Conditions: Hepatitis B Virus Infection
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 55
Healthy volunteers: yes

Brief summary:
This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses in healthy volunteers (HV) and participants diagnosed with chronic hepatitis B (CHB).

Detailed description:

Arms:
arm 1: Healthy volunteers will be administered a single dose of RO7239958 or placebo subcutaneously (SC). arm 2: Participants with chronic hepatitis B will be administered different dose levels of RO7239958 or placebo SC. Dosages will be determined from data collected from Part 1. arm 3: Additional study arm to open based on data collected from Part 2a. Participants with chronic hepatitis B will be administered different doses and frequencies of RO7239958 or placebo SC.

Interventions: intervention 1: RO7239958 intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for injection, subcutaneous use (SC). intervention 2: Sodium chloride solution for injection, SC

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: A Randomized, Placebo-controlled,Observer-blinded Study, to 
Evaluate Safety,Tolerability, Pharmacokinetics and 
Pharmacodynamics of RO7239958 in Healthy Volunteers and Patients 
With Chronic Hepatitis B Virus Infection 
NCT Number: NCT03762681 
Document Date: Protocol Version 4: 18-February-2020 
 
 


FINAL PROTOCOL APPROVAL
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The information contained in this document, especially any unpublished data, is the property of 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.
RO7239958—F. Hoffmann-La Roche Ltd
Protocol NP40520, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, PLACEBO-CONTROLLED, 
OBSERVER-BLINDED STUDY, TO EVALUATE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF RO7239958 IN HEALTHY 
VOLUNTEERS AND PATIENTS WITH CHRONIC 
HEPATITIS B VIRUS INFECTION
PROTOCOL NUMBER:
NP40520
VERSION:
4
EUDRACT NUMBER:
2018-003530-32
TEST PRODUCT:
RO7239958
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 01 October 2018
DATE AMENDED:
Version 2: 08 February 2019
Version 3: 24 April 2019
Version 4: See electronic stamp below
18-Feb-2020 17:42:59
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7239958—F. Hoffmann-La Roche Ltd
2/Protocol NP40520, Version 4
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, PLACEBO-CONTROLLED, 
OBSERVER-BLINDED STUDY, TO EVALUATE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF RO7239958 IN HEALTHY 
VOLUNTEERS AND PATIENTS WITH CHRONIC 
HEPATITIS B VIRUS INFECTION
PROTOCOL NUMBER:
NP40520
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003530-32
TEST PRODUCT:
RO7239958
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.


RO7239958—F. Hoffmann-La Roche Ltd
3/Protocol NP40520, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE


RO7239958—F. Hoffmann-La Roche Ltd
4/Protocol NP40520, Version 4


RO7239958—F. Hoffmann-La Roche Ltd
5/Protocol NP40520, Version 4
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 13
1.1
Synopsis................................................................................ 13
1.2
Schematic of Study Design.................................................... 23
1.3
Schedule of Activities ............................................................ 23
2.
INTRODUCTION ........................................................................................ 34
2.1
Study Rationale ..................................................................... 34
2.2
Background ........................................................................... 35
2.2.1
Background on Disease......................................................... 35
2.3
Benefit/Risk Assessment....................................................... 36
3.
OBJECTIVES AND ENDPOINTS ............................................................... 39
4.
STUDY DESIGN......................................................................................... 42
4.1
Overall Design ....................................................................... 42
4.1.1
Length of the Study ............................................................... 44
4.1.2
Dose Escalation Decision...................................................... 45
4.1.2.1
Part 1 - Dose-Escalation Decision Criteria............................. 46
4.1.3
Stopping Rules Criteria.......................................................... 46
4.1.4
Communication Strategy ....................................................... 48
4.2
Scientific Rationale for Study Design..................................... 49
4.2.1
Rationale for Study Population .............................................. 50
4.2.2
Rationale for Control Group................................................... 50
4.2.3
Rationale for Biomarker Assessments................................... 50
4.4
End of Study Definition .......................................................... 55
5.
STUDY POPULATION................................................................................ 55
5.1
Inclusion Criteria.................................................................... 56
5.2
Exclusion Criteria................................................................... 58
5.3
Lifestyle Considerations......................................................... 62
5.3.1
Meals and Dietary Restrictions.............................................. 62
5.4
Screen Failures ..................................................................... 62


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5.5
Recruitment Procedures........................................................ 62
6.
TREATMENTS............................................................................................ 62
6.1
Treatments Administered....................................................... 63
6.2
Preparation/Handling/Storage/Accountability ........................ 63
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 64
6.3.1
Method of Treatment Assignment.......................................... 64
6.3.2
Blinding.................................................................................. 65
6.4
Treatment Compliance .......................................................... 66
6.5
Concomitant Therapy ............................................................ 66
6.5.1
Permitted Therapy................................................................. 67
6.5.2
Prohibited Therapy ................................................................ 67
6.6
Dosage Modification .............................................................. 68
6.7
Treatment After the End of the Study..................................... 68
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 68
7.1
Discontinuation of Study Treatment....................................... 69
7.1.1
Temporary Interruption .......................................................... 69
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 69
7.3
Lost to Follow-Up................................................................... 70
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 70
8.1
Efficacy Assessments............................................................ 71
8.2
Safety Assessments .............................................................. 71
8.2.1
Physical Examinations........................................................... 71
8.2.2
Vital Signs.............................................................................. 72
8.2.3
Electrocardiograms................................................................ 72
8.2.4
Clinical Safety Laboratory Assessments................................ 74
8.2.5
Medical History and Demographic Data ................................ 75
8.3
Adverse Events and Serious Adverse Events ....................... 75
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 76


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8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 76
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 77
8.3.3.1
Investigator Follow-Up........................................................... 77
8.3.3.2
Sponsor Follow-Up ................................................................ 77
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 77
8.3.4.1
Emergency Medical Contacts................................................ 78
8.3.5
Pregnancy ............................................................................. 78
8.3.6
Non-Serious Adverse Events of Special Interest................... 78
8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs ............................ 79
8.4
Treatment of Overdose.......................................................... 79
8.5
Pharmacokinetics .................................................................. 79
8.5.1
Immunogenicity Assessments ............................................... 80
8.6
Pharmacodynamics and Biomarkers ..................................... 81
8.6.1
Viral Dynamic Biomarkers ..................................................... 81
8.6.2
Viral Genetic Analyses........................................................... 81
8.6.3
Exploratory Safety Biomarkers .............................................. 81
8.7
Pharmacodynamics and Biomarker Samples........................ 81
8.7.1
Mandatory samples ............................................................... 82
8.8
Samples for Research Biosample Repository ....................... 82
8.8.1
Overview of the Research Biosample Repository.................. 82
8.8.1.1
Sample Collection.................................................................. 83
8.9
Medical Resource Utilization and Health 
Economics............................................................................. 83
8.10
Timing of Study Assessments ............................................... 83
8.10.1
Screening and Pre-Treatment Assessments ......................... 83
8.10.2
Assessments during Treatment............................................. 84
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 84
8.10.4
Follow-Up Assessments ........................................................ 84
8.10.5
Section Assessments at Unscheduled Visits......................... 84


RO7239958—F. Hoffmann-La Roche Ltd
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9.
STATISTICAL CONSIDERATIONS ............................................................ 85
9.1
Statistical Hypotheses ........................................................... 85
9.2
Sample Size Determination ................................................... 85
9.3
Populations for Analyses ....................................................... 85
9.4
Statistical Analyses................................................................ 86
9.4.1
Demographics and Baseline Characteristics ......................... 86
9.4.2
Safety Analyses..................................................................... 86
9.4.2.1
ECG Data Analysis................................................................ 87
9.4.2.2
Exploratory Safety Biomarkers Analysis................................ 87
9.4.3
Pharmacokinetic Analyses..................................................... 88
9.4.4
Pharmacodynamic Analyses ................................................. 88
9.4.4.1
PK/Safety and PK/PD Relationships Analysis ....................... 89
9.4.4.2
Immunogenicity Analyses...................................................... 90
9.5
Summaries of Conduct of Study............................................ 90
10. REFERENCES ........................................................................................... 91
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.................................................................................... 92
LIST OF TABLES
Table 1
Schedule of Activities – Main Table, Part 1 (SAD in HV) ............ 24
Table 2
Schedule of Assessments – Detailed Table, Part 1 (SAD in 
HV).............................................................................................. 26
Table 3
Schedule of Assessments – Main Table, Part 2a and Part 2b 
(CHB [
], 5 weeks) ....................................... 27
Table 4
Schedule of Assessments – Detailed Table, Part 2a and Part 
2b (CHB 
], 5 weeks)................................... 30
Table 5
Schedule of Assessments – Main Table, Part 2b (CHB [
 
] 12 weeks – as of Week 6) ...................................... 31
Table 6
Schedule of Assessments – Detailed Table, (CHB [
 
] 12 weeks – as of Week 6) ...................................... 33
Table 7
Objectives and Endpoints ........................................................... 39
Table 8
Comparison of plasma, kidney and liver exposures between 
human starting dose and NOAEL in 4-week GLP toxicity 
studies ........................................................................................ 54
Table 9
Safety margins at the tentative dose levels in Part 1 (based 
on the 4-week GLP toxicity study in NHPs)................................. 55
Table 10
Summary of Treatments Administered........................................ 63


RO7239958—F. Hoffmann-La Roche Ltd
9/Protocol NP40520, Version 4
Table 11
Analysis Populations................................................................... 85
Table 12
Safety Statistical Analysis Methods ............................................ 87
Table 13
Viral Dynamic Response Statistical Analysis Methods ............... 89
Table 14
Exploratory  Viral  Dynamic  Response  Statistical  Analysis  
Methods ...................................................................................... 89
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 23
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations........... 93
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting........................................................... 101
Appendix 3
Procedures for Recording Adverse Events ............................... 110
Appendix 4
Clinical Laboratory Tests .......................................................... 116
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 119
Appendix 6
CKD-EPI GFR........................................................................... 123
Appendix 7
Grading of Injection Site Reactions (ISRs)................................ 124


RO7239958—F. Hoffmann-La Roche Ltd
10/Protocol NP40520, Version 4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BP
Blood pressure
ccc DNA
Covalently closed circular DNA
CL
Clearance
CL/F
Apparent clearance
CLU
Clusterin
CMC
Chemistry manufacturing and control
CNS
Central nervous system
CRO
Contract research organization
CSAP
Clinical statistical analysis plan
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
CTD
Common technical document
CYS-C
Cystatin-C
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLAE
Dose-limiting adverse event
DNA
Deoxyribonucleic acid
DRF
Dose range finding
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ESF
Eligibility screening form
EU
European Commission
FDA
Food and Drug Administration
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice


RO7239958—F. Hoffmann-La Roche Ltd
11/Protocol NP40520, Version 4
HBcAb
Total hepatitis B core antibody
HBeAg
Hepatitis B envelope antigen
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C Virus
HED
Human equivalent dose
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IFN
Interferon
IEC
Independent Ethics Committee
IMC
Internal Monitoring Committee
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IRF
Independent review facility
IRC
Independent Review Committee
ISR
Injection Site Reaction
IUD
Intrauterine device
IxRS
Interactive (voice/web) response system
KIM-1
Kidney injury molecule-1
LDH
Lactate dehydrogenase
LLQ
Lower Limit of Quantification
LNA
Locked nucleic acid
LPLV
Last participant, last visit
MAD
Multiple-ascending doses
MD
Multiple doses
NAG
N-acetyl-beta-D-glucosaminidase
NCI
National Cancer Institute
NGAL
Neutrophil gelatinase-associated lipocalin
NHP
Non-human primate
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
NUC
Nucleoside/nucleotide analogues
OTC
Over-the-counter
OPN
Osteopontin


RO7239958—F. Hoffmann-La Roche Ltd
12/Protocol NP40520, Version 4
PD
Pharmacodynamic
PK
Pharmacokinetic
PT
Prothrombin time
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBR
Research biosample repository
RNA
Ribonucleic acid
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SD
Single dose
SoA
Schedule of activities
SOP
Standard operating procedure
SPA
Statistical Programmer
SSO
Single stranded oligonucleotide
SUSAR
Suspected unexpected serious adverse reaction
TQT
Thorough QT
ULN
Upper limit of normal
US
United States
V
Volume
VAS
Visual analogue scale
V/F
Apparent volume of distribution
WBC
White blood cell


RO7239958—F. Hoffmann-La Roche Ltd
13/Protocol NP40520, Version 4
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A RANDOMIZED, PLACEBO-CONTROLLED, OBSERVER-
BLINDED STUDY, TO EVALUATE SAFETY, TOLERABILITY,
PHARMACOKINETICS AND PHARMACODYNAMICS OF 
RO7239958 IN HEALTHY VOLUNTEERS AND PATIENTS 
WITH CHRONIC HEPATITIS B VIRUS INFECTION
SHORT TITLE
SAD/ DRF Study to Evaluate Safety, PK, PD of RO7239958 in 
Healthy Volunteers and Patients with Chronic Hepatitis B
PROTOCOL NUMBER:
NP40520
VERSION:
4
TEST PRODUCT:
RO7239958
PHASE:
I
RATIONALE
This is the first study with RO7239958 in humans, designed to assess the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses in
healthy participants and participants diagnosed with chronic hepatitis B (CHB). Data collected in 
this study will be critical to define optimal doses and dosing regimens to be studied in Phase II 
clinical trials in CHB patients.




RO7239958—F. Hoffmann-La Roche Ltd
15/Protocol NP40520, Version 4
OBJECTIVES AND ENDPOINTS (CONT.)
Part 2a and 2b
(cont.)
Pharmacodynamics (PD) (cont.)
In participants that are HBeAg 
positive at study entry, incidence of 
HBeAg loss and incidence of hepatitis 
B e antibody (anti-HBe) 
seroconversion. 
Participants will have a suppressed 
HBV DNA at study entry and will be 
monitored to ensure that HBV DNA 
suppression is maintained during the 
study.
OVERALL DESIGN
The study will be conducted in two parts, of which Part 1 will be in healthy participants and Part 2 
will be in CHB patients. Both parts of the study are randomized and Observer-blinded. 
Part 1 will evaluate the safety, tolerability and PK of RO7239958 following SC administration of 
single ascending doses in healthy participants. Part 2 will evaluate the safety, tolerability, PK, and 
pharmacodynamics (PD) of multiple SC doses of RO7239958 in CHB patients on stable NUC 
therapy, and comprises two subparts, Part 2a and Part 2b. Part 2 is a dose range finding study 
(DRF).
Study Design
Part 1 – In Part 1, at least four cohorts will receive a single dose of RO7239958 or placebo. An 
optional cohort with participants receiving RO7239958 or placebo may be included, based on the 
need for further safety or PK data. Ten healthy participants, eight receiving RO7239958 and two
receiving placebo, will be enrolled in each cohort using a 4:1 randomization scheme. 
 
 
 Each cohort will implement sentinel dosing to 
monitor acute reactions over 24 hours post-dosing: Two participants will be dosed on Day 1, and 
at least one of the two participants will have received RO7239958; the remaining eight
participants shall be dosed the following day (i.e., after 24 hours) following satisfactory clinical 
safety review of the first two participants by the Investigator. For each cohort, safety will be 
monitored for 28 days (21 days for safety assessment plus 7 days of clinical safety observation, 
before escalating to the next cohort. A dose escalation meeting will take place prior to starting the 
next cohort. In all participants, safety will be monitored for a total of 12 weeks post-dosing.
Part 2a – In Part 2a, CHB patients will be enrolled into one of two arms (Arms 1 and 2), which will 
run in parallel. Each arm will enroll seven participants using a 6:1 randomization scheme. To 
ensure balance between arms, enrolment of HBeAg positive participants will be capped. The 
Sponsor will communicate to the investigators the capping level arm prior to respective start of 
enrollment. Participants of each arm will receive RO7239958 or placebo over 4 weeks. 
 
 
 


RO7239958—F. Hoffmann-La Roche Ltd
16/Protocol NP40520, Version 4
. Two additional, parallel arms (Arms 3 and 4) will open after Arms 1 and 2 have 
enrolled and followed-up for at least 28 days a sufficient number of participants to provide the 
safety and PK/PD information required to further inform dose and regimen optimization. An 
optional Arm 5 will open if further doses or regimens need to be explored based on data from Arms 3 and 4.
A data review meeting will also take place before opening Arms 3 and 4 (and potentially optional 
Arm 5). Decision on dose levels and regimens for Arms 3 and 4 will be based on the safety, PK, 
and PD data from Arms 1 and 2 and all available safety and PK data from Part 1. If efficacious 
dose levels cannot be reliably predicted from PK/PD modeling and Part 1 data, the doses 
administered in Part 2a will be within the range demonstrated to be safe and well tolerated in Part 
1.
 
 
 In all patients, safety will 
be monitored for a total of 12 weeks post-dosing.
Part 2b (optional) – The two additional arms (Arms 6 and 7) of Part 2b will open if further doses 
or regimens need to be explored based on the data from Part 2a, or a dose or regimen from 
Part 2a needs to be optimized and additional data evaluated. There may be inclusion of 
participants who are not treated with NUCs, or inclusion of a larger number of participants of a 
given HBeAg status. Each arm in Part 2b will comprise seven participants randomized to 
RO7239958 or placebo using a 6:1 randomization scheme. 
 
 In all 
patients, safety will be monitored for a total of 12 weeks post-dosing.
Treatment Groups and Duration
The IMPs are RO7239958 (active) and placebo. The dose given will be in milligrams per 
kilogram of body weight and administered SC. 
Part 1: The total duration of the study for each participant will be up to 16 weeks, divided as 
follows:

Screening: Up to 28 days 

In clinic period: Days -1 to 3.

Treatment Period: Day 1 

Safety follow-up: up to at least 84 days after the dose of RO7239958 or placebo.
Part 2a: The total duration of the study for each participant will be up to 20 weeks divided as 
follows:

Screening: Up to 28 days.

In clinic period (optional): Days 1 to 3 and Days 29 to 30 (overnight stay optional).

Treatment Period: Day 1 to 29.

Safety follow-up: up to 84 days after the last dose of RO7239958 or placebo.


RO7239958—F. Hoffmann-La Roche Ltd
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Part 2b: The total duration of the study for each participant will be up to 28 weeks divided as 
follows:

Screening: Up to 28 days.

In clinic period (optional): Days 1 to 3 and Days 29 to 30 (overnight stay optional).

Treatment Period: Day 1 up to Day 85. Safety follow-up: up to 84 days after last dose of 
RO7239958 or placebo.
End of Study
The end of the study is defined as the date when the last participant last visit (LPLV) occurs 
(includes the safety and follow-up visit), or the date at which the last data point from the last 
participant required for statistical analysis is received, whichever is the later date, unless the 
participant was prematurely discontinued.
Data Monitoring: No
No Internal Data Monitoring Committee is planned for this study. A communication strategy will 
detail the data review and decision making prior to dose-escalation and initiation of study arms.
PARTICIPANT POPULATION
Participants will be healthy female and male volunteers and patients diagnosed with chronic HBV
infection who fulfill all of the given inclusion criteria.
INCLUSION/ EXCLUSION CRITERIA
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
ALL STUDY PARTS
Informed Consent: 
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to ICH and local regulations.
Age:
2.
Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent.
Weight:
3.
Body weight of at least 45 kg and maximally 150 kg, and BMI within the range of 18 to 32 
kg/m2 (inclusive).
Sex: 
4.
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 to meet enrolment 
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 
contraception.


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a)
Female participants: Should be women of non-childbearing potential (WONCBP).
b)
Male participants: During the treatment period and for at least 105 days after the last 
dose of RO7239958 or placebo, agreement to: 
i.
With partners who are women of childbearing potential (WOCBP): 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. 
ii.
With pregnant female partners, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo. 
iii.
Refrain from donating sperm for at least 105 days after last dose of 
RO7239958 or placebo.
PART 1 (SAD HV) ONLY
Type of participants:
1.
Healthy, as judged by the Investigator. Healthy status will be defined as the absence of 
evidence of any active or chronic disease following a detailed medical and surgical history, 
concomitant drug use (including hormonal supplements), a complete physical examination 
including vital signs, 12-lead ECG, hematology, blood chemistry, serology, and urinalysis.
Others Inclusions:
2.
Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1, 
and agrees to remain non-smoker during the study.
PART 2 (CHB) ONLY
Type of Participants and Disease Characteristics
1.
Positive serum HBsAg status for > 6 months prior to screening.
2.
Serum HBsAg level 250 IU/mL at screening.
3.
On stable entecavir or tenofovir (alone or in combination) treatment, and having received the 
same NUC in the 3 months prior to randomisation, and expected to remain on the same 
NUC for the duration of study participation.
4.
HBV DNA below the lower limit of quantification (LLQ < 20 IU/mL) for ≥6 months prior to 
screening by local testing, and confirmed at screening.
5.
Screening laboratory values (including hematology, chemistry, urinalysis) within normal 
ranges, or judged to be not clinically significant by the Investigator and Medical Monitor, and:
a)
Screening alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
2 × upper limit of normal (ULN), confirmed between Day -7 to Day -4. 
b)
Screening gamma-glutamyl transferase (GGT) ULN (Note: GGT 1.5 x ULN is 
acceptable if considered not clinically significant) and alkaline phosphatase (ALP) ULN, 
and normal values of prothrombin time (PT), INR, and activated partial thromboplastin 
time (aPTT). PT and/or aPTT > ULN is acceptable if considered not clinically significant and 
INR and other parameters of liver function are within normal limits and there are no current 
and historical concerns. Whenever the Screening tests are repeated, the mean of the repeat values 
will be considered.


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c)
Screening total bilirubin of ULN (Note: isolated bilirubin 1.5 ULN is acceptable for 
patients with Gilbert’s syndrome.
d)
Screening neutrophil count 1500 cells/mm3 (Note: 1200 cells/mm3 is acceptable in 
participants of black race).
e)
Screening hemoglobin 11 g/dL in females and 12.5 g/dL in males.
f)
Screening platelet count 150,000 cells/L.
6.
No past or current diagnosis of cirrhosis. Transient elastography at screening showing a kPa 
value consistent with a degree of liver fibrosis not higher than F3. By FibroScan, a cut-off of 
< 8.5 kPa in the fasted status (last meal 3 hours prior) is recommended.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
ALL STUDY PARTS
Medical Conditions
1.
Participants who have donated over 500 mL of blood or blood products or had significant 
blood loss within three months prior to screening.
PART 1 (SAD HV) ONLY:
Medical Conditions
1.
History or presence of significant (as judged by the investigator) cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, haematological disorders, or diagnosed central or 
peripheral neurological disease, capable of significantly altering the absorption, metabolism, 
or elimination of drugs, or constituting a risk when taking the study treatment, or of interfering 
with the interpretation of the data.
2.
Screening ECG showing clinically relevant abnormalities (including arrhythmias or marked 
QT abnormalities [QTcF < 300 msec or > 450 msec], or other cardiac abnormalities that are 
considered clinically significant by the Investigator. Known risk factors for Torsade de 
Pointes (e.g., hypokalemia, heart failure), or a personal or family history of congenital long 
QT syndrome. 
3.
Abnormal blood pressure: supine systolic blood pressure (SBP) <90 mmHg or >140mmHg 
or diastolic blood pressure (DBP) <45mmHg or >90mmHg at the time of screening and at 
Day -1, confirmed by two consecutive triplicate measurements, properly measured with well-
maintained equipment.
4.
History of lymphoma, leukaemia, or malignancy within the past five years, except for 
squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for three years.
5.
History or presence of liver disease, or known hepatic or biliary abnormalities (with the 
exception of Gilbert’s syndrome or asymptomatic gallstones).
6.
ALT ≥1.5 ULN at screening and at Day 1. 
7.
Any clinically significant out of range findings in other laboratory test results or any other 
clinically significant (as judged by the Investigator) abnormalities in the physical examination 
at screening and on Day -1. 


RO7239958—F. Hoffmann-La Roche Ltd
20/Protocol NP40520, Version 4
8.
Sensitivity to any of the study treatments, or components thereof, or drug or other allergy 
that, in the opinion of the Investigator, contraindicates the participation in the study.
9.
Any clinically relevant history of hypersensitivity or allergic reactions, either spontaneous or 
following drug administration, or exposure to foods or environmental agents.
10. Any major illness within one month preceding the screening visit, or any febrile illness within 
the two weeks preceding the screening visit. 
11. Concomitant disease or condition that could interfere with, or treatment of which might 
interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose 
an unacceptable risk to the participant in this study.
Prior/Concomitant Therapy
12. Used or intend to use of over-the-counter (OTC) or prescription medication (including herbal 
and traditional remedies) before study start and during the study as described in list of 
prohibited medications. 
13. Live vaccine(s) within 28 days of screening, or plans to receive live vaccines during the 
study or within 28 days of the last dose.
14. Likely to need concomitant medication during the study period.
15. Treatment with biologic agents (such as monoclonal antibodies, including marketed drugs) 
within three months or five half-lives (whichever is longer) prior to dosing.
Prior/Concurrent Clinical Study Experience
16. Currently enrolled in or have participated within the last 90 days or five times the half-life of 
the investigational drug (whichever is longer) from signing of consent in this or any other 
clinical study involving an investigational product or in any other type of medical research.
17. Exposure to more than four new chemical entities within 12 months prior to the first dosing 
day.
Diagnostic Assessments
18. Known positive for hepatitis B surface antigen (HBsAg), or hepatitis B core total antibody 
[anti-HBc]), or hepatitis C virus (HCV) antibody test result at screening. 
19. Known positive for human immunodeficiency virus (HIV) infection and/or positive for HIV 
infection at screening.
20. Positive pre-study drugs and alcohol screen. 
Other Exclusions
21. History or evidence of alcohol abuse (consumption of more than two standard drinks per day 
on average; one standard drink equals 10 grams of alcohol), and/or drug abuse within one 
year of screening.
22. Any suspicion or history of substance abuse or dependence.
23. Dietary restrictions that would prohibit the consumption of standardised meal.
24. Healthy participants under judicial supervision, guardianship or curatorship.
PART 2 (CHB) ONLY
Medical Conditions
1.
History or presence of significant (as judged by the Investigator) cardiovascular (including 
poorly controlled blood hypertension), respiratory, hepatic, renal, gastrointestinal, endocrine, 
haematological disorders, or diagnosed central or peripheral neurological disease, capable 
of altering the absorption, metabolism, or elimination of drugs, or constituting a risk when 
taking the study treatment, or of interfering with the interpretation of the data.
2.
History or presence of bridging fibrosis or cirrhosis or decompensated liver disease.


RO7239958—F. Hoffmann-La Roche Ltd
21/Protocol NP40520, Version 4
3.
History or presence of a medical condition associated with liver disease other than HBV 
infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin 
exposure, thalassemia, non-alcoholic steatohepatitis). Other known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
4.
History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) 13 ng/mL at 
screening.
5.
History of lymphoma, leukaemia, or malignancy within the past five years, except for 
squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for three years.
6.
History of having received (in the last six months) or currently receiving any systemic anti-
neoplastic (including radiation) or immune-modulatory treatment (including systemic 
corticosteroids).
7.
History of organ transplantation.
8.
Any major illness within one month preceding the screening visit, or any febrile illness within 
the two weeks preceding randomisation. 
9.
Clinically significant (multiple or severe) drug allergies, or intolerance to topical 
corticosteroids, or history of severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, 
or exfoliative dermatitis).
10. Estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73m2 (CKD-epi equation).
11. Confirmed QT interval corrected using Fridericia’s formula (QTcF) 450 ms. Patients with 
correctable risk factors for prolonged QT (e.g., electrolyte abnormalities) can be re-assessed 
after correction of the risk factor(s).
Prior/Concomitant Therapy
12. Live vaccine(s) within 28 days of screening, or plans to receive live vaccines during the 
study or within 28 days of the last dose.
13. Expected to need any other systemic antiviral therapy at any time during participation in the 
study, with the exception of current NUC treatment and / or oral/ topical therapy for Herpes 
Simplex Virus (HSV).
Prior/Concurrent Clinical Study Experience
14. Currently enrolled in (i.e., the end of study visit has not been performed) or have received 
investigational treatment within the last 90 days or five times the half-life of the investigational 
drug (whichever is longer) from signing of consent in this or any other clinical study involving 
an investigational product or in any other type of medical research, or the total volume of all 
blood samples provided during the follow-up visits of the former clinical trial exceeds 100 mL.
Diagnostic Assessments
15. Positive hepatitis C antibody at screening.
16. Known positive for human immunodeficiency virus (HIV) infection and/or positive for HIV 
infection at screening.
17. Positive pre-study treatment/alcohol screen.
Other Exclusions
18. History or evidence of alcohol abuse (consumption of more than two standard drinks per day 
on average; one standard drink equals 10 grams of alcohol) and/or drug abuse within one 
year of screening; positive test result for drugs of abuse at screening.
19. Patients under judicial supervision, guardianship or curatorship.


RO7239958—F. Hoffmann-La Roche Ltd
22/Protocol NP40520, Version 4
20. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, 
in the opinion of the Investigator contraindicates the participation in the study.
NUMBER OF PARTICIPANTS
In Part 1, approximately 40-50 participants will be enrolled in four to five cohorts of 10 participants 
each (eight to receive RO7239958 and two to receive placebo). In Part 2, approximately 28-49 
CHB patients will be enrolled in four to seven arms of seven participants each (six to receive 
RO7239958 and one to receive placebo). Part 2a will include approximately 28-35 participants in
four to five arms. Part 2b will include approximately 14 participants in two arms.
CONCOMITANT MEDICATIONS
All medications (prescription and over-the-counter [OTC]) taken within 30 days of study 
screening until the follow-up visit will be recorded in the electronic case report form (eCRF). 
For all parts of the study, paracetamol/acetaminophen, at doses of up to 1 g/day, is permitted for 
use any time during the study. Hormone replacement therapy (HRT) is allowed during the study.
As a general rule, no prescribed concomitant medication will be prohibited for Part 2 of the study.
All concomitant medications (except standard NUC therapy) need to be discussed with the 
Medical Monitor prior to enrolling study participants. 
Participants must abstain from taking nonprescription drugs (including OTC medication, vitamins, 
dietary, herbal supplements, protein powders or fish oils) within 7 days before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the Investigator and the 
Medical Monitor, the medication or the vitamins, dietary, herbal supplements, protein powders or 
fish oils are necessary and will not interfere with the study. Some supplements, herbal and 
traditional remedies, and OTC drugs may affect laboratory values. Abnormal values may lead to 
screening failures or withdrawal from the study. As such, participants should be carefully 
questioned regarding such substances at screening, and advised to refrain from them, if deemed
possible. Pre-existing medications and medications that may be newly needed during 
participation in the study should be discussed with the Medical Monitor.
For all parts of the study, there are restrictions that should be maintained:

Live vaccine(s) can be given provided this is done at least more than 28 days ahead of 
screening. The participant should not receive live vaccines during the study or within 28 days 
of the last dose.

In the event that a participant requires additional medication during the course of the trial, 
this may be allowed after consultation with the Investigator and Sponsor. 
For CHB patients, NUC-related food restrictions may apply.




RO7239958—F. Hoffmann-La Roche Ltd
24/Protocol NP40520, Version 4
Table 1
Schedule of Activities – Main Table, Part 1 (SAD in HV)
Period
Screening
Period 1
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Early 
Termination
Day
Day -28 to Day 
-2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 8
Day 15
Day 22
Day 43
Day 85e)
NA
Time relative (h)
***
***
0
24
48
72
96
120
168
336
672
1008
2016
Visit Window (days)
±1
±2
±7
±7
In-clinic Period 
Ambulatory Visit
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Eligibility
X
X
Randomisation
X
Demography
X
Medical History
X
Anthropometric Measurements
X
Physical Examinationa)
X
X
X
X
X
X
X
X
ECG-12 leadb)
X
X
5
X
X
X
X
X
X
X
Vital Signs
X
X
5
X
X
X
X
X
X
X
X
X
X
X
Substance Usef)
X
X
Serology
X
Blood Chemistry
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
Anti-Drug Antibody c)
X
X
X
Pregnancy test
X
X
X
X
X
Blood PK Sample
12
3
X
X
X
X 
X
X
Xg
Urine PK Sample
4
Administration of Study Medication
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Previous and Concomitant 
Treatments
X
X
X
X
X
X
X
X
X
X
X
X
X


RO7239958—F. Hoffmann-La Roche Ltd
25/Protocol NP40520, Version 4
Table 1
Schedule of Activities – Main Table, Part 1 (SAD in HV) (cont.)
a)
A complete physical examination is required at screening. At all other visits (or as clinically indicated), limited, symptom-directed physical
examinations should be performed at the discretion of the Investigator. Height and weight will be recorded at the Screening visit only.  BMI will 
be calculated at Screening.
b)
Twelve-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs in less than 5 minutes) after the participant has 
been in a supine position for at least 10 minutes, and prior to dosing when applicable.
c)
Anti-drug antibody (ADA) samples to be taken pre-dose.
e)
If necessary, participants may be asked to return for additional follow-up visits.
f)
Includes alcohol testing.
g)
PK sample at early termination visit is optional.


RO7239958—F. Hoffmann-La Roche Ltd
26/Protocol NP40520, Version 4
Table 2
Schedule of Assessments – Detailed Table, Part 1 (SAD in HV)
a)
Urine collection periods [0-4], [4-8], [8-12] and [12-24] hours post-dose. Subject should void 
bladder immediately before dosing. Within a given collection period, all urine voids should be 
collected and pooled; the sample should be taken from the pooled urine for the respective 
collection period.
Study Period
Day
Scheduled 
Time (h)
Vital 
Signs
ECG-12 
lead
Blood PK 
Sample
Urine PK 
Samplea
ADA 
Sample
Screening
Day -28 to 
Day -2
X
X
Day -1
X
X
Day 1
Pre-dose
X
X
X
X
0
X
0.25
X
0.5
X
1
X
X
X
1.5
X
2
X
3
X
4
X
X
X
X
Period 1
6
X
8
X
X
X
X
12
X
X
X
X
18
X
24
X
X
X
Day 2
30
X
36
X
Day 3
48
X
X
Day 4
72
X
X
Day 5
96
X
X
Day 6
120
X
X
Day 8
168
X
X
X
Follow Up Visit
Day 15
X
X
Day 22
X
X
X
X
Day 43
X
X
Day 85
X
X
X
Early termination
Anytime
X
X
X


RO7239958—F. Hoffmann-La Roche Ltd
27/Protocol NP40520, Version 4
Table 3
Schedule of Assessments – Main Table, Part 2a and Part 2b (CHB [
], 5 weeks)
Period
Screening
Discontinuation
Reboundk)
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up Visit
Week 1
Week 2
Week 3
Week 4
Week 5
Day
Day -29 to Day -
2
Day -7 to -4
Day 1
Day 2
Day 8
Day 15
Day 22
Day 29
Day 30
14 days after 
last dose
28 days after 
last dose
56 days 
after last 
dose
84 days after 
last dose
Time Relative (h)
***
***
0
24
168
336
504
672
696
***
Visit Window (days) a)
±3
±3
±7
±7
In-clinic Period b)
Ambulatory Visit
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Eligibility
X
X
Randomization
X
Demography
X
Medical History
X
Elastography
X
Physical Examination
X c)
X 
X
X c)
X
X c)
X c)
X c)
ECG-12 lead d, e)
X
4
X
X
X
4
X
X
X
X
X
Vital Signs e)
X
4
X
X
X
X
4
X
X
X
X
X
Substance Usel)
X
X
Serology
X
Blood Chemistry e)
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology e)
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis e)
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation e)
X
X
X
X
X
X
X
X
X
X
X
X
Anti-Drug Antibody f)
X
X
X
Urine Injury Biomarkerse)
X
X
X
X
X
X
X
X
Blood Liver Injury Biomarkerse)
X
X
X
X
X
X
X
X
Pregnancy Teste)
X
X
X
X
X
X
X
Alpha Fetoprotein
X




RO7239958—F. Hoffmann-La Roche Ltd
29/Protocol NP40520, Version 4
Table 3
Schedule of Assessments – Main Table, Part 2a and Part 2b (CHB [
 
], 5 weeks) (cont.)
a)
All visits can be done ±3 days, if applicable, with the exception of the safety and follow-up 
visits 56 and 84 days after last dose (±7 days). The safety and follow-up visits in Table 3
will only apply to Part 2a (for Part 2b, see Table 5).
At home nurse visits: vital signs, AEs and previous and concurrent treatments will be 
assessed; Blood for PK may be collected as specified, and other laboratory specimens 
may be collected as specified in the SoA table. ECG may be performed if appropriate. If 
site is not participating in home nurse visit, this will be an outpatient visit in clinic.
b)
Optional overnight stay in the clinic: On Day 1 as well as on Day 29 participants can 
either stay overnight in the clinic or can be discharged after completion of the 8 hours 
post-dose assessments and return the next morning for the subsequent assessments, at 
the Investigator’s discretion.
c)
Complete physical examination is required. At all other visits (or as clinically indicated), 
limited, symptom-directed physical examinations should be performed at the discretion of 
the Investigator. Height and weight will be recorded at the Screening visit only. BMI will 
be calculated at Screening.
d)
Twelve-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead 
ECGs in less than 5 minutes) after the participant has been in a supine position for at 
least 10 minutes.
e)
Pre-dose (on days of study treatment administration). For ECG and VS as given in the 
Detailed Table for Part 2a.
f)
ADA samples to be taken pre-dose (when applicable) 
i)
HBV serology will include HBsAg (quantitative), anti-HBs (quantitative), HBeAg
(qualitative) and anti-HBeAb (qualitative). 
k)
In case of HBV DNA rebound an unscheduled confirmatory HBV DNA quantification 
sample should be taken, a sample for HBV DNA genotyping and a sample for NUC PK.
l)
Includes alcohol testing.


RO7239958—F. Hoffmann-La Roche Ltd
30/Protocol NP40520, Version 4
Table 4
Schedule of Assessments – Detailed Table, Part 2a and Part 2b 
(CHB [
], 5 weeks)
a)
Urine collection periods [0-4] and [4-8] hours post-dose. Patient should void bladder 
immediately before dosing. Within a given collection period, all urine voids should be 
collected and pooled; the sample should be taken from the pooled urine for the respective 
collection period.
Visit
Day
Scheduled 
Time (h)
Vital signs
ECG
PK Blood 
PK Blood 
PK Blood 
PK Urinea
ADA
Screening
Day -29 
to -2
X
X
Day 1
Predose
X
X
X
X
X
X
0
X
0.5
X
X
X
1
X
X
X
X
X
Week 1
2
X
X
X
4
X
X
X
X
X
X
6
X
X
X
8
X
X
X
X
X
Day 2
24
X
X
X
X
Week 2
Day 8
Predose
X
X
X
X
X
2
X
Week 3
Day 15
Predose
X
X
X
X
X
2
X
X
Week 4
Day 22
Predose
X
X
X
X
X
2
X
Week 5
Day 29
Predose
X
X
X
X
X
X
0
X
0.5
X
X
X
1
X
X
X
X
X
2
X
X
X
4
X
X
X
X
X
X
6
X
X
X
8
X
X
X
X
X
Day 30
24
X
X
X
Discontinuation
X
X
X
X
X
Follow up Visits
14 days 
after last 
dose
X
X
X
X
X
28 days 
after last 
dose
X
X
X
X
X
X
56 days 
after last 
dose
X
X
X
X
X
84 days 
after last 
dose
X
X
X
X
X


RO7239958—F. Hoffmann-La Roche Ltd
31/Protocol NP40520, Version 4
Table 5
Schedule of Assessments – Main Table, Part 2b (CHB [
] 12 weeks – as of Week 6)
Period
Discontinuation
Reboundi)
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Week 6 a)
Week 7
Week 8
Week 9
Week 10
Week 11
Week 12
Day
Day 36
Day 43
Day 50
Day 57
Day 64
Day 71
Day 78
14 days after 
last dose
28 days after 
last dose
56 days 
after last 
dose
84 days 
after last 
dose 
Time Relative (h)
840
1008
1176
1344
1512
1680
1848
Visit Window (days)
±3
±3
±7
±7
Ambulatory Visit
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X b)
X
X
X
ECG 12 lead c, d)
X
X
X
X
X
X
X
X
Vital Signs d)
X
X
X
X
X
X
X
X
Blood Chemistry d)
X
X
X
X
X
X
X
X
Hematology d)
X
X
X
X
X
X
X
X
Urinalysis d)
X
X
X
X
X
X
X
X
Coagulation d)
X
X
X
X
X
X
X
X
Anti Drug Antibody e)
X
X
X
Urine Injury Biomarkers d)
X
X
X
X
X
X
X
X
Blood Injury Biomarkers d)
X
X
X
X
X
X
X
X
Pregnancy Test
X
X
X
X
Blood PK Sample
2
2
2
2
2
2
2
X
X
X
X
X
Blood PK Sample 
2
2
2
X
X
X
X
X
Blood PK Sample 
2
X
X
X
X
X
Urine PK Sample
2
NUC PK
X
HBV DNA quant d)
X
X
X
X
X
X
X
X
X
HBV serology d,g)
X
X
X
X
X
X
X
X
HBV RNA quant d)
X
X
X
X
X
X
X
X
HBV core related antigen d)
X
X
X
X
X
X
X
X
HBV DNA Genotyping (Rebound)
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Previous and Concomitant Treatments
X
X
X
X
X
X
X
X
X
X
X
X


RO7239958—F. Hoffmann-La Roche Ltd
32/Protocol NP40520, Version 4
Table 5
Schedule of Assessments – Main Table, Part 2b (CHB [
] 12 weeks – as of Week 6) (cont.)
a)
For the assessments of Weeks 1 to 5, see the Part 2a/ Part 2b (CHB, 5 Week) Main SoA table. All visits can be done ±3 days with the 
exception of the safety and follow-up visits on D134 and 182 (±7 days).
At home nurse visits: vital signs, AEs and previous and concurrent treatments will be assessed; Blood for PK and other laboratory 
specimen may be collected as specified in the SoA table. ECG may be performed if appropriate. If site is not participating in home nurse 
visits, this will be an outpatient visit in clinic.
b)
Complete physical examination is required. At all other visits (or as clinically indicated), limited, symptom-directed physical examinations 
should be performed at the discretion of the Investigator.
c)
Twelve-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs in less than 5 minutes) after the participant 
has been in a supine position for at least 10 minutes.
d)
Pre-dose (on days of study treatment administration). 
e)
ADA samples to be taken pre-dose (when applicable).
g)
HBV serology will include HBsAg (quantitative), anti-HBs (quantitative), HBeAg (qualitative) and anti-HBeAb (qualitative). 
i)
In case of HBV DNA rebound an unscheduled confirmatory HBV DNA quantification sample should be taken, a sample for HBV DNA 
genotyping and a sample for NUC PK.


RO7239958—F. Hoffmann-La Roche Ltd
33/Protocol NP40520, Version 4
Table 6
Schedule of Assessments – Detailed Table, (CHB [
 
] 12 weeks – as of Week 6)
a)
Urine collection periods [0-4] and [4-8] hours post-dose. Patient should void bladder 
immediately before dosing. Within a given collection period, all urine voids should be 
collected and pooled; the sample should be taken from the pooled urine for the respective 
collection period.
Visit
Day
Scheduled 
Time (h)
Vital signs
ECG
PK Blood PK Blood PK Blood 
PK Urinea
ADA
Week 6
Day 36
Predose
X
2
X
Week 7
Day 43
Predose
X
X
X
X
X
2
X
X
Week 8
Day 50
Predose
X
2
X
Week 9
Day 57
Predose
X
X
X
X
X
0
X
2
X
X
X
4
X
Week 10
Day 64
Predose
X
2
X
Week 11
Day 71
Predose
X
X
X
X
X
2
X
X
Week 12
Day 78
Predose
X
2
X
Discontinuation
X
X
X
X
X
Follow up Visits
14 days 
after last 
dose
X
X
X
X
X
28 days 
after last 
dose
X
X
X
X
X
X
56 days 
after last 
dose
X
X
X
X
X
84 days 
after last 
dose
X
X
X
X
X


RO7239958—F. Hoffmann-La Roche Ltd
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2.
INTRODUCTION
2.1
STUDY RATIONALE
This is the first study with RO7239958 in humans, designed to assess the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple 
ascending doses in healthy participants and participants diagnosed with chronic hepatitis 
B (CHB). Data collected in this study will be critical to define optimal doses and dosing 
regimens to be studied in Phase II clinical trials in CHB patients.
 
 
 
 
 
The 
ASGPR is expressed predominantly by hepatocytes with low to no expression in other 
cell types (Stockert 1995; Zelensky et al 2005).
 
 
 
 
 
 
 


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For further information, see the RO7239958 Investigator’s Brochure.
2.2
BACKGROUND 
2.2.1
Background on Disease
Chronic HBV infection is a major global cause of liver disease, and substantial morbidity 
and mortality result from its main complications – cirrhosis, liver failure, and 
hepatocellular carcinoma. An estimated 257 million people worldwide are chronic HBV 
carriers, defined by the persistent detection of hepatitis B surface antigen (HBsAg) in 
serum. Nearly 900,000 people die annually due to the complications of chronic hepatitis 
B (CHB), and mortality rates are predicted to continue to rise over the next five decades 
(Nayagam et al 2016; WHO 2018). 
RO7239958 is being developed for the curative treatment of chronic HBV infection. In 
patients with CHB, the current goal of antiviral therapy is to prevent liver disease 
progression, induce remission of liver inflammation and improvement of liver fibrosis, 
and reduce the risk of morbidity and mortality. Currently, there are 2 main treatment 
options for CHB: subcutaneous interferon alpha preparations (IFNα; conventional or 
pegylated) and oral nucleoside/nucleotide analogues (NUCs), including tenofovir, 
entecavir, adefovir, telbivudine, and lamivudine (EASL 2017). IFNα is administered by 
subcutaneous injections and shows overall modest efficacy and poor tolerability (Terrault 
et al 2018). NUCs, the current mainstay of therapy, inhibit transcription of pre-genomic 
HBV RNA into HBV DNA. NUCs have a more favorable tolerability profile than IFNα, and 
treatment guidelines recommend use of tenofovir or entecavir due to their greater 
potency and very low risk of drug resistance relative to other NUCs. Treatment with 
tenofovir or entecavir results in suppression of HBV replication in most patients. Over 
time, this is typically accompanied by normalized indices of liver inflammation and 
improved indices of liver fibrosis. Whereas IFNα treatment has a finite duration of 
typically 48-52 weeks, NUCs are commonly administered long-term. Neither form of 
treatment commonly achieves a “functional cure”, defined by the loss of detectable 
hepatitis B surface antigen (HBsAg) in serum. Loss of HBsAg signals virus control and 
indicates that NUC treatment may be stopped. However, loss of HBsAg occurs in 0-3% 


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of patients after 1 year of NUC treatment (vs. 3-7% with IFNα). Rates increase slowly 
over several years of NUC treatment among hepatitis B e antigen (HBeAg) positive 
subjects, while still remaining below 14% after 5 to 8 years in this group. Rates of HBsAg 
loss among HBeAg negative patients are approximately 0-1% despite years of therapy 
(EASL 2017; Terrault et al 2018). In the absence of HBsAg loss, virological relapse is 
common if NUC treatment is discontinued. 
Even in subjects that achieve HBsAg loss, HBV persists as covalently closed circular 
DNA (cccDNA) in the nucleus of infected hepatocytes, posing a challenge to the 
achievement of a “complete cure”, i.e., virus eradication. HBV sequences can also 
integrate in the host chromosome, a phenomenon that appears to be especially common 
in HBeAg negative patients. The integrated viral DNA does not encode a complete virus 
genome and cannot sustain production of virus particles; however, surface HBV 
sequences that encode HBsAg can be expressed from integrated HBV DNA, allowing 
persistent HBsAg production (Allweiss et al 2017; Woddell et al 2017; Pfefferkorn et al 
2017). New treatments of finite duration that are well tolerated and can produce greater 
rates of durable HBsAg loss, and potentially contribute to virus eradication, are required.
2.3
BENEFIT/RISK ASSESSMENT
Within current standard of care HBV therapies, NUCs have a more favorable tolerability 
profile than IFNbut commonly have to be administered long term, possibly lifelong, in 
order to maintain viral suppression. Neither form of treatment commonly achieves a 
“functional cure”, defined by the loss of detectable hepatitis B surface antigen (HBsAg) in 
serum. Study NP40520 will provide the key information necessary to support further 
clinical development of RO7239958, with the ultimate aim of providing patients with a 
curative combination treatment for chronic HBV infection. 
Study NP40520 is designed to evaluate the safety, tolerability, PK and PD properties of 
RO7239958. The study will be conducted in two parts, of which Part 1 will be a single 
ascending dose (SAD) study in healthy participants, and Part 2 will be a dose range 
finding (DRF) study in CHB patients established on NUC therapy. Part 2 comprises two 
sub-parts (Part 2a and Part 2b). Patients will receive RO7239958 or placebo for 4 weeks
in Part 2a, and for up to 12 weeks in Part 2b. The study is randomized to control for 
known and unknown factors between active treatment and placebo. The aims of the 
study are to obtain data on safety (primary end-point) and PK (secondary end-point). 
Although antiviral activity will be explored in CHB patients, there is no expected direct 
benefit for study participants. The benefit is to be intended for the overall CHB 
population. Results will be used to inform future trials of RO7239958 and guide further 
clinical development as a treatment against CHB. 


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No prior clinical experience with RO7239958 exists. In Study NP40520 healthy 
participants and CHB patients will be kept under medical observation and monitored 
closely for clinical and laboratory adverse events. CHB patients eligible to join study 
NP40520 will be established on effective NUC therapy, have preserved hepatic function, 
and have no current or past history of cirrhosis, thus reducing the risk of liver-related 
adverse events. The evaluation of the potential risks of treatment, and the specific tests, 
observations, and precautions required for clinical studies with RO7239958 are based 
on information obtained preclinically from 2-week and 4-week studies in rats and NHPs, 
and a 39-week exploratory study in NHPs. In addition, there is prior experience with 
other LNA SSOs, such as that derived from study BP39405 (a two-part randomized 
SAD/multiple ascending dose study to evaluate RO7062931 in healthy volunteers and 
CHB patients).
 
 A reduction of expression
levels for a certain subset of host transcripts could not be detected (Lim et al 2018). 
 
 
 
 
 
 
 
 
 
 
 
 
 


RO7239958—F. Hoffmann-La Roche Ltd
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RO7239958 will be administered in a hospital or clinic environment under supervision of 
an experienced clinician. Detailed instructions on dosage and administration of 
RO7239958 are provided. SC administration of LNA SSOs carries a risk of injection-site 
reactions (ISRs). At higher doses, there is also a potential risk for LNA SSO-related liver 
and kidney toxicity (Chen et al 2015; van Poelgeest et al 2015). Furthermore, it is 
hypothesized that HBsAg suppression may potentially contribute to restoring HBV-
specific immunity in CHB patients, which may result in a transaminase flare. Frequent 
monitoring of full blood count, clotting, serum biochemistry and urinalysis will be 
performed during the course of the study, and close monitoring of renal and hepatic 
safety parameters will be included, comprising testing for renal function, urine sediment, 
serum transaminases, and hepatic synthetic and secretory function. Defined stopping 
criteria are proposed for dosing of individual study participants, cohorts and arms. In 
addition to standard measures of renal and liver safety, exploratory markers of renal and 
liver injury will be analyzed in urine and blood samples, respectively. Safety monitoring
will be extended post-dosing for 12 weeks in both healthy participants and CHB patients. 
 
 
More detailed information about known and expected benefits in the context of potential 
risks and reasonably expected adverse events of RO7239958 is provided in the
RO7239958 Investigator’s Brochure.






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Table 7
Objectives and Endpoints (cont.)
All parts
Parts 2a and 
2b
Safety
To study the effect of multiple 
ascending SC doses of 
RO7239958
on exploratory markers of 
kidney and liver injury.
Time course profiles of:

Renal injury markers in urine (e.g., 
clusterin [CLU], cystatin C [CYS-C], 
kidney injury molecule-1 [KIM-1], 
neutrophil gelatinase-associated 
lipocalin [NGAL], 
N-acetyl-beta-D-glucosaminidase 
[NAG], osteopontin [OPN]); plus 
creatinine, albumin, and total protein.

Liver injury markers in peripheral blood 
(e.g., glutamate dehydrogenase 
[GLDH], MCSFR1, OPN, CK18, 
ccCK18, total HMGB1).

Anti-drug antibodies (ADA).
Parts 2a and 
2b
PK/PD
To explore the relationship 
between PK and 
pharmacodynamics (PD) 
after multiple SC doses in 
CHB patients on stable NUC 
therapy.

Relationship between dose and/or
plasma exposure of RO7239958 and 
quantitative measures of antiviral 
activity.


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Table 7
Objectives and Endpoints (cont.)
Parts 2a and 
2b 
PD
To explore the anti-viral
activity of RO7239958 after 
multiple SC doses in CHB 
patients on stable NUC 
therapy.
The following parameters will be measured: 
Time course profile of HBV RNA levels.
Time course profile of HBV core-
related antigen (HBcrAg) levels
Time course profile of HBeAg levels.
Time course profile of HBeAg levels 
(in HBeAg positive patients).
4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.
The study will be conducted in two parts, of which Part 1 will be in healthy participants 
and Part 2 will be in CHB patients (see Section 1.2). All parts of the study are
Observer-blind (see Section 6.3.2). All members of the project and study team who are 
not in direct contact with the participants may be unblinded. Part 1 will evaluate the 
safety, tolerability and PK of RO7239958 following subcutaneous (SC) administration of 
single ascending doses in healthy participants. Part 2 will evaluate the safety, tolerability, 
PK, and pharmacodynamics (PD) of multiple SC doses of RO7239958 in CHB patients 
established on NUC therapy, and comprises two subparts, Part 2a and Part 2b. Part 2 is 
a dose range finding study (DRF).


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Part 1 – Single-Ascending Dose (SAD) Study in Healthy Participants
In Part 1, at least four cohorts will receive a single dose of RO7239958 or placebo. An 
optional cohort with participants receiving RO7239958 or placebo may be included, 
based on the need for further safety or PK data. Ten healthy participants, eight receiving 
RO7239958 and two receiving placebo, will be enrolled in each cohort using a 4:1 
randomisation scheme.
 
 
Each cohort will implement sentinel dosing to monitor acute reactions 
over 24 hours post-dosing. Two participants will be dosed on Day 1, and at least one of 
two participants will have received RO7239958; the remaining eight participants shall be 
dosed the following day (i.e., after 24 hours) following satisfactory clinical safety review 
of the first two participants by the Investigator. For each cohort, safety will be monitored 
for 28 days (21 days for safety assessment plus 7 days of clinical safety observation), 
before escalating to the next cohort. A dose escalation meeting will take place prior to 
starting the next cohort. In all participants, safety will be monitored for a total of 12 
weeks post-dosing.
Part 2 – Dose Range Finding (DRF) Study in CHB Patients
Part 2 is a placebo-controlled, adaptive, parallel multiple-dose study in participants with 
CHB on stable NUC therapy, with the aim to study the safety, tolerability, PK and PD of 
RO7239958, and the relationship between RO7239958 PK and PD parameters. Dosing 
will be initiated in CHB patients with a safe dose as determined in Part 1, which will fall 
within the human efficacious dose range predicted with PK/PD modeling. Part 2 is 
divided into two parts, Part 2a and Part 2b.
Part 2a
In Part 2a, CHB patients will be enrolled into one of two arms (Arms 1 and 2), which will 
run in parallel. Each arm will enroll seven participants using a 6:1 randomization scheme. 
To ensure balance between arms, enrolment of HBeAg positive participants will be 
capped. Participants of each arm can receive up to five doses of RO7239958 or placebo 
over 4 weeks.


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 Two additional, parallel arms (Arms 3
and 4) will open after Arms 1 and 2 have enrolled and followed-up for at least 28 days a 
sufficient number of participants to provide the safety and PK/PD information required to 
further inform dose and regimen optimization. An optional Arm 5 will open if further doses 
or regimens need to be explored based on data from Arms 3 and 4. A data review meeting will 
also take place before opening Arms 3 and 4 (and potentially optional Arm 5). Decision on 
dose levels and regimens for Arms 3 and 4 will be based on the safety, PK, and PD data 
from Arms 1 and 2 and all available safety and PK data from Part 1. If efficacious dose 
levels cannot be reliably predicted from PK/PD modeling and Part 1 data, the doses 
administered in Part 2a will be within the range demonstrated to be safe and well 
tolerated in Part 1.
 
 
 
 In all patients, safety will be monitored for a total of 12 weeks 
post-dosing.
Part 2b (optional)
The two additional arms (Arms 6 and 7) of Part 2b will open if further doses or regimens 
need to be explored based on the data from Part 2a, or a dose or regimen from Part 2a 
needs to be optimized and additional data evaluated. There may be inclusion of 
participants who are not treated with NUCs, or inclusion of a larger number of 
participants of a given HBeAg status. Each arm in Part 2b will comprise seven 
participants randomized to RO7239958 or placebo using a 6:1 randomization scheme. 
 
 In all patients, safety will be monitored for 
a total of 12 weeks post-dosing.
4.1.1
Length of the Study
Part 1: The total duration of the study for each participant will be up to 16 weeks, divided 
as follows:

Screening: Up to 28 days 

In clinic period: Days -1 to 3.

Treatment Period: Day 1 

Safety follow-up: up to at least 84 days after the dose of RO7239958 or placebo.
Part 2a: The total duration of the study for each participant will be up to 20 weeks 
divided as follows:

Screening: Up to 28 days.




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4.1.2.1
Part 1 - Dose-Escalation Decision Criteria
Part 1 uses an adaptive dose-escalation process that may be modified if:

Events emerge that the Sponsor and/or the Investigator consider indicators that the 
planned dose-escalation step would result in unacceptable risks for the safety of 
healthy participants.

The Sponsor and the Investigator agree to do so, and neither considers that the 
proposed subsequent dose level poses an unacceptable risk to the study subjects.
Single doses will not be escalated if the dose-escalation stopping criteria are met (see 
Section 4.1.3).
4.1.3
Stopping Rules Criteria
Liver-related 
Isolated elevations in liver transaminases (ALT or AST) in the absence of liver function 
abnormalities may occur after administration of RO7239958 as a recognized LNA SSO 
class effect. In addition to the LNA SSO class effect, CHB patients may also 
hypothetically experience transaminase flares if HBsAg suppression leads to immune-
restoration. Stopping criteria have been developed to take these potential effects into 
account.
Part 1: If, at a given dose level, one or more of the criteria described below is fulfilled, 
dose-escalation to the next cohort will be paused in order to assess the possible 
underlying causes and relation to RO7239958. If a relation to study treatment cannot be 
excluded by the Investigator and the Sponsor’s Medical Monitor, dose escalation will be 
halted. 
Criteria: 

At least two of eight healthy participants receiving RO7239958 experience
dose-limiting AEs (DLAEs) of an ALT or AST increase 5x the upper limit of normal 
(ULN; confirmed by retesting within 48 hours) with preserved measures of liver 
function (total bilirubin, and INR or prothrombin time [PT]),
or

At least one of eight healthy participants receiving RO7239958 experiences one of 
the following DLAEs: confirmed (within 48 hours) increase in ALT or AST 3x ULN 
accompanied by confirmed total bilirubin 2x ULN, INR 1.5, or PT 1.5x ULN, or 
appearance of jaundice or symptoms suggestive of drug-induced liver injury (e.g., 
fatigue, nausea, vomiting, right upper quadrant abdominal pain or tenderness, fever, 
rash, and eosinophilia).




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Criteria: At least two of eight healthy participants or at least two of six CHB patients 
receiving RO7239958 experience one or more of the following DLAEs:

Confirmed decline in eGFR 60 ml/min

Grade 3 or 4, or otherwise significant (as defined by the Investigator) RO7239958-
related AEs of the same character, or Grade 3 or 4 laboratory abnormalities.

Other findings (regardless of the incidence rates) that at the joint discretion of the 
Sponsor and the Investigator indicate that dosing and any dose escalation should 
be halted (see Section 7.1). 
General considerations
Part 1: In case dose-escalation is stopped, lower doses within the tolerated dose-range
could be investigated or a previous dose could be repeated in subsequent cohorts, by 
mutual agreement between the Sponsor and Investigator, in order to increase the 
amount of data within the tolerated dose-range.
Part 2: In case an arm is stopped, alternative regimens within a previously tolerated
dose/exposure range could be further investigated, or a previous regimen could be 
repeated in subsequent arms, by mutual agreement between the Sponsor and 
Investigator, in order to increase the amount of data within the tolerated dose/exposure
range. 
4.1.4
Communication Strategy
Information will be communicated, as follows:

The Investigator must confirm to the Sponsor that a participant has been dosed and 
provide a brief summary of the status of the participant in terms of safety and 
tolerability to RO7239958 or placebo, communicated by email or telephone. 

In Part 1, the Investigator will provide a safety assessment feedback to the Sponsor 
of the first two sentinel-dosed healthy participants of each cohort before proceeding 
to dosing the remaining participants.

For all parts of the study and in the event of a dose-limiting adverse event (DLAE),
the Investigator will contact the Sponsor immediately to discuss participant status 
and action taken or to be taken.

After completion of each cohort in Part 1 (i.e., after the last participant in the cohort 
has reached the last day of the evaluation period, comprising 21 days of monitoring 
plus a further 7 days of clinical observation, for a total of 28 days), the Sponsor will 
organize a teleconference with the Investigators to discuss the safety and tolerability 
of RO7239958 or placebo, and to discuss the dose for the next cohort. 


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During each teleconference:
o
Safety and tolerability (see Appendix 2) will be discussed along with the 
results of available PK data, in addition to safety laboratory results and 
any other available data that may assist the decision process. 
o
Dose escalation will only proceed if the Investigator and the Sponsor are 
satisfied with the safety profile of the previous cohort and agree to 
escalate to the next dose level. 
o
The decision of these meetings will be documented in writing and both 
the Sponsor and Investigator will approve the minutes of these meetings 
to confirm agreement.
For Part 2, a teleconference will be organized to discuss accumulated data from Arms 1 
and 2 in Part 2a prior to the start of Arms 3 and 4; a teleconference will also be 
organized as above after completion of Arms 3 and 4 (and optional Arm 5) and before the 
start of subsequent arms in Part 2b if applicable.
In addition to these communications, the Sponsor and investigators will be in regular 
contact throughout the study by email or telephone, as per normal interactions during the 
conduct of a clinical study, and the Sponsor will arrange regular teleconferences and 
meetings to discuss study status.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
 
 
 
 
 
 
In order to reduce safety risks, the effects of each dose level will be reviewed carefully 
before escalating to the next dose level. Dose escalation will take place after a review of 
safety, tolerability, and available PK data, as described in Section 4.1.2. Stopping rules 
are detailed in Section 4.1.3. The safety observation period has been set to 21 days for 
the safety laboratory assessments and to 28 days for adverse event monitoring, and this 
approach is supported by data from the BP39405 study (RO7062931) which has 
completed dosing in healthy participants (see the RO7062931 Investigator’s Brochure).


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The DRF part of the study, Part 2a, will evaluate the safety, tolerability, PK and PD 
effects of multiple doses of RO7239958 in CHB patients. Part 2b is an extension part of 
Part 2a to evaluate alternative regimens, additional safety, PK and PD data, if required.
 
 The approach is based on the 
consideration that the PK profile of RO7239958 is anticipated to show minimal variation 
between healthy participants and patients, and that the doses in Part 2 will never exceed 
the maximum safe dose defined in healthy volunteers in Part 1. Opening Part 2a with 
two parallel dosing levels will increase the likelihood of detecting antiviral activity and 
identifying a dose for regimen optimization in subsequent arms, while remaining within
acceptable safety margins, based upon non-clinical data and data from Part 1. 
In this study RO7239958 will be given as an add-on to NUC treatment. It is envisaged 
that in future studies RO7239958 will contribute to combination regimens with one or 
more antiviral agents or immune-enhancers, with the aim of inducing a HBV cure.
4.2.1
Rationale for Study Population
Part 1 will be conducted in healthy males and female subjects of non-childbearing 
potential, 18 to 65 years of age. The absence of confounding diseases and co-
medications in healthy volunteers allows for a more consistent and comprehensive 
assessment of the drug disposition and the safety profile.
Part 2 will be conducted in CHB patients established on effective NUC therapy that have 
no current or previous history of cirrhosis and have preserved liver function, thus 
reducing the risk of liver-related adverse events. The PD effects of RO7239958 in 
humans can only be tested in patients with CHB and will comprise both standard and 
exploratory markers of antiviral activity. The results will provide essential information for 
supporting future development, including dose-selection for a Phase II study in CHB 
patients.
4.2.2
Rationale for Control Group
This study is designed to be adequate and controlled. Participants will be randomized to 
RO7239958 or placebo in each cohort of Part 1 and each arm of Part 2. The 
randomization scheme to active and placebo groups is considered necessary to 
generate an adequate within-study comparator dataset and allow a proper initial 
evaluation of the magnitude of any treatment effects. The study is 
Investigator/participant-blind to eliminate potential bias.
4.2.3
Rationale for Biomarker Assessments
In Part 2 of Study NP40520 blood samples will be taken at defined time-points (as 
shown in the Schedule of Activities, see Section 1.3) to monitor viral parameters in 
correlation with administered doses and PK parameters of RO7239958.


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RO7239958 inhibits the expression of HBV RNA transcripts in HBV-infected human 
hepatocytes and suppresses production of viral proteins, including HBsAg and HBeAg. 
Thus, it is proposed that in Part 2, RO7239958 may cause a reduction of serum HBsAg 
in CHB patients. HBsAg loss is the recognized endpoint of effective antiviral therapy in 
international guidelines (Terrault et al 2018; EASL 2017; APASL 2016). The main 
virological end-point in Study NP40520 is therefore the time-course of serum HBsAg 
levels (see Section 8.1). CHB patients will have an HBsAg level 250 IU/ml at screening
and the kinetics of HBsAg decline during dosing will be monitored together with the 
kinetics of rebound post-dosing. 
Additional parameters will include markers that are well established for the assessment 
of HBV treatment outcomes, including the time-course of anti-HBs levels, and evolution 
of HBeAg and anti-HBe status. 
 
 
 
 
 
Several exploratory virological end-points have recently emerged in the field that may 
provide an indication of improved virus control and achievement of a HBV cure. Among 
these, pregenomic HBV RNA that bypasses reverse transcription and is released in 
plasma is proposed to provide a direct measure of the transcriptional activity of cccDNA. 
Consistent with this view, in NUC-treated patients with suppressed HBV DNA, presence 
of detectable circulating HBV RNA signals an increased probability of HBV DNA rebound 
upon NUC cessation (Wang J et al 2016). 
Circulating HBcrAg levels provide one additional exploratory biomarker that will be 
monitored in patients pre-dosing, during dosing and post-dosing. HBcrAg is a composite 
circulating biomarker made of 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 treatment 
outcomes (Mak et al 2018; Chen et al 2017). 
 
 


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Patients in Part 2 will be established on effective NUC therapy at study entry and will 
have shown a circulating HBV DNA level below the assay lower limit of quantification for 
at least 6 months, and confirmed at screening. During Study NP40520, patients will be 
monitored to ensure that HBV DNA suppression is maintained. Patients who experience 
HBV DNA rebound during the study will be recalled for repeat testing. If the HBV DNA 
level is confirmed 100 IU/ml, the patients will be assessed for evidence of NUC 
resistance using sequencing and potentially phenotyping, and the viral genotype will be 
determined by sequencing. In patients with no detectable HBV DNA, any sample with 
detectable HBV RNA will be used in an attempt to determine the HBV genotype by RNA 
sequencing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In Part 2, blood and urine samples will be collected during the course of the study for the 
analysis of exploratory safety biomarkers (see Section 1.3). Renal tubular injury is a 
known potential class effect of LNA SSOs and a potential safety risk of RO7239958
based on data obtained preclinically. The FDA recently approved six urinary markers 
(clusterin, cystatin C, KIM-1, NAG, NGAL, and osteopontin) as an integrated composite 
measure (CM) of a kidney tubular injury response (FNIH and PSTC Collaboration 
Briefing Book). By measuring the fold change from baseline of these urine markers 
(normalized to urine creatinine), the CM panel is intended to: i) evaluate the likelihood of 
a renal injury response in an arm or dose group, and ii) complement the standard 
measures used for kidney safety monitoring such as serum creatinine, blood urea 
nitrogen (BUN), urinary albumin/creatine ratio, and urinary total protein/creatinine ratio. 
The CM panel is not yet intended for individual patient safety monitoring. Due to the 
exploratory nature of the tests, the results will only be analyzed retrospectively and will 
not be used for decision making. 
When measuring the above, the creatinine- and cystatin C-based estimated glomerular 
filtration rate (eGFR) will be also calculated by the CKD-epi equation  as a standard 
measure of renal function (see Appendix 4  and Appendix 6). 
Another potential safety risk of RO7239958 is hepatic injury, based on preclinical 
findings in NHPs and reflecting the intrinsic potential class effect of liver-targeted LNA 
SSOs. 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). Study NP40520 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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4.4
END OF STUDY DEFINITION
The end of the study is defined as the date when the last participant last visit (LPLV) 
occurs (includes the safety and follow-up visit), or the date at which the last data point 
from the last participant required for statistical analysis is received, whichever is the later 
date, unless the participant was prematurely discontinued.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.1.


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The participants in this study will be healthy female and male volunteers and patients 
diagnosed with chronic HBV infection, between 18 and 65 years of age, inclusive, who 
fulfill all of the given inclusion criteria.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
ALL STUDY PARTS
Informed Consent: 
1. Able and willing to provide written informed consent and to comply with the study 
protocol according to ICH and local regulations.
Age:
2. Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Weight:
3. Body weight of at least 45 kg and maximally 150 kg, and BMI within the range 18 to 
32 kg/m2 (inclusive).
Sex: 
4.
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 to meet 
enrolment 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 contraception.
a)
Female participants: Should be women of non-childbearing potential 
(WONCBP; see Appendix 5).


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b)
Male participants: During the treatment period and for at least 105 days after 
the last dose of RO7239958 or placebo, agreement to: 
i.
With partners who are women of childbearing potential (WOCBP): 
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. 
ii.
With pregnant female partners, remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures such as a 
condom to avoid exposing the embryo. 
iii.
Refrain from donating sperm for at least 105 days after last dose of 
RO7239958 or placebo.
PART 1 (SAD HV) ONLY
Type of participants:
1. Healthy, as judged by the Investigator. Healthy status will be defined as the 
absence of evidence of any active or chronic disease following a detailed medical 
and surgical history, concomitant drug use (including hormonal supplements), a 
complete physical examination including vital signs, 12-lead ECG, hematology, 
blood chemistry, serology, and urinalysis.
Others Inclusions:
2. Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on 
Day 1, and agrees to remain non-smoker during the study.
PART 2 (CHB) ONLY
Type of Participants and Disease Characteristics
1. Positive serum HBsAg status for > 6 months prior to screening.
2. Serum HBsAg level 250 IU/mL at screening.
3. On stable entecavir or tenofovir (alone or in combination) treatment, and having 
received the same NUC in the 3 months prior to randomisation, and expected to 
remain on the same NUC for the duration of study participation.
4. HBV DNA below the lower limit of quantification (LLQ < 20 IU/mL) for ≥ 6 months 
prior to screening by local testing, and confirmed at screening.
5. Screening laboratory values (including hematology, chemistry, urinalysis) within 
normal ranges, or judged to be not clinically significant by the Investigator and 
Medical Monitor, and:
a) Screening alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) 2 × upper limit of normal (ULN), confirmed between Day -7 to Day -4. 


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b) Screening gamma-glutamyl transferase (GGT) ULN (Note: GGT ≤1.5 x ULN is 
acceptable if considered not clinically significant) and alkaline phosphatase 
(ALP) ULN, and normal values of prothrombin time (PT), INR, and activated 
partial thromboplastin time (aPTT). PT and/or aPTT > ULN is acceptable if 
considered not clinically significant and INR and other parameters of liver function are 
within normal limits and there are no current and historical concerns. Whenever the 
Screening tests are repeated, the mean of the repeat values will be considered.
c) Screening total bilirubin of ULN (Note: isolated bilirubin 1.5 ULN is 
acceptable for patients with Gilbert’s syndrome).
d) Screening neutrophil count 1500 cells/mm3 (Note: 1200 cells/mm3 is 
acceptable in participants of black race).
e) Screening hemoglobin 11 g/dL in females and 12.5 g/dL in males.
f)
Screening platelet count ≥150,000 cells/L.
6.
No past or current diagnosis of cirrhosis. Transient elastography at screening 
showing a value consistent with a degree of liver fibrosis not higher than F3. By 
FibroScan, a cut-off of <8.5 kPa in the fasted status (last meal ≥3 hours prior) is 
recommended.
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
ALL STUDY PARTS
Medical Conditions
1.
Participants who have donated over 500 mL of blood or blood products or had 
significant blood loss within three months prior to screening.
PART 1 (SAD HV) ONLY:
Medical Conditions
1. History or presence of significant (as judged by the investigator) cardiovascular, 
respiratory, hepatic, renal, gastrointestinal, endocrine, haematological disorders, or 
diagnosed central or peripheral neurological disease, capable of significantly 
altering the absorption, metabolism, or elimination of drugs, of constituting a risk 
when taking the study treatment, or of interfering with the interpretation of the data.
2.
Screening ECG showing clinically relevant abnormalities (including arrhythmias or 
marked QT abnormalities [QTcF < 300 msec or > 450 msec], or other cardiac 
abnormalities that are considered clinically significant by the Investigator. Known 
risk factors for Torsade de Pointes (e.g., hypokalemia, heart failure), or a personal 
or family history of congenital long QT syndrome. 


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3. Abnormal blood pressure: supine systolic blood pressure (SBP) <90 mmHg 
or >140mmHg or diastolic blood pressure (DBP) <45mmHg or >90mmHg at the time 
of screening and at Day -1, confirmed by two consecutive triplicate measurements, 
properly measured with well-maintained equipment.
4. History of lymphoma, leukaemia, or malignancy within the past five years, except for 
squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for three years.
5. History or presence of liver disease, or known hepatic or biliary abnormalities (with 
the exception of Gilbert’s syndrome or asymptomatic gallstones).
6. ALT ≥1.5 ULN at screening and at Day 1.
7. Any clinically significant out of range findings in other laboratory test results or 
any other clinically significant (as judged by the Investigator) abnormalities in the 
physical examination at screening and on Day -1. 
8. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates the participation in the 
study.
9. Any clinically relevant history of hypersensitivity or allergic reactions, either 
spontaneous or following drug administration, or exposure to foods or environmental 
agents.
10. Any major illness within one month preceding the screening visit, or any febrile 
illness within the two weeks preceding the screening visit. 
11. Concomitant disease or condition that could interfere with, or treatment of which 
might interfere with, the conduct of the study, or that would, in the opinion of the 
Investigator, pose an unacceptable risk to the participant in this study.
Prior/Concomitant Therapy
12. Used or intend to use of over-the-counter (OCT) or prescription medication 
(including herbal and traditional remedies) before study start and during the study as 
described in list of prohibited medications. 
13. Live vaccine(s) within 28 days of screening, or plans to receive live vaccines during 
the study or within 28 days of the last dose.
14. Likely to need concomitant medication during the study period (including dental 
conditions).
15. Treatment with biologic agents (such as monoclonal antibodies, including marketed 
drugs) within three months or five half-lives (whichever is longer) prior to dosing.
Prior/Concurrent Clinical Study Experience
16. Currently enrolled in or have participated within the last 90 days or five times the 
half-life of the investigational drug (whichever is longer) from signing of consent in 
this or any other clinical study involving an investigational product or in any other 
type of medical research.
17. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.


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Diagnostic Assessments
18. Known positive for hepatitis B surface antigen (HBsAg or hepatitis B core total 
antibody [anti-HBc]) and/or hepatitis C, or positive HBsAg or hepatitis C virus (HCV) 
antibody test result at screening. 
19. Known positive for human immunodeficiency virus (HIV) infection and/or positive for 
HIV infection at screening.
20. Positive pre-study drugs and alcohol screen. 
Other Exclusions
21. History or evidence of alcohol abuse (consumption of more than two standard drinks 
per day on average; one standard drink equals 10 grams of alcohol), and/or drug 
abuse within one year of screening.
22. Any suspicion or history of substance abuse or dependence.
23. Dietary restrictions that would prohibit the consumption of standardised meal.
24. Healthy participants under judicial supervision, guardianship or curatorship.
PART 2 (CHB) ONLY
Medical Conditions
1. History or presence of significant (as judged by the Investigator) cardiovascular 
(including poorly controlled blood hypertension), respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological disorders, or diagnosed central or 
peripheral neurological disease, capable of altering the absorption, metabolism, or 
elimination of drugs, of constituting a risk when taking the study treatment, or of 
interfering with the interpretation of the data.
2. History or presence of bridging fibrosis or cirrhosis or decompensated liver disease.
3. History or presence of a medical condition associated with liver disease other than 
HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, 
toxin exposure, thalassemia, non-alcoholic steatohepatitis). Other known hepatic or 
biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones).
4. History of or suspicion of hepatocellular carcinoma or alpha fetoprotein 
(AFP) 13 ng/mL at screening.
5. History of lymphoma, leukaemia, or malignancy within the past five years, except for 
squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for three years.
6. History of having received (in the last six months) or currently receiving any 
systemic anti-neoplastic (including radiation) or immune-modulatory treatment 
(including systemic corticosteroids).
7. History of organ transplantation.
8. Any major illness within one month preceding the screening visit, or any febrile 
illness within the two weeks preceding randomisation. 


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9. Clinically significant (multiple or severe) drug allergies, or intolerance to topical 
corticosteroids, or history of severe post-treatment hypersensitivity reactions 
(including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic 
epidermal necrolysis, or exfoliative dermatitis).
10. Estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73m2 (CKD-epi equation).
11. Confirmed QT interval corrected using Fridericia’s formula (QTcF) 450 ms. 
Patients with correctable risk factors for prolonged QT (e.g., electrolyte 
abnormalities) can be re-assessed after correction of the risk factor(s).
Prior/Concomitant Therapy
12. Live vaccine(s) within 28 days of screening, or plans to receive live vaccines during 
the study or within 28 days of the last dose.
13. Expected to need any other systemic antiviral therapy at any time during participation 
in the study, with the exception of current NUC treatment and / or oral/ topical 
therapy for Herpes Simplex Virus (HSV).
Prior/Concurrent Clinical Study Experience
14. Currently enrolled in (i.e., the end of study visit has not been performed) or have received
investigational treatment within the last 90 days or five times the half-life of the 
investigational drug (whichever is longer) from signing of consent in this or any other 
clinical study involving an investigational product or in any other type of medical 
research, or the total volume of all blood samples provided during the follow-up visits of the 
former clinical trial exceeds 100 mL.
Diagnostic Assessments
15. Positive hepatitis C antibody at screening.
16. Known positive for human immunodeficiency virus (HIV) infection and/or positive for 
HIV infection at screening.
17. Positive pre-study treatment/alcohol screen.
Other Exclusions
18. History or evidence of alcohol abuse (consumption of more than two standard drinks 
per day on average; one standard drink equals 10 grams of alcohol) and/or drug 
abuse within one year of screening; positive test result for drugs of abuse at 
screening.
19. Patients under judicial supervision, guardianship or curatorship.
20. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator contraindicates the participation in the 
study.


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5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
It is unlikely that food will have an impact on the PK of RO7239958; however 
RO7239958 doses will be administered in the fasted state (either two hours before or 
two hours after a meal). Taking RO7239958 in a fasted state will apply to healthy 
participants and CHB patients.
In CHB patients, any food restrictions applicable to NUCs should continue to be 
observed throughout the study.
In Part 1, participants must abstain from alcohol for 24 hours before the start of dosing 
until after collection of the final PK and PD sample. In Part 2, participants must abstain 
from alcohol abuse.
For Part 1, the use of tobacco products will not be allowed for at least 90 days prior to 
dosing on Day1 until after the final follow-up visit.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized to study treatment. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure. Individuals of Parts 1 and 2 who do not initially 
meet the criteria for participation in this study can be re-screened if deemed appropriate 
by the Investigator. Participants with borderline laboratory assessments can be re-tested 
within the assigned screening period or rescreened for the next cohort or arm.
5.5
RECRUITMENT PROCEDURES
Participants in Part 1 of the study might be identified for potential recruitment using 
pre-screening enrollment logs, clinical database and IEC/IRB approved 
newspaper/radio/social-media advertisements prior to consenting to participate in this 
study. In Part 2, more participants than the minimum numbers may prove eligible throughout 
the screening process and to respect and recognize the participants’ commitment, over-enrollment 
by a maximum of two patients per Arm will be accepted.  
6.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.


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The investigational medicinal products (IMP) required for completion of this study are 
RO7239958 and placebo. RO7239958 will be provided by the Sponsor. Placebo will be 
provided by the site. All RO7239958 doses and placebo will be administered by
investigational staff (i.e., the Investigator or study nurse) at the study clinic in the 
morning and in the fasted state (either two hours before or two hours after a meal). After 
SC administration of study drug, Part 2 participants should remain at the site at least 
until the post-dose assessments are completed.
6.1
TREATMENTS ADMINISTERED
Table 10 summarizes the treatments administered.
Table 10 Summary of Treatments Administered
Study Treatment Name:
RO7239958
Placebo
Dosage Formulation:
Yellow, brownish yellow or 
greenish yellow sterile liquid.
Sodium chloride
Unit Dose Strength:
100 mg/mL
NA
Route of Administration:
SC
SC
Dosing Instructions:
The dose given will be in 
milligrams per kilogram of 
body weight.

Manufacturer
Hoffmann-La Roche Ltd.
(provided by the site)
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the RO7239958 Investigator’s Brochures and Pharmacy Manual for more 
details.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging for RO7239958 will be overseen by the Roche clinical trial 
supplies department and 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 (active IMP) will be in accordance 
with Roche standard and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.


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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 Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the Pharmacy Manual.
The Investigator or delegate must confirm 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 
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
6.3.1
Method of Treatment Assignment
Participants will be randomized to placebo or, active treatment in each dose cohort or 
arm. Randomization numbers for healthy participants will be generated by independent
representatives of the Sponsor, or its designee, for Part 1 of the study. The randomized 
treatment assignment will be allocated from the list sequentially to participants in the 
order in which they are enrolled.


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The patient randomization numbers for Part 2 will be generated by the Interactive 
voice/web response system (IxRS), according to specifications provided by the Sponsor 
to the external randomization vendor. Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log in information and directions for the 
IWRS will be provided to each site. Study treatment will be dispensed at the study visits 
summarized in SoA (see Section 1.3). Returned study treatment should not be re-
dispensed to the participants.
The Investigator or designee will enter the corresponding participant number for 
allocation to the dosing groups/cohorts in the appropriate place on each participant’s 
eCRF.
6.3.2
Blinding
The study is Observer-blind. This means that the participant, the Investigator and all 
individuals in direct contact with the participant at the site will be blinded to the individual 
treatment assignment except the pharmacist handling the study drug. All members of the 
project and study team who are not in direct contact with the participants may be 
unblinded.
To allow informed recommendations or decisions regarding dosing in this study, an 
integrated assessment of the safety and tolerability data and available PK data will be 
made prior to each dose-escalation decision. The Clinical Pharmacologist and the 
Clinical Pharmacology Scientist who perform this assessment, together with the 
Statistician, Data Acquisition Specialist and Clinical/Statistical Programmer will be 
unblinded with regard to the treatment allocation of participants. PK/PD data can be 
received and cleaned on an ongoing basis. The data will be handled and cleaned in a 
secure area which is not accessible by any blinded member. Likewise, the Bioanalyst 
and the Pharmacometrician will be unblinded. Other members of the Sponsor’s project 
and study teams who do not have direct contact with the participant may be unblinded, 
at the Clinical Science Lead’s discretion. The Clinical Pharmacologist or Clinical 
Pharmacology Scientist may share aggregated reports (e.g., tabular summaries or mean 
graphs by treatment group) with other individuals (e.g., Drug Safety Physician, Principal 
Investigator) who are involved in the dose decision process, but should not disclose 
individual treatment assignment.
In order to maintain the blind in Part 1, the unblinded pharmacist at the site will be 
responsible for the dispensation of all study-treatment. The randomization list will be 
made available to the Pharmacist preparing the study treatment. A sealed envelope that 
contains the treatment assignment for each participant will be provided to the 
Investigator. The sealed envelope will be retained by the Investigator (or representative) 
in a secured area. Once the study is complete, all envelopes (sealed and opened) must 
be inventoried and returned to the Sponsor.


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In order to maintain the blind in Part 2, the unblinded pharmacist at the site will be 
responsible for the dispensation of all study treatment (i.e., RO7239958 [active IMP] and 
placebo). For Part 2, the Investigator will be able to break the treatment code by 
contacting the IxRS. Treatment codes should not be broken except in emergency 
situations when necessary for medical management of the patient. If the Investigator 
wishes to know the identity of the study drug for any other reason, he or she should 
contact the Medical Monitor directly before the code is broken, if possible. The
Investigator should document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding due to a serious adverse event [SAE]).
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs (see Appendix 2) that are considered by the Investigator 
to be related to study treatment.
The Sponsor must be notified before the blind is broken unless identification of the study 
treatment is required for medical emergency in which the knowledge of the specific 
blinded treatment will affect the immediate management of the participant’s conditions 
(e.g., antidote is available). In this case, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be 
recorded and the name of all the person(s) who had to be unblinded in the source 
documentation and eCRF, as applicable.
Whenever disclosure of the identity of the test medication is necessary, adequate
procedures will be in place to ensure integrity of the data. Any unblinding from the 
Investigator side will be documented in the study report with date, reason for identifying 
the drug and the name(s) and role(s) in the study of the person(s) unblinded.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule. This individual will write the date 
dispensed and participant number on the study treatment vial label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study.
6.5
CONCOMITANT THERAPY
All medications (prescription and OTC) taken within 30 days of study screening until the 
follow-up visit will be recorded in electronic case report form (eCRF).
Any prescription or OTC medicine (including nutritional supplements and herbal and 
traditional remedies) or vaccine used by a participant from 4 weeks prior to screening 
until the last follow-up visit must be recorded along with reason for use, dates of 
administration (including start and end dates), and regimen information (including dose 
and frequency).


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Participants of Part 2 should take the standard NUC treatment as normally prescribed. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be recorded on the Concomitant Medications 
electronic Case Report Form (eCRF).
All therapy or medication administered to manage AEs should be recorded on the 
Adverse Event eCRF.
6.5.1
Permitted Therapy
Concomitant medication includes any medication, e.g., prescription drugs, 
over-the-counter drugs, approved dietary and herbal supplements, nutritional 
supplements used by a patient from 30 days prior to screening until the follow-up visit.
For all parts of the study, paracetamol/acetaminophen, at doses of up to 1 g/day, is 
permitted for use any time during the study. Other concomitant medication may be 
considered on a case-by-case basis by the Investigator in consultation with the Medical 
Monitor, if required.
Hormone replacement therapy (HRT) is allowed during the study.
Standard NUC therapy will be expected to be continued throughout study participation, 
and recorded on the NUC Concomitant Medications eCRF.
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF.
6.5.2
Prohibited Therapy
As a general rule, no prescribed medication will be prohibited for Part 2 of the study. All
concomitant prescribed medications (except standard NUC therapy) need to be 
discussed with the Medical Monitor prior to enrolling study participants.
Participants must abstain from taking nonprescription drugs (including OTC medication, 
vitamins, dietary, herbal supplements, protein powders or fish oils) within 7 days before 
the start of study treatment until completion of the follow-up visit, unless, in the opinion of 
the Investigator and Medical Monitor, the medication is necessary and will not interfere
with the study. 
Some supplements, herbal and traditional remedies, and OTC drugs may affect 
laboratory values. Abnormal values may lead to screening failures or withdrawal from 
the study. As such, participants should be carefully questioned regarding such 
substances at screening, and advised to refrain from them, if deemed necessary. 


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For all parts of the study, there are restrictions that should be maintained:

Live vaccine(s) are not to be given within 28 days prior to screening. The participant 
should not receive live vaccines during the study or within 28 days after the last 
dose.

In the event that a participant requires additional medication during the course of the 
trial, this may be allowed after consultation with the Investigator and Medical Monitor. 
For CHB patients, NUC-related food restrictions may apply (see Section 5.3.1).
6.6
DOSAGE MODIFICATION
 
The decision to proceed to the next dose level of RO7239958 (either an increase or a 
decrease), will be made by the Study Team (and the Investigator) based on safety, 
tolerability and available PK and/or PD data obtained described as in Section 4.1.2.
If unacceptable adverse events, or pharmacological effects, reasonably attributable to 
RO7239958 in the opinion of the Investigator are observed in the participants in a cohort
or an arm, dosing and any dose-escalation will be temporarily halted for maximally
3 weeks (see Section 4.1.2) and no further participants will be dosed until a full safety 
review of the study has taken place. Relevant reporting and discussion with the Medical 
Monitor, relevant site personnel (i.e., Investigator), and the IRB/IEC will take place 
before resumption of dosing.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7239958 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal.
7.
DISCONTINUATION OF STUDY TREATMENT AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
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 patients to comply with all the study specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.


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7.1
DISCONTINUATION OF STUDY TREATMENT
See the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
Participant must discontinue study treatment if they experience any of the following:

Participant withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the participant.

Pregnancy

If stopping criteria are met (see Section 4.1.3)

If non-compliance with study requirements as judged by the Investigator and 
consultation with the Sponsor.
Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for a study completion/early termination visit (see Section 1.3) and may undergo 
follow‑up assessments (see Section 1.3). The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. Participants 
who discontinue study treatment prematurely can be replaced in both Parts 1 and 2.
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined in Section 6 of 
Appendix 3 or if the Investigator believes that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
investigator or qualified designee will determine if the participant can continue in the 
study and if any change in participant management is needed. This review of the ECG 
taken at the time of collection must be documented. Any new clinically relevant finding 
should be reported as an AE.
7.1.1
Temporary Interruption
Temporary interruption will not be allowed for the study (e.g., because of holidays, 
weekends, inclement weather, or other justifiable events).
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.


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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 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 remain as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of specimens 
donated to the Research Biosample Repository (RBR).
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons can be replaced.
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and 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.
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 are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the Schedules of Activities 
(SoA; Section 1.3). Protocol waivers or exemptions are not allowed.


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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.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-frame defined in the SoA.
8.1
EFFICACY ASSESSMENTS
Efficacy assessment endpoints are measured through markers of antiviral activity in 
Part 2 of the study. The short duration of treatment with RO7239958 is not anticipated to 
provide CHB patients with therapeutic benefit, but rather to provide evidence on the 
effect of multiple doses of RO7239958 on HBsAg and the other viral parameters under 
evaluation (see SoA, Section 1.3). Blood samples will be taken at defined time-points in 
Part 2 (as shown in the Schedule of Activities, see Section 1.3) to monitor viral markers, 
and study their correlation with administered doses and PK data. The main virological 
end-point is the time-course of serum HBsAg levels, measured as actual values pre-
dosing, during dosing and post-dosing, and as changes from baseline over time (see 
Section 8.1). As this is the first study of RO7239958 in CHB patients and eligible patients 
are established on effective NUC with suppressed circulating HBV DNA, HBsAg levels 
are being explored as part of the secondary endpoints in this study. Additional 
parameters include incidence of HBsAg loss and anti-HBs seroconversion, the time-
course of anti-HBs levels, and changes in HBeAg and anti-HBe status in the course of 
the study. Exploratory viral parameters include serum HBeAg levels, and circulating
HBcrAg and HBV RNA levels.
The efficacy assessments will include all patients in the efficacy analysis population
analyzed according to the treatment group (dose-level/regimen/extension) 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 (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination should be performed at the time-points specified in the 
SoA tables (see Section 1.3) and include an evaluation of the head, eyes, ears, nose, 
throat, neck and lymph nodes, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems. Height and weight will be 
collected at the screening visit only. Further examination of other body systems may be 
performed in case of evocative symptoms at the Investigator’s discretion.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.


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At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities will be 
recorded in the medical file of the healthy volunteer or patients. New or worsened,
clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
8.2.2
Vital Signs
Vital signs will be obtained after the subject has been resting in a supine position for at 
least 5 minutes. 
Blood pressure (BP; systolic and diastolic), pulse rate and body temperature (tympanic) 
will be recorded at the time-points specified in the SoA tables (see Section 1.3). Blood 
pressure and pulse rate will be performed in triplicate (can be as short as 20 seconds to 
1-minute interval between measurements). The mean of three consecutive replicates will 
be used as the value for the defined time-point. Vital signs should be measured prior to 
blood draw. When possible, the same arm should be used for all blood pressure 
measurements.
Blood pressure and heart rate should be obtained in a quiet room at a comfortable 
temperature, with the subject's arm unconstrained by clothing or other material. Where 
possible all measurements will be obtained from the same arm and, with the same cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (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]). The study subject should 
be asked to remove all clothing that covers the location of cuff placement. 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).
8.2.3
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QTc 
intervals. ECGs will be collected after the participant has been in a supine position for at 
least 10 minutes prior to each ECG evaluation. At the specified time-points, 12-lead 
ECGs will be obtained in triplicate, i.e., three consecutive interpretable 12-lead ECGs 
within a 3-5-minute period, and recorded in the case report form (CRF). Triplicate 
recordings should be taken for any unscheduled ECG.
At each time-point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, and the full set of triplicates 
should be completed in less than 5 minutes.


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All ECG recordings must be performed using a standard digital high-quality, high-fidelity 
ECG machine equipped with computer-based interval measurements. Automated ECG 
intervals (PR [PQ], QRS, QT, QTcF [Fridericia’s correction; to be derived in eCRF]) and 
heart rate (HR) will be captured or calculated, and the changes in T-wave and U-wave 
morphology will be documented. Changes in T-wave and U-wave morphology and 
overall ECG interpretation will be documented on the eCRF. T-wave information will be 
captured as normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
The following are requirements for ECG assessments:
1.
Digital ECG recordings, storage and analysis.
2.
Three useful recordings must be collected without artefacts, per time-point. 
3.
Body position should also be consistently maintained for each ECG performed. In 
particular, changes in HR should be avoided. The absence of any environmental 
distractions (television, radio, conversation) during the pre-ECG rest and the ECG 
recording in the clinic must be emphasized.
4.
Avoid ECG recordings within 3 hours after meals (it is accepted that this is not 
possible after the light breakfast which is administered prior to dosing in the fed 
period for the relevant cohort).
5.
Strictly match timing and conditions of ECG recording to baseline. Conditions to be 
standardized include food intake, activity level, stressors, and room temperature.
6.
If possible, the same machine, brand and model, should be used for the same study 
subject throughout the study.
7.
ECGs should be 12-lead, recorded at 25 mm/sec for at least 10 seconds.
8.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper 
lead placement as contributing to the ECG abnormality.
9.
ECG machines should have periodic calibration and service records (minimum once 
a year).
10. If any QT/QTc values500 msec or increases from pre-dose on Day 1 QTc
60 msec (as provided by the machine and read by the cardiologist), the site should 
repeat the ECG (triplicate) within the next 5 minutes and notify the Sponsor. If 
confirmed, ECG recordings should be repeated at least hourly until two successive 
ECGs show QTc values below the threshold value that triggered the repeated 
measurement.
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.


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8.2.4
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. 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 (Section 1.3).
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 which 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 up 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.

If laboratory values from non-protocol specified laboratory assessments performed 
at the local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or 
dose-modification) the results must be recorded in the CRF.
Results of clinical laboratory testing will be recorded in the eCRF or be received as 
electronically produced laboratory reports submitted directly from the 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 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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8.2.5
Medical History and Demographic Data
Medical history includes clinically significant diseases, i.e., surgeries, cancer history, 
reproductive status, smoking history, use of alcohol and drugs of abuse, and all 
medications (e.g., prescription drugs, OTC drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the study subject within 30 days prior to the Screening 
visit.
For CHB patients, the detailed HBV history will be documented, which will include date 
of HBV diagnosis, any previous assessment of liver fibrosis (including date and outcome
of any liver biopsy), HBV genotype (if documented), all previous HBV treatments and 
outcomes of treatments, occurrence of any NUC resistance.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious 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 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:

Diagnosis versus signs and symptoms:
–
ISR
–
Other AEs

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values

Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Worsening of CHB

Hospitalization or prolonged hospitalization


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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.
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 105 days after the last dose of study treatment.
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period (105 days after the last dose of study treatment).
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.


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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 until, the event is assessed as stable by the Investigator, the 
event is otherwise explained, the participant is lost to follow-up (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 trial-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.
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, non-serious 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 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.


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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 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 patients, access to the Medical monitors is available. 
24 hours a day 7 days a week. Medical monitors contact details will be available on a 
separate list generated by the study management team.
8.3.5
Pregnancy
Male participants will be instructed through the Informed Consent Form (ICF) to 
immediately inform the Investigator if their partner becomes pregnant during the study or 
within 105 days after the last dose of study drug.
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, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest
Non-serious adverse events of special interest (NSAESI) 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).
NSAESI for this study include the following:

Dose-dependent gastrointestinal disorders (including nausea, vomiting and 
diarrhea).

Confirmed ALT or AST > 5x ULN (in healthy participants) or 8x baseline (in CHB 
patients).

Confirmed ALT or AST > 3x ULN (in healthy participants) or 3x baseline (in CHB 
patients) accompanied with increased total bilirubin 2x ULN (or clinical jaundice).

Confirmed ALT or AST > 3x baseline (in CHB patients) accompanied with INR 1.5 
(or PT 1.5 ULN).

Confirmed ALT or AST >3x baseline (in CHB patients) with the appearance of 
fatigue, nausea, vomiting, right upper quadrant abdominal pain or tenderness. fever, 
rash, and eosinophilia


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
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 patient exposed to a medicinal product. This term applies only
when a contamination of the study treatment is suspected.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
The following disease-related events can be observed in CHB patients:

ALT or AST increase 5-fold the baseline value with preserved hepatic function  
Because these events may be associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs. These 
events will be recorded on the corresponding CRF page in the participant’s CRF within 
the appropriate time-frame.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental administration of a drug in a quantity that is
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an adverse event unless it results in untoward medical effects (see 
Sections 5 and 5.2 of Appendix 2 for further details).
In the event of an overdose, the Investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Document the quantity of the excess dose, as well as the reason and circumstances, 
and duration of the overdose, in the CRF.
8.5
PHARMACOKINETICS
Blood samples to evaluate concentrations of RO7239958 and its metabolite(s) if 
applicable, and urine samples to evaluate concentrations of RO7239958 will be collected
as outlined in the SoA tables (see Section 1.3). During the course of the study, PK 
sampling time-points may be modified on the basis of emerging data to ensure the PK of 
RO7239958 can be adequately characterized. Additional PK samples will be taken at the 
time of treatment discontinuation, if the participant experiences an injection-related AE
(such as an ISR), or if the participant experiences an adverse event leading to 
dose-reduction or delayed RO7239958 administration (see Section 6.6 Dosage 
Modifications). The date and time of each RO7239958 administration and of each
sample collection will be recorded in the eCRF.


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RO7239958 levels will be analyzed by using validated assays.

Metabolites may be measured by a specific validated LC-MS/MS assay, or other fit 
for purpose methods as appropriate.

Placebo-treated participants may not be analyzed in the first instance, but retained 
for subsequent analysis if appropriate.

Any volume of blood samples remaining after the specified analyses may also be 
used for additional validation experiments (e.g., anti-drug antibodies).
The blood samples for PK analyses will be destroyed within 2 years after the date of final 
CSR. Details on sampling procedures, sample storage and shipment are given in the 
Sample Handling Manual.
For participants who consent to RBR, leftover samples will be transferred to RBR. Genetic 
analyses will not be performed on these samples unless consent for this was included in 
the RBR informed consent. Participant confidentiality will be maintained.
Drug concentration information that would unblind the study, will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.5.1
Immunogenicity Assessments 
As RO7239958 is an oligonucleotide, there is a risk that anti-drug antibody (ADA) 
against RO7239958 could develop, potentially reducing its efficacy or potentially 
resulting in hypersensitivity reactions, in particular immune-complex reactions.
Antibodies to RO7239958 may be evaluated in blood samples collected from all 
participants according to the SoA (Section 1.3). Additional ADA samples may also be 
collected at the time of treatment discontinuation or at safety follow-up visits in 
participants who experience a Grade3 ISR or have clinical signs of a hypersensitivity 
reaction. For each collected ADA sample, a paired PK sample will be collected at the 
same time-point for the determination of RO7239958 concentrations. The date and time 
of each sample will be recorded in the eCRF.
Validated screening, confirmatory, and titer assays will be employed to detect ADAs 
against RO7239958. Samples from placebo-treated participants may not be analyzed in 
the first instance, but retained for subsequent analysis if appropriate.
If required, remaining ADA samples may also be used for assay development/validation 
experiments.
Leftover blood samples will be destroyed within 2 years after the date of final CSR. For 
participants who consent to RBR, leftover samples will be transferred to RBR.
Details on sampling procedures, sample storage and shipment are described in the 
sample documentation.


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8.6
PHARMACODYNAMICS AND BIOMARKERS
For assessment time points please see the SoA (Section 1.3).
8.6.1
Viral Dynamic Biomarkers
Standard viral dynamics biomarkers include:

Quantitative HBsAg

Quantitative anti-HBs 

Qualitative HBeAg and anti-HBe 
Exploratory viral dynamics biomarkers include:

Quantitative HBcrAg

Quantitative HBV RNA

Semi-quantitative HBeAg 
8.6.2
Viral Genetic Analyses 
The samples for HBV RNA extraction will be collected for quantitative purposes as 
outlined in the SoA (see Section 1.3). If RNA can be quantified, viral genotyping will be 
performed by sequencing. In addition, should HBV DNA rebound occur during the study, 
the HBV DNA will be tested to determine genotype and NUC resistance by sequencing 
and potentially NUC resistance by phenotyping. 
8.6.3
Exploratory Safety Biomarkers
A number of exploratory safety liver and kidney biomarkers will be analyzed from blood 
and urine samples in Part 2, including but not limited to:

Urinary renal injury biomarkers: CLU, cystatin C, KIM-1, NAG, NGAL, and OPN. 

Liver blood injury biomarkers: HMGB, GLDH, MCSFR1, OPN, CK18, and ccCK18
8.7
PHARMACODYNAMICS AND BIOMARKER SAMPLES
Samples should be collected as specified in the SoA (see Section 1.3).
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 may be stopped at any time if 
the data from the samples collected does not produce useful information. 
Details on processes for collection and shipment of these samples can be found in 
Sample Handling Manual.


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Unless otherwise specified below, samples (including plasma/serum, slides, extracts, 
etc.) will be destroyed no later than 5 years after the date of final CSR. For participants 
who consent to RBR, leftover samples will be transferred to RBR (see Section 8.8).
8.7.1
Mandatory samples
The following samples for pharmacodynamics and biomarker research are required and 
will be collected from all participants in this study.
Blood Sampling
Blood samples will be collected for extraction of HBsAg, HBsAb, HBeAg, HBeAb, viral 
RNA and HBcrAg and exploratory liver biomarkers. For time points see the SoA 
(Section 1.3).
 
Urine Sampling
Urine samples will be collected for exploratory renal (urine) injury biomarkers.
 
8.8
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY
8.8.1
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 specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins). The collection, storage 
and analysis of these specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens will be collected from participants who give specific consent to participate in 
this optional RBR. Collected specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease.

To increase knowledge and understanding of disease biology.

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.


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8.8.1.1
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7239958 or diseases:

Leftover serum, plasma, urine and liver tissue samples 
 
 for development of biomarkers and associated assays.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate Sample Handling Manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The Research Biosample Repository storage period will be in accordance 
with the IRB/EC‑approved Informed Consent Form and applicable laws (e.g., Health 
Authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1).
8.9
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
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. ICFs for enrolled 
participants and for participants who are not subsequently enrolled will be maintained at 
the study site.
All screening and pre-treatment assessments 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.
An Eligibility Screening Form (ESF) 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 28 days prior to Day 
1, unless otherwise specified. Results of standard-of-care elastography examinations 
performed prior to obtaining informed consent and within 3 months prior to screening
may be used (and do not need to be repeated for screening).


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Re-screening is allowed for participants who were screened in the study and met study 
inclusion/exclusion criteria but failed to be randomized within 28 days after the start of 
screening period because of an administrative reason. In order to re-screen such a 
patient, all inclusion and exclusion criteria should be re-evaluated and all applicable 
screening assessments repeated if done more than 28 days before randomization. For 
re-screening, there is no need to repeat the fibroscan (elastography) if done for this 
study within 6 months if reliably documented.
 
Re-screened participants should be assigned the same participant number as for the 
initial screening. 
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study.
All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study (see Section 4.1.1) or discontinue from the study 
early will be asked to return to the clinic for a total of four safety and follow up visits after 
the last dose of study drug. 
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 8.3.1 and 8.3.3
8.10.5
Section Assessments at Unscheduled Visits
For activities that are required to be performed in case of an unscheduled visit, 
assessments and samples may be taken at the discretion of the Investigator as specified 
in Section 1.3


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9.
STATISTICAL CONSIDERATIONS
Statistical summaries will be descriptive in nature and will be reported separately for 
each part of the study within the clinical study report (CSR). All study participants who 
are randomized to receive placebo in Part 1 will be pooled as a respective placebo 
control group for Part 1. Placebo from Part 2a and Part 2b will be pooled separately.
9.1
STATISTICAL HYPOTHESES
No statistical hypothesis testing is planned for this study.
9.2
SAMPLE SIZE DETERMINATION
The sample size was determined by practical considerations and not based on statistical 
power calculations. In Part 1, approximately 40-50 participants will be enrolled in four to 
five cohorts of 10 participants each (eight to receive RO7239958 and two to receive 
placebo). In Part 2, approximately 28-49 CHB patients will be enrolled in four to seven 
arms of seven participants each (six to receive RO7239958 and one to receive placebo). 
Part 2a will include approximately 28-35 participants in four to five arms. Part 2b will 
include approximately 14 participants in two arms.
9.3
POPULATIONS FOR ANALYSES
For the purpose of analysis, the following populations are defined in Table 11.
Table 11 Analysis Populations
Population
Description
Safety
All study subjects who have received at least one dose of the 
study medication, whether prematurely withdrawn from the 
study or not, will be included in the safety analysis. 
Pharmacokinetic
Study subjects will be excluded from the PK analysis 
population if they significantly violate the inclusion or 
exclusion criteria or deviate significantly from the protocol, or 
if data are unavailable or insufficiently complete to allow the 
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.
Efficacy 
The analyses of viral dynamic response in Part 2a (and 
potentially Part 2b) of the study will include all patients who 
were randomized and received at least one dose of study 
drug (RO7239958 or placebo) and with at least one post-
treatment assessment. Participants will be analyzed 
according to the treatment group to which they are 
randomized.


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9.4
STATISTICAL ANALYSES
9.4.1
Demographics and Baseline Characteristics
Descriptive statistics will be used for demographic and baseline disease characteristics 
as applicable for each part of the study. These will include for Part 1 and Part 2 age, 
gender, race, ethnicity, country of origin, weight, height, body mass index; and for Part 2 
only, HBV baseline characteristics (e.g., HBsAg levels) and HBV history (e.g., duration 
of HBV diagnosis HBV treatment history, fibrosis status), and where measurable 
(participants with detectable HBV RNA), the viral genotype. All study participants who 
are randomized to receive placebo will be pooled as respective placebo control groups, 
according to each part of the study.
For continuous variables, mean, standard deviation, median, and minimum and 
maximum values will be presented. For categorical data, the proportion of study 
participants in each category will be summarized.
9.4.2
Safety Analyses
All safety analyses will be based on the entire safety analysis population (see Table 11). 
The objectives of the safety analyses are to assess the safety and tolerability of 
RO7239958 compared to placebo after single SC ascending doses in healthy 
participants and multiple SC ascending doses in CHB patients.
Participants randomized to receive RO7239958 will be analyzed by cohort or arm. All
study subjects who are randomized to receive placebo will be pooled as respective 
placebo control groups, according to each part of the study (See Section 9).
The safety data, including AEs, ISRs, reason for withdrawal from study, laboratory data, 
ECG, concomitant medications, vital signs, and physical examination results will be 
listed and summarized descriptively. Marked abnormalities of laboratory data will be 
flagged. As appropriate, listings, summary tables and graphs (participant plot and/or 
mean plots) will be provided to describe safety and tolerability assessments.


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Table 12 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 these were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results.
Summary tables of change from baseline over time will be displayed. 
Shifts in NCI CTCAE grades v5.0 from baseline to the worst grade 
observed during treatment will be presented for selected laboratory 
parameters. 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 For the analyses of ECG data, see Section 8.2.3.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and 
listings.
9.4.2.1
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. Summary descriptive statistics for 
the actual values and changes from baseline will be tabulated by nominal time for HR, 
QRS duration, PR and QTcF. For multiple measurements taken at a nominal time-point, 
the average of these measurements will be used as the value at that nominal time-point 
in all summaries. In addition, QTcF will be categorized at each time-point as ≤ 450 
msec, > 450-480 msec, > 480-500 msec and > 500 msec and summarized. Similarly, a 
summary will be provided of the QTcF changes from baseline at each time-point 
categorized as < 30 msec, 30-60 msec, and > 60 msec. Changes of the overall ECG 
interpretation, T-wave and U-wave morphology will be summarized. QTcF will be 
assessed by a central group.
9.4.2.2
Exploratory Safety Biomarkers Analysis 
The exploratory safety parameters (see Section 8.6.3), will be analyzed graphically. 
Plots will include longitudinal plots for both actual result and change from baseline. 
Longitudinal plots will include means/medians by arm as well as individual subject 
responses by dose. Box and whisker plots may also be used to detect outliers.


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9.4.3
Pharmacokinetic Analyses
Non-compartmental analysis will be used to calculate PK parameters where appropriate. 
Summary descriptive statistics of plasma PK parameters including Cmax, Tmax, AUC, and 
t1/2 for RO7239958 may be presented by cohort/arm including means, geometric means, 
standard deviation (SD), coefficient of variation (CV), medians and ranges. Other 
parameters may be calculated, e.g. C168hr, CL and Vss.
Listing summary tables and graphs (individual plots and/or mean plots) by treatment 
group will be provided. 
Descriptive statistics of urine PK parameters, e.g. Ae, Fe, for RO7239958 and any 
metabolites, if applicable, will be presented, where available. 
A population PK modeling approach may also be used to describe plasma and urine PK. 
PK data from this study may be pooled with data from other studies to develop the 
population PK model. 
9.4.4
Pharmacodynamic Analyses
The viral dynamic response analysis is only applicable to Part 2 of the study and is 
based on the Efficacy Population (Table 10). Blood samples for measuring standard 
(e.g., HBsAg, anti-HBs) and exploratory (e.g., HBV RNA) viral dynamic parameters will 
be collected as detailed in the SoA (see Section 1.3).
Descriptive statistics will be utilized to summarize the main viral dynamic response 
outcome measure of serum HBsAg levels (in log10 IU/mL) as actual and change from 
baseline, at each time-point and by arm. Plots of HBsAg levels (in log10 IU/ml) including 
actual and change from baseline over time will be utilized to compare the longitudinal 
profiles across doses and frequencies of dosing. Further exploration may include plots of 
quantitative HBsAg over time, grouped by HBeAg status or baseline characteristics of 
interest as appropriate. 


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Table 13 Viral Dynamic Response Statistical Analysis Methods
Endpoints
Statistical Analysis Methods
HBsAg and anti-HBs
Time course profile: summary descriptive statistics of values (in 
log10 IU/mL), including actual and change from baseline 
(including mean, standard deviation, median, minimum and 
maximum) at each time-point.
HBsAg loss
Proportion of HBsAg loss (below lower limit of sensitivity) at
each time-point. 
HBeAg 
In participants that are HBeAg positive at study entry, 
proportion of serum HBeAg loss (below lower limit of 
sensitivity) and proportion of serum anti-HBe seroconversion.
Maintenance of suppressed 
HBV DNA levels
Proportion of patients with HBV DNA below the assay lower 
limit of quantification at each time-point. In case of rebound,
this will be confirmed by repeat testing, further evaluated and 
eventually correlated with NUC resistance and NUC plasma 
levels.
Table 14 Exploratory Viral Dynamic Response Statistical Analysis methods
Endpoint
Statistical Analysis Methods
HBV RNA, HBcrAg, HBeAg
Summary descriptive statistics to summarize values (in log10), 
including actual and change from baseline (including mean, 
standard deviation, median, minimum and maximum) at each 
time-point.
The population PK analysis and PD analyses may be presented separately from the 
main CSR.
9.4.4.1
PK/Safety and PK/PD Relationships Analysis
Relationship between dose and plasma exposure of RO7239958 and any PD 
parameters and/or outcome (e.g., safety-related marker, adverse events, exploratory 
safety biomarkers, viral dynamic markers, viral response) may be done by graphical 
analysis and further development of a model. 


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9.4.4.2
Immunogenicity Analyses
The immunogenicity analyses will include participants with at least one pre-dose and 
one post-dose ADA assessment.
The numbers and proportions of ADA-positive patients and ADA-negative participants 
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).

Patients 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).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported descriptively.
9.5
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed. Data for study drug administration and concomitant 
medication will be listed. The number of participants who were randomized, discontinued 
and completed the study will be summarized and listed.


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10.
REFERENCES
Allweiss L, Dandri M. The Role of cccDNA in HBV Maintenance. Viruses. 2017;9(6):pii 
E156.
Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: 
Interactions between drug properties and host factors. J Hepatol. 2015; 63:503-14.
Chen EQ, Feng S, Wang ML, Liang LB, Zhou LY, Du LY, Yan LB, Tao CM, Tang H. 
Serum hepatitis B core-related antigen is a satisfactory surrogate marker of 
intrahepatic covalently closed circular DNA in chronic hepatitis B. Sci Rep. 2017 
7:173-180..
APASL Guidelines for HBV -“Asian-Paciﬁc clinical practice guidelines on the 
management of hepatitis B: a 2015 update”. Hepatol Int 2016; 10:1–98.
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(2):370-98.
FDA. Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers. International 
Conference On Harmonisation. July 2005.
Sauer JM, Walker, EG, Porter AC. The predictive safety testing consortium: safety 
biomarkers, collaboration and qualification. FNIH and PSTC Collaboration Briefing 
Book. Published online July 2015.
 
Investigator’s Brochure, RO7239958, Version 1.
Investigator’s Brochure RO7062931, Version 3.
Lim J. Kim D, Lee Y. Mixed tailing by TENT4A and TET4B shields mRNA from rapid 
deadenylation. Science. 2018. 10.1126/science.aam5794.
Mak LY, Wong DKH, Cheung KS,Seto WK, Lai CL, Yuen MF. Review article: hepatitis B 
core-related antigen (HBcrAg): an emerging marker forchronic hepatitis B virus 
infection. Aliment Pharmacol Ther. 2018;47:43–54. 
Nayagam S, Thursz M, Sicuri E, et al. Requirements for global elimination of hepatitis B: 
a modelling study. Lancet Infect Dis. 2016;16(12):1399-408.
Pfefferkorn M, Böhm S, Schott T, et al. Quantification of large and middle proteins of 
hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of 
inactive HBV carriers. Gut. 2017;pii: gutjnl-2017-313811.
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, 
and expression. Physiol Rev. 1995:75(3):591-609.


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Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and 
treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 
2018;67(4):1560-99.
Zelensky AN, Gready JE. The C-type lectin-like domain superfamily. FEBS J. 
2005;272:6179-217.
Van Campenhout  MJH, Van Bömmel F, Pfefferkorn M, et al. Host and viral factors 
associated with serum hepatitis B virus RNA levels among patients in need for 
treatment. Hepatology 2018 (Epub ahead of print).
Van Poelgeest EP, Hodges MR, Moerland M, Tessier Y, Levin AA, Persson R, Lindholm 
MW, Dumong EK, Ørum H, Cohen AF, Burggraaf J. Antisense-mediated reduction 
of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human 
randomized, placebo-controlled trial. British journal of clinical pharmacology. 2015; 
80:1350-61.
Wang J, Shen T, Huang X, Renuka Kumar G, Chen X, Zeng Z, Zhang R, Chen R, Li T, 
Zhang T, Yuan Q, Li PC, Huang Q, Colonno R, Jia J, Hou J, McCrae MA, Gao Z, 
Ren H, Xia N, Zhuang H, Lu F. Serum hepatitis B virus RNA is encapsidated 
pregenome RNA that may be associated with persistence of viral infection and 
rebound. Journal of Hepatology 2016 65:700–710.
Woddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected 
patients and chimpanzees reveals that integrated hepatitis B virsu DNA is a source 
of HBsAg. Sci TRansl Med. 2017;9(409):pii eaan0241.
World Health Organization. Hepatitis B fact sheet [resource on the internet], 2018 
[updated July 2018]. Available from: http://www.who.int/news-room/fact-
sheets/detail/hepatitis-b.
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, reporting) 
Appendix 3 (procedures of recording)
Appendix 4 (clinical laboratory tests)
Appendix 5 (contraceptive guidance and collection of pregnancy information)
Appendix 6 (CKD-EPI GFR)
Appendix 7 (Grading of ISRs)


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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 EU/EEA 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.


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1.3.
INFORMED CONSENT
The Sponsor’s Master ICF (and ancillary sample ICFs such as a RBR ICF and pregnant 
partner ICF, 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 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.
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 as per 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. 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.
A participant who is re-screened is required to sign another Consent Form, only if 
significant new information/findings led to a more recent version of the Consent Form (or 
addendum in accordance with applicable laws and IRB/EC policy).


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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 specimens 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 specimens. 
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 subject who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR 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 specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a participant wishes to withdraw 
consent to the testing of his or her specimens, the Investigator must inform the Medical 
Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if the 
trial 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 trial is closed. A participant's withdrawal from study NP40520 does not, 
by itself, constitute withdrawal of specimens from the RBR. Likewise, a participant’s 
withdrawal from the RBR does not constitute withdrawal from study NP40520. 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. 


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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.
Confidentiality for Research Biosample Repository
Data generated from RBR specimens 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 specimens 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 specimen analysis on individual participants will generally not be 
provided to study investigators unless a request for research use is granted. The 
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 
exploratory 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 specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.
Monitoring and Oversight Research Biosample Repository
Specimens 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 specimens 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.


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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.
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.
2.1.2.
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, patient files, and records 
kept at pharmacies, laboratories, and medico‑technical departments involved in a 
clinical trial.
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 trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.3.
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 CAs 
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 patients 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 trial will be available at http://www.ClinicalTrials.gov.
2.3.4.
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.


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4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study 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.
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.
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 patient 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:

Any 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.

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. 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 (for Part 1):

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments, unless judged by the Investigator to be 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 
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
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.
Events NOT Meeting the AE Definition (for Part 2):

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.

The disease being studied or expected progression, signs, or symptoms of the 
disease 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.


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
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.

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 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 eCRF.
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 Sponsor’s 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 Sponsor’s 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.


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3.1.
ASSESSMENT OF SEVERITY
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing adverse event severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
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 NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 1
Adverse Event Severity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily livinga
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily livingb,c
4
Life-threatening consequences or urgent intervention indicatedd
5
Death related to adverse eventd
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who 
are not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 6 of this Appendix for reporting instructions), per the definition 
of serious adverse event in Section 2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for 
reporting instructions), per the definition of serious adverse event in Section 2.
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.

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.


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For participants 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 
Sponsor’s 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.
New or updated information will be recorded in the originally completed eCRF.
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 trial. 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

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)
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.


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5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS 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).
Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious 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.


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5.2
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR
Accidental overdose and medication error (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

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.
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 RO7239958 or placebo, 
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.

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. 
In addition, all special situations associated with RO7239958 or placebo, 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.

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 
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.


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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 NSAESI 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}:

RO7239958 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.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study treatment exposure and will be excluded from expedited 
reporting. These anticipated events include, but are not limited to, the following:

Isolated ALT/AST elevation 5x ULN (with normal liver function tests) in healthy 
participants 

Isolated ALT/AST elevation 8x baseline (with normal liver function tests) in CHB 
patients 


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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
1.1.
INJECTION-SITE REACTIONS
Adverse events that occur during or after study drug administration and are judged to be 
related to study treatment injection should be captured as a diagnosis (e.g., " ISR", 
"anaphylactic reaction") on the Adverse Event eCRF. If possible, avoid ambiguous terms 
such as “systemic reaction”. Associated signs and symptoms should be recorded on the 
dedicated Injection Reaction eCRF. If a participant 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 Injection Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS
For adverse events other than injection reactions (see Section 1.1), 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.


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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 
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.


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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., dosage 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.
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., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.


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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.
6.
ABNORMAL LIVER TRANSAMINASES AND FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN in healthy participants or 3x baseline 
in CHB patients) in combination with either an elevated total bilirubin (2ULN) or 
clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia is 
considered to be an indicator of severe liver injury. Therefore, investigators must report 
as an adverse event the occurrence of either of the following:

Treatment-emergent ALT or AST3ULN (or 3x baseline) in combination with 
total bilirubin2ULN.

Treatment-emergent ALT or AST3ULN (or 3x baseline) in combination with 
clinical jaundice.

Treatment-emergent ALT or AST3ULN (or 3x baseline) in combination with
INR/PT 1.5 

Treatment-emergent ALT or AST 3x ULN (or 3x baseline) with the appearance of 
fatigue, nausea, vomiting, right upper quadrant abdominal pain or tenderness, fever, 
rash and/or eosinophilia.
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), either as a 
serious adverse event or a non-serious adverse event of special interest (see Section 
8.3.6).
7.
DEATHS
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), 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.


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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”).
9.
WORSENING OF CHB
Lack of RO7239958 efficacy in terms of changes in HBsAg does not qualify for adverse 
event in Part 2 of this study.
Medical occurrences or symptoms of deterioration in a course of chronic HBV infection 
should be recorded as adverse events if judged by the Investigator to have unexpectedly 
worsened in severity or frequency or changed in nature at any time during the study.
Virological breakthrough (HBV DNA rebound) and abnormal liver function tests (total 
bilirubin > 2x ULN, INR/PT > 1.5) should be reported as adverse events.
Medical occurrences or symptoms of deterioration that are anticipated as part of chronic 
HBV infection 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 CHB on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., “worsening of CHB”).
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.


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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

Hospitalization for a preexisting condition, 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 Table 1 will be performed locally for Part 1 of the study and by the 
central laboratory for Part 2 (with the exception of urinalysis specific gravity, urine 
dipstick, and alcohol testing which will be performed locally).
In Part 2, local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 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 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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Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose, 
urea, creatinine, cystatin C (and estimated creatinine-
and cystatin C-based eGFR by CKD-epi equation [see 
Appendix 6]) total protein, albumin, phosphate, 
calcium, total and direct bilirubin, gamma-glutamyl 
transferase (GGT), alkaline phosphatase, ALT, AST, 
urate. In Part 2, Creatinine Kinase (CK) will be performed 
as reflex testing on any AST value ≥2 x ULN.
For additional assessments relating to exploratory 
safety BMs, please see Section 8.6.1.
Coagulation

INR, aPTT/ PT.
Viral Serology (Part 1)

HIV (HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), Hepatitis B surface antigen (HBsAg), total 
hepatitis B core antibody (anti-HBc), hepatitis C virus 
(HCV) antibody.
Viral Serology (Part 2)

HIV (HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis C virus (HCV) antibody.
Pregnancy Test

All women will have a blood pregnancy test at 
screening. Urine pregnancy tests will be performed at 
specified subsequent visits. 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
leukocytes, nitrites. 
If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine will 
be sent to the laboratory for microscopy and culture. 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, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if there is a 
clinically significant positive result.
Other Screening Tests

Alcohol and drug screen as per local procedure (to 
include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)}.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study, will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.


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Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most 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, 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 each laboratory parameter. 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.

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. 
–
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.


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2.
CONTRACEPTION GUIDANCE

Female Participants
Only female participants of non-childbearing potential are eligible to participate. 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 Table 1 below.
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

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User-Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

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.
a) 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.
3.
PREGNANCY TESTING
For WONCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to SoA tables (see Section 1.3). If a urine pregnancy test is positive, 
it must be confirmed by a blood pregnancy test.


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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). This applies only to male participants who receive 
RO7239958.
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 
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.


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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 Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal 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 
Section 5 of Appendix 2).
Elective abortion not associated with 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.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female  partner of a male patient 
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; see Section 8.3.5).


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Appendix 6
CKD-EPI GFR
References:
Levey AS, Lesley AS, Schmid CH et al. A New Equation to Estimate Glomerular Filtration Rate. 
Ann Intern Medicine. 2009; 150(9):604-612.
Stevens LA, Coresh, J, Schmid CH et al. Estimating GFR using Serum Cystatin C Alone and in 
Combination with Serum Creatinine: A pooled Analysis of 3418 Individuals with CKD. Am J 
Kidney Dis. 2008; 51(3):395-406.
Zhu Y, Ye X, Zhu B, et al. Comparisons between the 2012 New CKD-EPI (Chronic Kidney 
Disease Epidemiology Collaboration) equations and other four approved equations. PLoS One. 
2014;9(1):1-9.