES 
Blaising J, Yu Y, Zhou X, et al. American Association for the Study of Liver Diseases . 
Posters (Abstracts 289–2348). Hepatology 2019; 70: 188–1382. 
Chen J, Wang X-M, Wu X-J, et al. Intrahepatic levels of PD-1/PD-L correlate with liver 
inflammation in chronic hepatitis B. Inflamm Res. 2011;60(1):47-53. 
Chen EQ, Feng S, Wang ML, et al. Serum hepatitis B core-related antigen is a 
satisfactory surrogate marker of intrahepatic covalently closed circular DNA in 
chronic hepatitis B. Sci. Rep. 2017;7(1):173. 
Dong DR, Hao MN, Li C, et al. Acoustic radiation force impulse elastography, 
FibroScan(R), Forns’ index and their combination in the assessment of liver 
fibrosis in patients with chronic hepatitis B, and the impact of inflammatory activity 
and steatosis on these diagnostic methods. Mol Med Rep. 2015;11:4174-4182. 
Durantel D, Zoulim F. New antiviral targets for innovative treatment concepts for 
hepatitis B virus and hepatitis delta virus. J Hepatol. 2016;64:S117-S131.  
European Association for the Study of the Liver. EASL clinical practice guidelines: 
management of chronic hepatitis B virus infection. J Hepatol. 2012;57:16785. 
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines 
on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-398. 
European Association for the Study and Asociacion Latinoamericana para el Estudio del 
Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation 
of liver disease severity and prognosis. J Hepatol. 2015;63:23764. 
Fan R, Sun J, Yuan Q, et al. Baseline quantitative hepatitis B core antibody titre alone 
strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated 
with peginterferon or nucleos(t)ide analogues. Gut. 2016;65:313-20. 
Fan R, Zhou B, Xu M, et al. Association between negative results from tests for HBV 
DNA and RNA and durability of response after discontinuation of nucles(t)ide 
analogue therapy. Clin Gastroenterol Hepatol 2020;18:719-27. 
FDA. Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment Guidance for 
Industry. Nov 2018. Available at: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM624695.pdf 
Fernández M, Quiroga JA, Carreño V. Hepatitis B virus downregulates the human 
interferon-inducible MxA promoter through direct interaction of precore/core 
proteins. J Gen Virol. 2003;84:2073-82. 
Fidock MD, Souberbielle BE, Laxton C. The innate immune response, clinical outcomes, 
and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin 
Pharmacol Ther. 2011;89:821-829. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
68/Protocol WV41073, Version 7.0 
Funk E, Kottilil S, Gilliam B. Tickling the TLR7 to cure viral hepatitis. J Transl Med. 
2014;12:129. 
Gruffaz M, Testoni B, Luangsay S, et al. Hepatitis B core (HBC) protein is a key and very 
early negative regulator of the interferon response [abstract]. J Hepatol. 
2013;58(Suppl 1):S155-6. 
Gupta A. Asialoglycoprotein Receptor and the Macrophage Galactose-Type Lectin. In: 
Animal Lectins: Form, Function and Clinical Applications. Springer, Vienna, 
Austria; 2012:709-724. 
Hai-Jun Li, Nai-Cui Zhai, Hong-Xiao Song, et al. The Role of Immune Cells in Chronic 
HBV Infection. J Clin Transl Hepatol. 2015 Dec 28; 3(4): 277–283. 
HBV Forum 1, Boston, Massachusetts, November 15th, 2016. Available at: 
http://www.hivforum.org/projects/hbv-forum/hbv-forum-meetings. 
Horscroft NJ, Pryde DC, Bright H. Antiviral applications of toll-like receptor agonists. J 
Antimicrob Chemother. 2012;67:789-801. 
Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, et al. Magnetic 
resonance elastography for the noninvasive staging of liver fibrosis. 
Gastroenterology. 2008;135:32–40. 
Inoue T and Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. 
Clin Mol Hepatol. 2020 Jul; 26(3): 261–279. 
Investigator’s Brochure, RO7020531. 
Investigator’s Brochure, RO7049389. 
Investigator’s Brochure, RO7445482.  
Investigator’s Brochure, RO7191863. 
Isogawa M, Robek MD, Furuichi Y, et al. Toll-like receptor signaling inhibits hepatitis B 
virus replication in vivo. J Virol. 2005;79:7269-7272. 
Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. 
Nat. Immunol. 2004;5:987-995. 
Jia W, Song LW, Fang YQ, et al. Antibody to hepatitis B core antigen levels in the 
natural history of chronic hepatitis B: a prospective observational study. Medicine. 
2014;93:e322. 
Kaewdech A, Tangkijvanich P, Sripongpun P, et al. Hepatitis B surface antigen, core-
related antigen and HBV RNA: Predicting clinical relapse after NA therapy 
discontinuation. Liver Int. 2020 Jul 15. 
Lester SN, Li K. Toll-like receptors in antiviral innate immunity. J Mol Biol. 
2014;426:1246-1264. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
69/Protocol WV41073, Version 7.0 
Li Feng-Cai, Li Yue-Kai, Fan Yu-Chen, et al. Plasma concentration of diamine oxidase 
(DAO) predicts 1-month mortality of acute-on-chronic hepatitis B liver failure. 
Clinica Chimica Acta. Volume 484, September 2018, Pages 164-170. 
Li Feng-Cai, Li Yue-Kai, Fan Yu-Chen. Biomarkers for hepatitis B virus replication: an 
overview and a look to the future. Expert Rev Gastroenterology Hepatology Clin 
Mol Hepatol. abstract. 04 Sep 2020. 
Liu J, Goicochea P, Block T, Brosgart CL, Donaldson EF, Lenz O, et al. Advancing the 
regulatory path on hepatitis B virus treatment and curative research: a 
stakeholders consultation. J Virus Erad. 2017;3:1–6. Lok AS, Zoulim F, Dusheiko 
G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. J Hepatol. 
2017;67:847861. 
Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory 
approval. J Hepatol. 2017;67:847861. 
Lu, K. Cochran-Mantel-Haenszel weighted Miettinen & Nurminen method for confidence 
intervals of the difference in binomial proportions from stratified 2 × 2 samples. 
JSM Proceedings, Denver, CO: American Statistical Association. 2008; 3888– 
3893. 
Mak LY, Wong DK, Cheung KS et al. Hepatitis B core-related antigen (HBcrAg): An 
emerging marker for chronic hepatitis B virus infection. Aliment Pharmacol Ther. 
2018;47(1):43-54. 
Man-Fung Yuen, Kosh Agarwal, Xiaoli Ma, et al. Antiviral activity and safety of the 
hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse 
transcriptase inhibitor in patients with HBeAg positive chronic hepatitis B infection 
in a long-term extension study. Presented at the EASL Digital International Liver 
Conference, August 27–29, 2020. 
Marcellin P, Wong D, Sievert W, et al. Ten-year efficacy and safety of tenofovir 
disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 
2019;39:1868–75. 
NUC local prescribing information. 
Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, 
Touloumi G, Petersen J. Discontinuation of oral antivirals in chronic hepatitis B: A 
systematic review. Hepatology. 2016;63:1481–1492. 
Pegasys® local prescribing information  
Li Q, Chen L, Zhou Y. Diagnostic accuracy of liver stiffness measurement in chronic 
hepatitis B patients with normal or mildly elevated alanine transaminase levels. 
Scientific Reports. 2018;8:5224.  
Rajoriya N, Combet C, Zoulim F, et al. How viral genetic variants and genotypes 
influence disease and treatment outcome of chronic hepatitis B. Time for an 
individualised approach? J Hepatol. 2017;67(6):1281-1297. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
70/Protocol WV41073, Version 7.0 
RO7191863 Interim Data Memo: Summary of Safety, Pharmacodynamic, Pharmacokinetic Data 
from MAD Cohorts 4-7 of Study NP40479 Supporting RO7191863 Phase 2 Dosing 
Regimen Selection for Study WV41073; 2022 May 11. 
Seto WK, Liu KS, Mak LY, et al. Role of serum HBV RNA and hepatitis B surface 
antigen levels in identifying Asian patients with chronic hepatitis B suitable for 
entecavir cessation. Gut 2020 Aug 5. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides—harmonized terminology 
and tactical recommendations. The AAPS journal. 2014;16(4):658-673. 
Strader DB, Wright T, Thomas L, et al. Diagnosis, management and treatment of 
hepatitis C. Hepatol. 2004;39:1147-1171. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, 
and expression. Physiol Rev. 1995;75(3):591-609. 
Sunbul M. Hepatitis B virus genotypes: global distribution and clinical importance. World 
J Gastroenterol. 2014; 20 (18):5427-5434. 
Tanwar S, Dusheiko G. Is there any value to hepatitis B virus genotype analysis? Curr 
Gastroenterol Rep. 2012;14(1):37-46 
Tayama Y, Sugihara K, Sanoh S. Effect of tea beverages on aldehyde oxidase activity. 
Drug Metab Pharmacokinet. 2011;26:94-101. 
Twu JS, Lee CH, Lin PM, et al. Hepatitis B virus suppresses expression of human beta-
interferon. Proc Natl Acad Sci U.S.A. 1988;85:252-6. 
Wang XY, Chen HS. Emerging antivirals for the treatment of hepatitis B. World J 
Gastroenterol. 2014;20:77077717. 
Wang J, Shen T, Huang X, et al. Serum hepatitis B virus RNA is encapsidated 
pregenome RNA that may be associated with persistence of viral infection and 
rebound. J Hepatol. 2016;65(4):700-710. 
Woodcock J and LaVange LM. Master protocols to study multiple therapies. Multiple 
diseases, or both. N Engl J Med. 2017;377:62-70. 
World Health Organization. Global Hepatitis Report [resource on the Internet]. 2017 
[updated 2017; cited 29 August 2018]. Available from: 
http://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ 
World Health Organization. Hepatitis B fact sheet [resource on the Internet]. 2018 
[updated July 2018; cited 13 August 2018]. Available from: 
http://www.who.int/mediacentre/factsheets/fs204/en/. 
Yang S, Zeng W, Zhang J, Lu F, Chang J, Guo JT. Restoration of a functional antiviral 
immune response to chronic HBV infection by reducing viral antigen load: if not 
sufficient, is it necessary? Emerg Microbes Infect. 2021;10(1):1545-1554. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Yuan Q, Song LW, Liu CJ, et al. Quantitative hepatitis B core antibody level may help 
predict treatment response in chronic hepatitis B patients. Gut. 2013;62:182-4. 
Zelensky AN, Gready JE. The C-type lectin-like domain superfamily. FEBS J. 
2005;272(24):6179-6217. 

 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
The following section includes standard appendices such as Appendix 1 (For regulatory, 
ethical, and study oversight considerations), Appendix 2 (For AE definitions and 
reporting) and Appendix 3 (Procedures of recording), Appendix 4 (Clinical laboratory 
tests), Appendix 5 (Contraceptive guidance and collection of pregnancy information).  
Additional study-related appendices, in order of appearance in the protocol, are listed 
below.  
Appendix 6 Planned Treatment Arms  
Appendix 7 Study Details Specific to NUC Control Arm 
Appendix 8 Study Details Specific to CpAM (RO7049389) + TLR7 (RO7020531) + NUC 
Arm 
Appendix 9 Study Details Specific to siRNA (RO7445482) + NUC Arm 
Appendix 10 Study Details Specific to siRNA (RO7445482) + PEG-IFN + NUC Arm 
Appendix 11 Study Details Specific to siRNA (RO7445482) + CpAM (RO7049389) + 
NUC Arm 
Appendix 12 Study Details Specific to siRNA (RO7445482) + TLR7 (RO7020531) + 
NUC Arm 
Appendix 13 Study Details Specific to siRNA (RO7445482) + PD-L1 LNA (RO7191863) 
+ NUC Arm 
 

 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
1.1. COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European 
Commission/European Economic Area will comply with the EU Clinical Trial Directive 
(2001/20/EC). 
1.2. INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the participant (e.g., 
advertisements, diaries etc.), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix). 
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 
1.3. INFORMED CONSENT 
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants or their 

 
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legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample ICFs or any alternate consent forms 
proposed by the site (collectively, the “Consent Forms”) before IRB/EC submission. The 
final IRB/EC‑approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative. 
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative before his or her participation in the study. The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required according 
to local regulations. 
Participants must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s study file or in the site file and must be available for 
verification by study monitors at any time. 
Participants who are re-screened are required to sign a new ICF. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research, as appropriate. A separate signature will be 
required to document a participant's agreement to allow any remaining samples to be 
used for exploratory research. 

 
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Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR. Participants will 
be told that they are free to refuse to participate and may withdraw their samples at any 
time and for any reason during the storage period. A separate, specific signature will be 
required to document a participant’s agreement to provide optional RBR samples. 
Participants who decline to participate will not provide a separate signature. 
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF. 
In the event of death or loss of competence of a participant who is participating in the 
Research, the participant's samples and data will continue to be used as part of the 
RBR. 
For sites in the United States, each Consent Form may also include participant 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the 
site utilizes a separate Authorization Form for participant authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies. 
Approval by the Institutional Review Board or Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board or Ethics Committee (IRB/EC) and, if 
applicable, an appropriate regulatory body. If a site has not been granted approval for 
RBR sampling, this section of the protocol will not be applicable at that site 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
WV41073 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 

 
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WV41073. Data already generated before time of withdrawal of consent to RBR will still 
be used. 
1.4. CONFIDENTIALITY 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes. 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request. 
Confidentiality for Research Biosample Repository 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the Informed Consent Form (or 
separate authorization for use and disclosure of personal health information) signed by 
the participant, unless permitted or required by law. 
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study investigators unless a request for research use is granted. The 

 
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aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and nature of 
these analyses, genetic data and analyses will not be shared with investigators or 
participants unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of Roche, except where agreed otherwise. 
Monitoring and Oversight Research Biosample Repository 
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the 
Informed Consent Form. Roche monitors and auditors will have direct access to 
appropriate parts of records relating to participant participation in RBR for the purposes 
of verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the samples. 
1.5. FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV). 
2. 
DATA HANDLING AND RECORD 
2.1. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

 
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The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
In addition, the Sponsor will implement a system to manage the quality of the study, 
focusing on processes and data that are essential to ensuring subject safety and data 
integrity. Prior to first subject entry into the study, the Sponsor will identify potential risks 
associated with critical trial processes and data and will implement plans for the control 
and review of these risks. Risk control includes the selection of risk-based parameters 
and establishing associated quality tolerance limits. Detection of deviations from defined 
quality tolerance limits will trigger an evaluation to determine if action is needed. Details 
on the management and review of quality tolerance limits will be provided in a separate 
Quality Tolerance Limit plan. 
2.1.2. 
CLINICAL OUTCOME ASSESSMENT DATA 
Not applicable.  
2.1.3. 
SOURCE DATA RECORDS 
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, participant files, and 
records kept at pharmacies, laboratories, and medico‑technical departments involved in 
a clinical study. 
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 

 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities. 
2.1.4. 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
2.2. RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
2.3. STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IEC and regulatory 
authorities according to local regulatory requirements and timelines of each country 
participating in the study. 
2.3.1. 
Protocol Amendments 
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements. 

 
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Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
2.3.3. 
Dissemination of Clinical Study Data 
A description of this clinical study will be available at http://www.ClinicalTrials.gov. 
2.3.4. 
Management of Study Quality 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity. 
Prior study initiation, the Sponsor will identify and evaluate potential risks associated 
with critical trial processes and data and will implement controls for the communication, 
review and reporting of these risks. Details regarding the applied approach for the study 
will be provided in the integrated Risk Based Quality Management Plan.  
Risk control includes the selection of risk-based parameters and establishing associated 
quality tolerance limits. Detection of deviations from defined quality tolerance limits will 
trigger an evaluation to determine if action is needed. Details on the management and 

 
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review of quality tolerance limits will be provided in a separate Quality Tolerance Limit 
plan. 
2.3.5. 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
3. 
ADMINISTRATIVE STRUCTURE 
Internal Monitoring Committee (IMC) and Scientific Oversight Committee (SOC) 
The IMC will perform periodic safety data review to ensure that continuation of the study 
does not pose a health hazard to participants, and review the results from the interim 
analyses to make decision about initiating new treatment arms.  
IMC meetings will be scheduled following each of the planned interim analyses. 
Additional review meetings may be scheduled as determined by the IMC. Membership of 
the IMC will include representatives from Clinical Science (Translational Medicine), 
Clinical Safety, Biostatistics. If required, additional functional representatives may attend 
an IMC meeting.  
A SOC will act as a consultative body to the Sponsor, providing external expert opinions 
on the safety data collected during the study. This committee will consist of an external 
group of at least two CHB therapeutic area experts who will advise the Sponsor on the 
interpretation of study data.  
Data being evaluated by the SOC will include demographic, adverse event, serious 
adverse event, and relevant laboratory data. SOC may review efficacy data if safety 
concerns necessitate benefit-risk assessments. The Sponsor will retain all decision-
making authority for this study. 
Further details on the IMC and SOC, including membership, roles and responsibilities, 
are provided in the IMC and SOC Charter. 
4. 
STUDY ARM, STUDY, AND SITE CLOSURE 
The Sponsor (or designee) has the right to close a study site, terminate this study, study 
arms or certain NMEs in combination at any time. Reasons for terminating the study, 

 
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study sites, study treatment arms or certain NMEs may include, but are not limited to, 
the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants. 
 
Participant enrollment is unsatisfactory. 
 
Emerging data and/or prioritization of assets. 
 
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program or 
terminate study arms or terminate certain NMEs in combination. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
 
Inadequate recruitment of participants by the Investigator. 
 
Discontinuation of further study treatment development. 
 
 

 
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Appendix 2  
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up, and Reporting 
1. 
DEFINITION OF ADVERSE EVENTS 
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a participant or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An adverse event can therefore be: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
 
Events Meeting the AE Definition: 
 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a 
change in study treatment or concomitant treatment or discontinuation from study 
treatment (see Appendix 3, Section 4). 
 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting, such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an 
AE or SAE. 
 
Events NOT Meeting the AE Definition: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 

 
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 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that at any 
dose: 
 
Results in death. 
 
Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant 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 was more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(see Appendix 3). 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
 
Results in persistent or significant disability/incapacity 
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 

 
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 
Is a congenital anomaly/birth defect. 
 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include  
- 
elevated ALT or AST (> 3 × ULN and > 3x baseline) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia (Potential Hy’s law). 
- 
invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. 
 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Medical Monitor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Medical Monitor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
3.1. ASSESSMENT OF SEVERITY 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (according to pre-defined Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events [DAIDS] criteria); the event itself may be 
of relatively minor medical significance (such as severe headache without any further 
findings). 

 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event). 
The adverse event severity grading scale for the DAIDS (v2.1) will be used for assessing 
severity for adverse events (see Appendix 2-Table 1). 
Appendix 2-Table 1 DAIDS Adverse Event Severity Grading Scale 
Grade 
Description 
1 
Mild; symptoms causing no or minimal interference with usual social & functional 
activities with intervention not indicated 
2 
Moderate; symptoms causing greater than minimal interference with usual social & 
functional activities with intervention indicated 
3 
Severe; symptoms causing inability to perform usual social & functional activities with 
intervention or hospitalization indicated  
4 
Potentially life-threatening; symptoms causing inability to perform basic self-care 
functions with intervention indicated to prevent permanent impairment, persistent 
disability, or death 
5 
Death 
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to definition of a 
serious adverse event (see above). DAIDS v2.1 grading scale is available at: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
Pyrexia will be graded by using the following DAIDS V2.1 (see Appendix 2-Table 2). 
Appendix 2-Table 2 DAIDS Pyrexia Severity Grading Scale 
Grade 
Temperature 
1 (mild) 
38.0 to < 38.6°C (100.4 to < 101.5°F) 
2 (moderate) 
≥ 38.6°C to < 39.3 (≥ 101.5 to < 102.7°F) 
3 (severe) 
≥ 39.3 to < 40°C (≥ 102.7 to < 104°F)  
4 (life threatening) 
≥ 40°C or ≥ 104°F 
 
If the treatment regimen will include NME(s) that may trigger immune activation (and 
potentially CRS (cytokine release syndrome), additional AEs and the associated clinical 
management will be specifically reported into the eCRF by the Investigator: flu-like 

 
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symptom specific eCRF page for capturing each of the symptoms experienced, 
presence of hypotension (requiring fluid or use of vasopressors), and presence of 
hypoxia (requiring medical intervention). Data from eCRF pages on pyrexia and flu-like 
symptoms in combination with the data on eCRF pages on hypoxia and hypotension will 
allow the Sponsor to evaluate the severity of AEs associated with immune activation 
following specific CRS consensus grading (ASTCT Consensus Grading for Cytokine 
Release Syndrome. Biol Blood Marrow Transplant, 25; (2019) 625-38). 
3.2. ASSESSMENT OF CAUSALITY 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration: 
 
Temporal relationship of event onset to the initiation of study treatment. 
 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.  
 
Known association of the event with the study treatment or with similar treatments. 
 
Known association of the event with the disease under study. 
 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event. 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
4. 
FOLLOW-UP OF AES AND SAES 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
New or updated information will be recorded in the originally completed eCRF. 

 
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The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
5. 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events 
 
Adverse events of special interest (AESI) 
 
Pregnancies (see Section 8.3.5) 
 
Accidental overdose or medication errors (see Appendix 2, Section 5.2)  
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis. 
 
Significant new diagnostic test results. 
 
Change in causality based on new information. 
 
Change in the event’s outcome, including recovery. 
 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC. 
5.1 REPORTING REQUIREMENTS OF SERIOUS ADVERSE EVENTS AND 
ADVERSE EVENTS OF SPECIAL INTEREST 
Events that Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event). 

 
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Events that Occur after Study Treatment Initiation 
For reports of serious adverse events and adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event). 
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
Reporting of Post-Study Adverse Events and Serious Adverse Events 
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period, if the event is believed to be related to prior study 
treatment the event should be reported directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or 
email address provided to investigators. 
5.2 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL OVERDOSE 
OR MEDICATION ERROR, OVERDOSE, MEDICATION ERROR, DRUG 
ABUSE, OR DRUG MISUSE 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse} 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose} 
 
Medication error:  accidental deviation in the administration of a drug. In some 
cases, a medication error may be intercepted prior to administration of the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm} 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse. In cases where drug is to be self-administered by the 

 
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participant, drug misuse could involve the drug being administered to someone 
other than the participant. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events. Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). For study treatments, adverse 
events associated with special situations should be recorded as described below for 
each situation: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term. Check the "Intentional overdose" box. If drug abuse is suspected, check the 
"Drug abuse" box. If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term. 
Check the "Accidental overdose" and "Medication error" boxes.  
 
Drug abuse that does not qualify as an overdose: Enter the adverse event term. 
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose: Enter the adverse event term. Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term. 
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term. Check 
the "Intentional overdose" and "Drug misuse" boxes.} 
 
In addition, all special situations associated with the study treatments, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Appendix 2, Section 5.1). Special situations should be 
recorded as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term. Check the "Intentional overdose" box. If drug abuse is suspected, check the 
"Drug abuse" box. If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 

 
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dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details. 
 
Drug abuse that does not qualify as an overdose: Enter the drug name and "drug 
abuse" as the event term. Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term. Check the "Drug misuse" 
 
Drug misuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the participant:  Enter the drug name and 
"patient supplied drug to third party" as the event term. Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and AESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document{s}: 
 
IMPs Investigator's Brochure 
 
NUC prescribing information in required territories 
 

 
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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
 
 

 
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Appendix 3 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
1. 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
1.1. 
INJECTION-SITE REACTIONS/INJECTION REACTIONS  
Adverse events that occur during or after study drug administration and are judged to be 
local and related to the SC study drug injection should be captured as a diagnosis (e.g., 
“injection site reaction)" on the Adverse Event eCRF and if judged to be systemic should 
be captured as a diagnosis ‘’injection reaction (IR)’’. If possible, avoid ambiguous terms 
such as "systemic reaction"). Associated signs and symptoms should be recorded on the 
dedicated Injection Reaction eCRF. 
Injection Site Reactions (ISR) are usually immunological with delayed onset. The SAP 
will include analyses of ISR using a modified (mISR) definition of ISR of onset of 4 or 
more hours post-dose.  
Grading of pre-defined ISR signs and symptoms (pain, erythema swelling and pruritus) 
should be based on DAIDS (Appendix 2, Section 3.1). If a patient experiences both a 
local and systemic reaction to the same dose of study drug, each reaction should be 
recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated signs and symptoms eCRF for Systemic Injection 
Reaction and ISR. 
2. 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 

 
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severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time points. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent adverse event is one that resolves between participant evaluation time 
points and subsequently recurs. Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF. 
4. 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy. 
 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 

 
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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5. 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention or a change in concomitant therapy. 
 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 

 
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6. 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST ( 3  ULN and > 3  baseline) in combination 
with either an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia (Potential Hy’s law) is considered to be 
an indicator of severe liver injury (DILI). Therefore, investigators must report as an 
adverse event the occurrence of either of the following: 
 
Treatment-emergent ALT/AST  3  ULN and  3  baseline, in combination with total 
bilirubin  2  ULN. 
 
Treatment-emergent ALT or AST  3  ULN and  3  baseline, in combination with 
clinical jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event) as a AESI 
(Section 8.3.6) and serious adverse event, if the SAE definition criteria is met. 
7. 
DEATHS 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Appendix 2, Section 5), regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor. This includes 
death attributed to progression of CHB. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
8. 
PREEXISTING MEDICAL CONDITIONS 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 

 
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9. 
WORSENING OF CHRONIC HEPATITIS B 
Lack of efficacy in terms of changes in HBsAg does not qualify for adverse event in this 
study. 
Medical occurrences or symptoms of deterioration in the course of chronic hepatitis B 
should be recorded as an adverse event if judged by the Investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study. When recording an unanticipated worsening of Chronic Hepatitis B on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., Progression of Chronic Hepatitis B). 
Hepatitis B virological breakthrough, hepatitis B virological relapse, and abnormal liver 
function tests (see Section 8.3.8) should be reported as adverse events.  
10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration) 
 
For administrative reasons (e.g., participant lives far away and is kept in the 
clinic/hospital for participant and/or site convenience) 
 
Hospitalization for a preexisting condition (not CHB), provided that all of the 
following criteria are met: 
- 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
- 
The participant has not suffered an adverse event. 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 

 
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Appendix 4 
Clinical Laboratory Tests 
The tests detailed in Appendix 4-Table 1 below will be performed by the central 
laboratory, with the exception of urinalysis, alcohol and drugs of abuse screen, which will 
be performed locally. 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment administration (including for the 
randomization/dosing day) and/or a response evaluation. If a local sample is required, it 
is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make either a study treatment 
decision or a response evaluation, the results must be captured in source documentation 
and entered as a comment into the eCRF.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
 
 

 
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Appendix 4-Table 1 Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
 
Leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration 
(MCHC) and glycated hemoglobin (HbA1c). 
Clinical Chemistry  
 
Sodium, potassium, chloride, bicarbonate, phosphorus, 
calcium, magnesium, urea, uric acid, blood urea nitrogen 
(BUN), creatinine and cystatin C, estimated glomerular 
filtration rate (eGFR), glucose, total protein, albumin, total 
and direct bilirubin, alkaline phosphatase (ALP), ALT, AST, 
gamma-glutamyl transferase (GGT), alpha fetoprotein, 
glutamate dehydrogenase (GLDH), lipase, creatine 
kinase/creatine phosphokinase (CK/CPK), LDH and 
amylase. 
Lipids 
 
Total cholesterol, low-density lipoproteins (LDL) cholesterol, 
high-density lipoproteins (HDL) cholesterol, triglycerides. 
Thyroid Function Tests 
 
TSH, free T3 and free T4. 
Coagulation 
 
INR, activated partial thromboplastin time, PT. 
Viral Serology 
 
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis A virus (HAV IgM antibody), hepatitis B 
surface antigen (HBsAg), hepatitis C virus (HCV) antibody, 
hepatitis D virus (HDV) antibody, hepatitis E virus (HEV) 
antibody. 
Pregnancy Test 
 
All women of childbearing potential (including those who 
have had a tubal occlusion/ligation) will have a blood 
pregnancy test at screening. Urine pregnancy tests will be 
performed at subsequent visits according to SOAs. If a urine 
pregnancy test is positive, it must be confirmed by a blood 
pregnancy test. 
Urinalysis 
 
Specific gravity. 
 
Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrites, leukocytes. 
If there is a clinically significant positive result (e.g., 2+ or 
greater for blood, protein or leukocytes) confirmed by a 
positive repeated sample, urine will be sent to the central 
laboratory for microscopy and culture. In addition, if there is 
clinically significant proteinuria (2+ or greater for protein), 
central laboratory will measure the urine protein: creatinine 
ratio.  
If there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no need to 
perform microscopy and culture. 
 
Microscopic examination (sediment, red blood cells [RBCs], 
WBCs, casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal. 
Other Screening Tests 
 
Alcohol and drug screen according to local procedure to 
include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids, and benzodiazepines. 
 
Auto-antibodies (ANA, AMA, ASMA, a-TPO). 

 
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Investigators must document their review of each laboratory safety report. 
Additional Statistical Considerations for Clinical Laboratory Data 
 
Standard Reference Ranges and Transformation of Data 
Potential analysis considerations for analyzing laboratory data includes the use of 
standard reference ranges and potential transformation of data for specific lab tests.  
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these parameters, the 
measured laboratory test result will be assessed directly using the Roche standard 
reference range. Certain laboratory parameters will be transformed to Roche’s standard 
reference ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data. 
 
Definition of Laboratory Abnormalities 
For all laboratory parameters included in this analysis, there exists a Roche predefined 
standard reference range. Laboratory values falling outside this standard reference 
range will be labeled “H” for high or “L” for low in participant listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for these laboratory parameters. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low. 

 
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Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information 
1. 
DEFINITIONS 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
 
Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP) 
a) Pre-menarchal 
b) Pre-menopausal female with one of the following: 
– 
Documented hysterectomy. 
– 
Documented bilateral salpingectomy. 
– 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
c) 
Post-menopausal female 
– 
A post-menopausal state is defined as no menses for  12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
– 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
 
2. 
CONTRACEPTION GUIDANCE 
 
Female Participants 
Unless otherwise stated in the respective appendix of each treatment arm, female 
participants of childbearing potential are eligible to participate if they agree to use highly 

 
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effective method of contraception consistently and correctly as described in Appendix 5-
Table 1 below. 
Per ICH M3 (R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly as described in Appendix 5-Table 1 below. 
Appendix 5-Table 1 Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependenta 
(Failure rate of  1% per year when used consistently and correctly) 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Injectable  
Highly Effective Methods That Are User-Independent 
(Failure rate of  1% per year) 
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
 
 

 
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Appendix 5-Table 1 Highly Effective Contraceptive Methods (cont.) 
Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective 
(Failure rate of  1% per year when used consistently and correctly) 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
Male or female condom with or without spermicide b 
 
Cap, diaphragm or sponge with spermicide b 
a) 
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method. 
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
b) 
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely. 
 
3. 
PREGNANCY TESTING 
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to respective treatment arm specific Schedule of Activities table. If 
a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
 
Male participants with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy).  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 

 
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child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
 
Female participants who become pregnant 
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant’s pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Appendix 2. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. 
5 
ABORTIONS 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Appendix 2, Section 5). 
Any induced abortion due to maternal toxicity and/or embryofetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Appendix 2, Section 5). 
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form. 

 
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6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female participant, or female 
partner of a male participant exposed to study treatment, should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). 

 
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Appendix 6 
Planned, Ongoing, and Terminated Treatment Arms And 
Terminated Arm Safety Follow Up 
An overview of the planned, ongoing, and terminated treatment arms is shown in 
Appendix 6-Table 1. 
Arms depicted in Appendix 6-Table 1 as 2 and 6, were terminated due to Sponsor’s 
decision to discontinue the development of CpAM (RO7049389) in the NUC-suppressed 
CHB participant population. At the time this decision was taken the CpAM+TLR7+NUC 
arm was fully recruited and the siRNA+CpAM+NUC arm was partially recruited. As a 
result of this decision, no further participants were enrolled in the siRNA+CpAM+NUC 
arm and the participants who were already randomized to both treatment arms were 
asked to attend an early termination visit to discontinue both study drugs, maintain NUC 
therapy, and enter the safety follow-up period.  
Appendix 6-Table 1 Planned, Ongoing, and Terminated Treatment Arms 
Arm 
Treatment Arm 
Arm Status 
Number of 
Participants 
Link to 
Appendix 
1 
NUC control  
Ongoing 
30b 
Appendix 7  
2 
CpAM (600 mg) (RO7049389) + TLR7 (150 
mg) (RO7020531) + NUC 
Terminatedc 
~30 
Appendix 8  
3 
siRNA (100 mg) (RO7445482) + NUC 
Ongoing 
~30 
Appendix 9  
4 
siRNA (200 mg) (RO7445482) + NUC 
Ongoing 
~30 
Appendix 9 
5 
siRNA (200 mg) (RO7445482) + PEG-IFN 
(180 µg)+ NUC 
Ongoing 
~30 
Appendix 10  
6 
siRNA (200 mg) (RO7445482) + CpAM 
(600 mg) (RO7049389) + NUC 
Terminatedc 
~30 
Appendix 11  
7 
siRNA (200 mg) (RO7445482) + TLR7 
(150 mg) (RO7020531) + NUC 
Ongoing 
~30 
Appendix 12  
8 
siRNA (200 mg) (RO7445482) + PD-L1 LNA 
(RO7191863) + NUC – 24 week 
treatment 
Planned 
~30 
Appendix 13 
9 
siRNA (200 mg) (RO7445482) + PD-L1 LNA 
(RO7191863) + NUC – 36 week 
treatment 
Planned 
~30 
Appendix 13 
TBDa 
TBD 
 
TBD 
TBD 
Abbreviations:  NUC=nucleos(t)ide; TBD=to be determined. 
 a Additional treatment arms may be added to the study. 
b Additional participants will be added as additional treatment arms are added to the study. 
c Treatment arms terminated; patients performed early termination visit and entered in the safety follow-up 
period. 
 

 
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Appendix 6-Table 2 
Mechanism of Action Classification for Investigational 
Medicinal Products 
IMP 
Target 
Mechanism of Action 
CpAM (RO7049389) HBV core protein DAA: Core protein allosteric modulator (class I) 
TLR7 (RO7020531) 
Human toll-like 
receptor 7 
IM: Toll-like receptor 7 agonist 
siRNA (RO7445482) 
HBV RNA 
transcripts 
DAA: HBV gene expression inhibitor 
PD-L1 LNA 
(RO7191863) 
PD-1/PD-L1 
checkpoint 
inhibitory 
pathway 
IM: PD-L1 inhibitor 
 
Appendix 6-Table 3 Applicable Inclusion/Exclusion Criteria 
Treatment arm 
Applicable Exclusion Criteria 
NUC Control Arm 
Section 5.2 
CpAM (RO7049389) + TLR7 (RO7020531) + 
NUC  
Section 5.2 and Section A8.4 in Appendix 8  
siRNA (100 mg) (RO7445482) + NUC 
Section 5.2 and Section A9.4 in Appendix 9 
siRNA (200 mg) (RO7445482) + NUC 
Section 5.2 and Section A9.4 in Appendix 9 
siRNA + PEG-IFN + NUC  
Section 5.2 and Section A10.4 in Appendix 10  
siRNA (RO7445482) + CpAM (RO7049389) + 
NUC 
Section 5.2 and Section A11.4 in Appendix 11 
siRNA (RO7445482) + TLR7 (RO7020531) + 
NUC  
Section 5.2 and Section A12.4 in Appendix 12  
siRNA (RO7445482) + PD-L1 LNA 
(RO7191863) + NUC  
Section 5.2 and Section A13.4 in Appendix 13 
 
 
SAFETY FOLLOW UP FOR PARTICIPANTS FROM EARLY TERMINATED 
STUDY TREATMENT ARM BY THE SPONSOR 
Participants, who permanently discontinue study treatment as part of an early 
termination of a treatment arm due to Sponsor’s decision, will undergo safety follow-up 
assessments as described in Appendix 6-Table 4 and participants will remain on their 
NUC therapy. 
All participants will be followed up for 24 weeks according to the following Schedule of 
Assessments. 

 
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Appendix 6-Table 4 Schedule of Activities of Safety Follow-up Period for Early 
Terminated Study Treatment Arms 
 
Follow-up Perioda 
Week 
4 
8 
12 
24 
Day 
28 
(±3) 
56 
(±3) 
84 
(±7) 
168 
(±7) 
Physical examination, vital signs b, c 
 
 
 
x 
ECG 
 
 
 
x 
Abdominal ultrasound 
 
 
 
x 
Alfa-fetoprotein 
 
 
 
x 
Pregnancy test d 
x 
x 
x 
x 
Thyroid function tests 
 
 
 
x 
Hematology  
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
HBV DNA quantitative 
x 
x 
x 
x 
HBV RNA quantitative 
x 
x 
x 
x 
NME ADAe  
 
 
x 
x 
Diary review 
x 
x 
x 
x 
Adverse events & concomitant medications  
x 
x 
x 
x 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; GLDH = glutamate dehydrogenase; 
HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; RNA = ribonucleic acid. 
 
a Safety follow-up is mandatory for 24 weeks for all participants. Additional unscheduled visits 
may be performed if deemed clinically relevant.  
b Limited symptom-directed physical exam and as clinically indicated.  
c Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes 
after participant has been in supine/sitting position.  
d Pregnancy testing for females of childbearing potential only to be conducted monthly at the visit 
or at home using pregnancy kits supplied by sponsor or obtained locally; If urine test is 
positive, it must be confirmed by a serum test. 
e As applicable according to impacted study arm. 
 
Note, for participants who are in treatment arms NOT terminated by the sponsor, the 
above safety follow-up is not applicable. The follow up period for these patients is as per 
the SoA of the respective treatment arm.  
 
 

 
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Appendix 7 
Study Details Specific to NUC Control Arm 
An overview of the nucleos(t)ide (NUC) control treatment arm is shown in Appendix 7-
Figure 1. 
Participants will continue their background NUC therapy for the 48-week treatment 
period. At the end of the treatment period, in line with current CHB treatment guidelines, 
participants will continue NUC treatment during the follow-up unless the NUC 
discontinuation criteria have been met (see Section 6.8).  
Initially, 30 participants will be randomized to the NUC control arm. The subsequent 
randomization ratio will depend on the number of actively enrolling NME treatment arms, 
with the stipulation that no more than 17% of participants will be randomly allocated to 
the NUC control arm.  
Participants in the NUC control arm who complete the follow-up Week 48 visit, and 
continue to meet the study eligibility criteria, may be offered to participate in an 
expansion cohort of a combination regimen within this study. This will allow access for 
NUC control participants to an investigational combination regimen that has shown a 
positive benefit/risk profile, as this is a pre-requisite for an expansion cohort to 
commence. 
Appendix 7-Figure 1  
NUC Control Treatment Arm  
 
 
A7.1 
BACKGROUND SPECIFIC TO NUC CONTROL ARM 
Not applicable. 
A7.2 
BENEFIT/RISK ASSESSMENT SPECIFIC TO NUC CONTROL ARM 
Although participants randomized to the control arm are not expected to receive 
additional benefit within this arm beyond that attained with their current treatment, the 
control arm is important to increase the robustness of the study in terms of the clinical 
data generated, and in identifying efficacious combination regimens. In turn, their 
participation will guide further clinical development and thereby benefit the overall CHB 
population. 

 
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Furthermore, after completing the follow-up Week 48 visit, participants who meet the 
study eligibility criteria may be offered to participate in an expansion cohort of a 
combination regimen within this study. The expansion cohort may result in additional 
therapeutic benefit for the participants. 
A7.3 
JUSTIFICATION FOR DOSE SPECIFIC TO NUC CONTROL ARM 
Not applicable. 
A7.4 
LIFESTYLE CONSIDERATIONS SPECIFIC TO NUC CONTROL ARM 
NUCs will be given according to the local prescribing information.  
A7.5 
TREATMENT ADMINISTERED SPECIFIC TO NUC CONTROL ARM 
Appendix 7-Table 1 summarizes the treatments administered. 
 
Appendix 7-Table 1 
Summary of Treatments Administered for NUC Control 
Treatment Arm 
Study Treatment Name 
NUC 
IMP and NIMP 
NIMP* 
Dose Formulation 
Film-coated tablet 
Unit Dose Strength(s)/Dosage Level(s) 
Refer to local prescription information 
Dose 
ETV: 0.5 mg 
TDF: 300 mg 
TAF: 25 mg 
Route of Administration 
oral 
Sourcing 
Provided centrally by the Sponsor or locally by 
the study site 
Packaging and Labeling 
Study treatment will be packaged and labeled 
as required per local regulation. 
 
*NUC are considered IMP in the UK only. 
For guidelines for dosage modification, please refer to the NUC local prescribing 
information.  
For more details, refer to the NUC local prescribing information and the Pharmacy 
Manual. 

 
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A7.6 
PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO NUC CONTROL ARM 
A7.6.1  
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1). Known candidate genes of interest that are stated in 
appendices for NME combination arms will be queried in the NUC control arm as well. 
A7.7 
SCHEDULE OF ACTIVITIES (NUC CONTROL ARM) 
An overview of the schedule of the activities is provided in Appendix 7-Table 2.  

 
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Appendix 7-Table 2 Schedule of Activities for NUC Control Arm 
 
Screening 
Treatment Period 
Follow-up Period 
VB/VR 
UV(Flu 
like/ ET) p 
Week 
 
 
1 
4 
12 
24 
36 
48 n 
2 o 
4 o 
6 o 
8 o 
10 o 
12 
16 o 
20 o 
24q 
36 
48 
 
- 
Day -56 to 
-7 
-14 to 
-7 
1 
28 
(± 3) 
84 
(± 3) 
168 
(± 7) 
252 
(± 7) 
336 
(± 7) 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital 
signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Transient 
elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse 
screen e 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test f 
 
x 
 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
x 
x 
x 
 
 
Thyroid function tests 
x 
 
 
 
x 
x 
 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology (include HbA1c g) 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 

 
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Appendix 7-Table 2 Schedule of Activities for NUC Control Arm (cont.) 
 
Screening 
Treatment Period 
Follow-up Period 
VB/VR 
UV(Flu 
like/ ET) p 
Week 
 
 
1 
4 
12 
24 
36 
48 n 
2 o 
4 o 
6 o 
8 o 
10 o 
12 
16 o 
20 o 
24q 
36 
48 
 
- 
Day -56 to 
-7 
-14 to 
-7 
1 
28 
(± 3) 
84 
(± 3) 
168 
(± 7) 
252 
(± 7) 
336 
(± 7) 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, HBeAg, 
anti-HBs, anti-HBe) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitativer 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg i 
 
 
x  
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
 
x 
x 
 
HBcrAg 
 
 
x  
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
X 
 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
 
x  
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
RBR l 
 
 
x 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Study treatment administration 
&/or diary review 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant 
medications m  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET= early termination; GLDH = glutamate 
dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related antigen; HBeAg = hepatitis B e 
antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR = magnetic resonance; NUC = nucleos(t)ide analogue; 
PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb 
complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV= unscheduled visit. 
a Full physical exam at screening and Week 48. Limited symptom-directed physical exam at other visits and as clinically indicated. Height at 
screening only. Weight at screening, Day 1, and Week 12, 24, 36, 48. 
 
 

 
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Appendix 7-Table 2 Schedule of Activities for NUC Control Arm (cont.) 
b Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR/2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine pregnancy test is positive, 
the pregnancy must be confirmed by a serum test. 
g HbA1c should be assessed only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse, blood sample to be collected up to 6 times. 
k Plasma PK samples for NUC to be collected at pre-dose. During the PK assessments for VB/VR visits, only one predose sample is required for 
collection, no other additional time points should be collected. 
l RBR samples collected only from RBR-consenting participants.  
m Pre-treatment, only serious adverse events should be reported. 
n Participants who achieve HBsAg loss during treatment or during follow-up will discontinue NUC. 
o Additional post-treatment visits for participants who discontinued NUC at Week 48. If participants discontinue NUC later in the follow-up additional 
visits should be scheduled with a frequency of every 2 weeks for the first three months and every 4 weeks up to week 48 of follow-up period. 
p Participants who permanently discontinue study treatment will need to attend an unscheduled/early termination visit. 
q Visit window may be extended to +6 weeks in extreme circumstances such as pandemic, natural disasters, supply chain disruption, outbreak of hostilities. 
r Participants with HBV DNA > 2,000 IU/mL during the follow-up period will undergo weekly monitoring. Participants with HBV DNA >20 IU/mL but < 2,000 
IU/mL, should undergo monitoring every two weeks. Participants, who have discontinued NUC therapy at EOT, should have monthly visits from follow-up Week 
24 to Week 48, instead of the 3 monthly follow-up visits shown in SoA, to enable early detection and appropriate management of HBV DNA rebound. At these 
additional unscheduled monitoring visits, the following laboratory assessments should be performed using the unscheduled lab kit: hematology, chemistry, 
coagulation, GLDH, urinalysis, HBV serology, HBV DNA quantitative, total HBsAg, HBcrAg, and HBV RNA quantitative.  
Note: Additional assessments may be conducted before randomization if required by other arms that are currently recruiting as described in 
Section 5.2.  
 
 

 
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Appendix 8 
Study Details Specific to CpAM (RO7049389) + TLR7 
(RO7020531) + NUC Arm 
An overview of CpAM + TLR7 + NUC treatment arm is shown in Appendix 8-Figure 1.  
Participants will receive RO7049389 (600 mg QD) in addition to their background NUC 
therapy for the 48-week treatment period. RO7020531 (150 mg once every other day 
[QOD]) will be administered during Weeks 1-12 and Weeks 25-36 (i.e., 2 treatment 
cycles of 12 weeks’ duration each and 42 doses of RO7020531 for each cycle). At the 
end of the treatment period, participants will continue NUC treatment during the follow-
up unless the NUC discontinuation criteria have been met (see Section 6.8).  
Approximately 30 participants will be randomized to this treatment arm.  
If a 30% delta for HBsAg loss is observed at Week 48 (EOT) or follow-up Week 12 or 
24 (primary endpoint) the treatment arm may be expanded to accrue additional efficacy 
and safety data, and to contribute to Phase 3 design planning. If a successful interim 
analysis is observed at Weeks 12 or 24, shorter treatment duration arms (12 and 
24 weeks’ duration) and/or a response-guided therapy (RGT) arm may be added. 
Appendix 8-Figure 1  
CpAM + TLR7 + NUC Treatment Arm  
 
A8.1 
BACKGROUND SPECIFIC TO CpAM + TLR7 + NUC ARM 
A8.1.1  
BACKGROUND ON RO7049389 
RO7049389 is a core protein allosteric modulator (CpAM) and belongs to the well-
studied class of heteroaryldihydropyrimidine (HAP) compounds. This class of 
compounds induces formation of abnormal HBV core protein aggregates, which are 
subsequently recognized and depleted. Depleting functional core protein results in 
interruption of viral assembly and inhibition of HBV replication.  
The HBV core protein is involved in multiple steps of the viral life cycle such as 
encapsulation of pre-genomic ribonucleic acid (pgRNA), subsequent initiation of reverse 

 
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transcription, and is an important component of covalently closed circular DNA (cccDNA) 
mini-chromosome. Furthermore, literature suggests that the HBV core protein may play 
a role in suppressing host innate immune responses (Twu et al 1988; Fernandez et al 
2003; Gruffaz et al 2013). Depletion of functional core protein may therefore facilitate 
host immune restoration. RO7049389 can therefore potentially provide anti-HBV benefits 
by both direct inhibition of viral replication and augmentation of host immune responses 
against the virus. 
RO7049389 has shown potent antiviral activity through the induction of HBV core protein 
misassembly and subsequent degradation, and has a high degree of selectivity against 
HBV. RO7049389 demonstrated activity against most prevalent HBV genotypes (A, B, 
C, D) and against a panel of nucleos(t)ide analogue-resistant HBV variants tested in 
vitro. 
To date, clinical experience with RO7049389 includes three Phase 1 clinical studies:  an 
entry-into-human (EIH) study in healthy volunteers (HV) and patients (YP39364), a study 
in HVs of Chinese descent (YP39406), and a drug-drug interaction (DDI) study in HVs 
(YP40218). 
A8.1.2  
BACKGROUND ON RO7020531 
RO7020531 is an oral double prodrug of the toll-like receptor 7 (TLR7)-specific agonist 
RO7011785. A prodrug approach was chosen for oral delivery of the TLR7 agonist 
RO7011785 in order to improve bioavailability and limit TLR7 activation in the 
gastrointestinal (GI) tract, which may be associated with GI intolerability.  
TLRs are a family of pathogen-recognition receptors that activate the innate immune 
response. The stimulation of TLR7 mediates an endogenous type I IFN response, which 
is critical in development of a broad, effective, and protective immunity against hepatitis 
viruses (Horscroft et al 2012, Funk et al 2014). Compared to pegylated interferon-alpha 
(PEG-IFN-) therapy, treatment with a TLR7 agonist induces broader 
immunomodulatory effects that are likely to lead to more effective control and functional 
cure of chronic HBV infection (Strader et al 2004, Isogawa et al 2005). TLR7 agonists 
induce the production of multiple isotypes of IFN from plasmacytoid dendritic cells 
(pDCs) which have been shown in vitro to possess additive or synergistic antiviral effects 
compared to exogenous PEG-IFN. 
Non-clinical studies with RO7020531 suggest that it is rapidly converted to the active 
metabolite RO7011785 and data from in vivo studies with RO7020531 and in vitro 
studies with RO7011785 support immune activation as the mechanism of action.  

 
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To date, clinical experience with RO7020531 includes two Phase 1 clinical studies:  an 
EIH study in HVs and CHB patients (NP39305) and a study in HVs of Chinese descent 
(YP39553). 
A8.2 
BENEFIT/RISK ASSESSMENT SPECIFIC TO CpAM + TLR7 + NUC 
ARM 
The 48-week treatment with RO7049389 and RO7020531 treatment in combination with 
NUC aims to result in therapeutic benefit for participants, including possibly higher 
functional cure rates than observed currently with standard-of-care therapies 
(monotherapy with NUC or PEG-IFN). The concurrent RO7049389 and RO7020531 
administrations in the initial 12 weeks aim to test the scientific hypothesis whether early 
concurrent direct-acting antiviral and immunomodulatory agent combination therapy 
maximizes the efficacy outcomes.  
This concept is supported by in vivo non-clinical data, whereby in a recombinant adeno-
associated virus carrying HBV genome (AAV-HBV) mouse model the combination of 
RO7049389 (a direct antiviral agent that works as a core protein allosteric modulator) 
and toll-like receptor 7 (TLR7)-agonist, RO7020531 (an immune modulator) resulted in 
significantly greater HBV DNA and hepatitis B surface antigen (HBsAg) reductions post 
treatment (Day 84) than either agent as monotherapy (Appendix 8-Table 1). HBsAg loss 
(< lower limit of quantification [LLOQ]) was observed in 5 of 7 mice by the end of the 6-
week combination treatment and sustained in the 6-week off-treatment period but in 
none of the monotherapy groups, suggesting a transformational efficacy impact with the 
combination treatment of RO7049389 and RO7020531.  
Appendix 8-Table 1 
Summary of Viral Marker Reductions (AAV-HBV Mouse 
Model) 
Treatment 
HBV DNA Reduction (Log) 
HBsAg Reduction (Log) 
Day 14 
Day 42 
Day 84 
Day 14 
Day 42 
Day 84 
RO7020531: 100 mg/kg QOD 
1.2±0.2 
1.9±0.4 
0.2±0.1 
0.6±0.4 
1.6±0.5 
0.4±0.2 
RO7049389: 20 mg/kg QD 
3.5±0.1 
3.8±0.1 
1.5±0.2 
0.0±0.1 
1.5±0.2 
1.9±0.3 
Combination therapy 
3.8±0.1 
4.1±0.1 
3.4±0.5 
0.9±0.5 
3.1±0.3 
3.1±0.3 
Vehicle 
0.0±0.1 
0.0±0.1 
0.0±0.1 
0.0±0.1 
0.0±0.2 
0.0±0.2 
Notes: Day 84 is 42 days post-treatment. Data presented as mean ± SEM (7 mice per group). 
 
Non-clinical chronic toxicology in rats and non-human primates has provided data 
supporting the QOD dosing regimen for RO7020531 over 12 week intervals for 
evaluation in CHB participants. 

 
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118/Protocol WV41073, Version 7.0 
RO7049389 and RO7020531 separately, have shown acceptable safety/tolerability in 
Phase 1 studies involving healthy volunteers and CHB participants, and non-clinical 
toxicology and safety pharmacology studies support the proposed 48-week combination 
regimen. 
For details, refer to the RO7049389 and RO7020531 Investigator’s Brochures. 
A8.3 
JUSTIFICATION FOR DOSE SPECIFIC TO CpAM + TLR7 + NUC ARM 
For RO7049389, a dose of 600 mg QD has been selected for this Phase 2 study. This 
dose is within the predicted therapeutic dose-range in humans and is expected to be 
safe and well tolerated. A summary of the key data supporting the selected dose is 
provided below: 
 
RO7049389 doses up to 1000 mg QD (for 28 days), 800 mg BID (for 6 days) and 
2500 mg (single dose) have been observed to be safe and well tolerated in three 
Phase 1 studies involving healthy volunteers and CHB participants. 
 
Although 200 mg to 600 mg QD doses resulted in robust pharmacodynamic effects 
(HBV DNA decline 2.66 – 3.2 log10 IU/mL) in the Phase 1 studies, a trend of 
increased HBV DNA decline was observed with higher doses. In addition, disease-
modelling utilizing non-clinical and clinical PK/PD data predicts an increased PD 
effect with the 600 mg QD dose. 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for the 
600 mg QD dose.  
For RO7020531, a dose of 150 mg QOD has been selected for this Phase 2 study, to be 
administered continuously over two 12-week cycles separated by a 12-week dosing 
holiday (for RO7020531 only). This dose and regimen is within the predicted therapeutic 
dose-range in humans and is expected to be safe and well tolerated. A summary of the 
key data supporting the selected dose is provided below: 
 
RO7020531 doses up to 170 mg QOD and 150 mg QOD (both for 6 weeks) have 
been observed to be safe and with acceptable tolerability in two Phase 1 studies 
involving healthy volunteers and CHB participants. 
 
Pharmacodynamic effects consistent with TLR7 activation was observed in the 100-
170 mg QOD dose-range, with increasing magnitude of response associated with 
higher doses.  
Further details are provided in the RO7049389 and RO7020531 Investigator’s 
Brochures. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
119/Protocol WV41073, Version 7.0 
A8.4 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO CpAM + TLR7 + NUC 
ARM 
Participants must meet the following criterion for inclusion in the CpAM + TLR7 + NUC 
treatment arm; 
Sex 
1. 
Female participants: 
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
 
Woman of non-childbearing potential (WONCBP). 
 
Woman of childbearing potential (WOCBP), who: 
– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or use 
two acceptable contraceptive methods of which at least one is considered 
highly effective (result in a failure rate of < 1% per year) during the 
treatment period and for at least 6 months after the final dose of study 
treatment (see A8.7 and Appendix 5).  
– Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month during 
treatment and up to 6 months follow-up, thereafter every 3 months until end of 
follow-up. Where the subsequent visit is greater than 4 weeks, pregnancy test 
will be done at home using kits supplied by the sponsor. 
Participants are excluded from the CpAM + TLR7 + NUC arm if any of the following 
criteria apply: 
Weight 
1. 
Body mass index < 21 and weight at screening:  55 kg for men or < 45 kg for 
women  
Medical Conditions 
2. 
Current symptoms of depression or history of depression requiring treatment.  
3. 
History of autoimmune hepatitis or other autoimmune disorders.  
4. 
Diabetes that is not well controlled (HbA1c  7% at screening) 
5. 
Pre-existing ophthalmologic disorders (known history or as assessed by eye 
examination at screening), which in the opinion of the investigator would increase 
the likelihood of clinical significance of potential drug-induced retinopathy (e.g., 
diabetic or hypertensive retinopathy, glaucoma, dense cataract, visual field 
abnormalities, severe retinopathy). 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
120/Protocol WV41073, Version 7.0 
6. 
History of pulmonary disorders including interstitial pneumonitis, bronchiolitis 
obliterans, pulmonary hypertension, and sarcoidosis.  
7. 
History of pancreatitis. 
8. 
Participants with history or present evidence of orthostatic hypotension. 
 
A8.5 SAFETY ASSESSMENTS SPECIFIC TO CPAM + TLR7 + NUC ARM 
Physical Examinations 
Eye examination will be performed at screening, preferably by an ophthalmologist, and 
will include funduscopic examination with dilation, visual acuity, assessment, visual field 
testing, and color visual testing. 
Vital signs 
Assessment of orthostatic hypotension will be done at screening. To assess the 
presence of orthostatic hypotension, blood pressure will be measured both while the 
participant is sitting and while standing. Participants will be excluded if a drop of 
20 millimeters of mercury (mm Hg) in systolic blood pressure or a drop of 10 mm Hg in 
diastolic blood pressure within two to five minutes of standing up, or if standing causes 
signs and symptoms of hypotension. 
A8.6 
LIFESTYLE CONSIDERATIONS SPECIFIC TO CpAM + TLR7 + NUC 
ARM 
Both RO7049389 and RO7020531 will be given in fasted state (at least 2 hours after a 
meal or 2 hours before the next meal). NUCs will be given according to the local 
prescribing information.  
For RO7049389, any nutrients known to modulate activity of CYP enzymes (e.g., 
grapefruit-, or Seville orange-containing products) will be prohibited within 3 days before 
Day -1 through to the last dose of RO7049389. 
For RO7020531, consumption of green tea beverages should be minimized during the 
treatment period, as these may inhibit aldehyde oxidase activity (Tayama et al 2011). 
For CHB participants who routinely take herbal medicines that in Investigator’s opinion 
may have immune-modulatory effects, herbal medicines should strongly be discouraged. 
A8.7 
CONTRACEPTIVE REQUIREMENTS SPECIFIC TO CpAM + TLR7 + 
NUC ARM 
For WOCBP: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use two acceptable contraceptive methods of which at least one is considered highly 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
121/Protocol WV41073, Version 7.0 
effective (see Appendix 5), during the study and for at least 6 months after the last dose 
of study drug.  
 
Examples of acceptable highly effective contraceptive methods (< 1% failure rate 
per year) include combined or progesterone-only hormonal contraception, 
intrauterine device, and vasectomized partner.  
 
Examples of acceptable not as highly effective contraceptive methods (> 1% 
failure rate per year) include progesterone only hormonal contraception (where 
inhibition of ovulation is not the primary mode of action) and male or female 
condoms with or without spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree 
to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:  
 
Men must remain abstinent or use a condom during the treatment period and for 
at least 6 months after the last dose of study drug to avoid exposing the embryo.  
 
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
A8.8 
TREATMENT ADMINISTERED SPECIFIC TO CpAM + TLR7 + NUC 
ARM 
Appendix 8-Table 2 summarizes the treatments administered. 
Paracetamol/acetaminophen are considered non investigational medicinal products 
(NIMPs). 
 
 

 
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Appendix 8-Table 2 
Summary of Treatments Administered for CpAM + TLR7 + 
NUC Treatment Arm 
Study Treatment Name 
CpAM 
(RO7049389) 
TLR7  
(RO7020531) 
NUC 
IMP and NIMP 
IMP 
IMP 
NIMP* 
Dose Formulation 
film-coated tablet 
film-coated tablet 
film-coated tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
200 mg 
150 mg 
100 mg 
Refer to local 
prescription 
information 
Dose: 
600 mg 
150 mg QOD 
100 mg QOD 
100 mg QW 
ETV: 0.5 mg  
TDF: 300 mg  
TAF: 25 mg  
Route of Administration 
Oral 
oral 
oral 
Sourcing 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the study 
site 
Packaging and Labeling 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
*NUC are considered IMP in the UK only. 
 
Guidelines for dosage modification and treatment interruption/discontinuation are in 
Section A8. (in this Appendix).  
For more details, refer to the RO7049389 and RO7020531 Investigator’s Brochures, 
NUC local prescribing information, and the Pharmacy Manual. 
A8.9 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
123/Protocol WV41073, Version 7.0 
Drug 
Document 
RO7020531 
RO7020531 Investigator's Brochure  
RO7049389 
RO7049389 Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A8.10 CONCOMITANT THERAPY SPECIFIC TO CpAM + TLR7 + NUC ARM  
The following concomitant medications are prohibited:  
 
Inducers of CYP3A enzyme: e.g., efavirenz, nevirapine, pioglitazone, rifampin, 
rifabutin, troglitazone, phenobarbital, phenytoin, carbamazepine, and St. John’s wort 
within 14 days or 5 half-lives (whichever is longer) before the first administration of 
RO7049389 and while on study treatment with RO7049389. 
 
Inhibitors of CYP3A enzyme: e.g., indinavir, nelfinavir, clarithromycin, itraconazole, 
ketoconazole, nefazodone, ketoconazole, verapamil, suboxone, diltiazem, 
cimetidine, amiodarone, fluvoxamine, troleandomycin, and voriconazole within 7 
days or 5 half-lives (whichever is longer) before the first administration of 
RO7049389 and while on study treatment with RO7049389. 
 
Strong inducers of UDP-glucuronosyltransferase (UGT) 1A3 enzymes: e.g., 
carbamazepine and nicotine within 14 days, or 5 half-lives (whichever is longer) 
before the first administration of RO7049389 and while on study treatment with 
RO7049389. 
 
Strong inhibitors of UGT1A3/1A1 enzymes: e.g., indinavir, atazanavir, gemfibrozil, 
indinavir, and ketoconazole within 7 days, or 5 half-lives (whichever is longer) before 
the first administration of RO7049389 and while on study treatment with 
RO7049389. 
 
Inhibitors of OATP1B transporters: e.g., cyclosporine, rifampicin, eltrombopag, 
lapatinib, lopinavir, ritonavir within 7 days, or 5 half-lives (whichever is longer) before 
the first administration of RO7049389 and while on study treatment with 
RO7049389. 
 
Inhibitors of Organic Anion Transporter 1 and 3 (OAT 1 and OAT 3): e.g., 
p-aminohippuric acid (PAH), probenecid, and teriflunomide, within 7 days, or 5 half-
lives (whichever is longer) before the first administration of RO7020531 and while 
on study treatment with RO7020531. 
 
Inhibitors of P-gp transporters: e.g., amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, 

 
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ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil within 7 days, or 5 half-lives (whichever is longer) before the first 
administration of RO7020531 and while on study treatment with RO7020531. 
The following concomitant medications are to be used with caution and the Sponsor 
should be informed before these drugs are administered. When co-administered with 
study drugs, the recommendation is to use the lowest necessary dose of the substrate, 
titrate the dose carefully, and monitor closely for substrate-associated adverse reactions. 
 
Substrates of OATP1B: e.g., atrasentan, bosentan, ezetimibe, irinotecan, statins 
(e.g., atorvastatin, rosuvastatin, simvastatin, pitavastatin, pravastatin), repaglinide, 
rifampin, valsartan, and olmesartan.  
 
CYP3A4 substrates with a narrow therapeutic range. 
 
Drugs metabolized by aldehyde oxidase including famciclovir and/or inhibiting this 
enzyme including tamoxifen, raloxifen, cimetidine, promethazine, clozapine, and 
chlorpromazine, which could decrease the formation of RO7011785. 
 
Drugs that reduce renal function or compete for active tubular secretion that 
may increase serum concentrations of RO7011785 study drug. 
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication inhibits or induces above mentioned 
enzymes or transporters or renal function. In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications that are not listed above. 
A8.11 MANAGEMENT OF ADVERSE EVENTS SPECIFIC TO CpAM + TLR7 
+ NUC ARM 
TLR-RELATED AES  
TLR7 agonist activates innate and adaptive immune responses, and these mechanisms 
include induction of type I interferon (IFNα). Safety data from the ongoing Phase 1 
studies showed IFN-related flu-like symptoms (headache, pyrexia, chills, myalgia, 
nausea), mostly of mild intensity; and in some participants, hematological abnormalities 
(e.g., neutropenia, lymphopenia). During the two clinical studies with RO7020531 
(NP39305 and YP39553), all hematological abnormalities were asymptomatic and in 
most cases reversible within 24 to 48 hours.  
TLR7 agonists as a class may have the potential, in a dose-dependent manner, to lead 
to hypotension and distributive shock due to excessive cytokine release (cytokine 
release syndrome [CRS])—e.g., IL-1, IL-6,IL-10, IFN-γ, TNF-α etc.—by immune 
activation. CRS can present with a variety of symptoms, from mild symptoms 
overlapping with mild flu-like symptoms to severe or life-threatening manifestations. Mild 

 
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symptoms of CRS include fever, fatigue, headache, rash, arthralgia, and myalgia. More 
severe cases are characterized by hypotension that requires vasopressor treatment 
and/or hypoxia that requires medical intervention. They can progress to an uncontrolled 
systemic inflammatory response with circulatory shock, vascular leakage, disseminated 
intravascular coagulation, and multi–organ-system failure. Flu-like symptoms were 
observed during the two clinical studies with RO7020531 (NP39305 and YP39553) at 
140 mg to 170 mg single or multiple QOD doses up to 6 weeks. These symptoms 
overlap with and are not distinguishable from mild cases of CRS.  
A8.12 ENHANCED SAFETY MONITORING DURING COMBINATION 
TREATMENT WITH CpAM + TLR7 + NUC 
Based on the emerging data from Phase 1 studies NP39305 (HV and patient cohorts) 
and YP39553 (single– and multiple–ascending-dose clinical study in Chinese HVs), it 
became evident that in all cases of flu-like symptoms, the initial onsets emerged within 
the initial 3 doses of RO7020531. For this reason, pre-dose laboratory analyses and 
optional extended in-hospital stay with frequent vital sign monitoring (every 2 to 4 hours) 
and ECGs (pre-dosing and 6 to 8 hours after dosing at each visit) are scheduled for the 
initial 3 doses of each combination cycle and guided by emerging AEs as follows: 
 
on Day 1 and/or Day 169 (first day of the second cycle of TLR7 dosing), participants 
will stay in the clinical unit for 12 hours with an option to stay in the clinic for up to 24 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerge and do not respond to symptomatic treatment 
(paracetamol/acetaminophen up to 2 g/day) during the first 12 hours post-
combination dosing. For those participants who stay up to 24 hours, an additional 24 
hours post-dose laboratory assessment will be done on Day 2 and Day 170, 
respectively.  
 
on Day 3 and Day 171 (third day of the second cycle of TLR7 dosing), participants 
will stay in the clinical unit for 8 hours with an option to stay in the clinic for up to 12 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerged and would not respond to symptomatic treatment 
(paracetamol/acetaminophen up to 2 g/day) during the first 8 hours post-
combination dosing.  
 
on Day 5 and Day 173 (fifth day of the second cycle of TLR7 dosing), participants 
will stay in the clinical unit for 8 hours with an option to stay in the clinic for up to 12 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerged during the first 8 hours and would not respond to symptomatic 
treatment (paracetamol/acetaminophen up to 2 g/day) during the first 8 hours post-
combination dosing.  
The Sponsor will promptly communicate to the Investigator any change to the proposed 
enhanced monitoring plan based on emerging data and interim safety evaluations. In 

 
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case the prolonged hospital stay is not required but participants live far away and may 
need to be back on the following day, the investigator may decide to allow them to stay 
at a hotel nearby. 
The Sponsor will provide participants a thermometer to use for temperature 
self-monitoring in case flu-like symptoms and pyrexia emerge. If at any time during the 
combination cycles (CpAM + TLR7 + NUC) participants experience flu-like symptoms 
with pyrexia (Grade 2 or above), it will be recommended to call the site and the PI or the 
medical personnel on site: 
 
may recommend participants visit the clinic for an unscheduled visit according to the 
SOA in Appendix 8.  
 
may recommend symptomatic treatment with paracetamol/ acetaminophen up to 
2 g/day.  
 

 
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Appendix 8-Figure 2. 
Safety monitoring and RO7020531 dosing interruption for 
flu-like symptoms and cytopenia during combination 
treatment with CpAM + TLR7 + NUC 
 
*Based either on central laboratory (as per the SoA in this appendix) and/or local 
laboratory if performed for participant management and/or decision-making. In such a 
scenario, if local laboratory tests are performed, an additional sample will be sent to the 
central laboratory, but decisions will be based on local laboratory results.  
 
A8.13 DOSE MODIFICATION 
Dose reduction to 100 mg QOD with RO7020531 for intolerability associated with 
adverse events should be considered following discussion with the Medical Monitor (if 
possible) during the treatment phase in the following situations:   
 
Grade 3 (severe) TLR7 agonist-related AEs of flu-like symptoms that 
persist > 24 hours despite prophylactic and/or symptomatic treatment with 
acetaminophen (paracetamol)  
 
Grade 3 (severe) hematological (e.g., cytopenia) laboratory abnormalities that 
persist for > 48 hours 

 
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 
TLR7 agonist-related SAE 
 
Flu-like symptoms that are not tolerated 
In the above situations, RO702053 150 mg QOD dosing should be interrupted until AEs, 
laboratory abnormalities, or SAEs improve to Grade 1 or less, before initiating a dose 
reduction to RO7020531 100 mg QOD.  
For repetitive/recurrent flu-like symptoms/pyrexia (either responsive or unresponsive 
despite symptomatic treatment with acetaminophen or poorly manageable despite 
prophylactic treatment with acetaminophen) or other TLR7 agonist-related AEs 
(including repetitive AEs) which are not well manageable, the Investigator in discussion 
with the participant should consider a RO7020531 dose reduction to 100 mg QOD. The 
Medical Monitor is available to the Investigator to answer any medical questions. 
Following the RO7020531 dose reduction to 100 mg QOD, the Investigator should 
interrupt RO7020531 dosing if any of the following situations occur: 
 
Grade 3 (severe) TLR7 agonist-related AEs of flu-like symptoms that persist 
for > 24 hours despite prophylactic and/or symptomatic treatment with 
acetaminophen (paracetamol)  
 
Grade 3 (severe) hematological (e.g., cytopenia) laboratory abnormalities that 
persist for > 48 hours 
 
TLR7 agonist-related SAE 
 
Following the RO7020531 dose reduction to 100 mg QOD, if flu-like symptoms are still 
not tolerated by the participants, a reduction of the dosing frequency of RO7020531 to 
100 mg QW (once a week) should be considered. 
Appendix 8-Table 3 summarizes possible reasons for dose modification, interruption 
/discontinuation guidelines of study treatment (or withdrawal from the study) for the 
CpAM+TLR7+NUC arm. 

 
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Appendix 8-Table 3 
Dose Interruption/Modification/Discontinuation Guidelines 
for CpAM+TLR7+NUC Combination Arm  
 
In general, when addressing tolerability issues with RO7020531, prior to the investigator 
making a decision to discontinue study treatment or participant withdrawal of consent 
from study treatment, a dose reduction should be discussed and evaluated if considered 
in the participant’s best interest. The Medical Monitor is available to the Investigator to 
answer any medical questions. 
The first dose of RO7020531 100 mg QOD should be administered in the clinic, and 
participants should be monitored for at least 8 hours as per SoA (with pre-dose safety 
laboratory assessment, every 2 to 4 hours for vital signs, and ECG assessment at pre-
dose and 6 to 8 hours post-dose). This first visit should be synchronized with the 
participant’s current RO7020531 QOD dosing schedule. 
In case participants are changed to 100 mg QW dosing, at least 5 days should have 
elapsed since the last dose. If Grade 2 flu-like symptoms occur, the Investigator may 
recommend symptomatic treatment with paracetamol/ acetaminophen. If symptoms 
respond to symptomatic treatment and the treatment is tolerable, participants will 
continue QW dosing. If there is poor tolerability, participants will permanently discontinue 
further RO7020531 dosing. Participants changed to the QW dosing will follow the same 
SOA of participants in the QOD dosage, with two 12-week combination treatment cycles 
(Weeks 1 to 12 and 25 to 36) and a 12-week holiday period (Weeks 13-24). 

 
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Participants who change to 100 mg QW dosing or discontinue because of non-safety 
reasons may be replaced at the sponsor’s discretion. This is to ensure the number per 
arm of the randomized QOD dose regimen remains close to the planned 30 participants.  
Participants on RO7020531 100 mg QOD will follow the SoA as included in Appendix 8. 
In case of RO7020531 100 mg QW dosing, participants will follow the SoA as included in 
Appendix 8, but QW dosing administration will be aligned with SoA visits.  
For ALT elevations, refer to Section 8.3.8.3. 
A8.14 PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO CpAM + TLR7 + NUC ARM 
A8.14.1 
TLR7 ACTIVITY BIOMARKERS  
TLR7 is expressed on human pDC and B-cells, and its activation induces both humoral 
and cellular changes (Iwasaki and Medzhitov 2004, Lester and Li 2014). These changes 
include the production of cytokines and chemokines such as IFN- α, IL-6, TNF-α, IL-10, 
IL-12p40, IP-10, and changes in the expression of ISGs, e.g., MX1 and myxovirus 
resistance 1 gene (MX1) and of the TLR7 gene itself (Fidock et al 2011), as well as 
changes in markers of immune stimulation such as neopterin. 
To characterize TLR7 PD biomarkers (secondary objective), blood samples will be 
collected at time points according to the SoA (see Appendix 8-Table 4 and Appendix 8-
Table 5) to measure cytokines including INF-α and IP-10, IL-6, TNF-α as well as a panel 
of transcriptional response of Interferon Stimulated Genes (ISG15, OAS1, MX1, and 
TLR7) if appropriate. Following review of these PD biomarkers and the AEs, further 
cytokines may be tested using a separate aliquot collected at the same time points 
including IL-1, IL-10, and IFN-γ. 
A8.14.2 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the two NMEs and with primary and secondary endpoints. Known 
candidate genes of interest that are specific to TLR7 and/or CpAM include AOX1, TLR7, 
UGT1A1, PGP, OATP1B1, OATP1B3, CYP3A4, and UGT1A3. Further genes may be 
queried from the data based on progressing knowledge on these NMEs and their 
targets. 

 
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A8.15 SCHEDULE OF ACTIVITIES CpAM + TLR7 + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 8-Table 4 and 
Appendix 8-Table 5.  

 
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Appendix 8-Table 4 
Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR 
UV 
(Flu-
like/ET) v 
Week 
 
 
1 
2 
3 
4 
8 
12 o, q 
18 
25 p, q 
28 
32 
36 
42 
48 
 
- 
- 
Day 
-56 
to 
-7 
-14 to 
-7 
1 
3 s 5 s 
14 
(±2) 
21 
(±2) 
28 
(±2) 
56 
(±3) 
83 
(-2 r) 
126 
(±3) 
169 
(±3) +2 s +2 s 
196 
(±6) 
224 
(±6) 
251 
(-5/+3 r) 
294 
(±3) 
336 
(-3 q) 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical 
history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
vital signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x t 
x t 
x t 
x 
x 
x 
x 
x 
 
x t 
x t 
x t 
x 
x 
x 
 
x 
x t 
 
 
Transient 
elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
HAV, HCV, HDV, HEV, 
HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of 
abuse screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Pregnancy test f 
 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 

 
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Appendix 8-Table 4 
Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR 
UV 
(Flu-
like/ET) v 
Week 
 
 
1 
2 
3 
4 
8 
12 o, q 
18 
25 p, q 
28 
32 
36 
42 
48 
 
- 
- 
Day 
-56 to 
-7 
-14 to 
-7 
1 
3 s 5 s 
14 
(±2) 
21 
(±2) 
28 
(±2) 
56 
(±3) 
83 
(-2 r) 
126 
(±3) 
169 
(±3) +2 s +2 s 196 
(±6) 
224 
(±6) 
251 
(-5/+3 r) 
294 
(±3) 
336 
(-3 q) 
 
 
 
Hematology (include 
HbA1c g) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, 
HBeAg, anti-HBs, anti-
HBe) 
x 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
x 
x 
HBV DNA quantitative 
x 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
x 
x 
Total HBsAg i 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
HBcrAg 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
Total anti-HBc 
quantitative 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
 
 
HBV RNA quantitative 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
HBV RNA sequencingh 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 

 
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Appendix 8-Table 4 
Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR 
UV 
(Flu-
like/ET) v 
Week 
 
 
1 
2 
3 
4 
8 
12 o, q 
18 
25 p, q 
28 
32 
36 
42 
48 
 
- 
- 
Day 
-56 to 
-7 
-14 to 
-7 
1 
3 s 5 s 
14 
(±2) 
21 
(±2) 
28 
(±2) 
56 
(±3) 
83 
(-2 r) 
126 
(±3) 
169 
(±3) +2 s +2 s 196 
(±6) 
224 
(±6) 
251 
(-5/+3 r) 
294 
(±3) 
336 
(-3 q) 
 
 
 
Plasma PK (TLR7) k 
 
 
x 
x 
x 
 
 
 
 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
x 
 
Plasma PK (CpAM) k 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
Cytokine panel l 
 
 
x 
x 
x 
 
 
 
 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
x 
ISG panel l 
 
 
x 
x 
x 
 
 
 
 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
x 
RBR m 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
Study treatment 
administration and 
diary review 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & 
concomitant 
medications n 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ARFI = acoustic radiation force impulse; CpAM = Core protein allosteric modulator; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ET=early termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-
related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IFN- α+ interferon 
alpha; IP-10 = interferon gamma-induced protein 10; ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide 
analogue; PK = pharmacokinetics; QW = first day of RO7020531 dosing after switching to QW regimen; RBR = Research Biosample Repository; 
RNA = ribonucleic acid; TLR = toll-like receptor; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = 
virological breakthrough/relapse; UV = unscheduled visit. 
 
 

 
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Appendix 8-Table 4 
Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
a Full physical exam at screening and at the end-of-treatment. Limited symptom-directed physical exam at other visits and as clinically indicated. 
Height at screening only. Weight at screening, Day 1, and Week 12, 25, 36, 48. Eye examination (including fundoscopy) only at screening. 
b Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
Orthostatic hypotension test only at screening. Vital signs assessments on Days 1 and 169: predose, 2-4 hrs, 4-6 hrs, 6-8 hrs and 8-12 hrs; Vital 
signs assessments on Days 3 (second dose), 5 (third dose) of the first RO7020531 cycle, on the first day of those switching to QW dosing and 
on the days of the second and third RO7020531 dose in the second cycle: predose, 2-4hrs, 4-6hrs, 6-8hrs (and 8-12 hours optional in case of 
extended in-clinic stay). 
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR/2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. Where the subsequent visit is 
greater than 4 weeks duration, pregnancy test will be done at home. If urine test is positive, it must be confirmed by a serum test. 
g HbA1c should be included in hematology, and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse, blood sample to be collected up to 6 times. 
k Plasma PK samples for CpAM and TLR7 to be collected at pre-dose, 1-3 and 4-6 hours post-dose. Plasma PK samples for NUC to be collected at 
pre-dose. During the PK assessments for VB/VR visits, only one pre-dose sample is required for collection, no other points required. 
l Cytokine panel (INF-α, IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α) and ISG panel to be collected at pre-dose and 6 hours post-dose of TLR7. At an 
unscheduled visit or early termination visit, preferably a pre-dose, otherwise, just a sample for cytokine and ISG panels should be collected if the 
visit is linked to a TLR7 related adverse reaction (e.g., influenza-like symptoms). No samples are required, for unscheduled visit or early 
termination visit not linked to TLR7 related adverse reaction (e.g., influenza-like symptoms).  
m RBR samples collected only from RBR-consenting participants.  
n Pre-treatment, only serious adverse events should be reported. 
o End-of-treatment visit for participants in the 12-week finite treatment arm (if commenced after an interim analysis). 
p End-of-treatment visit for participants in the 24-week finite treatment arm (if commenced after an interim analysis). 

 
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Appendix 8-Table 4 
Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
q End-of-treatment visit for participants with HBsAg loss in the 48-week response-guided therapy arm (if commenced after an interim analysis).  
r visit will be on dosing days for PK and PD sampling: -7 if the participant is on QW dosing. 
s Not applicable to participants who switched to QW RO7020531 dosing. 
t ECGs to be assessed predose and 6-8hrs post-dose on the first 3 doses of each 12-week RO7020531 cycle and on first dose if 100 mg QOD 
dosing is started. 
u For participants who move from 150 mg QOD to 100 mg QOD, this first dose of 100 mg QOD should be administered in the clinic and should be 
synchronized with the participants’ current RO7020531 QOD dosing schedule e.g., if the next current QOD dosing falls over the weekend, then it 
would be acceptable to miss doses for the first dose visit to take place outside the weekend. 
v Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
 

 
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Appendix 8-Table 5 Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Follow-up period) 
 
Follow-up period 
VB/VR 
UV 
(Flu 
like/ET)i 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitative 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg e 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (TLR7)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (CpAM)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 8-Table 5 Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Follow-up period) (cont.) 
 
Follow-up period 
VB/VR 
UV 
(Flu 
like/ET)i 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Plasma PK (NUC) f 
 
 
 
 
 
 
 
 
 
 
 
x 
 
RBR g 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ARFI = acoustic radiation force impulse; CpAM = Core protein allosteric modulator; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ET=early termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-
related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IP-10 = interferon 
gamma-induced protein 10; ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide analogue; PK = 
pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; TLR = toll-like receptor; Total HBsAg = post-dissociation of 
HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits can be scheduled with a frequency of every 2 weeks for the first three 
months and every 4-12 weeks up to week 48 of follow-up period, similarly to the monitoring proposed for those who will discontinue NUC and 
CpAM at week 48 at the end-of-treatment period. 
 
 

 
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Appendix 8-Table 5 Schedule of Activities for CpAM + TLR7 + NUC Treatment Arm (Follow-up period) (cont.) 
a Full physical exam at screening and at the end-of-treatment. Limited symptom-directed physical exam at other visits and as clinically indicated. 
Height at screening only. Weight at screening, Day 1, and Week 12, 25, 36, 48. 
b Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
Orthostatic hypotension test only at screening. Eye examination (fundoscopy) only at screening. 
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
f During the PK assessments for VB/VR visits only one sample is required, pre-dose sample if on NUC therapy, no other additional time points 
should be collected. 
g RBR samples collected only from RBR-consenting participants.  
h Pre-treatment, only serious adverse events should be reported. 
i Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
 

 
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Appendix 9 
Study Details Specific to siRNA (RO7445482) + NUC Arms 
An overview of short interfering RNA (siRNA) + nucleos(t)ide (NUC) treatment arms is 
shown in Appendix 9-Figure 1.  
Participants will receive RO7445482 (also known as DCR-HBVS; 100 mg or 200 mg 
every 4 weeks [Q4W]) in addition to their background NUC therapy for the 48-week 
treatment period. At the end of the treatment period, participants will continue NUC 
treatment during the follow-up unless the NUC discontinuation criteria have been met 
(see Section 6.8).  
Approximately 30 participants will be randomized to this treatment arm.  
If a 30% delta for hepatitis B surface antigen (HBsAg) loss is observed at Week 48 (end-
of-treatment [EOT]) or follow-up Weeks 12 or 24 (primary endpoint), the treatment arm 
may be expanded to accrue additional efficacy and safety data and to contribute to 
Phase 3 design planning. If a successful interim analysis is observed at Weeks 12 or 24, 
shorter treatment duration arms (12 and 24 weeks’ duration) and/or a response-guided 
therapy (RGT) arm may be added. 
Appendix 9-Figure 1  
siRNA + NUC Treatment Arms  
 
 
 
 

 
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A9.1 
BACKGROUND SPECIFIC TO siRNA + NUC ARM 
A9.1.1  
BACKGROUND ON RO7445482 (DCR-HBVS) 
RO7445482 (DCR-HBVS) is an siRNA conjugated to N-acetyl-D-galactosamine 
(GalNAc), which enables liver targeting through binding to the asialoglycoprotein 
receptor (ASGPR) that is highly expressed in the liver. After forming the RNA-induced 
silencing complex (RISC), the RO7445482 antisense strand targets HBV RNA for 
degradation by triggering RNAi-mediated cleavage within the HBsAg coding sequence, 
thereby inhibiting HBV gene expression.  
Literature indicates that HBV antigens suppress the host immune response through 
several pathways, including the direct effects of long-term exposure to high 
concentration of viral antigens resulting in T-cell immune tolerance and T-cell exhaustion 
(Hai-Jun et al 2015). Depletion of viral antigens through inhibition of hepatitis B virus 
(HBV) gene expression may therefore facilitate the restoration of the host immune 
response. 
Non-clinical studies with RO7445482 have shown potent antiviral activity. HBsAg 
reductions of up to 3.5 log10 for more than 7 weeks, as well as significant reductions in 
HBcAg, were observed after a single translationally relevant dose in mice, demonstrating 
duration of action suitable for infrequent dosing.  
To date, clinical experience with RO7445482 is based on a Phase I clinical study 
(DCR-HBVS-101) involving healthy volunteers and participants with CHB.  
A9.2 
BENEFIT/RISK ASSESSMENT SPECIFIC TO siRNA + NUC ARM 
The 48-week treatment with RO7445482 in combination with NUC aims to result in 
therapeutic benefit for participants, including possibly higher functional cure rates than 
observed currently with standard-of-care therapies (monotherapy with NUC or PEG-
IFN). The concurrent RO7445482 and NUC administrations aims to test the hypothesis 
whether prolonged reduction in HBV antigens, including but not limited to HBsAg, will 
result in immune-restoration and potentially functional cure. 
Interim Phase 1 data have shown significant and durable antiviral activity with 4 monthly 
doses of RO7445482 in NUC-suppressed participants with chronic hepatitis B (CHB). At 
Day 112, mean HBsAg log10 IU/mL reduction from baseline were 1.39, 1.80, and 1.84 for 
participants who received 1.5 mg/kg, 3.0 mg/kg or 6 mg/kg, respectively. Approximately 
80% of participants achieved > 1.5 log10 IU/mL reduction (irrespective of hepatitis B early 
antigen [HBeAg]-status), 60% had HBsAg levels < 100 IU/mL, and durability of response 
was demonstrated up to Day 392.  
Based on the interim Phase 1 data, RO7445482 was safe and well tolerated in healthy 
volunteers (HV) and CHB patients. The safety profile appears to be similar between HVs 
and patient participants, and there were no safety signals or dose related trends 

 
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identified. No severe or serious treatment-emergent adverse events (TEAEs) or TEAEs 
leading to treatment discontinuation, apart from generally mild injection site reactions 
(ISRs), there was absence of other potential oligonucleotide class effects. 
RO7445482 has shown acceptable safety/tolerability in the Phase 1 study involving 
healthy volunteers and CHB participants, and non-clinical toxicology and safety 
pharmacology studies support the proposed 48-week combination regimen. 
For details, refer to the RO7445482 Investigator’s Brochure. 
A9.3 
JUSTIFICATION FOR DOSE SPECIFIC TO siRNA + NUC ARM 
For RO7445482, fixed dose of 200 mg Q4W (equivalent to 3 mg/kg monthly) has been 
selected for Phase 2 study in combination with other IMPs/NMEs. This dose is within the 
anticipated therapeutic dose-range in humans and is expected to be safe and well 
tolerated. A summary of the key data supporting the selected dose is provided below: 
 
The dose-response trend in the HBsAg declines, together with PK/PD modeling 
of interim Phase 1 data, supports the proposed 200 mg Q4W dosing regimen. 
Preliminary PK/PD modeling predicts that the proportion of participants who will 
achieve > 1.5 and > 2 log10 IU/mL reductions in HBsAg, following Q4W doses up 
to Week 12, will be higher with a 200mg Q4W regimen (97% and 56%, 
respectively) compared to a 100 mg Q4W regimen (89% and 6%, respectively). 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for 
the 200 mg Q4W fixed dose (3 mg/kg equivalent) for treatment period of 48 
weeks. 
 
PK/PD modelling supports use of fixed (200 mg) instead of weight-based (3 
mg/kg) RO7445482 dosing. 
An additional RO7445482 fixed dose of 100 mg Q4W (equivalent to 1.5 mg/kg) is 
included for the evaluation of dose-response over the 48-week treatment period. This 
dose is within the anticipated therapeutic dose-range in humans and is expected to be 
safe and well tolerated.  
Further details are provided in the RO7445482 Investigator’s Brochure. 
 
 

 
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A9.4 
 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO siRNA + NUC 
ARM 
Participants must meet the following criterion for inclusion in the siRNA+ NUC treatment 
arm: 
Sex 
1. Female participants:  
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
 
Woman of non-childbearing potential (WONCBP). 
 
Woman of childbearing potential (WOCBP), who: 
– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods, of which at least 1 is 
considered highly effective (result in a failure rate of < 1% per year) 
during the treatment period and for at least 6 months after the final 
dose of study treatment (see A9.6 and Appendix 5).  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month 
during treatment and up to 6 months follow-up, thereafter every 3 
months until end of follow-up.  
A9.5 
LIFESTYLE CONSIDERATIONS SPECIFIC TO siRNA + NUC ARM 
NUCs will be given according to the local prescribing information.  
For CHB participants who routinely take herbal medicines that, in the Investigator’s 
opinion, may have immune-modulatory effects, herbal medicines should strongly be 
discouraged. 
A9.6 
CONTRACEPTIVE REQUIREMENTS SPECIFIC TO siRNA + NUC 
ARM 
For WOCBP: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods of which at least one is considered highly 
effective (see Appendix 5) during the study and for at least 6 months after the last dose 
of study drug.  
 
Examples of acceptable highly effective contraceptive methods (< 1% failure rate 
per year) include combined or progesterone-only hormonal contraception, 
intrauterine device, and vasectomized partner.  

 
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 
Examples of acceptable not as highly effective contraceptive methods (> 1% failure 
rate per year) include progesterone-only hormonal contraception (where inhibition of 
ovulation is not the primary mode of action) and male or female condoms with or 
without spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree 
to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:  
 
Men must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of study drug to avoid exposing the embryo.  
 
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
A9.7 
TREATMENT ADMINISTERED SPECIFIC TO siRNA + NUC ARM 
Appendix 9-Table 1 summarizes the treatments administered. 
Appendix 9-Table 1 
Summary of Treatments Administered for siRNA + NUC 
Treatment Arm 
Study Treatment Name 
siRNA 
(RO7445482) 
NUC 
IMP and NIMP 
IMP 
NIMP* 
Dose Formulation 
Sterile colorless to yellow 
solution of drug substance 
RO7445482 in water for 
injection 
film-coated tablet 
Unit Dose Strength(s)/Dosage 
Level(s) 
120 mg/mL, 2 mL filled in a 6 
mL vial 
Refer to local prescription 
information 
Dose: 
Fixed dose 100 or 200 mg 
Q4W 
ETV: 0.5 mg OD 
TDF: 300 mg OD 
TAF: 25 mg OD 
Route of Administration 
SC 
oral 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor or locally by the 
study site 
Packaging and Labeling 
Study treatment will be 
provided in vials, packaged, 
and labeled as required per 
local regulation. 
Study treatment will be 
packaged and labeled as 
required per local 
regulation. 
*NUC are considered IMP in the UK only. 

 
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RO7445482 administrations will be via the subcutaneous (SC) route utilizing sterile 
technique. RO7445482 doses will be administered at the study clinic preferably in the 
morning by investigational staff.  
The SC administration site (e.g., left abdomen, right abdomen, etc.) should be rotated 
between visits.  
Guidelines for dosage modification and treatment interruption/discontinuation are in 
Section A9.8 (in this Appendix).  
For more details, refer to the RO7445482 Investigator’s Brochure, NUC local prescribing 
information, and the Pharmacy Manuals.  
A9.8. EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
RO7445482 
RO7445482 Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A9.9 DOSE MODIFICATIONS 
Appendix 9-Table 2 summarizes the dose interruption/discontinuation guidelines for the 
siRNA+NUC combination arm.  

 
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Appendix 9-Table 2 Dose Interruption/Discontinuation Guidelines for siRNA+NUC 
Combination Arm 
 
 
 
A9.10 PHARMACOKINETICS ANALYSES SPECIFIC TO siRNA + NUC ARM 
A9.10.1 
OPTIONAL LIVER BIOPSY SUB-STUDY 
At one or more selected sites with established expertise, participants may be offered to 
participate in a liver biopsy sub-study, which will involve collection of paired liver biopsy 
samples. This procedure will be performed during the treatment period (Days 169 or 
337) and the follow-up period (Day 168). Liver biopsy tissue will be used to measure 
intra-hepatic RO7445482 exposure levels (including metabolites, if applicable). 
Participation in the liver biopsy sub-study will require a separate consent and will involve 
a select number of participants. 
For further details, refer to the study operations manual. 
A9.11 PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO siRNA + NUC ARM 
A9.11.1 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the NME and with primary and secondary endpoints. Known candidate 
genes of interest that are specific to siRNA includes ASGR1. Further genes may be 
queried from the data based on progressing knowledge on these NMEs and their 
targets. 
A9.11.2 
OPTIONAL LIVER BIOPSY SUB-STUDY 
At one or more selected sites with established expertise, participants may be offered to 
participate in a liver biopsy sub-study, which will involve collection of paired liver biopsy 
samples. This procedure will be performed during the treatment period (Days 169 or 
337) and the follow-up period (Day 168). Liver biopsy tissue will be used to measure 

 
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intra-hepatic viral parameters including but not limited to HBsAg, HBV DNA, HBcrAg, 
HBV RNA, cccDNA. Where feasible, residual tissue samples may be used to measure 
immunological parameters (e.g., HBV specific T-cells) and/or routine histopathology. 
Participation in the liver biopsy sub-study will require a separate consent and will involve 
a select number of participants. 
For further details, refer to the study operations manual. 
A9.12 SCHEDULE OF ACTIVITIES siRNA + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 9-Table 3 and 
Appendix 9-Table 4. 

 
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Appendix 9-Table 3 
Schedule of Activities for siRNA (100 mg or 200mg) + NUC Treatment Arm (Screening and 
Treatment Periods) 
 
Screening 
Treatment Period 
VB/VR ET/UVq 
Week 
 
 
1  
3 
5 
9 
13n, p 
17 
21 
25o,p 
29  
33 
37 
41 
45 
49p 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3 ) 
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3) 
309 
(±3) 
337 
(±3) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Transient elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Pregnancy test f 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
Hematology (includes HbA1cg) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, HBeAg, anti-HBs, 
anti-HBe) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

 
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Appendix 9-Table 3 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Screening and 
Treatment Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVq 
Week 
 
 
1  
3 
5 
9 
13n, p 
17 
21 
25o,p 
29  
33 
37 
41 
45 
49p 
 
Day -56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3 ) 
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3) 
309 
(±3) 
337 
(±3) 
 
 
HBV DNA quantitative 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg i 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBcrAg 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
HBV RNA quantitative 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma ADA (siRNA) s 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Liver Biopsy r 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
RBRl 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Clinic siRNA 100 mg or 200 mg sc Q4W 
treatment administration  
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
NUC treatment administration OD 
 
 
x 
 
 
Adverse events, concomitant medications, 
and diary review m 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 

 
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Appendix 9-Table 3 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Screening and 
Treatment Periods) (cont.) 
ADA = anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early 
termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related 
antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR = magnetic resonance; 
NUC = nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; siRNA= short 
interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological 
breakthrough/relapse; UV = unscheduled visit. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 13, 25, 37, and 49.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR /2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse; blood sample to be collected up to 6 times. 
k Plasma PK samples for siRNA to be collected at pre-dose, 1-3 and 4-6 hours post-dose. Plasma PK samples for NUC to be collected at pre-dose. 
During the PK assessments for VB/VR visits, only one pre-dose sample is required for collection, no other points required. 
l RBR samples collected only from RBR-consenting participants.  
m Pre-treatment, only serious adverse events should be reported. 
n End-of-treatment visit for participants in the 12-week finite treatment arm (if commenced after an interim analysis). 
0 End-of-treatment visit for participants in the 24-week finite treatment arm (if commenced after an interim analysis). 
p End-of-treatment visit for participants with HBsAg loss in the 48-week response-guided therapy arm (if commenced after an interim analysis).  

 
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Appendix 9-Table 3 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Screening and 
Treatment Periods) (cont.) 
q Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
r Only for participants in the liver biopsy sub-study. Liver biopsy sample will be collected during the treatment period on Day 169 or 337. 
Participation for liver biopsy is optional and will require a separate consent from participant. Additional safety assessments may be required as 
per local practice and guidelines prior to the liver biopsy (refer to study operations manual).  
s Pre-dose plasma ADA sample  
 
 

 
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Appendix 9-Table 4 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Follow-up Period) 
 
Follow-up period 
VB/VR 
ET/UV i 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24k 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitativel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg e 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
Total anti-HBc quantitative  
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 9-Table 4 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Follow-up Period) 
(cont.) 
 
Follow-up period 
VB/VR 
ET/UV i 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24k 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Plasma PK (NUC) f 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma ADA (siRNA) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
Liver biopsy j 
 
 
 
 
 
 
 
 
x 
 
 
 
 
RBR g 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA=anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early termination; 
GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related antigen; HBeAg = 
hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR = magnetic resonance; NUC = 
nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; ; siRNA= short interfering 
ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; 
UV = unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits should be scheduled with a frequency of every 2 weeks for the first three 
months and every 4 weeks up to week 48 of follow-up period. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb/components of HBsAg. 
f During the PK assessments for VB/VR visits, only one sample is required for collection, no other time points required. Pre-dose if on NUC therapy. 
 

 
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Appendix 9-Table 4 
Schedule of Activities for siRNA (100 mg or 200 mg) + NUC Treatment Arm (Follow-up period) 
(cont.) 
g RBR samples collected only from RBR-consenting participants.  
h Pre-treatment, only serious adverse events should be reported. 
i Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
j Only for participants in the liver biopsy sub-study. Liver biopsy sample will be collected during the follow-up period on Day 168. Participation for 
liver biopsy is optional and will require a separate consent from participant. Additional safety assessments may be required as per local 
practice and guidelines prior to the liver biopsy (refer to study operations manual).  
k Visit window may be extended to +6 weeks in extreme circumstances such as pandemic, natural disasters, supply chain disruption, outbreak of hostilities. 
l Participants with HBV DNA > 2,000 IU/mL during the follow-up period will undergo weekly monitoring. Participants with HBV DNA >20 IU/mL but < 2,000 
IU/mL, should undergo monitoring every two weeks. Participants, who have discontinued NUC therapy, should have monthly visits from follow-up Week 24 to 
Week 48, instead of the 3 monthly follow-up visits shown in SoA, which are relevant for participants on NUC therapy, to enable early detection and appropriate 
management of HBV DNA rebound. At these additional unscheduled monitoring visits, the following laboratory assessments should be performed using the 
unscheduled lab kit: hematology, chemistry, coagulation, GLDH, urinalysis, HBV serology, HBV DNA quantitative, total HBsAg, HBcrAg, and HBV RNA 
quantitative.  
 

 
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Appendix 10 
Study Details Specific to siRNA (RO7445482) + PEG-IFN + NUC 
Arm 
An overview of short interfering RNA (siRNA) + pegylated interferon-alpha (PEG-IFN) + 
nucleos(t)ide (NUC) treatment arm is shown in Appendix 10-Figure 1.  
Participants will receive RO7445482 (also known as DCR-HBVS; 200 mg every 4 weeks 
[Q4W]) in addition to their background NUC therapy for the 48-week treatment period. 
PEG-IFN at a dose of 180 µg will be administered once weekly (QW) for 48 weeks. At 
the end of the treatment period, participants will continue NUC treatment during the 
follow-up unless the NUC discontinuation criteria have been met (see Section 6.8).  
Approximately 30 participants will be randomized to this treatment arm.  
If a 30% delta for hepatitis B surface antigen (HBsAg) loss is observed at Week 48 (end-
of-treatment [EOT]) or follow-up Weeks 12 or 24 (primary endpoint) the treatment arm 
may be expanded to accrue additional efficacy and safety data, and to contribute to 
Phase 3 design planning. If a successful interim analysis is observed at Weeks 12 or 24, 
shorter treatment duration arms (12 and 24 weeks’ duration) and/or a response-guided 
therapy (RGT) arm may be added. 
Appendix 10-Figure 1 
 
siRNA + PEG-IFN+ NUC Treatment Arm  
 
 
A10.1 BACKGROUND SPECIFIC TO SIRNA + PEG-IFN+ NUC ARM 
A10.1.1 
BACKGROUND ON RO7445482 
RO7445482 (DCR-HBVS) is an siRNA conjugated to N-acetyl-D-galactosamine 
(GalNAc), which enables liver targeting through binding to the asialoglycoprotein 
receptor (ASGPR) that is highly expressed in the liver. After forming the RNA-induced 
silencing complex (RISC), the RO7445482 antisense strand targets hepatitis B virus 
(HBV) RNA for degradation by triggering RNAi-mediated cleavage within the HBsAg 
coding sequence, thereby inhibiting HBV gene expression.  

 
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Literature indicates that HBV antigens suppress the host immune response through 
several pathways, including the direct effects of long-term exposure to high 
concentration of viral antigens resulting in T-cell immune tolerance and T-cell exhaustion 
(Hai-Jun et al 2015). Depletion of viral antigens through inhibition of HBV gene 
expression may therefore facilitate the restoration of the host immune response. 
Non-clinical studies with RO7445482 have shown potent antiviral activity. HBsAg 
reductions of up to 3.5 log10 for more than 7 weeks, as well as significant reductions in 
HBcAg, were observed after a single translationally relevant dose in mice, demonstrating 
duration of action suitable for infrequent dosing.  
To date, clinical experience with RO7445482 is based on a Phase I clinical study 
(DCR-HBVS-101) involving healthy volunteers and participants with CHB.  
A10.1.2 
BACKGROUND ON PEG-IFN (PEGASYS®) 
PEG-IFN is a chemically modified alpha interferon formed by the covalent attachment of 
a 40-kilodalton single branched methoxy polyethylene glycol (PEG) moiety to 
recombinant IFN alfa-2a. 
PEG-IFN is an inducer of the innate antiviral immune response through binding to the 
human type 1 interferon receptor. Subsequent activation of multiple intracellular signal 
transduction pathways results in broad pleiotropic biological effects. 
PEG-IFN is currently approved for the treatment of CHB. 
A10.2 BENEFIT/RISK ASSESSMENT SPECIFIC TO siRNA+ PEG-IFN + NUC 
ARM 
The 48-week treatment with RO7445482 and PEG-IFN treatment in combination with 
NUC aims to result in therapeutic benefit for participants, including possibly higher 
functional cure rates than observed currently with standard-of-care therapies 
(monotherapy with NUC or PEG-IFN). The concurrent RO7445482 and PEG-IFN 
administrations aim is to test the scientific hypothesis whether concurrent direct-acting 
antiviral and immunomodulatory agent combination therapy, maximizes the efficacy 
outcomes.  
The concept of the combination of a direct anti-viral with an immunomodulatory agent is 
supported by in vivo nonclinical combination of a HBV-targeting locked nucleic acid 
(LNA)-based antisense oligonucleotide (HBV-LNA ASO) and toll-like receptor 7 (TLR7)-
agonist, RO7020531, using a recombinant adeno-associated virus carrying HBV 
genome (AAV-HBV) mouse model. The combination resulted in (a) delayed and reduced 
rebound in HBsAg and HBV DNA, (b) transient increase in frequency of anti-HBsAg 

 
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positive mice, and (c) robust induction of anti-viral B-cell response. In detail, RO7020531 
and HBV-LNA combination resulted in significant delay (up to 4 weeks) in rebound and 
lower off-treatment levels of HBsAg. Three out of 8 mice in the HBV-LNA ASO and 
RO7020531 (QOD) combo group showed sustained HBsAg loss (< 1.4 log10 IU/ml). HBV 
DNA levels in the combination group remained at lower levels compared to monotherapy 
groups up to 9 weeks off-treatment. In addition, combination treatment further increases 
the number of animals exhibiting a transient elevation in anti-HBsAg response as well as 
long-term memory B-cell response. These data provides pre-clinical evidence that 
combination of a direct anti-viral with an immunomodulatory agent potentially increases 
cure rates in CHB patients (Blaising et al 2019).  
The data from the combination of RO7049389 (a direct antiviral agent that works as a 
core protein allosteric modulator) and toll-like receptor 7 (TLR7)-agonist, RO7020531 
(an immune modulator) demonstrated significantly greater HBV DNA and hepatitis B 
surface antigen (HBsAg) reductions post treatment (Day 84) than either agent as 
monotherapy further supports this concept (see Section A8.2). 
Interim Phase 1 data have shown significant and durable antiviral activity with four 
monthly doses of RO7445482 in NUC-suppressed participants with CHB. At Day 112, 
mean HBsAg log10 IU/mL reduction from baseline were 1.39, 1.80 and 1.84 for 
participants who received 1.5 mg/kg, 3.0 mg/kg, or 6 mg/kg, respectively. Approximately 
80% of participants achieved > 1.5 log10 IU/mL reduction (irrespective of HBeAg-status), 
60% had HBsAg levels < 100 IU/mL, and durability of response was demonstrated up to 
Day 392.  
Based on the interim Phase 1 data, RO7445482 was safe and well tolerated in healthy 
volunteers (HV) and CHB patients. The safety profile appears to be similar between HVs 
and patient participants, and there were no safety signals or dose related trends 
identified. No severe or serious treatment-emergent adverse events (TEAEs) or TEAEs 
leading to treatment discontinuation, apart from generally mild injection site reactions 
(ISRs), there was absence of other potential oligonucleotide class effects. 
RO7445482 has shown acceptable safety/tolerability in the Phase 1 study involving 
healthy volunteers and CHB participants, and non-clinical toxicology and safety 
pharmacology studies support the proposed 48-week combination regimen. 
For details, refer to the RO7445482 Investigator’s Brochure, Pegasys® local prescribing 
information, NUC local prescribing information, and the Pharmacy Manuals. 

 
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A10.3 JUSTIFICATION FOR DOSE SPECIFIC TO siRNA + PEG-IFN + NUC 
ARM 
For RO7445482, fixed dose of 200 mg Q4W (equivalent to 3 mg/kg monthly) has been 
selected for Phase 2 study in combination with other IMPs/NMEs. This dose is within the 
anticipated therapeutic dose-range in humans and is expected to be safe and well 
tolerated. A summary of the key data supporting the selected dose is provided below: 
 
The dose-response trend in the HBsAg declines, together with PK/PD modeling 
of interim Phase 1 data, supports the proposed 200 mg Q4W dosing regimen. 
Preliminary PK/PD modeling predicts that the proportion of participants who will 
achieve > 1.5 and > 2 log10 IU/mL reductions in HBsAg, following Q4W doses up 
to Week 12, will be higher with a 200 mg Q4W regimen (97% and 56%, 
respectively) compared to a 100 mg Q4W regimen (89% and 6%, respectively). 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for 
the 200 mg Q4W fixed dose (3 mg/kg equivalent) for treatment period of 48 
weeks. 
 
PK/PD modelling supports use of fixed (200 mg) instead of weight based (3 
mg/kg) RO7445482 dosing. 
For PEG-IFN, the approved regimen for the treatment of CHB (i.e., 180 mcg QW for 48 
weeks) will be used. 
For details, refer to the RO7445482 Investigator’s Brochure, Pegasys® local prescribing 
information, NUC local prescribing information, and the Pharmacy Manuals. 
A10.4 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO siRNA + PEG-IFN + 
NUC ARM 
Participants must meet the following criterion for inclusion in the siRNA + PEG-IFN + 
NUC treatment arm: 
Sex 
1. Female participants:  
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
• 
Woman of non-childbearing potential (WONCBP). 
 
 Woman of childbearing potential (WOCBP), who: 

 
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– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods, of which at least 1 is 
considered highly effective (result in a failure rate of < 1% per year) 
during the treatment period and for at least 6 months after the final 
dose of study treatment (see A10.7 and Appendix 5).  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month during 
treatment and up to 6 months follow-up, thereafter every 3 months until end 
of follow-up.  
Participants are excluded from the siRNA + PEG-IFN + NUC arm if any of the following 
criteria apply or if there is any condition which would preclude the patient from being 
treated with PEG-IFN, according to the Pegasys® local prescribing information: 
Medical Conditions 
1. 
Known hypersensitivity reactions such as urticaria, angioedema, 
bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome, to alpha 
interferons, including Pegasys®, or any of its components  
2. 
Current symptoms of depression or history of severe psychiatric condition, 
particularly severe depression, suicidal ideation, or suicidal attempt.  
3. 
History of autoimmune hepatitis or other autoimmune disorders.  
4. 
Diabetes that is not well controlled (HbA1c  7% at screening) 
5. 
Pre-existing ophthalmologic disorders (known history or as assessed by eye 
examination at screening), which in the opinion of the investigator would increase 
the likelihood of clinical significance of potential drug-induced retinopathy (e.g., 
diabetic or hypertensive retinopathy, glaucoma, dense cataract, visual field 
abnormalities, severe retinopathy). 
6. 
History of pulmonary disorders including interstitial pneumonitis, bronchiolitis 
obliterans, pulmonary hypertension, and sarcoidosis.  
7. 
History of pancreatitis. 
8. 
Participants with history or present evidence of orthostatic hypotension. 
 
A10.5 SAFETY ASSESSMENTS SPECIFIC TO SIRNA + PEG-IFN + NUC ARM 
Physical Examinations 
Eye examination will be performed at screening, preferably by an ophthalmologist, and 
will include funduscopic examination with dilation, visual acuity, assessment, visual field 
testing, and color visual testing. 
Vital signs 

 
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Assessment of orthostatic hypotension will be done at screening. To assess the 
presence of orthostatic hypotension, blood pressure will be measured both while the 
participant is sitting and while standing. Participants will be excluded if a drop of 20 
millimeters of mercury (mm Hg) in systolic blood pressure or a drop of 10 mm Hg in 
diastolic blood pressure within two to five minutes of standing up, or if standing causes 
signs and symptoms of hypotension. 
A10.6 LIFESTYLE CONSIDERATIONS SPECIFIC TO siRNA + PEG-IFN + 
NUC ARM 
Participants who take PEG-IFN should brush their teeth thoroughly twice daily and have 
regular dental examinations, as described in the local prescribing information. 
NUCs will be given according to the local prescribing information.  
For CHB participants, who routinely take herbal medicines that, in the Investigator’s 
opinion, may have immune-modulatory effects, herbal medicines should strongly be 
discouraged. 
A10.7 CONTRACEPTIVE REQUIREMENTS SPECIFIC TO siRNA + PEG-IFN 
+ NUC ARM 
For WOCBP: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods of which at least 1 is considered highly effective 
(see Appendix 5), during the study and for at least 6 months after the last dose of study 
drug.  
 
Examples of acceptable highly effective contraceptive methods (< 1% failure rate 
per year) include combined or progesterone-only hormonal contraception, 
intrauterine device, and vasectomized partner.  
 
Examples of acceptable not as highly effective contraceptive methods (> 1% failure 
rate per year) include progesterone only hormonal contraception (where inhibition of 
ovulation is not the primary mode of action) and male or female condoms with or 
without spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree 
to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:  
 
Men must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of study drug to avoid exposing the embryo.  
 
Men must refrain from donating sperm during this same period. 

 
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The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
A10.8 TREATMENT ADMINISTERED SPECIFIC TO siRNA + PEG-IFN + NUC 
ARM 
Appendix 10-Table 1 summarizes the treatments administered. 
Appendix 10-Table 1 Summary of Treatments Administered for siRNA + PEG-IFN 
+ NUC Treatment Arm 
Study Treatment Name 
siRNA 
(RO7445482) 
Pegasys® 
NUC 
IMP and NIMP 
IMP 
IMP 
NIMP* 
Dose Formulation 
Sterile colorless to 
yellow solution of 
drug substance 
RO7445482 in water 
for injection 
peginterferon alfa-
2a is a clear and 
colourless to light 
yellow sterile liquid 
film-coated tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
120 mg/mL, 2 mL 
filled in a 6 mL vial 
Each prefilled 
syringe of 0.5 mL 
solution contains 
180 µg peginterferon 
alfa-2a 
Refer to local 
prescription 
information 
Dose: 
Fixed dose 200 mg 
Q4W 
180 µg  
QW 
ETV: 0.5 mg OD 
TDF: 300 mg OD 
TAF: 25 mg OD 
Route of 
Administration 
SC 
SC 
oral 
Sourcing 
Provided centrally 
by the Sponsor 
Provided centrally by 
the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the 
study site 
Packaging and 
Labeling 
Study treatment will 
be provided in vials, 
packaged, and 
labeled as required 
per local regulation. 
Study treatment will be 
provided as prefilled 
syringes as single use. 
Will be packaged and 
labeled as required per 
local regulation. 
Study treatment 
will be packaged 
and labeled as 
required per local 
regulation. 
*NUC are considered IMP in the UK only. 
 

 
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RO7445482 and PEG-IFN administrations will be via the SC route utilizing sterile 
technique. RO7445482 doses will be administered at the study clinic preferably in the 
morning by investigational staff.  
The SC administration site (e.g., left abdomen, right abdomen etc.) should be rotated 
between visits or when multiple injections are administered during a single visit. On 
study days where RO7445482 and PEG-IFN are both administered (e.g., Day 1), PEG-
IFN SC administration should be administered after RO7445482 SC administration 
within an interval of 1 - 24 hours.  
Guidelines for dosage modification and treatment interruption/discontinuation are 
provided in Section A10.11 (in this Appendix).  
For more details, refer to the RO7445482 Investigator’s Brochure, Pegasys® local 
prescribing information, NUC local prescribing information, and the Pharmacy Manuals. 
A10.9 EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
RO7445482 
RO7445482 Investigator's Brochure 
PEG-IFN 
Pegasys® Summary of Product Characteristics 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 

 
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A10.10 MANAGEMENT OF ADVERSE EVENTS SPECIFIC TO siRNA + PEG-
IFN + NUC ARM 
A10.10.1 
PEG-IFN RELATED AES  
As PEG-IFN results in broad pleiotropic biological effects, PEG-IFN treatment is 
associated with a broad/heterogeneous adverse event (AE) profile. Commonly observed 
AEs in CHB participants include pyrexia (54%), headache (27%), fatigue (24%), myalgia 
(26%), alopecia (18%), and anorexia (16%).  
If severe adverse reactions or laboratory abnormalities develop during combination 
PEG-IFN therapy, the dose should be modified until the adverse reactions abate. If 
intolerance persists after dose adjustment, PEG-IFN therapy should be discontinued.  
Approximately 5% and 40% of participants discontinue PEG-IFN therapy early or require 
modification of the PEG-IFN dose, respectively. The most common reasons for dose 
modification are laboratory abnormalities, including neutropenia (20%), 
thrombocytopenia (13%), and ALT elevation (11%). 
A10.11 DOSE MODIFICATION 
When dose modification of PEG-IFN is required for adverse reactions (clinical and/or 
laboratory), an initial dose reduction to 135 µg (adjustment to the corresponding 
graduation mark for the prefilled syringes) is recommended. Dose reduction to 90 µg 
(adjustment to the corresponding graduation mark for the prefilled syringes) may be 
needed if the adverse reaction persists or recurs. Following improvement of the adverse 
reaction, re-escalation of the dose may be considered. Appendix 10-Table 2 provides 
guidelines for dose modifications and discontinuation of PEG-IFN for laboratory 
abnormalities as well as other NME dose interruption/discontinuation criteria. 

 
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Appendix 10-Table 2 
Summary of Dose 
Interruption/Modification/Discontinuation Guidelines for 
siRNA+PEG-IFN+NUC Combination Arm  
 
 
For participants who discontinue PEG-IFN early because of intolerability, the NUC and 
RO7445482 treatment should be continued up to 48 weeks. The reasons for 
discontinuation of PEG-IFN and length of treatment duration will be recorded in the 
eCRF. 
A10.12 PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO siRNA + PEG-IFN + NUC ARM 
A10.12.1 
SIRNA + PEG-IFN + NUC ACTIVITY BIOMARKERS  
To characterize PEG-IFN PD biomarkers (secondary objective), blood samples will be 
collected at time points according to the SoA (see Appendix 10-Table 3 and Appendix 
10-Table 4) to measure cytokines including IP-10, IL-6 and TNF-α as well as a panel of 
transcriptional response of Interferon Stimulated Genes (ISG15, OAS1, MX1, and TLR7) 
if appropriate. Following review of these PD biomarkers and the AEs, further cytokines 
may be tested using a separate aliquot collected at the same time points including, IL-1, 
IL-10, and IFN-γ. 

 
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A10.12.2 
 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the NME and with primary and secondary endpoints. Known candidate 
genes of interest that are specific to siRNA/PEG-IFN include ASGR1. Further genes 
may be queried from the data based on progressing knowledge on these NME/IMP and 
their targets. 
A10.13 SCHEDULE OF ACTIVITIES siRNA + PEG-IFN + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 10-Table 3 and 
Appendix 10-Table 4.  
 

 
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Appendix 10-Table 3 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Screening and Treatment 
Periods) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVr 
Week 
 
 
1 
3 
5 
9 
13o, q 
17 
21 
25p, q 
29 
33 
37 
41 
45 
49 q 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3 ) 
309 
(±3) 
337 
(±3) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ophthalmic Exam a 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Transient elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Pregnancy test f 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
Hematology (includes HbA1cg) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 10-Table 3 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVr 
Week 
 
 
1 
3 
5 
9 
13o,q 
17 
21 
25p,q 
29 
33 
37 
41 
45 
49 q 
 
Day -56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3 ) 
309 
(±3) 
337 
(±3) 
 
 
HBV serology (HBsAg, HBeAg, anti-
HBs, anti-HBe) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitative 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg i 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBcrAg 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Total anti-HBc quantitative  
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
HBV RNA quantitative 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Serum PK (PEG-IFN) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma ADA (siRNA) s 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Serum ADA (PEG-IFN) s 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Cytokine panel l 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
ISG panel l 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
RBR m 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Clinic siRNA 200 mg sc Q4W 
treatment administration  
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 

 
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Appendix 10-Table 3 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVr 
Week 
 
 
1 
3 
5 
9 
13o,q 
17 
21 
25p,q 
29 
33 
37 
41 
45 
49 q 
 
Day -56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3 ) 
309 
(±3) 
337 
(±3 ) 
 
 
PEG-IFN treatment administration 
QW 
 
x 
 
 
NUC treatment administration OD 
 
x 
 
 
Adverse events & concomitant 
medications & diary review n 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early 
termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related 
antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IFN- α+ interferon alpha; IP-
10 = interferon gamma-induced protein 10; ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide analogue; PK = 
pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; Total HBsAg = 
post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 13, 25, 37, and 49. Eye examination (including fundoscopy) only at 
screening. 
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Historical liver biopsy or transient elastography/ARFI/MR/2D-shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR/2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 10-Table 3 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse, blood sample to be collected up to 6 times. 
k Plasma PK samples for siRNA to be collected at pre-dose, 1-3 and 4-6 hours post-dose. Plasma PK samples for NUC to be collected at pre-dose. 
Serum PK samples for PEG-IFN is collected pre-dose. During the PK assessments for VB/VR visits, only 1 pre-dose sample is required for 
collection; no other points required. 
l Cytokine panel (IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α) and ISG panel to be collected at pre-dose and 6 hours post-dose of PEG-IFN. At an 
unscheduled visit or early termination visit, preferably a pre-dose, otherwise, just a sample for cytokine and ISG panels should be collected if the 
visit is linked to a PEG-IFN related adverse reaction (e.g., influenza-like symptoms). No samples are required, for unscheduled visit or early 
termination visit not linked to PEG-IFN related adverse reaction (e.g., influenza-like symptoms).  
m RBR samples collected only from RBR-consenting participants.  
n Pre-treatment, only serious adverse events should be reported. 
o End-of-treatment visit for participants in the 12-week finite treatment arm (if commenced after an interim analysis). 
p End-of-treatment visit for participants in the 24-week finite treatment arm (if commenced after an interim analysis). 
q End-of-treatment visit for participants with HBsAg loss in the 48-week response-guided therapy arm (if commenced after an interim analysis).  
r Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
s Pre-dose plasma ADA sample.  

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 10-Table 4 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Follow-up Period) 
 
Follow-up period 
VB/VR 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24j 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitativek 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAge 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
Total anti-HBc quantitative  
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 10-Table 4 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Follow-up Period) (cont.) 
 
Follow-up period 
VB/VR 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24j 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Serum PK (PEG-IFN)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (NUC) f 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma ADA (siRNA) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
Serum ADA (PEG-IFN) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
RBR g 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA= anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early termination; 
GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related antigen; HBeAg = 
hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IP-10 = interferon gamma-induced protein 10; 
ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research 
Biosample Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb 
complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits should be scheduled with a frequency of every 2 weeks for the first three 
months and every 4 weeks up to week 48 of follow-up period. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb/components of HBsAg. 
 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
172/Protocol WV41073, Version 7.0 
Appendix 10-Table 4 
Schedule of Activities for siRNA + PEG-IFN + NUC Treatment Arm (Follow-up Period) (cont.) 
f During the PK assessments for VB/VR visits, only 1 sample is required for collection; no other time points required. Pre-dose if on NUC therapy. 
g RBR samples collected only from RBR-consenting participants.  
h Pre-treatment, only serious adverse events should be reported. 
i Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
j Visit window may be extended to +6 weeks in extreme circumstances such as pandemic, natural disasters, supply chain disruption, outbreak of hostilities. 
k Participants with HBV DNA > 2,000 IU/mL during the follow-up period will undergo weekly monitoring. Participants with HBV DNA >20 IU/mL but < 2,000 
IU/mL, should undergo monitoring every two weeks. Participants, who have discontinued NUC therapy, should have monthly visits from follow-up Week 24 to 
Week 48, instead of the 3 monthly follow-up visits shown in SoA, which are relevant for participants on NUC therapy, to enable early detection and appropriate 
management of HBV DNA rebound. At these additional unscheduled monitoring visits, the following laboratory assessments should be performed using the 
unscheduled lab kit: hematology, chemistry, coagulation, GLDH, urinalysis, HBV serology, HBV DNA quantitative, total HBsAg, HBcrAg, and HBV RNA 
quantitative.  
 

 
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Appendix 11 
Study Details Specific to siRNA (RO7445482) + CpAM 
(RO7049389) + NUC Arm 
An overview of short interfering RNA (siRNA) + core protein allosteric modulator (CpAM) 
+ nucleos(t)ide (NUC) treatment arm is shown in Appendix 11-Figure 1.  
Participants will receive RO7445482 (also known as DCR-HBVS; 200 mg every 4 weeks 
[Q4W]) and RO7049389 (600 mg once a day [QD]) in addition to their background NUC 
therapy for the 48-week treatment period. At the end of the treatment period, participants 
will continue NUC treatment during the follow-up unless the NUC discontinuation criteria 
have been met (see Section 6.8).  
Approximately 30 participants will be randomized to this treatment arm.  
If a 30% delta for hepatitis B surface antigen (HBsAg) loss is observed at Week 48 (end-
of-treatment [EOT]) or follow-up Weeks 12 or 24 (primary endpoint) the treatment arm 
may be expanded to accrue additional efficacy and safety data, and to contribute to 
Phase 3 design planning. If a successful interim analysis is observed at Weeks 12 or 24, 
shorter treatment duration arms (12 and 24 weeks’ duration) and/or a response-guided 
therapy (RGT) arm may be added. 
Appendix 11-Figure 1 
siRNA + CpAM + NUC Treatment Arm  
 
 
A11.1 BACKGROUND SPECIFIC TO siRNA + CpAM + NUC ARM 
A11.1.1 
BACKGROUND ON RO7445482 
RO7445482 (DCR-HBVS) is an siRNA conjugated to N-acetyl-D-galactosamine 
(GalNAc), which enables liver-targeting through binding to the asialoglycoprotein 
receptor (ASGPR) that is highly expressed in the liver. After forming the RNA-induced 
silencing complex (RISC), the RO7445482 antisense strand targets hepatitis B virus 
(HBV) RNA for degradation by triggering RNAi-mediated cleavage within the HBsAg 
coding sequence, thereby inhibiting HBV gene expression.  

 
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174/Protocol WV41073, Version 7.0 
Literature indicates that HBV antigens suppress the host immune response through 
several pathways, including the direct effects of long-term exposure to high 
concentration of viral antigens resulting in T-cell immune tolerance and T-cell exhaustion 
(Hai-Jun et al 2015). Depletion of viral antigens through inhibition of HBV gene 
expression may therefore facilitate the restoration of the host immune response. 
Non-clinical studies with RO7445482 have shown potent antiviral activity. HBsAg 
reductions of up to 3.5 log10 for more than 7 weeks, as well as significant reductions in 
HBcAg, were observed after a single dose in mice, demonstrating duration of action 
suitable for infrequent dosing. 
To date, clinical experience with RO7445482 is based on a Phase I clinical study (DCR-
HBVS-101) involving healthy volunteers and participants with chronic hepatitis B (CHB).  
A11.1.2 
BACKGROUND ON RO7049389 
RO7049389 is a CpAM and belongs to the well-studied class of 
heteroaryldihydropyrimidine (HAP) compounds. This class of compounds induces 
formation of abnormal HBV core protein aggregates, which are subsequently recognized 
and depleted. Depleting functional core protein results in interruption of viral assembly 
and inhibition of HBV replication.  
The HBV core protein is involved in multiple steps of the viral life cycle such as 
encapsulation of pre-genomic ribonucleic acid (pgRNA), subsequent initiation of reverse 
transcription, and is an important component of covalently closed circular DNA (cccDNA) 
mini-chromosome. Furthermore, literature suggests that the HBV core protein may play 
a role in suppressing host innate immune responses (Twu et al 1988; Fernandez et al 
2003; Gruffaz et al 2013). Depletion of functional core protein may therefore facilitate 
host immune restoration. RO7049389 can therefore potentially provide anti-HBV benefits 
by both direct inhibition of viral replication and augmentation of host immune responses 
against the virus. 
RO7049389 has shown potent antiviral activity through the induction of HBV core protein 
misassembly and subsequent degradation, and has a high degree of selectivity against 
HBV. RO7049389 demonstrated activity against most prevalent HBV genotypes (A, B, 
C, D) and against a panel of NUC analogue-resistant HBV variants tested in vitro. 
To date, clinical experience with RO7049389 includes three Phase 1 clinical studies:  an 
entry-into-human (EIH) study in healthy volunteers (HV) and patients (YP39364), a study 
in HVs of Chinese descent (YP39406), and a drug-drug interaction (DDI) study in HVs 
(YP40218). 

 
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175/Protocol WV41073, Version 7.0 
A11.2 BENEFIT/RISK ASSESSMENT SPECIFIC TO siRNA+ CpAM + NUC 
ARM 
The 48-week treatment with RO7445482 and RO7049389 in combination with NUC aims 
to result in therapeutic benefit for participants, including possibly higher functional cure 
rates than observed currently with standard-of-care therapies (monotherapy with NUC or 
PEG-IFN). The concurrent RO7445482 and RO7049389 administrations aim is to test 
the hypothesis whether prolonged reduction in HBV antigens, including but not limited to 
HBsAg, will result in immune-restoration and potentially functional cure. 
In non-clinical rodent pharmacology studies, RO7445482 (DCR-HBVS) treatment 
resulted in a lowering of serum HBsAg of up to 3.5 log10 for > 7 weeks after a single, 
translationally relevant dose. Serum HBsAg levels did not return to within 2 log10 of 
baseline for at least 4 months, demonstrating duration of action suitable for infrequent 
dosing. These data support the use of DCR-HBVS in patients with CHB, who will require 
a sustained host response to achieve a functional cure. 
Emerging clinical trial data shows that CpAM exerts additional anti-viral activity when 
combined with NUC (Man-Fung Yuen et al 2020). This was demonstrated by the greater 
decline in HBV DNA and pgRNA levels, as well as the proportion of patients achieving 
undetectable HBV DNA and pgRNA levels.  
Interim Phase 1 data have shown significant and durable antiviral activity with 4 monthly 
doses of RO7445482 in NUC-suppressed participants with CHB. At Day 112, mean 
HBsAg log10 IU/mL reduction from baseline were 1.39, 1.80, and 1.84 for participants 
who received 1.5 mg/kg, 3.0 mg/kg or 6 mg/kg, respectively. Approximately 80% of 
participants achieved > 1.5 log10 IU/mL reduction (irrespective of HBeAg-status), 60% 
had HBsAg levels < 100 IU/mL, and durability of response was demonstrated up to Day 
392.  
Based on the interim Phase 1 data, RO7445482 was safe and well tolerated in healthy 
volunteers (HV) and CHB patients. The safety profile appears to be similar between HVs 
and patient participants, and there were no safety signals or dose related trends 
identified. No severe or serious treatment-emergent adverse events (TEAEs) or TEAEs 
leading to treatment discontinuation, apart from generally mild injection site reactions 
(ISRs), there was absence of other potential oligonucleotide class effects. 
RO7445482 and RO7049389 have shown acceptable safety/tolerability in the Phase 1 
studies involving healthy volunteers and CHB participants, and non-clinical toxicology 
and safety pharmacology studies support the proposed 48-week combination regimen. 
For details, refer to the RO7445482 and RO7049389 Investigator’s Brochures. 

 
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A11.3 JUSTIFICATION FOR DOSE SPECIFIC TO siRNA+ CpAM + NUC 
ARM 
For RO7445482, fixed dose of 200 mg Q4W (equivalent to 3 mg/kg monthly) has been 
selected for Phase 2 study in combination with other IMPs/NMEs. This dose is within the 
anticipated therapeutic dose-range in humans and is expected to be safe and well 
tolerated. A summary of the key data supporting the selected dose is provided below: 
 
The dose-response trend in the HBsAg declines, together with PK/PD modeling of 
interim Phase 1 data, supports the proposed 200 mg Q4W dosing regimen. 
Preliminary PK/PD modeling predicts that the proportion of participants who will 
achieve > 1.5 and > 2 log10 IU/mL reductions in HBsAg, following Q4W doses up to 
Week 12, will be higher with a 200 mg Q4W regimen (97% and 56%, respectively) 
compared to a 100 mg Q4W regimen (89% and 6%, respectively). 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for the 
200 mg Q4W fixed dose (3 mg/kg equivalent) for treatment period of 48 weeks. 
 
PK/PD modelling supports use of fixed (200 mg) instead of weight based (3 mg/kg) 
RO7445482 dosing 
 
For RO7049389, a dose of 600 mg QD has been selected for this Phase 2 study. This 
dose is within the predicted therapeutic dose-range in humans and is expected to be 
safe and well tolerated. A summary of the key data supporting the selected dose is 
provided below: 
 
RO7049389 doses up to 1000 mg QD (for 28 days), 800 mg BID (for 6 days) and 
2500 mg (single dose) have been observed to be safe and well tolerated in three 
Phase 1 studies involving healthy volunteers and CHB participants. 
 
Although 200 mg to 600 mg QD doses resulted in robust pharmacodynamic effects 
(HBV DNA decline 2.66 – 3.2 log10 IU/mL) in the Phase 1 studies, a trend of 
increased HBV DNA decline was observed with higher doses. In addition, disease-
modelling utilizing non-clinical and clinical PK/PD data predicts an increased PD 
effect with the 600 mg QD dose. 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for the 
600 mg QD dose.  
Further details are provided in the RO7445482 and RO7049389 Investigator’s 
Brochures. 
 
 

 
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A11.4 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO siRNA + CpAM + 
NUC ARM 
Participants must meet the following criterion for inclusion in the siRNA + CPAM + NUC 
treatment arm: 
Sex 
1. Female Participants:  
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
 
Woman of non-childbearing potential (WONCBP). 
 
Woman of childbearing potential (WOCBP), who: 
– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods, of which at least one is 
considered highly effective (result in a failure rate of < 1% per year 
during the treatment period and for at least 6 months after the final 
dose of study treatment (ref A11.6 and Appendix 5).  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month 
during treatment and up to 6 months follow-up, thereafter every 
3 months until end of follow-up.  
 
A11.5 LIFESTYLE CONSIDERATIONS SPECIFIC TO siRNA + CpAM + NUC 
ARM 
RO7049389 will be given in fasted state (at least 2 hours after a meal or 2 hours before 
the next meal). NUCs will be given according to the local prescribing information.  
For RO7049389, any nutrients known to modulate activity of CYP enzymes (e.g., 
grapefruit- or Seville orange-containing products) will be prohibited within 3 days before 
Day -1 through to the last dose of RO7049389. 
For CHB participants who routinely take herbal medicines that in Investigator’s opinion 
may have immune-modulatory effects, herbal medicines should strongly be discouraged. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
178/Protocol WV41073, Version 7.0 
A11.6 CONTRACEPTIVE REQUIREMENTS SPECIFIC TO siRNA + CpAM + 
NUC ARM 
For WOCBP: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods of which at least 1 is considered highly effective 
(see Appendix 5), during the study and for at least 6 months after the last dose of study 
drug.  
 
Examples of acceptable highly effective contraceptive methods (< 1% failure rate 
per year) include combined or progesterone-only hormonal contraception, 
intrauterine device, and vasectomized partner.  
 
Examples of acceptable not as highly effective contraceptive methods (> 1% failure 
rate per year) include progesterone only hormonal contraception (where inhibition of 
ovulation is not the primary mode of action) and male or female condoms with or 
without spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree 
to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:  
 
Men must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of study drug to avoid exposing the embryo.  
 
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
A11.7 TREATMENT ADMINISTERED SPECIFIC TO siRNA + CpAM + NUC 
ARM 
Appendix 11-Table 1 summarizes the treatments administered. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
179/Protocol WV41073, Version 7.0 
Appendix 11-Table 1 
Summary of Treatments Administered for siRNA + 
CPAM + NUC Treatment Arm 
Study Treatment Name 
siRNA 
(RO7445482) 
CpAM 
(RO7049389) 
NUC 
IMP and NIMP 
IMP 
IMP 
NIMP* 
Dose Formulation 
Sterile colorless to 
yellow solution of 
drug substance 
RO7445482 in water 
for injection 
film-coated tablet 
film-coated tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
120 mg/mL, 2 mL 
filled in a 6 mL vial 
200 mg 
Refer to local 
prescription 
information 
Dose: 
Fixed dose 200 mg 
Q4W 
600 mg OD 
ETV: 0.5 mg OD 
TDF: 300 mg OD 
TAF: 25 mg OD 
Route of Administration 
SC 
Oral 
oral 
Sourcing 
Provided centrally by 
the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the study 
site 
Packaging and Labeling 
Study treatment will 
be provided in vials, 
packaged, and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
*NUC are considered IMP in the UK only. 
RO7445482 administrations will be via the SC route utilizing sterile technique. 
RO7445482 doses will be administered at the study clinic preferably in the morning by 
investigational staff.  
The SC administration site (e.g., left abdomen, right abdomen etc.) should be rotated 
between visits.  
Guidelines for dosage modification and treatment interruption/discontinuation are in 
Section A11.8 (in this Appendix).  
For more details, refer to the RO7445482 and RO7049389 Investigator’s Brochures, 
NUC local prescribing information, and the Pharmacy Manuals. 

 
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A11.8 EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
RO7049389 
RO7049389 Investigator's Brochure 
RO7445482 
RO7445482 Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A11.9 DOSE MODIFICATIONS 
Appendix 11-Table 2 summarizes the dose interruption/discontinuation guidelines for the 
siRNA+CpAM+NUC combination arm. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
181/Protocol WV41073, Version 7.0 
Appendix 11-Table 2 Dose Interruption/Discontinuation Guidelines for 
siRNA+CpAM+NUC Combination Arm 
 
 
A11.10 CONCOMITANT THERAPY SPECIFIC TO siRNA + CpAM + NUC ARM  
The following concomitant medications are prohibited: 
 
Inducers of CYP3A enzyme: e.g., efavirenz, nevirapine, pioglitazone, rifampin, 
rifabutin, troglitazone, phenobarbital, phenytoin, carbamazepine, and St. John’s wort 
within 14 days or 5 half-lives (whichever is longer) before the first administration of 
RO7049389 and while on study treatment with RO7049389. 
 
Inhibitors of CYP3A enzyme: e.g., indinavir, nelfinavir, clarithromycin, itraconazole, 
ketoconazole, nefazodone, ketoconazole, verapamil, suboxone, diltiazem, 
cimetidine, amiodarone, fluvoxamine, troleandomycin, and voriconazole within 7 
days or 5 half-lives (whichever is longer) before the first administration of 
RO7049389 and while on study treatment with RO7049389. 
 
Strong inducers of UDP-glucuronosyltransferase (UGT) 1A3 enzymes: e.g., 
carbamazepine and nicotine within 14 days, or 5 half-lives (whichever is longer) 
before the first administration of RO7049389 and while on study treatment with 
RO7049389. 
 
Strong inhibitors of UGT1A3/1A1 enzymes: e.g., atazanavir, gemfibrozil, indinavir, 
and ketoconazole within 7 days, or 5 half-lives (whichever is longer) before the first 
administration of RO7049389 and while on study treatment with RO7049389. 
 
Inhibitors of OATP1B transporters: e.g., cyclosporine, rifampicin, eltrombopag, 
lapatinib, lopinavir, ritonavir within 7 days, or 5 half-lives (whichever is longer) before 
the first administration of RO7049389 and while on study treatment with 
RO7049389. 
The following concomitant medications are to be used with caution, and the Sponsor 
should be informed before these drugs are administered. When coadministered with 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
182/Protocol WV41073, Version 7.0 
RO7049389, the recommendation is to use the lowest necessary dose of the substrate, 
titrate the dose carefully, and monitor closely for substrate-associated adverse reactions. 
 
Substrates of OATP1B: e.g., atrasentan, bosentan, ezetimibe, irinotecan, statins 
(e.g., atorvastatin, rosuvastatin, simvastatin, pitavastatin, pravastatin), repaglinide, 
rifampin, valsartan, and olmesartan.  
 
CYP3A4 substrates with a narrow therapeutic range.  
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication inhibits or induces above mentioned 
enzymes or transporter. In addition, the investigator should contact the Medical Monitor 
if questions arise regarding medications that are not listed above.  
A11.11 PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO siRNA + CpAM + NUC ARM 
A11.11.1 
 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the two NMEs and with primary and secondary endpoints. Known 
candidate genes of interest that are specific to CpAM/siRNA include AOX1, UGT1A1, 
PGP, OATP1B1, OATP1B3, CYP3A4, UGT1A3, and ASGR1. Further genes may be 
queried from the data based on progressing knowledge on these NMEs and their 
targets. 
A11.12 SCHEDULE OF ACTIVITIES siRNA + CpAM + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 11-Table 3 and 
Appendix 11-Table 4.  
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
183/Protocol WV41073, Version 7.0 
Appendix 11-Table 3 
Schedule of Activities for siRNA + CPAM + NUC Treatment Arm (Screening and Treatment 
Periods) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVq 
Week 
 
 
1  
3 
5 
9 
13n,p 
17 
21 
25o,p 
29  
33 
37 
41 
45 
49p 
 
Day -56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3)  
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3) 
309 
(±3) 
337 
(-2) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Transient elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Pregnancy test f 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
Hematology (includes HbaA1c)g 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 11-Table 3 
Schedule of Activities for siRNA + CPAM + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVq 
Week 
 
 
1  
3 
5 
9 
13n,p 
17 
21 
25o,p 
29  
33 
37 
41 
45 
49p 
 
Day -56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3)  
169 
(±3) 
197 
(±3) 
225 
(±3) 
253 
(±3) 
281 
(±3) 
309 
(±3) 
337 
(-2) 
 
 
HBV serology (HBsAg, HBeAg, anti-
HBs, anti-HBe) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitative 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAgi 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBcrAg 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
HBV RNA quantitative 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma PK (CpAM) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
Plasma ADA (siRNA)r 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
RBR l 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Clinic siRNA 200 mg sc Q4W 
treatment administration 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
CpAM treatment administration OD 
 
 
x 
 
 
NUC treatment administration OD 
 
 
x 
 
 
Adverse events & concomitant 
medications & diary review m 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibodies; ARFI = acoustic radiation force impulse; CpAM = Core protein allosteric modulator; DNA = deoxyribonucleic acid; ECG 
= electrocardiogram; ET=early termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = 
hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR 
= magnetic resonance; NUC = nucleos(t)ide analogue; PK = pharmacokinetics; 

 
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Appendix 11-Table 3 
Schedule of Activities for siRNA + CPAM + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
RBR = Research Biosample Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of 
HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 13, 25, 37, and 49.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR/2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse, blood sample to be collected up to 6 times. 
k Plasma PK samples for CpAM and siRNA to be collected at pre-dose,1-3 and 4-6 hours post-dose. Plasma PK samples for NUC to be collected at 
pre-dose. During the PK assessments for VB/VR visits, only one pre-dose sample is required for collection, no other points required. 
l RBR samples collected only from RBR-consenting participants.  
m Pre-treatment, only serious adverse events should be reported. 
n End-of-treatment visit for participants in the 12-week finite treatment arm (if commenced after an interim analysis). 
0 End-of-treatment visit for participants in the 24-week finite treatment arm (if commenced after an interim analysis). 
p End-of-treatment visit for participants with HBsAg loss in the 48-week response-guided therapy arm (if commenced after an interim analysis).  
q Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
r Pre-dose plasma ADA sample.  
 

 
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Appendix 11-Table 4 
Schedule of Activities for siRNA + CPAM + NUC Treatment Arm (Follow-up Period) 
 
Follow-up period 
VB/VR 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitative 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAge 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (CpAM)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 11-Table 4 
Schedule of Activities for siRNA + CPAM + NUC Treatment Arm (Follow-up Period) (cont.) 
 
Follow-up period 
VB/VR 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Plasma PK (NUC) f 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma ADA (siRNA) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
RBR g 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibody; ARFI = acoustic radiation force impulse; CpAM = Core protein allosteric modulator; DNA = deoxyribonucleic acid; ECG = 
electrocardiogram; ET=early termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = 
hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency; MR = 
magnetic resonance; NUC = nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid ; 
siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = 
virological breakthrough/relapse; UV = unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits can be scheduled with a frequency of every 2 weeks for the first three 
months and every 4-12 weeks up to week 48 of follow-up period, similarly to the monitoring proposed for those who will discontinue NUC, siRNA, 
and CpAM at week 48 at the end-of-treatment period. 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb/components of HBsAg. 
f During the PK assessments for VB/VR visits, only one sample is required for collection, no other time points required. Pre-dose if on NUC therapy. 
g RBR samples collected only from RBR-consenting participants.  
h Pre-treatment, only serious adverse events should be reported. 
i Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 

 
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Appendix 12 
Study Details Specific to siRNA (RO7445482) + TLR7 
(RO7020531) + NUC Arm 
An overview of short interfering RNA (siRNA) + toll-like receptor 7 (TLR7) + nucleos(t)ide 
NUC treatment arm is shown in Appendix 12-Figure 1.  
Participants will receive RO7445482 (also known as DCR-HBVS; 200 mg Q4W) in 
addition to their background NUC therapy for the 48-week treatment period. RO7020531 
(150 mg once every other day [QOD]) will be administered during Weeks 13-24 and 
Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks’ duration each and 42 doses of 
RO7020531 for each cycle). At the end of the treatment period, participants will continue 
NUC treatment during the follow-up unless the NUC discontinuation criteria have been 
met (see Section 6.8).  
Approximately 30 participants will be randomized to this treatment arm.  
If a 30% delta for HBsAg loss is observed at Week 48 (EOT) or follow-up Weeks 12 or 
24 (primary endpoint) the treatment arm may be expanded to accrue additional efficacy 
and safety data, and to contribute to Phase 3 design planning. If a successful interim 
analysis is observed at Weeks 12 or 24, shorter treatment duration arms (12 and 24 
weeks’ duration) and/or a response-guided therapy (RGT) arm may be added. 
Appendix 12-Figure 1 
siRNA + TLR7 + NUC Treatment Arm  
 
 
A12.1 BACKGROUND SPECIFIC TO siRNA + TLR7 + NUC ARM 
A12.1.1 
BACKGROUND ON RO7445482 
RO7445482 (DCR-HBVS) is an siRNA conjugated to N-acetyl-D-galactosamine 
(GalNAc), which enables liver-targeting through binding to the asialoglycoprotein 
receptor (ASGPR) that is highly expressed in the liver. After forming the RNA-induced 
silencing complex (RISC), the RO7445482 antisense strand targets hepatitis B virus 
(HBV) RNA for degradation by triggering RNAi-mediated cleavage within the hepatitis B 
surface antigen (HBsAg) coding sequence, thereby inhibiting HBV gene expression.  

 
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189/Protocol WV41073, Version 7.0 
Literature indicates that HBV antigens suppress the host immune response through 
several pathways, including the direct effects of long-term exposure to high 
concentration of viral antigens resulting in T-cell immune tolerance and T-cell exhaustion 
(Hai-Jun et al 2015). Depletion of viral antigens through inhibition of HBV gene 
expression may therefore facilitate the restoration of the host immune response. 
Non-clinical studies with RO7445482 have shown potent antiviral activity. HBsAg 
reductions of up to 3.5 log10 for more than 7 weeks, as well as significant reductions in 
HBcAg, were observed after a single dose in mice, demonstrating duration of action 
suitable for infrequent dosing. 
To date, clinical experience with RO7445482 is based on a Phase I clinical study (DCR-
HBVS-101) involving healthy volunteers and participants with CHB.  
A12.1.2 
BACKGROUND ON RO7020531 
RO7020531 is an oral double prodrug of the TLR7-specific agonist RO7011785. A 
prodrug approach was chosen for oral delivery of the TLR7 agonist RO7011785 in order 
to improve bioavailability and limit TLR7 activation in the gastrointestinal (GI) tract, which 
may be associated with GI intolerability.  
TLRs are a family of pathogen-recognition receptors that activate the innate immune 
response. The stimulation of TLR7 mediates an endogenous type I IFN response, which 
is critical in development of a broad, effective, and protective immunity against hepatitis 
viruses (Horscroft et al 2012, Funk et al 2014). Compared to pegylated interferon-alfa 
(PEG-IFN-) therapy, treatment with a TLR7 agonist induces broader 
immunomodulatory effects that are likely to lead to more effective control and functional 
cure of chronic HBV infection (Strader et al 2004, Isogawa et al 2005). TLR7 agonists 
induce the production of multiple isotypes of IFN from plasmacytoid dendritic cells 
(pDCs) which have been shown in vitro to possess additive or synergistic antiviral effects 
compared to exogenous PEG-IFN. 
Non-clinical studies with RO7020531 suggest that it is rapidly converted to the active 
metabolite RO7011785, and data from in vivo studies with RO7020531 and in vitro 
studies with RO7011785 support immune activation as the mechanism of action.  
To date, clinical experience with RO7020531 includes two Phase 1 clinical studies:  an 
EIH study in HVs and CHB participants (NP39305) and a study in HVs of Chinese 
descent (YP39553). 

 
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A12.2 BENEFIT/RISK ASSESSMENT SPECIFIC TO siRNA+ TLR7 + NUC 
ARM 
The 48-week treatment with RO7445482 and RO7020531 in combination with NUC aims 
to result in therapeutic benefit for participants, including possibly higher functional cure 
rates than observed currently with standard-of-care therapies (monotherapy with NUC or 
PEG-IFN). The concurrent RO7445482 and RO7020531 administrations aim is to test 
the scientific hypothesis whether concurrent direct-acting antiviral and 
immunomodulatory agent combination therapy maximizes the efficacy outcomes.  
Given that reduction in viral antigens is anticipated to result in functional immune 
recovery, the potency of an immunomodulatory agent is expected to increase if 
administered following a reduction in HBsAg. Consequently, in this treatment arm, the 
RO7020531 12-week treatment cycles will commence at week 13 and week 37 following 
administration of RO7445482 i.e., ‘off/on’ immunomodulatory treatment approach. 
This concept is supported by in vivo non-clinical data, whereby in a recombinant adeno-
associated virus carrying HBV genome (AAV-HBV) mouse model the combination of 
RO7049389 (a direct antiviral agent that works as a core protein allosteric modulator) 
and toll-like receptor 7 (TLR7)-agonist, RO7020531 (an immune modulator) resulted in 
significantly greater HBV DNA and hepatitis B surface antigen (HBsAg) reductions post 
treatment (Day 84) than either agent as monotherapy (Appendix 12-Table 1). HBsAg 
loss (< lower limit of quantification [LLOQ]) was observed in 5 of 7 mice by the end of the 
6-week combination treatment and sustained in the 6-week off-treatment period but in 
none of the monotherapy groups, suggesting a transformational efficacy impact with the 
direct-acting antiviral and immunomodulatory agent combination therapy.  
Appendix 12-Table 1 
Summary of Viral Marker Reductions (AAV-HBV Mouse 
Model) 
Treatment 
HBV DNA Reduction (Log) 
HBsAg Reduction (Log) 
Day 14 
Day 42 
Day 84 
Day 14 
Day 42 
Day 84 
RO7020531: 100 mg/kg QOD 
1.2±0.2 
1.9±0.4 
0.2±0.1 
0.6±0.4 
1.6±0.5 
0.4±0.2 
RO7049389: 20 mg/kg QD 
3.5±0.1 
3.8±0.1 
1.5±0.2 
0.0±0.1 
1.5±0.2 
1.9±0.3 
Combination therapy 
3.8±0.1 
4.1±0.1 
3.4±0.5 
0.9±0.5 
3.1±0.3 
3.1±0.3 
Vehicle 
0.0±0.1 
0.0±0.1 
0.0±0.1 
0.0±0.1 
0.0±0.2 
0.0±0.2 
Notes: Day 84 is 42 days post-treatment. Data presented as mean ± SEM (7 mice per group). 
 
Furthermore, the combination of HBV-LNA ASO (a gene expression inhibitor) and TLR7 
agonist (an immune modulator) led to a delayed and reduced off-treatment rebound of 
HBsAg and HBV DNA in AAV-HBV mice than either agent alone (Blaising et al 2019).  

 
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Interim Phase 1 data have shown significant and durable antiviral activity with 4 monthly 
doses of RO7445482 in NUC-suppressed participants with CHB. At Day 112, mean 
HBsAg log10 IU/mL reduction from baseline were 1.39, 1.80 and 1.84 for participants 
who received 1.5 mg/kg, 3.0 mg/kg or 6 mg/kg, respectively. Approximately 80% of 
participants achieved > 1.5 log10 IU/mL reduction (irrespective of HBeAg-status), 60% 
had HBsAg levels < 100 IU/mL, and durability of response was demonstrated up to Day 
392.  
Based on the interim Phase 1 data, RO7445482 was safe and well tolerated in healthy 
volunteers (HV) and CHB patients. The safety profile appears to be similar between HVs 
and patient participants, and there were no safety signals or dose related trends 
identified. No severe or serious treatment-emergent adverse events (TEAEs) or TEAEs 
leading to treatment discontinuation, apart from generally mild injection site reactions 
(ISRs), there was absence of other potential oligonucleotide class effects. 
RO7445482 and RO7020531 separately, have shown acceptable safety/tolerability in 
the Phase 1 studies involving healthy volunteers and CHB participants, and non-clinical 
toxicology and safety pharmacology studies support the proposed 48-week combination 
regimen. 
For details, refer to the RO7445482 and RO7020531 Investigator’s Brochures. 
A12.3 JUSTIFICATION FOR DOSE SPECIFIC TO siRNA+ TLR7 + NUC ARM 
For RO7445482, fixed dose of 200 mg Q4W (equivalent to 3 mg/kg monthly) has been 
selected for Phase 2 study in combination with other IMPs/NMEs. This dose is within the 
anticipated therapeutic dose-range in humans and is expected to be safe and well 
tolerated. A summary of the key data supporting the selected dose is provided below: 
 
The dose-response trend in the HBsAg declines, together with PK/PD modeling of 
interim Phase 1 data, supports the proposed 200 mg Q4W dosing regimen. 
Preliminary PK/PD modeling predicts that the proportion of participants who will 
achieve > 1.5 and > 2 log10 IU/mL reductions in HBsAg, following Q4W doses up to 
Week 12, will be higher with a 200 mg Q4W regimen (97% and 56%, respectively) 
compared to a 100 mg Q4W regimen (89% and 6%, respectively). 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for the 
200 mg Q4W fixed dose (3 mg/kg equivalent) for treatment period of 48 weeks. 
 
PK/PD modelling supports use of fixed (200 mg) instead of weight based (3 mg/kg) 
RO7445482 dosing. 
For RO7020531, a dose of 150 mg QOD has been selected for this Phase 2 study, to be 
administered continuously over two 12-week cycles separated by a 12-week dosing 
holiday (for RO7020531 only). This dose and regimen is within the predicted therapeutic 

 
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dose-range in humans and is expected to be safe and with acceptable tolerability. A 
summary of the key data supporting the selected dose is provided below: 
 
RO7020531 doses up to 170 mg QOD and 150 mg QOD (both for 6 weeks) have 
been observed to be safe and with acceptable tolerability in two Phase 1 studies 
involving healthy volunteers and CHB participants. 
 
Pharmacodynamic effects consistent with TLR7 activation was observed in the 100-
170 mg QOD dose-range, with increasing magnitude of response associated with 
higher doses.  
Further details are provided in the RO7445482 and RO7020531 Investigator’s 
Brochures. 
A12.4 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO siRNA + TLR7 + 
NUC ARM 
Participants must meet the following criterion for inclusion in the siRNA + TLR7 + NUC 
treatment arm: 
Sex 
1. Female Participants:  
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
• 
Woman of non-childbearing potential (WONCBP). 
 
 Woman of childbearing potential (WOCBP), who: 
– 
Agrees to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods, of which at least 1 is 
considered highly effective (result in a failure rate of < 1% per year) 
during the treatment period and for at least 6 months after the final 
dose of study treatment (Appendix 5).  
– 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month during 
treatment and up to 6 months follow-up, thereafter every 3 months until end 
of follow-up.  
 
 

 
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Participants are excluded from the siRNA + TLR7 + NUC arm if any of the following 
criteria apply: 
Weight 
1. 
Body mass index < 21 and weight at screening:  55 kg for men or < 45 kg for 
women  
Medical Conditions 
2. 
Current symptoms of depression or history of depression requiring treatment.  
3. 
History of autoimmune hepatitis or other autoimmune disorders.  
4. 
Diabetes that is not well controlled (HbA1c  7% at screening) 
5. 
Pre-existing ophthalmologic disorders (known history or as assessed by eye 
examination at screening), which in the opinion of the investigator would increase 
the likelihood of clinical significance of potential drug-induced retinopathy (e.g., 
diabetic or hypertensive retinopathy, glaucoma dense cataract, visual field 
abnormalities, severe retinopathy). 
6. 
History of pulmonary disorders including interstitial pneumonitis, bronchiolitis 
obliterans, pulmonary hypertension, and sarcoidosis.  
7. 
History of pancreatitis. 
8. 
Participants with history or present evidence of orthostatic hypotension. 
 
A12.5 SAFETY ASSESSMENTS SPECIFIC TO SIRNA + TLR7 + NUC ARM 
Physical Examinations 
Eye examination will be performed at screening, preferably by an ophthalmologist, and 
will include funduscopic examination with dilation, visual acuity, assessment, visual field 
testing, and color visual testing. 
Vital signs 
Assessment of orthostatic hypotension will be done at screening. To assess the 
presence of orthostatic hypotension, blood pressure will be measured both while the 
participant is sitting and while standing. Participants will be excluded if a drop of 20 
millimeters of mercury (mm Hg) in systolic blood pressure or a drop of 10 mm Hg in 
diastolic blood pressure within 2 to 5 minutes of standing up or if standing causes signs 
and symptoms of hypotension. 

 
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A12.6 LIFESTYLE CONSIDERATIONS SPECIFIC TO siRNA + TLR7 + NUC 
ARM 
RO7020531 will be given in fasted state (at least 2 hours after a meal or 2 hours before 
the next meal). NUCs will be given according to the local prescribing information.  
For RO7020531, consumption of green tea beverages should be minimized during the 
treatment period, as these may inhibit aldehyde oxidase activity (Tayama et al 2011). 
For CHB participants who routinely take herbal medicines that in Investigator’s opinion 
may have immune-modulatory effects, herbal medicines should strongly be discouraged. 
A12.7 CONTRACEPTIVE REQUIREMENTS SPECIFIC TO siRNA + TLR7 + 
NUC ARM 
For WOCBP: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use 2 acceptable contraceptive methods of which at least 1 is considered highly effective 
(see Appendix 5), during the study and for at least 6 months after the last dose of study 
drug.  
 
Examples of acceptable highly effective contraceptive methods (< 1% failure rate 
per year) include combined or progesterone-only hormonal contraception, 
intrauterine device, and vasectomized partner.  
 
Examples of acceptable not as highly effective contraceptive methods (> 1% failure 
rate per year) include progesterone-only hormonal contraception (where inhibition of 
ovulation is not the primary mode of action) and male or female condoms with or 
without spermicide. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree 
to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:  
 
Men must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of study drug to avoid exposing the embryo.  
 
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 

 
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A12.8 TREATMENT ADMINISTERED SPECIFIC TO siRNA + TLR7 + NUC 
ARM 
Appendix 12-Table 2 summarizes the treatments administered. 
Paracetamol/acetaminophen is considered non investigational medicinal products 
(NIMPs). 
Appendix 12-Table 2 
Summary of Treatments Administered for siRNA + TLR7 
+ NUC Treatment Arm 
Study Treatment Name 
siRNA 
(RO7445482) 
TLR7  
(RO7020531) 
NUC 
IMP and NIMP 
IMP 
IMP 
NIMP* 
Dose Formulation 
Sterile colorless to 
yellow solution of 
drug substance 
RO7445482 in water 
for injection 
film-coated tablet 
film-coated tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
120 mg/mL, 2 mL 
filled in a 6 ml vial 
150 mg 
100 mg 
Refer to local 
prescription 
information 
Dose: 
Fixed dose 200 mg 
Q4W 
150 mg QOD 
100 mg QOD 
100 mg QW 
ETV: 0.5 mg OD 
TDF: 300 mg OD 
TAF: 25 mg OD 
Route of Administration 
SC 
oral 
oral 
Sourcing 
Provided centrally by 
the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the study 
site 
Packaging and Labeling 
Study treatment will 
be provided in vials, 
packaged, and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
*NUC are considered IMP in the UK only. 
RO7445482 administrations will be via the SC route utilizing sterile technique. 
RO7445482 doses will be administered at the study clinic preferably in the morning by 
investigational staff.  
The SC administration site (e.g., left abdomen, right abdomen etc.) should be rotated 
between visits.  

 
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Guidelines for dosage modification and treatment interruption/discontinuation are in 
Section A12. (in this Appendix).  
For more details, refer to the RO7445482 and RO7020531 Investigator’s Brochures, 
NUC local prescribing information, and the Pharmacy Manual. 
A12.9  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
RO7020531 
RO7020531 Investigator's Brochure  
RO7445482 
RO7445482 Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A12.10 CONCOMITANT THERAPY SPECIFIC TO siRNA + TLR7 + NUC ARM 
The following concomitant medications are prohibited: 
 
Inhibitors of Organic Anion Transporter 1 and 3 (OAT 1 and OAT 3): e.g., p-
aminohippuric acid (PAH), probenecid, teriflunomide within 7 days, or 5 half-lives 
(whichever is longer) before the first administration of RO7020531 and while on 
study treatment with RO7020531. 
 
Inhibitors of P-gp transporters: e.g., amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil within 7 days, or 5 half-lives (whichever is longer) before the first 
administration of RO7020531 and while on study treatment with RO7020531. 

 
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The following concomitant medications are to be used with caution, and the Sponsor 
should be informed before these drugs are administered. When coadministered with 
study drugs, the recommendation is to use the lowest necessary dose of the substrate, 
titrate the dose carefully, and monitor closely for substrate-associated adverse reactions 
 
Drugs metabolized by aldehyde oxidase including famciclovir and/or inhibiting this 
enzyme including tamoxifen, raloxifen, cimetidine, promethazine, clozapine, and 
chlorpromazine, which could decrease the formation of RO7011785. 
 
Drugs that reduce renal function or compete for active tubular secretion that 
may increase serum concentrations of RO7011785 study drug. 
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication inhibits or induces above mentioned 
enzymes or transporter or renal function. In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications that are not listed above. 
A12.11 MANAGEMENT OF ADVERSE EVENTS SPECIFIC TO siRNA + TLR7 
+ NUC ARM 
TLR-RELATED AES  
TLR7 agonist activates innate and adaptive immune responses, and these mechanisms 
include induction of type I interferon (IFNα). Safety data from the ongoing Phase 1 
studies showed IFN-related flu-like symptoms (headache, pyrexia, chills, myalgia, 
nausea), mostly of mild intensity; and in some participants, hematological abnormalities 
(e.g., neutropenia, lymphopenia). During the two clinical studies with RO7020531 
(NP39305 and YP39553), all hematological abnormalities were asymptomatic and in 
most cases reversible within 24 to 48 hours.  
TLR7 agonists as a class may have the potential, in a dose-dependent manner, to lead 
to hypotension and distributive shock due to excessive cytokine release (cytokine 
release syndrome [CRS])—e.g., IL-1,IL-6,IL-10, IFN-γ, TNF-α etc.—by immune 
activation. CRS can present with a variety of symptoms, from mild symptoms 
overlapping with mild flu-like symptoms to severe or life-threatening manifestations. Mild 
symptoms of CRS include fever, fatigue, headache, rash, arthralgia, and myalgia. More 
severe cases are characterized by hypotension that requires vasopressor treatment 
and/or hypoxia that requires medical intervention. They can progress to an uncontrolled 
systemic inflammatory response with circulatory shock, vascular leakage, disseminated 
intravascular coagulation, and multi–organ-system failure. Flu-like symptoms were 
observed during the two clinical studies with RO7020531 (NP39305 and YP39553) at 
140 mg to 170 mg single or multiple QOD doses up to 6 weeks. These symptoms 
overlap with and are not distinguishable from mild cases of CRS.  

 
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A12.12 ENHANCED SAFETY MONITORING DURING COMBINATION 
TREATMENT WITH SIRNA + TLR7 + NUC ARM 
Based on the emerging data from Phase 1 studies NP39305 (HV and patient cohorts) 
and YP39553 (single– and multiple–ascending-dose clinical study in Chinese HVs), it 
became evident that in all cases of flu-like symptoms, the initial onsets emerged within 
the initial 3 doses of RO7020531. For this reason, pre-dose laboratory analyses and 
optional extended in-hospital stay with frequent vital sign monitoring (every 2 to 4 hours) 
and ECGs (pre-dosing and 6 to 8 hours after dosing at each visit) are scheduled for the 
initial 3 doses of each combination cycle and guided by emerging AEs as follows: 
 
On Day 85 and/or Day 253 (first day of each cycle of TLR7 dosing), participants will 
stay in the clinical unit for 12 hours with an option to stay in the clinic for up to 24 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerge and do not respond to symptomatic treatment 
(paracetamol/acetaminophen up to 2 g/day) during the first 12 hours post-
combination dosing. For those participants who stay up to 24 hours, an additional 24 
hours post-dose laboratory assessment will be done on Day 2 and Day 170, 
respectively.  
 
On Day 87 and Day 255 (third day of each cycle of TLR7 dosing), participants will 
stay in the clinical unit for 8 hours with an option to stay in the clinic for up to 12 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerged and would not respond to symptomatic treatment 
(paracetamol/acetaminophen up to 2 g/day) during the first 8 hours post-
combination dosing.  
 
On Day 89 and Day 257 (fifth day of each cycle of TLR7 dosing), participants will 
stay in the clinical unit for 8 hours with an option to stay in the clinic for up to 12 
hours (at the Investigator’s discretion) in case pyrexia and additional flu-like 
symptom(s) emerged during the first 8 hours and would not respond to symptomatic 
treatment (paracetamol/acetaminophen up to 2 g/day) during the first 8 hours post-
combination dosing.  
The Sponsor will promptly communicate to the Investigator any change to the proposed 
enhanced monitoring plan based on emerging data and interim safety evaluations. In 
case the prolonged hospital stay is not required but participants live far away and may 
need to be back on the following day, the investigator may decide to allow them to stay 
at a hotel nearby. 
The Sponsor will provide participants a thermometer to use for temperature 
self-monitoring in case flu-like symptoms and pyrexia emerge. If at any time during the 
combination cycles (siRNA + TLR7 + NUC) participants experience flu-like symptoms 
with pyrexia (Grade 2 or above), it will be recommended to call the site and the PI or the 
medical personnel on site: 

 
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 
may recommend participants visit the clinic for an unscheduled visit according to the 
SOA in Appendix 12.  
 
may recommend symptomatic treatment with paracetamol/ acetaminophen up to 
2 g/day.  
 
Appendix 12-Figure 2.  
Safety Monitoring and RO7020531 Dosing Interruption for 
Flu-like Symptoms and Cytopenia during Combination 
Treatment with siRNA + TLR7 + NUC 
 
*Based either on central laboratory (as per the SoA in Appendix 12) and/or local 
laboratory if performed for participant management and/or decision-making. In such a 
scenario, if local laboratory tests are performed, an additional sample will be sent to the 
central laboratory, but decisions will be based on local laboratory results.  
 
 

 
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A12.13 DOSE MODIFICATION 
Dose reduction to 100 mg QOD with RO7020531 for intolerability associated with 
adverse events should be considered by the Investigator during the treatment phase in 
the following situations:   
 
Grade 3 (severe) TLR7 agonist-related AEs of flu-like symptoms that 
persist > 24 hours despite prophylactic and/or symptomatic treatment with 
acetaminophen (paracetamol)  
 
Grade 3 (severe) hematological (e.g., cytopenia) laboratory abnormalities that 
persist for > 48 hours 
 
TLR7 agonist-related SAE 
 
Flu-like symptoms that are not tolerated 
In the above situations, RO7020531 150 mg QOD dosing should be interrupted until 
AEs, laboratory abnormalities, or SAEs improve to Grade 1 or less, before initiating a 
dose reduction to RO7020531 100 mg QOD.  
For repetitive/recurrent flu-like symptoms/pyrexia (either responsive or unresponsive 
despite symptomatic treatment with acetaminophen or poorly manageable despite 
prophylactic treatment with acetaminophen) or other TLR7 agonist-related AEs 
(including repetitive AEs) which are not well manageable, the Investigator in discussion 
with the participant should consider a RO7020531 dose reduction to 100 mg QOD. The 
Medical Monitor is available to the PI to answer any medical questions. 
Following the RO7020531 dose reduction to 100 mg QOD, the Investigator should 
interrupt RO7020531 dosing if any of the following situations occur: 
 
Grade 3 (severe) TLR7 agonist-related AEs of flu-like symptoms that persist 
for > 24 hours despite prophylactic and/or symptomatic treatment with 
acetaminophen (paracetamol)  
 
Grade 3 (severe) hematological (e.g., cytopenia) laboratory abnormalities that 
persist for > 48 hours 
 
TLR7 agonist-related SAE 
 
Following the RO7020531 dose reduction to 100 mg QOD, if flu-like symptoms are still 
not tolerated by the participants, a reduction of the dosing frequency of RO7020531 to 
100 mg QW (once a week) should be considered. 
Appendix 12-Table 3 summarizes the dose interruption/modification/discontinuation 
guidelines for the siRNA+TLR7+NUC combination arm.  

 
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Appendix 12-Table 3. 
Dose Interruption/Modification/Discontinuation 
Guidelines for the siRNA+TLR7+NUC Combination Arm 
 
In general, when addressing tolerability issues with RO7020531, prior to the investigator 
making a decision to discontinue study treatment or participant withdrawal of consent 
from study treatment, a dose reduction should be discussed and evaluated if considered 
in the participant’s best interest. The Medical Monitor is available to the Investigator to 
answer any medical questions. 
The first dose of RO7020531 100 mg QOD should be administered in the clinic, and 
participants should be monitored for at least 8 hours as per SoA (with pre-dose safety 
laboratory assessment, every 2 to 4 hours for vital signs, and ECG assessment at pre-
dose and 6 to 8 hours post-dose). This first visit should be synchronized with the 
participant’s current RO7020531 QOD dosing schedule. 
In case participants are changed to 100 mg QW dosing, at least 5 days should have 
elapsed since the last dose. If Grade 2 flu-like symptoms occur, the Investigator may 
recommend symptomatic treatment with paracetamol/ acetaminophen. If symptoms 
respond to symptomatic treatment and the treatment is tolerable, participants will 
continue QW dosing. If there is poor tolerability, participants will permanently discontinue 
further RO7020531 dosing. Participants changed to the QW dosing will follow the same 
SOA of participants in the QOD dosage, with two 12-week combination treatment cycles 
(Weeks 13 to 25 and 37 to 49) and a 12-week holiday period in between. 
Participants who change to 100 mg QW dosing or discontinue because of non-safety 
reasons may be replaced at the sponsor’s discretion. This is to ensure the number per 
arm of the randomized QOD dose regimen remains close to the planned 30 participants.  

 
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Participants on RO7020531 100 mg QOD will follow the SoA as included in Appendix 
12. In case of RO7020531 100 mg QW dosing, participants will follow the SoA as 
included in Appendix 12, but QW dosing administration will be aligned with SoA visits.  
For ALT elevations, refer to Section 8.3.8.3. 
A12.14 PHARMACODYNAMICS AND BIOMARKERS ANALYSES SPECIFIC 
TO siRNA + TLR7 + NUC ARM 
A12.14.1 
TLR7 ACTIVITY BIOMARKERS  
TLR7 is expressed on human pDC and B-cells, and its activation induces both humoral 
and cellular changes (Iwasaki and Medzhitov 2004, Lester and Li 2014). These changes 
include the production of cytokines and chemokines such as IFN- α, IL-6, TNF-α, IL-10, 
IL-12p40, IP-10, and changes in the expression of ISGs, e.g., ISG15, OAS-1 and 
myxovirus resistance 1 gene (MX1) and of the TLR7 gene itself (Fidock et al 2011), as 
well as changes in markers of immune stimulation such as neopterin. 
To characterize TLR7 PD biomarkers (secondary objective), blood samples will be 
collected at time points according to the SoA (see Appendix 12-Table 4 and Appendix 
12-Table 5) to measure cytokines including INF-α, IP-10, IL-6 and TNF-α as well as a 
panel of transcriptional response of Interferon Stimulated Genes (ISG15, OAS1, MX1, 
and TLR7) if appropriate. Following review of these PD biomarkers and the AEs, further 
cytokines may be tested using a separate aliquot collected at the same time points 
including, IL-1, IL-10, and IFN-γ. 
A12.14.2 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the two NMEs and with primary and secondary endpoints. Known 
candidate genes of interest that are specific to siRNA/TLR7 include AOX1, TLR7, 
UGT1A1, and ASGR1. Further genes may be queried from the data based on 
progressing knowledge on these NMEs and their targets. 
A12.15 SCHEDULE OF ACTIVITIES siRNA + TLR7 + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 12-Table 4 and 
Appendix 12-Table 5.  
 

 
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Appendix 12-Table 4 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR ET/UV v 
Week 
 
 
1 
3 
5 
9 
13 o, q 
17 
21 
25p,q 
29 
33 
37 
41 
45 
49q 
 
- 
- 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±1 ) 
+2 s 
+2 s 
113 
(±3) 
141 
(±3) 
169 
(-5r) 
197 
(±3) 
225 
(±3) 
253 
(±2) 
+2 s 
+2 s 281 
(±3) 
309 
(±3) 
337 
(-6r) 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical 
history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital 
signs a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ophthalmic Exam a 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
x t 
x t 
x t 
x 
x  
x 
x 
x 
xt 
x t 
x t 
x 
x 
x 
x t 
 
 
Transient 
elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse 
screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Pregnancy test f 
 
x 
x 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
Hematology (includes 
HbA1c)g 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

 
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Appendix 12-Table 4 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR ET/UV v 
Week 
 
 
1 
3 
5 
9 
13 o, q 
17 
21 
25p,q 
29 
33 
37 
41 
45 
49q 
 
- 
- 
Day 
-56 to 
-7 
-14 
to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 85 (±1) +2 s 
+2 s 
113 
(±3) 
141 
(±3) 
169 
(-5r) 
197 
(±3) 
225 
(±3) 
253 
(±3) +2 s 
+2 s 281 
(±3) 
309 
(±3) 
337 
(-6r) 
 
 
 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, 
HBeAg, anti-HBs, anti-
HBe) 
x 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
x 
x 
HBV DNA quantitative 
x 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
x 
x 
Total HBsAg i 
 
 
x 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
HBcrAg 
 
 
x 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
Total anti-HBc 
quantitative 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
HBV RNA quantitative 
 
 
x 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (TLR7) k 
 
 
 
 
 
 
x 
x 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
x 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
 
x 
x 
 
 
 
x 
 
 
x 
x 
 
 
 
x 
 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
Plasma ADA (siRNA)w 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
x 

 
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Appendix 12-Table 4 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
 
Screening 
Treatment Period 
100 
mg 
QOD u 
VB/VR ET/UV v 
Week 
 
 
1 
3 
5 
9 
13 o, q 
17 
21 
25p,q 
29 
33 
37 
41 
45 
49q 
 
- 
- 
Day 
-56 to 
-7 
-14 to 
-7 
1 
15 
(±2) 
29 
(±3) 
57 
(±3) 
85 
(±1) 
+2 s 
+2 s 
113 
(±3) 
141 
(±3) 
169 
(-5r) 
197 
(±3) 
225 
(±3) 
253 
(±3) +2 s 
+2 s 281 
(±3) 
309 
(±3) 
337 
(-6r ) 
 
 
 
24 hour pooled urine 
PKx (siRNA) 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
Cytokine panel l 
 
 
x 
 
 
 
x 
x 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
x 
 
x 
ISG panel l 
 
 
x 
 
 
 
x 
x 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
x 
 
x 
RBR m 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
 
Clinic siRNA 200mg sc 
Q4W treatment 
administration  
 
 
x 
 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
 
TLR7 treatment 
administration QOD 
 
 
 
 
 
 
x 
 
 
x 
 
 
 
NUC treatment 
administration OD 
 
 
x 
 
 
 
Adverse events & 
concomitant 
medications & dairy 
review n 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibody; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early termination; 
GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = hepatitis B core-related antigen; HBeAg = 
hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IFN- α+ interferon alpha; IP-10 = interferon 
gamma-induced protein 10; ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide analogue; PK = 
pharmacokinetics;  

 
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Appendix 12-Table 4 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
RBR = Research Biosample Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; TLR = toll-like receptor; Total HBsAg = 
post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 13, 25, 37, and 49. Eye examination (including fundoscopy) only at 
screening. 
b Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
Orthostatic hypotension test only at screening. Vital signs assessments on Days 85 and 253: predose, 2-4 hours, 4-6 hours, 6-8 hours and 8-12 
hours; Vital signs assessments on day of the second and third RO7020531 dose of the first cycle , on the first day of those switching to QW 
dosing, and on the days of the second and third RO7020531 dose in the second cycle: predose, 2-4 hours, 4-6 hours, 6-8 hours (and 8-12 hours 
optional in case of extended in-clinic stay). 
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR/2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures.  
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology, and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse, blood sample to be collected up to 6 times. 
k Plasma PK samples for TLR7 to be collected at pre-dose, 1-3 and 4-6 hours post-dose. Plasma PK samples for NUC to be collected at pre-dose. 
Plasma PK samples for siRNA D85 and D253 at pre-dose, 1, 2, 4, 6, 8 and 48 hours post-dose; For D1, D169 and D337 to be collected at pre-
dose, 1-3 and 4-6 hours post-dose. During the PK assessments for VB/VR visits, only one pre-dose sample is required for collection, no other 
points required. 

 
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Appendix 12-Table 4 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Screening and Treatment Periods) 
(cont.) 
l Cytokine panel (INF-α, IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α) and ISG panel to be collected at pre-dose and 6 hours post-dose of TLR7. On 
Day 1, only a pre-dose cytokine and ISG panels should be collected. At an unscheduled visit or early termination visit, preferably a pre-dose, 
otherwise, just a sample for cytokine and ISG panels should be collected if the visit is linked to a TLR7 related adverse reaction (e.g., influenza-
like symptoms). No samples are required, for unscheduled visit or early termination visit not linked to TLR7 related adverse reaction (e.g., 
influenza-like symptoms). 
m RBR samples collected only from RBR-consenting participants.  
n Pre-treatment, only serious adverse events should be reported. 
o End-of-treatment visit for participants in the 12-week finite treatment arm (if commenced after an interim analysis). 
p End-of-treatment visit for participants in the 24-week finite treatment arm (if commenced after an interim analysis). 
q End-of-treatment visit for participants with HBsAg loss in the 48-week response-guided therapy arm (if commenced after an interim analysis).  
r visit will be on dosing days for PK and PD sampling: -7 if the patient is on QW dosing. 
s Not applicable to participants who switched to QW RO7020531 dosing. 
t ECGs to be assessed predose and 6-8hrs post-dose on the first 3 doses of each 12-week RO7020531 cycle and on first dose if 100 mg QOD 
dosing is started. 
u For patients who move from 150 mg QOD to 100 mg QOD, this first dose of 100 mg QOD should be administered in the clinic and should be 
synchronized with the patients’ current RO7020531 QOD dosing schedule e.g., if the next current QOD dosing falls over the weekend, then it 
would be acceptable to miss doses for the first dose visit to take place outside the weekend. 
v Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
w Pre-dose plasma ADA sample. 
x Timed urine collected for PK analyses of siRNA concentration and potential drug metabolites (if feasible). Participants will have provided a urine sample for 
safety analysis predose (urinalysis) and should then have an empty bladder. The 24 hours pooled (0-24 hours) urine collection to commence with first void and 
following siRNA administration and up to 24 hours post dose.  

 
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Appendix 12-Table 5 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Follow-up Period) 
 
Follow-up period 
VB/VR 
 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24j 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitativek 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg e 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (TLR7)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 12-Table 5 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Follow-up Period) (cont.) 
Follow-up period 
VB/VR 
ET/UVi 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24j 
36 
48 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
Plasma PK (siRNA)  
Plasma PK (NUC) f 
x 
Plasma ADA (siRNA) 
x 
x 
x 
x 
x 
x 
RBR g 
x 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibody; ARFI = acoustic radiation force impulse; CpAM = Core protein allosteric modulator; DNA = deoxyribonucleic acid; ECG = 
electrocardiogram; ET=early termination; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = 
hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IP-
10 = interferon gamma-induced protein 10; ISG = interferon-stimulated genes; MR = magnetic resonance; NUC = nucleos(t)ide analogue; PK = 
pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; TLR = toll-like 
receptor; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = 
unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits should be scheduled with a frequency of every 2 weeks for the first three 
months and every 4 weeks up to week 48 of follow-up period. 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated 
b Blood pressure, pulse rate, respiratory rate and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 12-Table 5 
Schedule of Activities for siRNA + TLR7 + NUC Treatment Arm (Follow-up Period) (cont.) 
f During the PK assessments for VB/VR visits, only one sample is required for collection, no other time points required. Pre-dose if on NUC therapy. 
g RBR samples collected only from RBR-consenting participants.  
h Pre-treatment, only serious adverse events should be reported. 
i Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
j Visit window may be extended to +6 weeks in extreme circumstances such as pandemic, natural disasters, supply chain disruption, outbreak of hostilities. 
k Participants with HBV DNA > 2,000 IU/mL during the follow-up period will undergo weekly monitoring. Participants with HBV DNA >20 IU/mL but 
< 2,000 IU/mL, should undergo monitoring every two weeks. Participants, who have discontinued NUC therapy, should have monthly visits from follow up Week 
24 to Week 48, instead of the 3 monthly follow up visits shown in SoA, which are relevant for participants on NUC therapy, to enable early detection and appropriate 
management of HBV DNA rebound. At these additional unscheduled monitoring visits, the following laboratory assessments should be performed using the 
unscheduled lab kit: hematology, chemistry, coagulation, GLDH, urinalysis, HBV serology, HBV DNA quantitative, total HBsAg, HBcrAg, and HBV RNA 
quantitative.  
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 13 
Study Details Specific to siRNA (RO7445482) + PD-L1 LNA 
(RO7191863) + NUC Arms 
An overview of short interfering RNA (siRNA) + programmed death ligand-1 locked 
nucleic acid (PD-L1 LNA) + nucleos(t)ide (NUC) treatment arms is shown in 
Appendix 13-Figure 1.  
Participants will receive RO7445482 (also known as DCR-HBVS; 200 mg every 4 weeks 
[Q4W]) and RO7191863
in addition to their background 
NUC therapy in one of two treatment arms that will run in parallel.  
 
One treatment arm will evaluate a 24-week treatment duration where 
RO7445482 (200 mg Q4W) will be given during Weeks 1-24 and RO7191863 
 will be given during Weeks 13-24.  
 
A second treatment arm will evaluate a 36-week treatment duration where 
RO7445482 (200 mg Q4W) will be given during Weeks 1-24 and RO7191863 
will be given during Weeks 25-36.  
In both treatment arms, participants will receive their background NUC therapy for the 
duration of study treatment. At the end of the treatment period, participants will continue 
NUC treatment during the follow-up unless the NUC discontinuation criteria have been 
met (see Section 6.8).  
Approximately 30 participants will be randomized to each treatment arm.  
If a 30% delta for hepatitis B surface antigen (HBsAg) loss is observed at end-of-
treatment (EOT) or follow-up Weeks 12 or 24 (primary endpoint) the treatment arm may 
be expanded to accrue additional efficacy and safety data, and to contribute to Phase 3 
design planning.  

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 13-Figure 1 
siRNA + PD-L1 LNA + NUC Treatment Arms  
24-Week Concurrent Treatment Arm 
 
36-Week Sequential Treatment Arm 
 
A13.1 BACKGROUND SPECIFIC TO siRNA + PD-L1 LNA + NUC ARM 
A13.1.1 
BACKGROUND ON RO7445482 
RO7445482 (DCR-HBVS) is a short interfering RNA (siRNA) conjugated to N-acetyl-D-
galactosamine (GalNAc), which enables liver-targeting through binding to the 
asialoglycoprotein receptor (ASGPR) that is highly expressed in the liver. After forming 
the RNA-induced silencing complex (RISC), the RO7445482 antisense strand targets 
HBV RNA for degradation by triggering RNAi-mediated cleavage within the HBV surface 
coding sequence, thereby inhibiting HBV gene expression.  
Literature indicates that hepatitis B virus (HBV) antigens suppress the host immune 
response through several pathways, including the direct effects of long-term exposure to 
high concentration of viral antigens resulting in T-cell immune tolerance and T-cell 
exhaustion (Hai-Jun et al 2015). Depletion of viral antigens through inhibition of HBV 
gene expression may therefore facilitate the restoration of the host immune response. 

 
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Non-clinical studies with RO7445482 have shown potent antiviral activity. HBsAg 
reductions of up to 3.5 log10 for more than 7 weeks, as well as significant reductions in 
HBcAg, were observed after a single dose in mice, demonstrating duration of action 
suitable for infrequent dosing. 
To date, clinical experience with RO7445482 is based on a Phase I clinical study (DCR-
HBVS-101) involving healthy volunteers and participants with chronic hepatitis B (CHB) 
infection. 
A13.1.2 
BACKGROUND ON RO7191863 
RO7191863 is a locked nucleic acid (LNA) antisense oligonucleotide (ASO) that induces 
RNAse H-mediated intracellular degradation of the messenger RNA (mRNA) encoding 
the host protein programmed death ligand-1 (PD-L1). In patients with CHB, increased 
expression of PD-L1 has been demonstrated on hepatocytes and non-parenchymal liver 
cells (NPLCs) including intra-hepatic antigen presenting cells (Chen et al 2011). 
RO7191863 is expected to result in the targeted inhibition of PD-L1 expression in the 
liver by conjugation of the LNA ASO with GalNAc. This mediates specific uptake by 
hepatocytes through engagement of the ASGPR, which is expressed predominantly by 
hepatocytes, with low to no expression in other cell types. (Stockert 1995; Zelensky et al 
2005; Gupta 2012). To a lesser extent, uptake is also expected to occur in NPLCs based 
on non-clinical in vivo data.  
Non-clinical in vivo data indicate that the inhibition of PD-L1 expression with GalNAc-
conjugated PD-L1 LNA results in the intra-hepatic expansion of immune cells, induction 
of HBV-specific immune responses in the liver (which are proposed to include CD8 T-
lymphocyte–mediated cytotoxic activity and cytokine release), and concomitant antiviral 
responses measurable in blood, including a decline of hepatitis B surface antigen, 
hepatitis B e antigen (HBeAg), and HBV DNA, which is sustained for several weeks off 
treatment.  
To date, clinical experience with RO7191863 includes a Phase 1 entry-into-human study 
in CHB participants (NP40479). 
A13.2 BENEFIT/RISK ASSESSMENT SPECIFIC TO siRNA+ PD-L1 LNA + 
NUC ARM 
The 24-week and 36-week treatment with RO7445482 and RO7191863, in combination 
with ongoing nucleos(t)ide analogue (NUC) treatment, aims to result in therapeutic 
benefit for participants by achieving higher functional cure rates (HBsAg loss) than 
observed currently with standard-of-care therapies (NUC or pegylated interferon-alpha 
[PEG-IFNa]). The administration of RO7445482 and RO7191863 in combination aims to 
test the scientific hypothesis that concurrent or sequential administration of a direct-

 
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214/Protocol WV41073, Version 7.0 
acting antiviral agent that reduces HBV antigen load and an immunomodulatory agent 
that counteracts immune-inhibition will synergistically maximize efficacy outcomes. The 
potency of the immunomodulatory agent is expected to increase if the immunomodulator 
is administered during and/or following a reduction in HBV antigen load including 
HBsAg. Thus, reduction in HBV antigen load with RO7445482 is anticipated to enable 
the optimal activity of RO7191863.  
This concept is supported by in vivo preliminary data generated in AAV-HBV mice in a new 
pilot study. The combination therapy showed synergistic effects of PD-L1 (mouse surrogate 
RTR20187, 5 weekly doses) when administered 1 week after HBV siRNA (RTR129313, tool 
compound, single dose) on HBsAg (Appendix 13-Figure 2 and Appendix 13-Table 1), HBeAg 
(Appendix 13-Figure 3 and Appendix 13-Table 2) and HBV DNA (Appendix 13-Figure 4 and 
Appendix 13-Table 3) levels (up to additional 1, 0.9 and 1.8 log drop respectively), compared to 
siRNA treatment alone 8 weeks after the last dose. The synergistic effect was maintained for up to 
9 weeks after the last dose suggesting a transformational efficacy impact with the direct-acting 
antiviral and immunomodulatory agent combination therapy. No safety findings were observed 
during the in-life phase (no body weight loss, no clinical signs, no mortality). Another efficacy 
study is currently ongoing to confirm these results and includes additional safety parameters in 
the serum to evaluate liver and kidney functional markers (blood chemistry panel for AST, ALP, 
GGT, BUN, total protein, albumin, creatinine, K+, P, and Ca2+). 
The sustained antiviral response may be associated with the recovery of the antigen specific 
immune response as demonstrated in another study where  mice receiving 5 weekly  doses of 
RTR20187 and showed an increased number of intrahepatic liver immune cells (primarily B- and 
T-lymphocytes, natural killer (NK) cells and antigen presenting cells) observed 1 week after the 
last dose (Day 35), together with an increase of IFN-gamma responses to stimulation of total liver 
immune cells with HBV surface and core peptide pools. No significant Interferon (IFN)-gamma 
responses were measured in non-infected mice treated with RTR20187 (RDR No. 1089260) 
(Appendix 13-Table 4). 
 

 
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Appendix 13-Table 4 
IFN-gamma Response to HBV Surface and Core Overlapping 
Peptide Pools of Liver Immune Cells Isolated from AAV 
HBV Mice After 5 Weekly Doses of Either RTR20187 at 
5mg/kg or Vehicle Control (at Day 35, 1 week after last dose) 
 
Vehicle 
PD-L1 LNA (Mouse RTR29187) 
mean (SFU) 
SEM 
N 
mean (SFU) 
SEM 
N 
HBs peptides 
9.2 
3.54 
8 
372.94 
114.61 
8 
HBc peptides 
40.43 
7.87 
8 
179.64 
60.31 
8 
HBs + HBc 
peptides 
15.62 
5.76 
8 
396.72 
142.43 
8 
SFU: spot forming unit 
Sem: standard error of mean 
N: number of mice 
 
For RO7445482, interim Phase 1 data have shown significant and durable antiviral 
activity with 4 monthly SC doses in NUC-suppressed participants with CHB. At Day 112, 
mean HBsAg log10 IU/mL reductions from baseline were 1.39, 1.80, and 1.84 for 
participants who received 1.5 mg/kg, 3.0 mg/kg, or 6 mg/kg, respectively. Approximately 
80% of participants achieved > 1.5 log10 IU/mL reduction (irrespective of HBeAg-status), 
60% had HBsAg levels < 100 IU/mL, and durability of response was demonstrated up to 
Day 392.  
Based on interim Phase 1 data, RO7445482 was safe and well tolerated in healthy 
volunteers (HV) and CHB patients. The safety profile appears to be similar between HVs 
and patient participants, and there were no safety signals or dose-related trends 
identified. No severe or serious treatment-emergent adverse events (TEAEs) or TEAEs 
leading to treatment discontinuation were reported. Apart from generally mild injection 
site reactions (ISRs), there were no other potential oligonucleotide class effects. 
For RO7191863, interim Phase 1 data have shown significant antiviral activity in 
NUC-suppressed participants with CHB, with an exposure-response relationship. At the highest 
dosing regimen explored
, the mean maximum HBsAg reduction from 
baseline was 0.5 log10 IU/mL. Approximately 43% of participants (3 out of 7) achieved marked 
declines in HBsAg in the range of 0.9 - 1.1 log10 IU/mL reduction from baseline. 
Based on the interim Phase 1 data, RO7191863 was safe in CHB patients with an overall 
acceptable tolerability profile. No serious or immune-related adverse events (AEs) were 
observed and there was no evidence of potential oligonucleotide class effects (e.g., renal 
toxicity events). An exposure-response relationship with ALT elevations was evident, which is 
consistent with the RO7191863 mechanism of action and anticipated effects of checkpoint 
inhibition on the restoration of a HBV-specific immune response. The ALT elevations 
predominantly occurred 
, were mostly 
low grade <5x ULN and often associated with concurrent decline in HBsAg, and all cases showed 

 
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preserved hepatic function. In consideration of the data available from the Phase 1 study, further 
PK/PD modeling was carried out to select an optimal dose, as discussed in Section  A13.3.  
RO7445482 and RO7191863 separately, have shown acceptable safety and tolerability 
in the Phase 1 studies involving healthy volunteers and/or CHB participants, and 
non-clinical toxicology and safety pharmacology studies support the proposed 24 and 
36-week combination regimens.  
For details, refer to the RO7445482 and RO7191863 Investigator’s Brochures, and the 
RO7191863 Interim Data Memo. 
A13.3 JUSTIFICATION FOR DOSE SPECIFIC TO siRNA+ PD-L1 LNA + NUC 
ARM 
For RO7445482, the fixed dose of 200 mg SC (equivalent to 3.0 mg/kg) Q4W has been 
selected for Phase 2 study in combination with other IMPs/NMEs. This dose is within the 
anticipated therapeutic dose-range in humans and is expected to be safe and well 
tolerated. A summary of the key data supporting the selected dose is provided below: 
 
The dose-response trend in the HBsAg declines, together with pharmacokinetic 
(PK)/pharmacodynamic (PD) modeling of interim Phase 1 data, supports the 
proposed 200 mg Q4W dosing regimen. Preliminary PK/PD modeling predicts that 
the proportion of participants who will achieve > 1.5 and > 2 log10 IU/mL reductions 
in HBsAg, following Q4W doses up to Week 12, will be higher with a 200 mg Q4W 
regimen (97% and 56%, respectively) compared to a 100 mg Q4W regimen (89% 
and 6%, respectively). 
 
The non-clinical chronic toxicology studies provide acceptable safety margins for the 
200 mg Q4W fixed dose for a treatment period of 48 weeks.  
 
PK/PD modelling supports use of fixed (200 mg) instead of weight based (3.0 
mg/kg) RO7445482 dosing. 
 
For RO7191863, a dose of 
 SC 
 has been selected for this Phase 2 study, 
to be administered over 12 weeks. This dose and regimen are predicted to be 
efficacious in humans and is expected to be safe and with acceptable tolerability. A 
summary of the key data supporting the selected dose is provided below: 
 
The non-clinical toxicology studies of RO7191863 support
for a 
treatment period of 12 weeks.  
 
RO7191863 doses
for 12 weeks have been observed to be safe and with 
acceptable tolerability in the Phase 1 study. Low-grade transient ALT elevations were 
frequent at the highest dosing regimen. 

 
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 
The exposure-response trends in HBsAg declines as well as ALT elevation, together with 
PK/PD modeling supports 
 for 12 weeks.  
o 
PopPK modeling predicts that
is expected to result in 
a 34% reduction in the mean cumulative liver AUC compared to the 
 
, which is anticipated to meaningfully reduce ALT liability without 
overtly impacting the HBsAg response. 
o 
PK/PD modeling predicts that the 
 will result in a 
clinically meaningful reduction in the proportion of subjects that exceed the 
ALT >5x ULN threshold compared to the 
 (~11% vs 
~17%). 
In the 24-week concurrent treatment arm where administration between RO7445482 and 
RO7191863 overlaps and dosing days coincide, RO7191863 will be administered first, 
followed by RO7445482. RO7445482 should be administered no earlier than 24 hours 
after RO7191863 and no later than 48 hours prior to the subsequent dose of 
RO7191863 to avoid any potential competition between both drugs for ASGPR-mediated 
drug uptake.  
Further details are provided in the RO7445482 and RO7191863 Investigator’s 
Brochures, and the RO7191863 Interim Data Memo. 
A13.4 INCLUSION/EXCLUSION CRITERIA SPECIFIC TO siRNA + PD-L1 LNA 
+ NUC ARM 
Participants must meet the following criterion for inclusion in the siRNA + PD-L1 LNA + 
NUC treatment arm: 
Sex 
1. Male and Female Participants:  
a. Female Participants 
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
• 
Woman of non-childbearing potential (WONCBP). 
 
 Woman of childbearing potential (WOCBP), who: 
 
- 
Agrees to remain abstinent (refrain from heterosexual intercourse) or 
use two acceptable contraceptive methods, of which at least one is considered 
highly effective (result in a failure rate of < 1% per year) before, during 
the treatment period, and for at least 6 months after the final dose of 
study treatment (see Appendix 5). 

 
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▪ 
Hormonal contraception must be in use at least 30 days prior to 
first study drug administration, and 
▪ 
Barrier methods must be in use for at least 14 days prior to first 
study drug administration. 
▪ 
A vasectomized partner must have had the vasectomy at least 
3 months prior to the first study drug administration or there 
must be confirmation of a zero sperm count.  
- 
Has a negative pregnancy test at screening (Day -14 to -7). In addition, 
willing to undergo a urine pregnancy test at Day 1 and every month 
during treatment and up to 6 months follow-up, thereafter every 3 months 
until end of follow-up.  
b. Male Participants 
During the treatment period and for at least 6 months after the final dose of 
study treatment, agree to:  
 
Remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures such as a condom plus an additional contraceptive 
method that together result in a failure rate of < 1% per year, with a partner 
who is a woman of childbearing potential (WOCBP). For a vasectomy to be 
considered a highly effective contraceptive method it must have been 
performed 3 months before first study drug administration or there must be 
confirmation of a zero sperm count. 
 
With pregnant female partner, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo. 
 
Refrain from donating sperm. 
 
Participants are excluded from the siRNA + PD-L1 LNA + NUC arm if any of the 
following criteria apply: 
Medical Conditions 
1. 
History and/or evidence of autoimmune hepatitis or other autoimmune disorders. 
 
 

 
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A13.5 LIFESTYLE CONSIDERATIONS SPECIFIC TO siRNA + PD-L1 LNA + 
NUC ARM 
NUCs will be given according to the local prescribing information.  
For CHB participants who routinely take herbal medicines that in Investigator’s opinion 
may have immune-modulatory effects, herbal medicines should strongly be discouraged. 
A13.6 CONTRACEPTIVE REQUIREMENTS SPECIFIC TO siRNA + PD-L1 
LNA + NUC ARM 
See Appendix 13-Section 13.4. 
A13.7 TREATMENT ADMINISTERED SPECIFIC TO siRNA + PD-L1 LNA + 
NUC ARM 
Appendix 13-Table 5 summarizes the treatments administered. 

 
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Appendix 13-Table 5 
Summary of Treatments Administered for siRNA + PD-
L1 LNA + NUC Treatment Arm 
Study Treatment Name 
siRNA 
(RO7445482) 
PD-L1 LNA  
(RO7191863) 
NUC 
IMP and NIMP 
IMP 
IMP 
NIMP* 
Dose Formulation 
Sterile colorless to 
yellow solution of 
drug substance 
RO7445482 in water 
for injection 
Yellow, brownish 
yellow or greenish 
sterile liquid 
Film-coated tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
120 mg/mL, 2 mL 
filled in a 6 ml vial 
Refer to local 
prescription 
information 
Dose: 
Fixed dose 200 mg 
Q4W 
ETV: 0.5 mg OD or 
TDF: 300 mg OD or 
TAF: 25 mg OD 
Route of Administration 
SC 
SC 
oral 
Sourcing 
Provided centrally by 
the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor or 
locally by the study 
site 
Packaging and Labeling 
Study treatment will 
be provided in vials, 
packaged, and 
labeled as required 
per local regulation. 
Study treatment will 
be provided in vials, 
packaged, and 
labeled as required 
per local regulation. 
Study treatment will 
be packaged and 
labeled as required 
per local regulation. 
*NUC are considered IMP in the UK only. 
RO7191863 and RO7445482 administrations will be via the SC route utilizing sterile 
technique. RO7191863 and RO7445482 should be administered at the study clinic 
preferably in the morning by investigational staff. On weeks where dosing of RO7191863 
and RO7445482 overlap (Weeks 13, 17, and 21), RO7191863 must be administered 
first, and RO7445482 can be administered no earlier than 24 hours after dosing of 
RO7191863. RO7445482 dose can be administered on a different day that week, but no 
later than 48 hours before the next planned dose of RO7191863 (see Appendix 13-
Table 7, Appendix 13-Table 8, and Appendix 13-Table 9).  
The SC administration site (e.g., left abdomen, right abdomen etc.) should be rotated 
between visits and different sites should be used for administration of RO7191863 and 
RO7445482 (on weeks where dosing overlaps).  

 
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Guidelines for dosage modification and treatment interruption/discontinuation are in 
Section A13.9.  
For more details, refer to the RO7445482 and RO7191863 Investigators Brochures, 
NUC local prescribing information, and the Pharmacy Manual. 
A13.8  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-serious AESIs against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
RO7191863 
RO7191863 Investigator's Brochure  
RO7445482 
RO7445482 Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A13.9  DOSE MODIFICATION 
Appendix 13-Table 6 summarizes the dose interruption/discontinuation guidelines for the 
siRNA+PD-L1 LNA+NUC combination arm.  

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
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Appendix 13-Table 6 
Dose Interruption/Discontinuation Guidelines for 
siRNA+PD-L1 LNA+NUC Combination Arm 
 
 
A13.10 PHARMACOKINETICS ANALYSES SPECIFIC TO siRNA + PD-L1 
LNA + NUC ARM 
 A13.10.1  
OPTIONAL LIVER BIOPSY SUB-STUDY 
At one or more selected sites with established expertise, participants may be offered to 
participate in a liver biopsy sub-study, which will involve collection of a liver biopsy 
sample. This procedure will be performed at the end of the treatment. Liver biopsy tissue 
will be used to measure intra-hepatic RO7445482 and RO7191863 exposure levels 
(including metabolites, if applicable). Participation in the liver biopsy sub-study will 
require a separate consent and will involve a select number of participants. 
For further details, refer to the study operations manual. 
A13.11 BIOMARKER ANALYSES SPECIFIC TO siRNA + PD-L1 LNA + NUC 
ARM 
A13.11.1 
SAFETY BIOMARKERS  
Blood samples will be collected during the course of the study for the analysis of 
exploratory liver safety biomarkers (see Appendix 13-Table 8, and Appendix 13-Table 9) 
given a potential safety risk of LNA ASOs and of RO7191863 is hepatic injury. The 
standard liver injury markers (ALT and AST) have several limitations in terms of 
specificity (e.g., AST is not liver-specific), sensitivity (the rise in ALT and AST indicates 
that liver injury has already occurred), and prognostic value (the magnitude of the ALT 
elevation does not predict the patient’s subsequent course). This study will evaluate 
several emerging liver injury biomarkers (e.g., GLDH, MCSFR1, OPN, CK-18, ccK-18, 
and total HMGB1) that may complement ALT and AST and standard measures of liver 
function for the early detection of liver injury. Due to the exploratory nature of the tests, 
the results will only be analyzed retrospectively and will not be used for decision making. 

 
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This information may provide an improved understanding of the safety profile of 
RO7191863 and of the association between ALT increases and PD activity. 
A13.11.2 
PD-L1 ACTIVITY BIOMARKERS  
The PD biomarker assessment plan specific for PD-L1-LNA comprises measures of 
target engagement, antiviral activity, and immunity. 
In addition to virological assessments described in Section 8.1, levels of soluble PD-L1 
will be monitored in plasma as an alternative potential readout of target engagement 
and/or PD effects, based on preliminary data from the Phase 1 study NP40479.  
Targeting the PD-1/PD-L1 inhibitory pathway is proposed to restore HBV-specific T-cell 
immunity at the site of infection. It is currently unclear whether this will translate into 
measurable HBV specific immune responses in peripheral blood at some time during or 
after the end of dosing. HBV-specific cellular immune function will be explored ex-vivo 
using cryopreserved PBMC collected at timepoints indicated in the SoA (see 
Appendix 13-Table 8, and Appendix 13-Table 9). These analyses will be considered as an 
exploratory optional objective, taking into consideration the logistic and technical 
challenges that might be experienced with the collection of viable PBMC during the 
conduct of a multi-center trial. Additionally, cellular immune phenotyping (by flow 
cytometry) will be performed at regular intervals during the study, using peripheral blood 
to study potential modulation by treatment. 
In an effort to measure intrahepatic target engagement using peripheral blood, blood 
samples will be collected from CHB participants for the extraction of liver-derived 
extracellular vesicles (EVs, predominantly exosomes). Liver origin can be determined 
based on the presence of the ASGPR in the EVs. It is assumed that multiple doses in 
the CHB population may induce a measurable reduction of EV-associated PD-L1. The 
application of this biomarker in this study will be gated based on the assessment of 
feasibility currently ongoing within the Phase 1 study NP40479.  
Liver targeting of RO7191863 is expected to reduce immune related risks associated 
with systemic exposure; nevertheless, soluble markers of immune activation and 
inflammation (soluble cytokines and chemokines which may include but are not limited to 
e.g., IFN-gamma, TNF-alpha, CXCL10/IP-10) will be assessed in participants. Measures 
of systemic immune activation and inflammation will be correlated with the safety profile 
and pharmacodynamic effects of siRNA and PD-L1 LNA in participants.  
A13.11.3 
FINE NEEDLE ASPIRATE (FNA) SUB-STUDY - OPTIONAL  
At one or more selected sites with established expertise, participants will be offered 
serial FNAs of the liver at four timepoints to explore one or more intra-hepatic PD 

 
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effects. The cellular material obtained with FNAs includes primarily immune cells with 
some hepatocytes, and these will be used for exploring PD-L1 and PD-1 expression, 
immune phenotype, immune genotype, and potentially viral parameters (e.g., HBV 
covalently closed circular deoxyribonucleic acid [cccDNA], integrated HBV DNA) as well 
as RO7191863 and RO7445482 exposure levels intra-hepatically. This will provide 
improved scientific understanding of the mechanism of action of RO7191863 as a liver-
target immune enhancer. Analysis techniques may include, but are not limited to, flow 
cytometry and gene expression. DNA and/or RNA will be extracted for exploratory 
research on immunological response modulated by the inhibition of PD-L1/PD-1 
pathway. A peripheral blood mononuclear cell sample obtained as part of the main study 
may be used for comparison tests with the intra hepatic measurements.  
A13.11.4 
CLINICAL GENOTYPING  
If safety or activity rationales develop, clinical genotyping will be performed (see 
Sections 8.7.4.1 and 8.8.1.1) if appropriate. This exploratory objective will aim at 
evaluating the association of genetic polymorphisms in known candidate genes with the 
PK profiles of the two NMEs and with primary and secondary endpoints. Known 
candidate genes of interest that are specific to siRNA, PD-L1, and ASGR1. Further 
genes may be queried (e.g., immune genotype) from the data based on progressing 
knowledge on these NMEs and their targets. 
A13.12 SCHEDULE OF ACTIVITIES siRNA + PD-L1 LNA + NUC ARM 
An overview of the schedule of the activities is provided in Appendix 13-Table 7, 
Appendix 13-Table 8, and Appendix 13-Table 9.  
 

 
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Appendix 13-Table 7 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm - 24 Week (Screening and 
Treatment Periods) 
 
Screening 
Treatment Period 
VB/VR 
ET/ 
UVu 
Week 
 
 
1 
5 
9 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
29 
(±2) 
57 
(±3) 
85 
(±3) 
89 
(-4) 
92 
(±3) 
99 
(±3) 
106 
(±3 ) 
113 
(±3) 
117  
(-4) 
120 
(±3) 
127 
(±3) 
134 
(±3) 
141 
(±3) 
145 
(-4) 
148 
(±3) 
155 
(±3) 
162 
(±3) 
169 
(±3) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical 
history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
vital signs a, b 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
Transient 
elastography/ARFI/MRc 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
HAV, HCV, HDV, HEV, 
HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of 
abuse screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Pregnancy test f 
 
x 
x 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
x 
Thyroid function tests 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematology (includes 
HbA1c g) 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, 
HBeAg, anti-HBs, anti-
HBe) 
x 
 
x 
x 
x 
x 
 
 
x 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
x 
x 

 
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Appendix 13-Table 7 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 Week (Screening and 
Treatment Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVu 
Week 
 
 
1  
5 
9 
13 
14 
15 
16 
17 
18  
19 
20 
21 
22 
23 
24 
25 
 
Day 
-56 
to -7 
-14 
to -7 
1 
29  
(±2) 
57 
(±3) 
85 
(±3) 
89 
(-4) 
92 
(±3) 
99 
(±3) 
106 
(±3 ) 
113 
(±3) 
117 
(-4) 
120 
(±3) 
127 
(±3) 
134 
(±3) 
141 
(±3) 
145 
(-4) 
148 
(±3) 
155 
(±3) 
162 
(±3) 
169 
(±3) 
 
 
HBV DNA quantitative 
x 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Total HBsAg i 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
 
HBcrAg 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
x 
 
Total anti-HBc 
quantitative 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
HBV RNA quantitative 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
 
Plasma PK (PD-L1 LNA) k 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
Plasma ADA (siRNA) l 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Plasma ADA (PD-L1 
LNA) l                                   
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
Liver injury markers 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
Extracellular vesicles 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
 
x 
Circulating immune 
phenotyping 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
 
x 
Soluble PD-L1 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
x 
 
x 
Cytokine panel m 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
x 
 
x 
PBMC n 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
FNA o 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 

 
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Appendix 13-Table 7 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 Week (Screening and 
Treatment Periods) (cont.) 
 
Screening 
Treatment Period 
VB/ VR 
ET/ UVu 
Week 
 
 
1  
5 
9 
13 
14 
15 
16 
17 
18  
19 
20 
21 
22 
23 
24 
25 
 
Day 
-56 to 
-7 
-14 
to 
-7 
1 
29 
(±2) 
57 
(±3) 
85 
(±3) 
89 
(-4) 
92 
(±3) 
99 
(±3) 
106 
(±3 ) 
113 
(±3) 
117 
(-4) 
120 
(±3) 
127 
(±3) 
134 
(±3) 
141 
(±3) 
145 
(-4) 
148 
(±3) 
155 
(±3) 
162 
(±3) 
169 
(±3) 
 
 
Liver Biopsy p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
RBR q 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
Clinic siRNA 200 
mg sc Q4W 
treatment 
administration r 
 
 
x 
x 
x 
 
xr 
 
 
 
 
xr 
 
 
 
 
xr 
 
 
 
 
 
 
Clinic PD-L1 LNA 
sc
treatment 
administration r, s 
 
 
NUC treatment 
administration OD 
 
 
x 
 
 
Adverse events, 
concomitant 
medications, and 
diary review t 
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
231/Protocol WV41073, Version 7.0 
Appendix 13-Table 7 Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 Week (Screening and 
Treatment Periods) (cont.) 
ADA = anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early 
termination; FNA = fine needle aspirate; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = 
hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR 
= magnetic resonance; NUC = nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; 
siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = 
virological breakthrough/relapse; UV = unscheduled visit. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 13, 17, 21, and 25. 
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR /2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures. 
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse; blood sample to be collected up to 6 times. 
k Plasma PK samples for PD-L1 LNA and siRNA should be collected pre-dose, 1-3 and 4-6 hours post-dose at all indicated visits, with the 
exception of EOT where only one PK timepoint is required. Plasma PK samples for NUC should be collected pre-dose. During the PK 
assessment for VB/BR visits, only one pre-dose sample is required for collection. 
l ADA is collected pre-dose. 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
232/Protocol WV41073, Version 7.0 
Appendix 13-Table 7 Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 Week (Screening and 
Treatment Periods) (cont.) 
m Cytokine panel (e.g., INF-α, IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α) to be collected pre-dose.  
n PBMC at selected sites only, three collections: Days 1, 85, and 169. The exact days of collection may be adjusted by the Sponsor based on 
emerging data.  
o Optional sub-study FNA at selected sites only. The days of collection may be adjusted by the Sponsor based on emerging data. 
p Only for participants in the liver biopsy sub-study. Participation for liver biopsy is optional and will require a separate consent from the participant. 
Additional safety assessments may be required as per local practice and guidelines prior to the liver biopsy (refer to study operations 
manual).  
q RBR samples collected only from RBR-consenting participants. 
r On weeks where dosing of RO7191863 and RO7445482 overlap (Weeks 13, 17, and 21), RO7191863 must be administered first, and 
RO7445482 can be administered no earlier than 24 hours after dosing of RO7191863 (Days 85, 113, and 141). RO74445482 dose can be 
administered on a different day that week (e.g., Days 89, 117, 145), but no later than 48 hours before the next planned dose of RO7191863. It 
should be noted that on the overlapping weeks, PK and ADA samples for RO7445482 should be collected on the same day as dosing of 
RO7445482. Different injection sites should be used for SC administration. 
s The PD-L1 LNA dose is weight based and should be calculated using the most recent per protocol assessment of participant weight at each dosing visit.   
t Pre-treatment, only serious adverse events should be reported. 
u Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
 
 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
233/Protocol WV41073, Version 7.0 
Appendix 13 -Table 8 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 36 Week (Screening and 
Treatment Periods) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVt 
Week 
 
 
1  
5 
9 
13 
17 
21 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
29 
(±2) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
176 
(±3) 
183 
(±3) 
190 
(±3) 
197 
(±3) 
204 
(±3) 
211 
(±3) 
218 
(±3) 
225 
(±3) 
232 
(±3) 
239 
(±3) 
246 
(±3) 
253 
(±3) 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs 
a, b 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Transient 
elastography/ARFI/MR c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Alfa-fetoprotein 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAV, HCV, HDV, HEV, HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and drugs of abuse 
screen e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Pregnancy test f 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
Thyroid function tests 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematology (includes HbA1c g) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical genotyping h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV serology (HBsAg, HBeAg, 
anti-HBs, anti-HBe) 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
234/Protocol WV41073, Version 7.0 
Appendix 13 -Table 8 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 36 Week (Screening and 
Treatment Periods) (cont.) 
 
Screening 
Treatment Period 
VB/VR 
ET/UVt 
Week 
 
 
1  
5 
9 
13 
17 
21 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
29 
(±2) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
176 
(±3) 
183 
(±3) 
190 
(±3) 
197 
(±3) 
204 
(±3) 
211 
(±3) 
218 
(±3) 
225 
(±3) 
232 
(±3) 
239 
(±3) 
246 
(±3) 
253 
(±3) 
 
 
HBV DNA quantitative 
x 
 
x 
 
 
 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
x 
Total HBsAg i 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
HBcrAg 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
Total anti-HBc quantitative 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
HBV RNA quantitative 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
HBV RNA sequencing h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA sequencing j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) k 
 
 
x 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (PD-L1 LNA) k 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
Plasma PK (NUC) k 
 
 
x 
 
 
x 
 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
Plasma ADA (siRNA) l 
 
 
x 
 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Plasma ADA (PD-L1 LNA) l          
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
x 
Liver injury markers 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
Extracellular vesicles 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Circulating immune phenotyping 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Soluble PD-L1 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
235/Protocol WV41073, Version 7.0 
Appendix 13-Table 8 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 36 Week (Screening and 
Treatment Periods) (cont.) 
 
Screening 
Treatment Period 
VB/ 
VR 
ET/UVt 
Week 
 
 
1  
5 
9 
13 
17 
21 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
 
Day 
-56 
to 
-7 
-14 
to 
-7 
1 
29 
(±2) 
57 
(±3) 
85 
(±3) 
113 
(±3) 
141 
(±3) 
169 
(±3) 
176 
(±3) 
183 
(±3) 
190 
(±3) 
197 
(±3) 
204 
(±3
) 
211 
(±3) 
218 
(±3) 
225 
(±3) 
232 
(±3) 
239 
(±3) 
246 
(±3) 
253 
(±3) 
 
 
Cytokine panel m 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
PBMC n  
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
FNA o 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Liver Biopsy p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
RBR q 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
x 
 
Clinic siRNA 200 mg sc Q4W 
treatment administration  
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic PD-L1 LNA
sc 
 treatment administration r  
 
 
 
 
NUC treatment administration 
OD 
 
 
x 
 
 
Adverse events, concomitant 
medications, and diary review s 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibodies; ARFI = acoustic radiation force impulse; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early 
termination; FNA = fine needle aspirate; GLDH = glutamate dehydrogenase; HAV/HBV/HCV/HDV/HEV = hepatitis A/B/C/D/E virus; HBcrAg = 
hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MR 
= magnetic resonance; NUC = nucleos(t)ide analogue; PK = pharmacokinetics; RBR = Research Biosample Repository; RNA = ribonucleic acid; 
siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb complexes/components of HBsAg; VB/VR = 
virological breakthrough/relapse; UV = unscheduled visit. 
 
a Full physical examination at screening and at the end-of-treatment. Limited symptom-directed physical examination at other visits and as clinically 
indicated. Height at screening only. Weight at screening, Day 1, and Weeks 25, 29, 33, and 37. 
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position. 
 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
236/Protocol WV41073, Version 7.0 
Appendix 13 -Table 8 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm (Screening and Treatment 
Periods) (cont.) 
c Historical liver biopsy or transient elastography/ARFI/MR/2D- shear wave elastography [2D-SWE] results obtained within 6 months prior to 
randomization are also acceptable. During screening transient elastography/ARFI/MR /2D-SWE are acceptable.  
d Autoantibodies refer to ANA, AMA, ASMA, and a-TPO. 
e Alcohol and drugs of abuse screen to be conducted according to local procedures. 
f Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
g HbA1c should be included in hematology and is required only at screening. 
h If not collected at Day 1, samples for clinical genotyping and HBV RNA sequencing can be collected at any subsequent time point. The sample for 
HBV RNA sequencing aims at determining the HBV genotype. The HBV genotype may also be inferred using alternative approaches, such as serovariant 
determination. 
i Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb complexes/components of HBsAg. 
j HBV DNA sequencing will be collected in case of virological breakthrough/relapse; blood sample to be collected up to 6 times. 
k Plasma PK samples for PD-L1 LNA and siRNA should be collected pre-dose, 1-3 and 4-6 hours post-dose at all indicated visits, with the 
exception of EOT where only one PK timepoint is required. Plasma PK samples for NUC should be collected pre-dose. During the PK 
assessment for VB/BR visits, only one pre-dose sample is required for collection. 
l ADA is collected pre-dose. 
m Cytokine panel (e.g., INF-α, IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α) to be collected pre-dose.  
n PBMC at selected sites only, three collections: Days 1, 169, and 253. The exact timepoints for collection may be adjusted by the Sponsor based 
on emerging data. 
o Optional sub-study FNA at selected sites only. The timepoints for collection may be adjusted by the Sponsor based on emerging data. 
p Only for participants in the liver biopsy sub-study. Participation for liver biopsy is optional and will require a separate consent from the participant. 
Additional safety assessments may be required as per local practice and guidelines prior to the liver biopsy (refer to study operations 
manual).  
q RBR samples collected only from RBR-consenting participants. 
r The PD-L1 LNA dose is weight based and should be calculated using the most recent per protocol assessment of participant weight at each dosing visit.  
 s Pre-treatment, only serious adverse events should be reported. 
t Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
237/Protocol WV41073, Version 7.0 
Appendix 13-Table 9 
Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 and 36 Week (Follow-up 
Period) 
 
Follow-up period 
VB/VR 
ET/UVk 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24l 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Physical examination, vital signs a, b 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
ECG 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Abdominal ultrasound 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alfa-fetoprotein 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Alcohol and drugs of abuse screen c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test d 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Thyroid function tests 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GLDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV serology (HBsAg, HBeAg, anti-HBs, anti-HBe) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV DNA quantitativem 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total HBsAg e 
 
x 
 
x 
 
x 
 
 
x 
 
x 
x 
 
HBcrAg 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Total anti-HBc quantitative  
 
 
 
 
 
x 
 
 
x 
 
x 
 
 
HBV RNA quantitative 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
HBV DNA sequencing 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK (siRNA) f  
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (PD-L1 LNA) f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (NUC) f 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma ADA (siRNA) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
Plasma ADA (PD-L1 LNA) 
 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
RBR g 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Extracellular vesicles 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Circulating immune phenotyping 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
Soluble PD-L1 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
238/Protocol WV41073, Version 7.0 
Appendix 13-Table 9 Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 and 36 Week (Follow-up 
Period) (cont.) 
 
Follow-up period 
VB/VR 
ET/UVk 
Week 
2 
4 
6 
8 
10 
12 
16 
20 
24l 
36 
48 
 
- 
Day 
14 
(±3) 
28 
(±3) 
42 
(±3) 
56 
(±3) 
70 
(±3) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
168 
(±7) 
252 
(±7) 
336 
(±7) 
 
 
Cytokine panel h 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 
x 
PBMC i  
 
 
 
 
 
x 
 
 
x 
 
 
 
 
FNA j  
 
 
 
 
 
x 
 
 
 
 
 
 
 
Diary review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events & concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibodies; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET=early termination; FNA = fine needle aspirate; GLDH = 
glutamate dehydrogenase; HBV = hepatitis B virus; HBcrAg = hepatitis B core-related antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis 
B surface antigen; NUC = nucleos(t)ide analogue; PD-L1 = programmed death ligand-1; PK = pharmacokinetics; RBR = Research Biosample 
Repository; RNA = ribonucleic acid; siRNA= short interfering ribonucleic acid; Total HBsAg = post-dissociation of HBsAg/HBsAb 
complexes/components of HBsAg; VB/VR = virological breakthrough/relapse; UV = unscheduled visit. 
Note: If participants discontinue NUC later in the follow-up, additional visits should be scheduled with a frequency of every 2 weeks for the first three months and 
every 4 weeks up to week 48 of follow-up period. 
a Full physical exam at screening and at the end-of-treatment. Limited symptom-directed physical exam at other visits and as clinically indicated.  
b Blood pressure, pulse rate, respiratory rate, and body temperature obtained at least 5 minutes after participant has been in supine/sitting position.  
c Alcohol and drugs of abuse screen to be conducted according to local procedures.  
d Pregnancy testing for females of childbearing potential only; serum test at screening, urine test at other visits. If urine test is positive, it must be 
confirmed by a serum test. 
e Total HBsAg refers to HBsAg measured post-dissociation of HBsAg/HBsAb/components of HBsAg. 
f No plasma PK samples are collected during the follow-up period. During the PK assessment for VB/BR visits, only one pre-dose sample is 
required for collection. 
g RBR samples collected only from RBR-consenting participants. 
h Cytokine panel (e.g., INF-α, IP-10, IL-1, IL-6, IL-10, IFN-γ, and TNF-α). 
i PBMC at selected sites only, two collections: Follow-up Days 84 and 168. The exact days of collection may be adjusted by the Sponsor based on emerging 
data. 
j Optional sub-study FNA at selected sites only. 
k Participants who discontinue study treatment prematurely will be required to attend an unscheduled/early termination visit. 

 
Combination Therapies for CHB—F. Hoffmann-La Roche Ltd 
239/Protocol WV41073, Version 7.0 
Appendix 13-Table 9 Schedule of Activities for siRNA + PD-L1 LNA + NUC Treatment Arm – 24 and 36 Week (Follow-up 
Period) (cont.) 
l Visit window may be extended to +6 weeks in extreme circumstances such as pandemic, natural disasters, supply chain disruption, outbreak of hostilities. 
m Participants with HBV DNA > 2,000 IU/mL during the follow-up period will undergo weekly monitoring. Participants with HBV DNA >20 IU/mL but 
< 2,000 IU/mL, should undergo monitoring every two weeks. Participants, who have discontinued NUC therapy, should have monthly visits from follow up Week 
24 to Week 48, instead of the 3 monthly follow up visits shown in the SoA, which are relevant for participants on NUC therapy, to enable early detection and 
appropriate management of HBV DNA rebound. At these additional unscheduled monitoring visits, the following laboratory assessments should be performed using 
the unscheduled lab kit: hematology, chemistry, coagulation, GLDH, urinalysis, HBV serology, HBV DNA quantitative, total HBsAg, HBcrAg, and HBV RNA 
quantitative.  
 

Signature Page for Protocol - WV41073 - TLR7(3) - Published
System identifier: RIM-CLIN-445742
Approval Task
Company Signatory
18-Jul-2022 10:49:36 GMT+0000