Conditions: Chronic Hepatitis B
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: yes

Brief summary:
This randomized study will be conducted in two parts to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of subcutaneous administration of RO7062931. Part 1 will include only healthy participants and Part 2 will include only participants with chronic hepatitis B (CHB). Part 1 is an adaptive, single-ascending dose study with an adaptive dose-escalating schedule to determine the best dose to be evaluated in participants with CHB. Part 2 is an adaptive, parallel multiple-dose study comprised of three sub-parts which will be used to further refine the dose and dosing regimen, and to evaluate the safety and efficacy of RO7062931 when administered with standard-of-care (SoC) therapy.

Detailed description:

Arms:
arm 1: Healthy volunteers will be enrolled in up to 8 cohorts with doses starting from 0.1 mg/kg and escalating sequentially after review of safety and pharmacokinetic (PK) data. arm 2: Participants with Chronic Hepatitis B will enrolled in Part 2. In Part 2a, participants will receive two monthly injections of either 3 doses equivalent to a multiple of the saturation dose or placebo in a 1:1:1:1 ratio. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts where they will be dosed weekly (QW) or bi-weekly (Q2W). Each of the cohorts in Part 2b will include participants receiving active drug or placebo in a 3:1 ratio. In Part 2c, NUC-suppressed CHB participants will receive either RO7062931+NUC for up to 24 weeks, or RO7062931+NUC+an immune modulator for up to 48 weeks, at a dose determined from Part 2a and 2b. Part 2c may also enroll treatment-naive immune-active CHB participants.

Interventions: intervention 1: RO7062931 intervention 2: Placebo intervention 3: Immune Modulator
Intervention descriptions: intervention 1: Administered subcutaneously in Parts 1 and 2. Part 1 will be administered in single-ascending doses after 0.1 mg/kg starting dose. Subsequent doses of 0.3, 1, 2 and 4 mg/kg may be administered based upon tolerability. In Part 2a, participants will receive two monthly doses of either 0.4, 0.8, 1.2 times the saturation dose or placebo. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts QW or Q2W. In Part 2c, participants will receive RO7062831 QW on top of another therapy for up to 24 or 48 weeks. intervention 2: Part 1 cohorts: active drug vs placebo 4:1. Part 2a 4 parallel cohorts of 3 active drug doses and placebo in 1:1:1:1. Part 2b active drug vs placebo in 3:1 in 2 parallel cohorts. intervention 3: Participants in Part 2c will receive an immune modulator subcutaneously QW for up to 48 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Randomized, Sponsor-Open, Placebo-Controlled Study to Evaluate 
Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of 
Subcutaneous Administration of RO7062931 With Single Ascending 
Doses in Healthy Volunteers and Multiple Doses and Modified 
Regimens in Virologically Suppressed Patients With Chronic Hepatitis 
B Virus Infection 
NCT Number: NCT03038113  
Document Date: Protocol Version 4: 12-March-2019 
 
 
 


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.
RO7062931—F. Hoffmann-La Roche Ltd
Protocol BP39405, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
PLACEBO-CONTROLLED STUDY TO EVALUATE 
SAFETY, TOLERABILITY AND PHARMACOKINETICS 
AND PHARMACODYNAMICS OF SUBCUTANEOUS
ADMINISTRATION OF RO7062931 WITH SINGLE 
ASCENDING DOSES IN HEALTHY VOLUNTEERS AND 
MULTIPLE DOSES AND MODIFIED REGIMENS IN 
VIROLOGICALLY SUPPRESSED PATIENTS WITH 
CHRONIC HEPATITIS B VIRUS INFECTION
PROTOCOL NUMBER:
BP39405
VERSION:
4
TEST PRODUCT:
RO7062931
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 24-October 2016
DATE AMENDED:
Version 2: 10-April-2017
Version 3: 30-November-2018
Version 4: See electronic date stamp below
 
12-Mar-2019 10:11:46
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7062931—F. Hoffmann-La Roche Ltd
2/Protocol BP39405, Version 4
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
PLACEBO-CONTROLLED STUDY TO EVALUATE 
SAFETY, TOLERABILITY AND PHARMACOKINETICS 
AND PHARMACODYNAMICS OF SUBCUTANEOUS
ADMINISTRATION OF RO7062931 WITH SINGLE 
ASCENDING DOSES IN HEALTHY VOLUNTEERS AND 
MULTIPLE DOSES AND MODIFIED REGIMENS IN 
VIROLOGICALLY SUPPRESSED PATIENTS WITH 
CHRONIC HEPATITIS B VIRUS INFECTION
PROTOCOL NUMBER:
BP39405
VERSION NUMBER:
4
TEST PRODUCT:
RO7062931
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.


RO7062931—F. Hoffmann-La Roche Ltd
3/Protocol BP39405, Version 4
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE
The following sections summarize the rationale for the changes made to the protocol.
Substantial changes
Protocol BP39405 has been amended to incorporate the following changes: 

Study Part 2c with up to four cohorts was added to evaluate the efficacy and safety 
of RO7062931 when administered with Standard of Care (SoC) for up to 48 weeks. 
a) Preliminary results from Part 2a and 2b of the study with RO7062931
administered over a short duration of 28 days showed that RO7062931 is 
associated with good safety and tolerability profile, and proof-of-mechanism
(PoM) was demonstrated with dose-dependent declines in hepatitis B surface 
antigen (HBsAg) compared with the placebo group.
 
 

Up to date non-clinical and clinical information was added to support the extension of 
the treatment duration in Part 2c. 

Clarification and additional information regarding the management of ALT 
abnormalities was added.

Dose modifications guidance for the management of PEG-IFN side effects was 
added.

For consistency and comparability of hepatitis B virus (HBV) clinical data, the 
severity of adverse events will be graded according to Division of AIDS (DAIDS).
 
 
 
 

A rationale was provided about why NUCs are classed as non-investigational 
medicinal products (NIMP) and about peginterferon (PEG-IFN) is classed as an IMP 
in this study. Accordingly, the dosage form of PEG-IFN and packaging and labeling 
instructions have been provided.


RO7062931—F. Hoffmann-La Roche Ltd
4/Protocol BP39405, Version 4
Non-Substantial Changes

It was clarified that NUC/PEG-IFN are marketed and commercially available and 
consequently, no post-study medication or drug reimbursement after the trial is 
provided as part of the protocol. 

A clarification was provided that herbal therapy or substances (e.g. 
tea)/supplements/traditional Chinese medicines), as well as over the counter (OTC 
drugs), may affect laboratory values and consequently lead to screening 
failures/patient withdrawal from study treatment. Therefore, Investigators have been 
instructed to carefully review the intake of such therapies with the patient and advise 
them to refrain from taking them, if considered necessary.

For patients in Part 2C taking NUC or PEG-IFN during the study, it was added that 
prescribing information or PEG-IFN Investigator Brochure should be followed as a 
guide as to whether concomitant medications are permitted or prohibited and that the 
sponsor may be contacted in case of doubt regarding potential prohibited 
concomitant medications.

Some formatting and typographical errors have been corrected.






RO7062931—F. Hoffmann-La Roche Ltd
7/Protocol BP39405, Version 4
 
 
 
 
 
 
1.2.2
Previous Clinical Studies
This Phase I study (BP39405) is the first-in-human study with RO7062931. One further 
clinical study with RO7062931 in Chinese Healthy Volunteers is currently ongoing.
Preliminary data from BP39405 study indicates that RO7062931 is safe and well 
tolerated: 

In the BP39405 study Part 1, 60 healthy volunteers in total, in six SAD cohorts 
(0.1, 0.3, 1.0, 2.0, 4.0, and 3.0 mg/kg) received a single dose of RO7062931 or 
placebo. Blinded data review demonstrated no dose dependency in the incidence 
and intensity of AEs. A total of 78 non-serious AEs were reported in 40 out of 
60 HVs; the majorities (74) of those AEs were mild in intensity and 4 were of 
moderate in intensity. 

In Part 2a and Part 2b of the BP39405 study, at the cut-off date of 22 November 
2018, 54 patients were enrolled. Part 2a enrolled 27 patients in four cohorts for 
monthly dosing (0.5, 1.5, 3.0 mg/kg of RO7062931 or placebo). Part 2b enrolled 
further 27 patients in three cohorts exploring 3 mg/kg weekly (QW) or bi-weekly 
dosing (Q2W) of RO7062931. There was no dose-dependent or regimen-
dependent increase in the frequency or severity of AEs. A total of 82 AEs were 
reported in 32 of the 54 CHB patients; most AEs were mild and had resolved, 
and five AEs observed in 4 CHB patients were moderate in intensity.

There were no severe or SAEs, AEs leading to treatment withdrawal, or AEs of 
special interest. No particular pattern or significant changes were observed for 
vital signs, ECGs parameters, laboratory safety test results, or urine microscopy. 
No patients discontinued study medication due to safety reasons.

In addition, proof-of-mechanism (POM) in CHB patients has been demonstrated 
with dose-dependent declines in HBsAg observed in patients treated with 
RO7062931 compared to placebo. Similar HBsAg declines were observed 
regardless of HBeAg status.


RO7062931—F. Hoffmann-La Roche Ltd
8/Protocol BP39405, Version 4
1.3 STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Study Rationale
Study BP39405 is the first clinical study of RO7062931, designed to assess: the safety, 
tolerability and pharmacokinetics (PK) of subcutaneously administered single-ascending 
doses (SAD) in healthy volunteers (HVs; Part 1); and safety, tolerability, PK, and 
pharmacodynamic (PD) effects of subcutaneously administered multiple doses to CHB 
patients for a short duration of treatment (Part 2a and Part 2b) and for an extended 
duration of treatment (Part 2c). In this protocol, both healthy volunteers and patients 
are referred to as study subjects.
[…]
 
 
 
 
 
 
 
 
 
 
 
 
[…]
Part 22a/2b will involve patients with CHB infection who have responded to standard 
treatment with NUC inhibitors of HBV reverse transcriptase.
 
 
 
However, the results from Part 22a/2b will provide essential 
information for selecting doses for future clinical trials and for supporting the 
development of a new treatment for chronic HBV infection.


RO7062931—F. Hoffmann-La Roche Ltd
9/Protocol BP39405, Version 4
Part 2c of the study will assess the efficacy and safety of RO7062931 when 
administered with Standard of Care (SoC; NUC with/without PEG-IFN) for up to 48 
weeks. Preliminary data from Part 2a/2b have demonstrated POM and RO7062931 
administration in CHB patients is associated with a good safety and tolerability profile 
following 4 weeks of treatment.
 
 
 
1.3.2
Benefit-Risk Assessment
NoBefore initiation of this first-in-human study, no prior clinical experience with 
RO7062931 existsexisted. The evaluation of the potential risks of treatment and the 
specific tests, observations, and precautions required for clinical studies with 
RO7062931 arewere based on information from non-clinical toxicology and safety 
pharmacology studies as well as prior experience with other oligonucleotide therapeutics. 
Safety and tolerability will be carefully assessed, and study subjects (referring to both 
healthy volunteers and patients in the protocol) will be closely monitored. The 
RO7062931 Investigator Brochure, Section 6 summarizes the key risk management 
activities to consider when administering this novel compound to study subjects.
[…]
The good safety and tolerability observed to date in CHB patients, the preliminary 
encouraging dose dependent declines in HBsAg levels, and the favorable results from 
pre-clinical chronic toxicity studies, support an evaluation of RO7062931 treatment at 
a dose level of up to 4mg/kg/week and for up to 48 weeks treatment duration when 
administered with standard of care (SoC) therapies. Consistent with current guidelines 
(FDA 2018), non-clinical combination studies of RO7062931 with approved SoC 
therapies (i.e. NUC or PEG-IFN) were not conducted, as available nonclinical data does 
not suggest a potential for serious synergistic toxicity. 
For further information please refer to the latest RO7062931 Investigator Brochure.
3.1.1
Overview of Study Design
The study will be conducted in two parts, of which Part 1 will be in healthy volunteers 
and Part 2 will be in CHB patients (see Figure 1). Both parts of the study are randomized. 
Part 1 will evaluate the safety, tolerability and PK of RO7062931, and if applicable 
metabolite(s), following SC administration of single doses in healthy volunteers. Part 2 
will evaluate the safety, tolerability PK and PD (viral dynamics) following administration 
of multiple SC doses of RO7062931 in CHB patients over short treatment duration 
(Figure 1) and extended treatment durations (Figure 2) (see Section 4.6).
The header of Figure 1 was changed to reflect the fact that there will be short treatment durations 
in Part 1, 2a, and 2b, in contrast to the newly added Part 2c.


RO7062931—F. Hoffmann-La Roche Ltd
10/Protocol BP39405, Version 4
Figure 2 was added to describe the study design for the newly added Part 2c with extended 
treatment durations.
The total duration of the study for each HV in Part 1 will be16 weeks.

Part 1 (1 dose) 
-
Screening: Up to 28 days;
-
In Clinic period: Days 1 to 3;
-
Safety Follow-up: up to at least Day 85.
The total duration of the study for each patient in Part 2 will be 24 weeks., except for 
Part 2c where the total duration may be 52 weeks.

Part 2a (2 doses, Q1M)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days 1 to 2 and Days 29 to 30;
-
Safety Follow-up: up to at least Day 113.

Part 2b (3 doses, Q2W)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days1 to 2 and Days 29 to 30;
-
Safety Follow-up: Up to at least Day 113.

Part 2b (4 doses, QW)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days 1 to 2 and Days 22 to 23;
-
Safety Follow-up: Up to at least Day 106.

Part 2b (5 doses, QW)
–
Screening: Up to 56 days;
–
In Clinic period (optional): Days 1 to 2 and Days 29 to 30;
–
Safety Follow-up: Up to at least Day 113.

Part 2c (QW)
–
Screening: Up to 28 days;
–
Treatment period: Up to 48 weeks;
–
Follow-up period: Up to 24 weeks.


RO7062931—F. Hoffmann-La Roche Ltd
11/Protocol BP39405, Version 4
3.1.1.2
Part 22a/2b: Proof-of-Mechanism in CHB Infected Patients
Part 22a/b is a multi-center randomized, Sponsor-open, Investigator-blinded, 
subject-blinded, placebo-controlled, adaptive, parallel multiple-dose study in chronically 
HBV infected patients, with the aim to study the safety, tolerability, PK of 
RO7062931(and if applicable metabolite[s]), and the relationship between RO7062931 
dose, dose regimen and viral dynamic response. Part 2 is comprised of two subparts.
[…]
In Part 2b, a dose identified from the dose-response analysis of Part 2a (based on either 
HBsAg decline or maximum dose evaluated and well tolerated) will be tested in different 
dosing regimens administered weekly (QW) or bi-weekly (Q2W). The total dose of 16 
mg/kg per month or 400of 400 mg per day will not be exceeded. The selection of 
dosing regimens will be guided by the analysis of safety, PK and PD data of all previous 
cohorts in Part 2.
[…[
Visits and assessments will be performed as indicated in the SoA tables (see Appendix 
1 to Appendix 14). 
All doses in Part 2a2 will be lower than, or equal to, the doses studied and considered to 
be well-tolerated in Part 1. Subsequent doses and regimens for Part 2b/2c will be 
selected on the basis of the analysis of Part 2a data. Part 2b will be initiated once 
Part 2a data have been analyzed. For all parts of the study, theThe total dose will not 
exceed 16 mg/kg per month or 400 mg per day.
[…]
3.1.1.3
Part 2c: Extended Duration of RO7062931 Therapy in CHB Infected 
Patients
Part 2c is an adaptive, open-label, non-controlled, multi-arm, multi-center, study to 
evaluate the efficacy and safety of RO7062931 following subcutaneous administration 
on top of SoC therapies (a NUC with/without PEG-IFN) in NUC-suppressed or 
treatment-naïve CHB patients (Figure 2). Both HBeAg positive and negative patients 
will be enrolled. 

Cohort 9 will enroll NUC-suppressed CHB patients. Patients will receive 
RO7062931 on top of a NUC for up to 24 weeks. RO7062931 will be administered
at a dose determined from study Parts 2a and 2b.


RO7062931—F. Hoffmann-La Roche Ltd
12/Protocol BP39405, Version 4

Cohort 10 will enroll NUC-suppressed CHB patients. Patients will receive 
RO7062931 on top of a NUC plus PEG-IFN for up to 48 weeks. RO7062931 will be 
administered at a dose determined from study Parts 2a and 2b.

Cohort 11 and 12 (optional cohorts) may enroll treatment-naïve immune-active 
CHB patients and/or different treatment combinations or treatment duration.
All cohorts will initially enroll approximately 8 CHB patients per cohort. Initially the 
enrollment will occur sequentially (Cohort 9 will be followed by Cohort 10, see 
Section 4.3). At the end of treatment (either 24 or 48 weeks depending on cohort), all 
study treatment (RO7062931 and PEG-IFN) will be discontinued and all patients will 
be followed up for at least 24 weeks post-treatment follow up. 
Based on emerging and accumulated PK, PD, efficacy and safety data from this study or 
other related studies, the initial cohorts may be expanded to enroll a total of 30 CHB 
patients. Enrollment of the expanded cohorts may be either sequential or parallel.
3.1.2
Dose-Review/Escalation Decisions
[…]
For Part 22a/2b

All available safety information, including AEs, ECGs, vital signs, clinical laboratory 
test results collected up to Day 57 visit (exception: Day 50 for the cohort with 
4 doses given QW).

Adequate data over the first week in Part 2a to characterize the RO7062931 PK and 
predict exposure in cohorts with different regimens or doses used in Part 2b.

HBsAg levels at least by two weeks after the last dose. 
For Part 2c

Commencement of optional cohorts, or expansion of existing cohorts, will be 
determined based on accumulated safety, tolerability, PK, and PD data from this 
study. 
Dose-escalation in Part 1 will not be implemented as planned in healthy volunteers 
dosed with RO7062931, and dosing for a treatment arm/cohort in Part 2 will be 
discontinued, if one of the below criteria is fulfilled, unless it is obvious that the 
occurrence is not considered to be related to RO7062931. 


RO7062931—F. Hoffmann-La Roche Ltd
13/Protocol BP39405, Version 4
Dose-escalation will be stopped if at a dose level, more than 2 of 8 healthy volunteers 
receiving RO7062931 in Part 1, or, within a treatment arm/cohort in Part 2 more than 
2 of 6 patients experience:

Severe or clinically significant (as defined by the Investigator) RO7062931-related 
AEs of the same character, or

Clinically Significant RO7062931-related laboratory abnormality of the same 
character, or

Clinically significant RO7062931-related changes in vital signs or ECGs of the same 
character (e.g., QTcF 500 msec, or 60 msec longer than the pre-dose baseline, 
within the first 48 hours post-dose).

Within two consecutive dose cohorts, four occurrences of any of the above 
conditions in HVs receiving active drug.
[…]
3.2 RATIONALE FOR STUDY DESIGN
A two-part study design has been chosen to characterize RO7062931 in this clinical trial. 
In Part 1, safety and PK of single RO7062931 doses will be characterized in healthy 
volunteers to determine the best liver-targeted dose to be evaluated in CHB patients. In 
Part 2, safety, PK, HBsAg decline and other possible PD effects will be assessed 
following multiple RO7062931 doses in CHB patients and data will be obtained to further 
refine the dose and dosing regimen. Part 2c will evaluate the efficacy and safety of 
RO7062931 when administered with SoC for up to 48 weeks. 
3.2.1
Rationale for Dosage Selection
[…]
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RO7062931—F. Hoffmann-La Roche Ltd
14/Protocol BP39405, Version 4
 
 
 
 
3.2.2
Rationale for Study Population
Part 1 will be conducted in healthy male 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 drug disposition and safety profile to be obtained.
Part 22a/2b will be conducted in nucleoside/nucleotide suppressed CHB infected 
patients. Only in this patient population can the pharmacodynamic effects of RO7062931 
in humans be tested. The PK and safety of RO7062931 will also be evaluated in this 
population. The results will provide essential information for supporting the future 
development, such as dose-selection for a Phase II study in CHB patients.
Part 2c of the study will be conducted in NUC-suppressed or potentially treatment-
naïve immune-active CHB patients, and will include both HBeAg positive and HBeAg 
negative patients. These patient populations are considered appropriate for trials of 
novel CHB therapeutics regimen, as highlighted in current guidelines (FDA 2018). 
3.2.3
Rationale for Control Group
This phase I study is designed to be adequate and well-controlled. In Part 1, 
randomization to RO7062931 or placebo will occur in a 4:1 ratio within each of the up to 
8 cohorts planned. This is considered sufficient to allow for comparisons of safety and 
tolerability of active to placebo both within and across cohorts.
In Part 2a, randomization to 3 doses of active or placebo will occur in a 1:1:1:1 ratio. In 
Part 2b, randomization to active or placebo will be 3:1 (within cohorts). The assessment 
of dynamic changes of HBsAg in CHB patients, will allow estimating the effect of 
RO7062931 over placebo. The control patients will also allow for the comparisons of 
safety of active with placebo. 
It is not considered necessary to include controls within the cohorts of Part 2c. Part 2a 
and 2b have shown that placebo controls have negligible change in HBsAg levels over 
time. This information can be leveraged in Part 2c for interpretation of HBsAg 
dynamics. The safety data from Part 2c will be compared qualitatively against Part 2a 
and Part 2b placebo data and against well-established historical safety profiles of SoC 
therapies.


RO7062931—F. Hoffmann-La Roche Ltd
15/Protocol BP39405, Version 4
3.2.4
Rationale for Biomarker Assessments
[…]
Based on nonclinical data (and class effect [Kynamro Solution for injection 189 mg, 
CHMP-EMA Assessment Report 2013]) RO7062931 is considered of to be low risk for 
acute reactions; however, cytokines and complement activation will be measured and 
sentinel dosing will be implemented.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[…]


RO7062931—F. Hoffmann-La Roche Ltd
16/Protocol BP39405, Version 4
3.3.2.2 Pharmacodynamic Outcome Measures (Part 2 only)
In Part 2, blood samples for quantitative and qualitative determination of viral dynamic 
response measurements of, but not limited to, HBsAg, HBV DNA, TNA,HBV RNA,
HBeAg, HBcAgHBcrAg, anti-HBe, anti-HBc, and, anti-HBs and HBsAg/anti-HBs 
complex, will be collected at the time-points indicated in the Schedule of Assessment 
tables (see Appendix 1 to see Appendix 1 to Appendix 14) and as detailed in 
Section 4.6.1.5.4.
The PD outcome measure to support the secondary objective is the change in 
quantitative HBsAg over time. Derived endpoints of quantitative HBsAg will include:

Quantitative HBsAg (qHBsAg) (log10) and its change from baseline

Maximum change from baseline in quantitative HBsAg across all time-points

Rate of decrease for HBsAg at each time-point

Proportion of patients with undetectable qHBsAg (< 0.05 IU/mL)
3.3.3
Exploratory Outcome Measures
Exploratory PD outcome measures:
These will include but may not be limited to HBeAg, qualitative HBsAg, anti-HBs, 
anti-HBe, and maintenance of HBV DNA levels less than 90IU/mL (for Part 2c lower 
limit of quantification [LLOQ]).
Viral resistance monitoring will be performed in any patient who experiences viral 
breakthrough. Please see Section 4.6.1.5.4.
 
 
 
Exploratory safety outcome measures
 


RO7062931—F. Hoffmann-La Roche Ltd
17/Protocol BP39405, Version 4
Exploratory PK outcome measure:
 
 
 
 
 
 
 
 
 
4.2 STUDY POPULATION
[…]
4.2.2
Inclusion Criteria
[…]
4.2.2.2
Parts 2Part 2a and Part 2b - CHB patients only:
[…]
4.2.2.3
Part 2c – CHB patients only:
1.
Ability and willingness of patients to provide written informed consent.
2.
Adult male and female patients, 18 to 65 years of age, inclusive.
3.
A BMI between 18 to 32 kg/m2 inclusive.
4.
CHB infection (HBsAg-positive for ≥ 6 months).
5.
For cohorts only enrolling NUC-suppressed CHB patients, patients must meet the 
following criteria: 
a.
Patients treated with a single NUC (entecavir, tenofovir alafenamide, or 
tenofovir disoproxil fumarate) for ≥12 months. Patients must be on the same 
NUC therapy for at least 3 months before screening. 
b. HBV DNA <LLOQ at screening and in preceding 6 months (at least one 
measurement >30 days prior to screening).
c.
ALT ≤2 x ULN for >6 months prior to screening and confirmed at screening. 
Total bilirubin within normal range at screening except for patients with 
Gilbert’s syndrome (TB ≤47 µmol/L [2.75 mg/dL]).


RO7062931—F. Hoffmann-La Roche Ltd
18/Protocol BP39405, Version 4
6.
For Cohorts only enrolling treatment-naïve and immune-active patients (e.g., 
Cohort 11), patients must meet the following criteria:
a.
HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, or 2 x 
103 IU/mL for HBeAg negative patients.
b.
Elevated serum ALT >2 ULN to ≤5 ULN, 2 values within 6 months, at least 
one of which is at screening and both results must be at least 14 days apart.
Total bilirubin within normal range at screening, except for patients with 
Gilbert’s syndrome (TB ≤ 47 µmol/L [2.75 mg/dL]).
7.
Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 
days prior to first study treatment within normal ranges, with the exception of 
otherwise specified criteria or judged to be not clinically significant by PI and 
Medical Monitor.
8.
Liver biopsy, Fibroscanor equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection without 
evidence of bridging fibrosis or cirrhosis (Metavir 3, recommended cut-off for
fibroscan 8.5 kPa).
9.
Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post-menarcheal but has not reached a post-
menopausal state ( 12 continuous months of amenorrhea with no identified cause 
other than menopause, confirmed by FSH, or amenorrhea for at least 24 months if 
on hormone replacement therapy), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom plus spermicide during the 
treatment period and up to 6 months after the last dose to avoid exposing the 
embryo. Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
4.2.3
Exclusion Criteria
[…]
4.2.3.2
Parts 2Part 2a and Part 2b - CHB patients only:
[…]


RO7062931—F. Hoffmann-La Roche Ltd
19/Protocol BP39405, Version 4
4.2.3.3
Part 2c - CHB patients only:
1.
Women who are lactating.
2.
History or other evidence of bleeding from esophageal varices.
3.
Evidence of liver cirrhosis or decompensated liver disease such as ascites, 
esophageal or gastric varices, splenomegaly, nodular liver, jaundice, hepatic 
encephalopathy, portal hypertension.
4.
One or more of the following laboratory abnormalities at screening:
a)
Total serum bilirubin > ULN (exception Gilbert’s disease). 
b) (INR >1.1 ULN.
c)
Serum albumin <3.5 g/dL (<35g/L).
d) AFP >13 ng/mL (if >ULN, hepatic imaging must exclude hepatocellular 
carcinoma [HCC]).
e)
Positive results for anti-mitochondrial antibodies (AMA >1:80), anti-nuclear 
antibody (ANA) (>1:80), anti–smooth muscle antibody (ASMA >1:40), anti-
thyroperoxidase antibodies (a-TPO), anti-thyroglobulin, or anti-platelet 
antibodies.
f)
Thyroid stimulating hormone (TSH) within normal ranges.
g) Platelet count <100,000 cells/mm3.
h) Hemoglobin <12 g/dL (females) or <13 g/dL (males).
i)
White blood cell count <2500 cells/mm3. 
j)
Neutrophil count <1500 cells/mm3 (<1200 cell/mm3 if considered a 
physiological variant in a patient of African descent).
5.
History or other evidence of a medical condition associated with chronic liver 
disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, 
alcoholic liver disease, toxin exposure, thalassemia, nonalcoholic steatohepatitis, 
etc.).
6.
History of thyroid disease poorly controlled on prescribed medications or clinically 
relevant abnormal thyroid function tests (TSH).
7.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
8.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C (quantitative anti-HCV), 
hepatitis D (total anti-HDV), hepatitis E (IgM and IgE anti-HEV), or human 
immunodeficiency virus (anti-HIV1/anti-HIV2).
9.
Expected to need systemic antiviral therapy other than that provided by the study 
at any time during their participation in the study, with the exception or oral 
therapy for HSV I or HSV II.
10. History of significant gastrointestinal disease (including but not limited to gastric 
ulcers).


RO7062931—F. Hoffmann-La Roche Ltd
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11. History of clinically significant cardiovascular, endocrine, renal, ocular, 
pulmonary, psychiatric, or neurological disease.
12. Evidence of an active or suspected cancer or a history of malignancy other than 
adequately treated basal cell carcinoma.
13. History of organ transplantation.
14. Participation in an investigational drug or device study within 30 days prior to 
screening or previous treatment with an investigational agent for HBV (6 months 
prior to screening).
15. Taking any drugs or nutrients listed in prohibited medications and prohibited food 
sections.
16. Significant acute infection (e.g., influenza, local infection) or any other clinically 
significant illness within 2 weeks of randomization.
17. ECG at screening with clinically significant abnormalities, including QTcF 
interval (QT corrected using Fridericia’s formula) ≥450 msec for males and 
≥470 msec for females.
18. Abnormal renal function including serum creatinine ULN or calculated 
creatinine clearance 70 mL/min (using the Cockcroft Gault formula).
19. Donation or loss of blood over 500 mL within 3 months prior to randomization.
20. Administration of any blood product within 3 months prior to randomization.
21. History of alcohol abuse (consumption of more than 2 standard drinks per day on 
average; 1 standard drink = 10 grams of alcohol) and/or drug abuse within one year 
of randomization; positive test result for drugs of abuse or alcohol breath test at 
screening.
22. Subjects under judicial supervision, guardianship, or curatorship. 
23. Medical or social conditions that would potentially interfere with the subject’s 
ability to comply with the study visit schedule or the study assessments.
4.3 METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This study isPart 1, Part 2a, and Part 2b are Sponsor-open, Investigator-blinded, 
subject-blinded. This means that the study subjects will be blinded, the Investigator(s), 
site staff observing the subjects will be blinded and the Sponsor will be unblinded. Part 
2c is open-label.
In Part 1, the site pharmacist and the study drug administrator will be unblinded. For 
Parts 2 2a and 2b, the site Pharmacist will be unblinded. Members of the Sponsor’s 
study team who do not have direct contact with the Investigator or study site staff will be 
unblinded. This does not include any CROs and any sponsor staff in direct contact with 
the investigators and the study sites, who will remain blinded. Part 2c of the study is a 
non-randomized, non-controlled, open-label study; therefore site staff observing the 
patients, patients, and the Sponsor will be unblinded.


RO7062931—F. Hoffmann-La Roche Ltd
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[…]
Part 2c
For Part 2c, the IxRS will be used to register patients to the open-label cohorts. 
Additionally, IxRS will be used to dispense RO7062931 and PEG-IFN for patients. The 
Sponsor may postpone or stop enrolment of, or only enroll certain patient subgroups, in 
order to evaluate pharmacodynamic parameters in different patient subgroups.  The 
initial 8 patients of cohort 9 will be enrolled prior to the enrollment of the initial 8 
patients in cohort 10. Either or both of these cohorts may be expanded up to a maximum 
of 30 patients in total. Assignment of patients at this expansion stage may be 
sequential or in parallel. Enrolment of subsequent cohorts 11 and 12 may be sequential 
or parallel. 
The treatment allocation will be managed by the Pharmacist and will be based on the 
IxRS assignment. 
The Principal Investigator(s) will receive a set of sealed treatment codes for Part 1. 
These may have the form of sealed envelopes or scratch codes. If the identity of the test 
medication needs to be known in order to manage the study subject’s condition (in the 
case of a serious adverse event), the treatment code for that study subject may be 
broken. For Parts 22a and 2b, the Investigator(s) will be able to break the treatment code 
by contacting the IxRS. Treatment codes should not be broken except in emergency 
situations. 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).
[…]
4.4.1.2
Standard of Care (NUC and PEG-IFN)
As NUCs (entecavir, tenofovir alafenamide or tenofovir disoproxil fumarate) are to be 
used as background SoC therapies, they are classed as non-investigational medicinal 
product (NIMP). Please see local prescribing information for additional information.
As PEG-IFN is not licensed for use in CHB patients receiving NUC therapy, it is thus 
classed as an IMP.
PEG-IFN is a clear and colourless to light yellow sterile liquid provided in prefilled 
syringes for single use. Each prefilled syringe of 0.5 mL solution contains 
180 µg peginterferon alfa-2a.
The list of excipients is as follows: sodium chloride, polysorbate 80, benzyl alcohol, 
sodium acetate, acetic acid, and water for injections.


RO7062931—F. Hoffmann-La Roche Ltd
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The packaging and labeling of PEG-IFN will be in accordance with Roche standard and 
local regulations. Study drug packaging 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. Study drug should be stored under the 
recommended storage conditions (2 to 8°C, protected from light). For further details, 
see the packaging label.
Upon arrival of investigational products at the site, site personnel should check them 
for damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.
4.4.2
Dosage, Administration and Compliance
4.4.2.1
RO7062931 and Placebo
[…]
For Part 2c:
All RO7062931 administrations will be via the SC route utilizing sterile technique.
RO7062931 doses will be administered SC once weekly for up to 24 weeks in Cohort 9 
and for up to 48 weeks in Cohort 10. All RO7062931 doses will be administered at the 
study clinic in the morning by investigational staff and should be administered in the 
fasted state either two hours before or two hours after a morning meal.
For cohorts involving PEG-IFN, RO7062931 and PEG-IFN SC doses should be 
administered at different sites (e.g. left thigh and right thigh), and the administration 
sites should be rotated on a weekly basis between doses. This will allow to better 
characterize and minimize the risk of injection site reactions. For convenience, consider 
SC treatment administrations in the same morning as the NUC administration and 
PEG-IFN SC administration should be at least 1 hour after RO7062931 SC 
administration.
PEG-IFN administration
All PEG-IFN administrations will be administered via the SC route utilizing sterile 
technique. PEG-IFN at a dose of 180 mcg will be administered once weekly for up to 48 
weeks. PEG-IFN will be administered weekly at study clinic. 
Specific guidelines for adjusting the doses of PEG-IFN for adverse event management 
are provided in Section 5.2.1.3. If PEG-IFN is interrupted or discontinued permanently, 
patients should continue treatment with RO7062931 and NUC until the end of the 
treatment period.
For further information on the PEG-IFN, please refer to PEG-IFN Investigator 
Brochure.


RO7062931—F. Hoffmann-La Roche Ltd
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NUC administration
NUC will be administered per local label or as per prescribing information and should 
be taken in the morning of RO7062931 or RO7062931 and PEG-IFN administration. 
NUC administration during the study, including the follow-up period, should be 
captured in the site documentation and eCRF. This information should include 
information about any missing doses during treatment and follow-up period. 
For further information on the NUCs used in this study, please follow local prescribing 
information.
4.4.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(RO7062931 and, placebo, and PEG-IFN) will be provided by the Sponsor. The 
investigational site will acknowledge receipt of IMPs, to confirm the shipment condition 
and content. Any damaged shipments will be replaced.
[…]
4.4.5
Post-Trial Access to NUC/PEG-IFN
NUC or PEG-IFN are marketed drugs and commercially available. No post-study 
medication or drug reimbursement is provided as part of this protocol. The investigator 
is responsible for ensuring that consideration has been given to the post-study care of 
the patient’s medical condition.
4.5 CONCOMITANT THERAPY AND FOOD
There are no concomitant treatment restrictions at this time as no drug-drug interactions 
are foreseen for RO7062931. In Part 1, there are some restrictions for healthy 
volunteers that should be maintained.
[…]

Herbal therapy or substances (e.g. tea)/supplements/traditional Chinese medicines, 
as well as OTC drugs, may affect patient laboratory values. Abnormal values may 
lead to screening failures or patient withdrawal from study treatment. As such, 
patients at screening should be carefully questioned regarding such practices/habits 
and should be advised to refrain from them, if deemed necessary.
4.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be prohibited. All concomitant 
medications need be discussed with the Sponsor prior to enrolling study subjects.


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For patients in Part 2c who take NUC or PEG-IFN during the study, please follow the 
prescribing information or the PEG-IFN Investigator Brochure, to guide as to whether 
concomitant medications are permitted or prohibited. 
In case of doubt, the Sponsor may be contacted regarding potential prohibited 
concomitant medications, which may be allowed if the rationale is discussed, agreed and 
documented between the Investigator and Sponsor Medical Monitor.
4.6.1.5.1
Safety Laboratory Assessments
[…]
The following blood and urine samples will be collected:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), mean 
corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration 
(MCHC).

Blood chemistry: ALT, AST, total and indirect bilirubin, ALP, blood urea nitrogen 
(BUN), gamma-glutamyl transferase (GGT) (at Screening only), glutamate 
dehydrogenase (GLDH), creatine phosphokinase (at Screening only), total protein, 
albumin, creatinine, and calculated creatinine clearance (using the Cockcroft Gault 
formula), glomerular filtration rate (GFR) calculated (MDRD4 method), uric acid, 
cystatin c, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides, sodium, chloride, potassium, calcium, magnesium, phosphate and 
bicarbonate. 

Coagulation: prothrombin time (PT), International Normalized Ratio (INR), activated 
partial thromboplastin time (aPTT)

Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocytes, specific gravity and pH. Urine will be 
also sent to the laboratory to perform microscopy to examine urine sediment for 
casts and cells. If there is a clinically significant positive dipstick result, (i.e., 
confirmed by a positive repeated sample), urine will be sent to the laboratory for 
culture. If there is an explanation for the positive dipstick result, e.g., menses, it 
should be recorded. Urine color may be evaluated from urinalysis or urine PK 
samples if considered necessary.

Viral serology: Human immunodeficiency virus (HIV-1 Antibody, HIV-2 Antibody), 
hepatitis A virus (HAV IgM Antibody), hepatitis B virus (surface antigen, HBsAg), 
hepatitis C virus (HCV RNA or HCV antibody) quantitative HCV antibody), hepatitis 
D (total HDV antibody) (Part 2c), and hepatitis E virus (IgM and IgG HEV 
antibodies) (Part 2c).

Auto-antibodies at Screening: AMA, ANA, ASMA, a-TPO, anti-thyroglobulin, and 
anti-platelet antibodies (Part 2c).


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
Pregnancy test
For all women enrolled in the study: Blood sample for determining beta-human 
chorionic gonadotropin (-HCG) 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.

Alpha fetoprotein: At Screening only for HBV patients.

Thyroid function test: TSH (Part 2c).

Hormones: FSH (females only to confirm post-menopausal status, performed at 
Screening only).

Drugs of abuse (urine): Cannabinoids, amphetamines, methamphetamines, opiates, 
methadone, cocaine, benzodiazepines, and barbiturates.

Alcohol breath or blood test will be performed.
4.6.1.5.2
Pharmacokinetic Assessments
[…]
 
 
 
  
Sparse sampling for tenofovir (including tenofovir alafenamide, if approved for HBV and 
applicable), entecavir, adefovir and telbivudine will be collected. for Parts 2a and 2b and 
entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate for Part 2c.
[…]
4.6.1.5.3
Assessments for Inflammatory Markers, Autoantibodies and
Anti-Drug Antibodies (ADA)
[…]
Inflammatory Markers
Blood samples for assessing inflammatory markers will be obtained for all study subjects 
at pre-specified time-points (see SoA, Appendix 1 to see Appendix 1 to Appendix 14). In 
addition, in case an immune driven AE/AE suggestive of immunological involvement 
occurs, an unscheduled sample will be collected as close to the onset of the AE as 
possible. Blood samples (both planned and unscheduled) will be taken to assess: 
complement, CRP, ESR, gamma globulin and other inflammatory biomarkers (such as, 
but not limited to, IL-6, IL-8, IL12, MCP1, TNF).


RO7062931—F. Hoffmann-La Roche Ltd
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For patients in Part 2c, a baseline (Day 1, pre-dose) sample for inflammatory markers 
will be assessed. In case an immune AE/AE suggestive of immunological involvement 
occurs, the samples collected at the other time-points as well as an unscheduled sample 
collected as close to the onset of the AE as possible will be assessed.
Auto-antibodies
Blood samples for assessing autoantibodies will be obtained for all study subjects before 
dosing, at baseline (also see SoA, Appendix 1 to see Appendix 1 to Appendix 14). In 
addition, in case of an autoimmune driven AE/ AE suggestive of autoimmunological 
involvement occurs, an unscheduled sample will be collected as close to the onset of the 
AE as is possible. The panel of autoantibodies to be assessed will be: anti-nuclear
antibodies, anti-ds-DNA antibodies, anti-histone antibodies, anti-ssDNA antibodies, 
anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibodies, and rheumatoid factor. 
ADA Assessment
Blood samples will be collected from all subjects at each time-point as specified in the 
SoA tables (see Appendix 1 see Appendix 1 to Appendix 14). All ADA blood samples 
shouldwill be collected prior to dosing of investigational drug. ADA blood samples will 
be stored and will only be analyzed in case there is an immune driven AE/AE suggestive 
of immunological, anti drug involvement or in case of an atypical PK result.
4.6.1.5.4
Pharmacodynamic Assessments
During the course of the study, PD sampling time-points may be modified on the basis of 
emerging data to ensure the pharmacodynamics of RO7062931 can be adequately 
characterized.
Blood samples for pharmacodynamics assessments will be collected as indicated in the 
SoA tables (see Appendix 1 to see Appendix 1 to Appendix 14). Samples for laboratory 
tests as specified below will be sent to one or several central laboratories or to the 
Sponsor for analysis. For sampling procedures, storage conditions, and shipment 
instructions, see the separate laboratory manual.
In Part 2c, based on continuous analysis of the data in this study and other studies, any 
sample type not considered to be critical for PD evaluation may be stopped at any time 
if the data from the samples collected does not produce useful information.
Handling of residual samples is described in Section 4.6.1.5. 


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4.6.1.5.5
Clinical Genotyping
A blood sample will be taken pre-dose on Day 1 for DNA extraction from all subjects. If, 
however, the genetic blood sample is not collected during the scheduled visit, it may be 
collected at any time during the conduct of the clinical study.
 
 
 
The sample collected for DNA extraction may be used for whole exome and/or whole 
genome sequencing and other genetic analysis and may be sent to one or more 
laboratories for analysis. These assessments will be performed if safety or scientific 
rationales develop.
Handling of residual samples is described in Section 4.6.1.5. 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4.
4.6.1.5.6
Other Assessments
 
 
 
 
 
 
 
 
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety evaluation may be stopped at any time if the 
data from the samples collected does not produce useful information.


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4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Pretreatment Assessments
[…]
If a subject fails an inclusion/exclusion criterion due to a transient and non-clinically 
significant condition at screening, the Investigator may repeat the relevant screening 
assessment(s) within the screening period (28 days for Part 1 and Part 2c and 56 days 
for Parts 2 screening period.2a and 2b). If the subject fails a second time, they will be 
classed as a screen failure and cannot be re-screened. Re-screening is allowed for 
subjects who were screened in the study and met study inclusion/exclusion criteria but 
failed to be randomized within 28 days for Part 1 or 56 days for Part 2 after the start of 
the screening period for Part 1 and Part 2c or within 56 days after the start of the 
screening period for Parts 2a and 2b. In order to re-screen such a subject, all inclusion 
and exclusion criteria should be re-evaluated and all applicable screening assessments 
repeated if done more than 28 days before randomization for Part 1 and Part 2c or more 
than 56 days before randomization for Parts 2 before randomization2a and 2b. There is 
no need to repeat alpha-fetoprotein test if done for the study in central laboratory within 
6 months before re-screening.
4.6.2.2
Assessments during Treatment
Under no circumstances will study subjects who enroll in any part of this study and have 
completed treatment as specified, be permitted to be allocated a new randomization 
number and re-enroll in the study.
All assessments must be performed as per SoA tables (see Appendix 1 to see Appendix 
1 to Appendix 14).
4.6.2.3
Follow-Up Assessments and Study Completion
Study subjects who complete the study or discontinue from the study early will be asked 
to return to the clinic after the last dose of study drug for a follow-up visit.
All follow up assessments must be performed as per SoA tables (see Appendix 1 to 
Appendix 14).
Adverse events should be followed as outlined in Section 5.5. 
4.7.1.1
Discontinuation from Study Drug
Study subjects must discontinue study drug if they experience any of the following:

Pregnancy

A serious adverse event (SAE) considered by the Investigator to be related to 
treatment with RO7062931.


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
If a dose of RO7062931 is omitted.
Study subjects who discontinue study drug prematurely will be asked to return to the 
clinic for a study completion/early termination visit and may undergo follow-up
assessments. The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF. 
Study subjects who discontinue study drug prematurely for safety reasons will not be 
replaced. Study subjects who discontinue study drug prematurely for non-safety reasons 
may be replaced. The Sponsor should be informed of subjects’ discontinuations from the 
study or from the study drug.
Part 2: CHB Patients
Individual patients must discontinue RO7062931/placebo if they experience any of the 
following:

Safety and tolerability issues, e.g., acute reactions, not tolerable and not 
manageable with symptomatic treatment.

Grade 4 ALT (i.e.,≥10ULN) as defined by the Division of Acquired 
Immunodeficiency Syndrome (AIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE grading table) confirmed within 48-72 hours
(not for Part 2c).

Grade 3 ALT (i.e.,5x to < 10 ULN) combined with total bilirubin2ULN (of 
which35% is direct bilirubin), or Grade 3 ALT and INR1.5.

Any other confirmed (within 48-72h) Grade 4 laboratory abnormality deemed 
clinically significant (based on Investigator’s assessment).

Development of liver decompensation (ascites, varices, Child-Pugh Class B or C 
clinical classification).

RenalGrade 3 renal adverse events defined as creatinine 1.5 ULN or increase 
of 50% from baseline and/or eGFR <60 ml/min/1.73 m2.

Development of resistance in a CHB patient is suspected if the patient experiences 
an increase in serum HBV DNA of1 log10 (10-fold) over nadir during the treatment 
period, i.e., virological breakthrough.

NUC analogue discontinuation due to safety issues or resistance development.
All prematurely discontinued patients will have assessments performed at the end of 
treatment with RO7062931/placebo listed in the SoAs tables. If a patient discontinues 
study drug between study visits, he/she should be called for an unscheduled visit to 
have these assessments performed.


RO7062931—F. Hoffmann-La Roche Ltd
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All patients who discontinued the study treatment prematurely should complete the 
4-week follow-up period (starting from the date of the last dose taken) and continue 
safety follow up as per SoAs (see Appendix 1 to Appendix 14). The primary reason for 
premature study drug discontinuation should be documented on the appropriate eCRF.
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions). Adverse events of special interest for 
this study include the following:

Cases of an isolated elevated ALT or AST ≥10 ULN (Section 5.2 and 5.3.5.6).

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6.

Suspected transmission of an infectious agent by the study drug, 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 drug is suspected.

Severe injection site reactions

Hepatic flare, defined as ALT10ULN

RenalGrade 3 renal adverse events defined as creatinine 1.5 ULN or increase 
of 50% from baseline and/or eGFR <60 mL/min/1.73 m2.
5.2.1
Management of Specific Adverse Events
Hepatic flares are identified by an abrupt elevation of serum ALT (defined as 
ALT≥10ULN), will be conducted for the duration of the study. 
5.2.1.1
Potential Drug-Induced Liver Injury (DILI)
Wherever possible, timely confirmation (within 48 to 72 hours) of initial liver-related 
laboratory abnormalities should occur prior to the reporting of a potential DILI event. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs, and discontinuation of all study medications (RO7062931, NUC, or PEG-IFN, 
where applicable) must be considered.


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In this study, a potential DILI is defined as follows:

For healthy volunteers (Part 1): ALT > 3 ULN accompanied total 
bilirubin > 2 ULN

For CHB patients (Part 2): ALT > 3 baseline / ULN (whichever is higher) 
accompanied by total bilirubin >2 ULN
AND

No other immediately apparent possible causes of ALT elevation and 
hyperbilirubinemia, including, but not limited to acute viral hepatitis, cholestasis, 
pre-existing hepatic disease excluding HCV/HEV or the administration of other 
drug(s), herbal medications, or substances known to be hepatotoxic.
5.2.1.2
Alanine Transaminase (ALT) Elevations
Abrupt elevation of serum ALT above normal is known to occur spontaneously in patients 
with CHB during the course of disease, and/or during anti-viral therapy. Transient 
ALT elevations are not always harmful and may be due to:

The underlying disease 

Immune clearance of infected hepatocytes 

Drug-induced immune-mediated hepatitis

DILI
Isolated ALT elevations of 2-3 times the baseline value that are self-limited are likely to
may reflect a desirable treatment-related immunologic response rather than drug toxicity. 
However, progressive increases, increases inconsistent with the time course of a “flare”,
or ALT elevations associated with increases in bilirubin and without alkaline 
phosphatase increase, should primarily be considered treated as adverse events, i.e. 
potential DILI.
In the event of ALT elevation > 5x ULN, more frequent monitoring of liver tests should 
be performed based on medical judgment and other causes of ALT elevations should be 
investigated. For patients with ALT > 5 ULN, the following management plan is 
recommended:
ALT elevations during treatment

Isolated ALT elevation with preserved hepatic function (e.g. no significant changes in 
bilirubin, INR/PT, albumin, and ALP): 


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-
Closely monitor liver function tests (LFTs) (i.e. ALT/AST, bilirubin, albumin, ALP and 
INR/PT): 
o
ALT 5 to 10 x ULN: Repeat LFTs every week. 
o
ALT >10 x ULN: Temporarily interrupt RO7062931 or RO7062931 and PEG-IFN 
treatment and repeat LFTs twice weekly until ALT level < 5 x ULN. Continue NUC 
treatment. Consider re-introducing RO7062931 or RO7062931 and PEG-IFN 
therapy following discussion with medical monitor based on subsequent laboratory
results.

ALT flare accompanied by declining liver synthetic and excretory functions (increased 
bilirubin >2 x ULN, or albumin decline >0.5 g/dL, or INR >1.5) or other signs of hepatic 
impairment (severe fatigue, nausea, vomiting, right upper quadrant pain):
-
RO7062931 or RO7062931 and PEG-IFN will be permanently discontinued, continue 
NUC treatment.
-
Closely monitor LFTs: 
o
ALT 5 to 10 x ULN: Repeat LFTs every week.
o
ALT >10 x ULN: Repeat LFTs twice weekly until ALT level < 5 x ULN.
-
Investigate the participant for potential etiologies of the laboratory changes.
-
If alternative reasons/diagnoses cannot explain the laboratory changes, a 
potential DILI will be considered. 
If ALT elevations are associated with increased HBV DNA levels, virological breakthrough will 
be suspected (see Section 4.6.1.5.4).
ALT elevations during follow-up

Isolated ALT elevation with preserved hepatic function: 
-
ALT 5 to 10 x ULN: Repeat LFTs every week.  
-
ALT >10 x ULN: Repeat LFTs twice weekly until ALT level <5 x ULN. 

ALT elevation accompanied by declining liver synthetic and excretory functions:
-
ALT 5 to 10 x ULN: Repeat LFTs and ALT/AST every week.
-
ALT >10 x ULN: Repeat LFTs and ALT/AST twice weekly until ALT level < 5 x ULN. 
-
Investigate the CHB patient for potential etiologies of the laboratory changes.
-
If alternative reasons/diagnoses cannot explain the laboratory changes, a potentially
delayed DILI will be suspected and CHB patient will be monitored accordingly.
In participants who have not discontinued NUC therapy, if ALT elevations are associated with
increased HBV DNA levels, virological breakthrough will be suspected (see Section 4.6.1.5.4). 


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The Investigator should aim to exclude development of decompensated liver disease. 
Patients who develop signs of decompensated liver disease (e.g., ascites, variceal 
hemorrhage, Child-Pugh Class B or C clinical classification [Appendix 16]) should 
discontinue study treatment (Section 4.7.1.1). Patients who develop flares should be 
monitored more closely with additional unscheduled visits and laboratory assessments.
No dose modification of RO7062931/placebo for safety reasons is expected in the study.
At the discretion of the Investigator, study treatment can be discontinued.
5.2.1.3
Dose Modifications with PEG-IFN
The intention of Part 2c of the protocol is that patients remain on PEG-IFN until the 
completion of the allocated treatment period. However, it is possible that some patients
will encounter transient or prolonged adverse effects or abnormal laboratory values at 
some juncture during their participation in the trial leading to potential need for 
adjustment of the PEG-IFN dosage.
If severe adverse reactions or laboratory abnormalities develop during PEG-IFN 
therapy, the dose should be modified until the adverse reactions abate. If intolerance 
persists after dose adjustment, PEG-IFN therapy should be discontinued. 
When dose modification of PEG-IFN is required for adverse reactions (clinical and/or 
laboratory), an initial dose reduction to 135 mcg (adjustment to the corresponding 
graduation mark for the prefilled syringes) is recommended. Dose reduction to 90 mcg 
(adjustment to the corresponding graduation mark for the prefilled syringes) may be 
needed if the adverse reaction persists or recurs. Following improvement of the adverse 
reaction, re-escalation of the dose may be considered. Table 1 provides guidelines for 
dose modifications and discontinuation of PEG-IFN for haematological laboratory 
abnormalities.
Table 1 PEG-IFN Hematological Dose Modifications Guidelines
Laboratory Values
Recommended Dose
ANC < 750 cells/mm³
ANC < 500 cells/mm³
Reduce to 135 mcg
Discontinue treatment until ANC values return to more 
than 1000 cells/mm3. Reinstitute at 90 mcg and monitor 
ANC.
Platelets < 50,000 cells/mm³
Platelets < 25,000 cells/mm³
Reduce to 90 mcg
Discontinue treatment 


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For patients who discontinue PEG-IFN early due to intolerability or if stopping criteria 
are met, then NUC and RO7062931 should be continued up to 48 weeks. The reasons
for discontinuation of PEG-IFN and length of treatment duration will be recorded in 
the eCRF.
5.3.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing adverse event severity in the study for Part 1 
and Parts 2a and 2b.
Table 2 Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2).
For Part 2c, DAIDS toxicity grading scales (Appendix 18) will be used to assess 
adverse event severity.
5.3.5.6
Abnormal Liver Function TestsAlanine and Aspartate Transaminase
(ALT/AST) Elevations
For Part 1: 
The finding of an elevated ALT or AST (3ULN) 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 (Hy’s 
Law). Therefore, investigators must report as an adverse event the occurrence of either 
of the following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.


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For Part 2:
TheCHB patients may have elevated baseline ALT levels without an increase in 
bilirubin. However, the finding of an elevated ALT or AST in combination with either an 
elevated total bilirubin or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of potential severe liver injury. or 
worsening of disease. Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST3 Baseline and >3 x ULN value in combination 
with total bilirubin2ULN (of which35% is direct bilirubin).. 

Treatment-emergent ALT or AST3 Baseline and >3x ULN value in combination 
with clinical jaundice.

Treatment emergent ALT≥10ULN
*For Part 2c (treatment- naïve and immune-active CHB patients), the threshold of 
ALT >3 ULN baseline will be capped at 10 ULN.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
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 5.4.2).
5.3.5.11 Overdoses
Study drug (including IMP and NIMP) overdose is the accidental or intentional use of 
the drug in an amount higher than the dose being studied. An overdose or incorrect 
administration of study drug is not an adverse event unless it results in untoward medical 
effects.
[…]


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female subjects of childbearing potential will not be allowed to participate in this study. 
Although highly unlikely, female subjects will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 105 days after the last 
dose of study drug (Parts 2a and 2b) or within 6 months after last dose (Part 2c). A 
Clinical Trial Pregnancy Reporting Form should be completed by the Investigator and 
submitted to the sponsor within 24 hours after learning of the pregnancy. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of 
the pregnancy.
6.1 DETERMINATION OF SAMPLE SIZE
[…]
For Parts 22a and 2b of the study, the PoM in CHB infected patients, a sample size of no 
more than 80 patients with CHB has been chosen (6 patients [Part 2a] and 8 patients 
[Part 2b] per dose cohort). It is anticipated that this sample size will allow 
characterization of the PK/PD (viral dynamic response) relationship, as well as safety 
and tolerability, in patients with CHB.
For Part 2c, approximately 16 patients will be enrolled into the initial 2 cohorts 
(8 patients in each cohort). If utilized, approximately 8 patients will be enrolled to each 
of the Cohorts 11 and 12. The sample size supports the assessment of response rate of 
undetectable qHBsAg at Week 24 follow-up in Cohorts 10, 11, and 12. 
A sample size of 8 ensures that the associated lower 90% confidence limit is above 10%, 
if the observed response rate is at least 38% (i.e. at least 3/8), assuming a binomial 
distribution. This sample size is also considered reasonable to support the safety and 
tolerability objectives of all cohorts, as well as to allow characterization of the qHBsAg 
profiles in Cohort 9.The cohorts may be expanded up to 30 subjects if warranted by 
emerging PD and/or safety data. A sample size of 30 ensures that the associated lower 
90% confidence limit is above 20%, if the observed response rate is at least 37% (i.e. at 
least 11/30).  


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6.6.2
PK/Viral Dynamic Response Analyses
The relationship between RO7062931 and dose, and metabolite(s) and dose if 
applicable, and the change of HBsAg at each time-point and rate of decrease will be 
explored by graphical analysis. The relationship between RO7062931 PK and urinary 
parameters and HBsAg will also be explored by graphical analysis. Assuming a 
monotonic relationship between HBsAg decrease and dose/plasma RO7062931, an 
appropriate exposure/dose-response model may be fitted to the data from Part 2a. This 
model may be used to guide dose selection for Part 2b, and will be further developed 
with data from Parts 2b and 2c.
6.6.3
Efficacy Analyses
The proportion of patients with undetectable qHBsAg and associated 95% binomial confidence 
intervals will be calculated at 24 week after the end of treatment. Patients with missing 
HBsAg measures at 24 weeks visit after the end of treatment and thereafter will be treated as 
non-responders.
6.7 PHARMACOKINETIC ANALYSES
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Summary descriptive statistics of plasma PK parameters 
including Cmax, Tmax, AUCinf, AUClast, and t1/2 for RO7062931 and any metabolites when 
available will be presented by cohort/treatment arm including mean, standard deviation 
(SD), coefficient of variation (CV), medians and ranges. Note: the geometric or 
arithmetic mean and associated CV% will be used to describe Cmax, AUCinf, AUClast; 
arithmetic means and t1/2. Median values will be used to describe Tmax and t1/2. Where 
appropriate, data may be pooled and analyzed, for example, all single dose data may be 
pooled. Listings, summary tables and graphs (individual plots and/or mean plots) by 
treatment group will be provided. Descriptive statistics of urine PK parameters for 
RO7062931 and any metabolites will be presented, where available. PK and PD data 
from this study may be used to develop a population PK/PD model.
Where appropriate, listings and summary tables of nucleoside/nucleotide-analogues, 
tenofovir, tenofovir, alafenamide, entecavir, adefovir, or telbivudine concentrations will 
be provided based on the sparse sampling throughout the study.
 


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6.11
INTERIM ANALYSES
No interim analysis is planned for Part 1s 2a, and 2b of this study.
In Part 2c, administrative interim analyses will be conducted at Weeks 12 and 24 for 
the initial 8 enrolled in both Cohorts 9 and 10. Given the hypothesis-generating nature 
of this study, the Sponsor may choose to conduct additional administrative interim PD 
analyses. The decision to conduct additional interim analyses and the timing of the 
analyses will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis. The interim analysis will be performed and interpreted by Sponsor 
study team personnel.
10. REFERENCES
[…]
 
 
Investigator’s Brochure PEG-Interferon.
[…]
Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood 
transfusion. N Engl J Med. 1966; 274(9): 473-81.
U.S. Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). Chronic Hepatitis B Virus Infection: Developing 
Drugs for Treatment. Guidance for Industry. Draft Guidance. November 2018.
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM624695.pdf)
Appendices:
Further appendices were added to the Schedule of Assessments regarding Part 2c of 
the study, i.e. QW Doses for 24 and 48 Weeks, Main and Detailed Tables and Division 
of AIDS (DAIDS) Table for Grading the Severity of Adverse Events (Appendices 11 to 14 
and Appendix 18).
.


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 46
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 60
1.
BACKGROUND AND RATIONALE ............................................................ 63
1.1
Background on Disease......................................................... 63
1.2
Background on RO7062931 .................................................. 64
1.2.1
Previous Non-Clinical Studies ............................................... 64
1.2.2
Previous Clinical Studies ....................................................... 65
1.3
Study Rationale and Benefit–Risk Assessment .................... 66
1.3.1
Study Rationale ..................................................................... 66
1.3.2
Benefit–Risk Assessment...................................................... 68
2.
OBJECTIVES.............................................................................................. 69
2.1
Primary Objectives ................................................................ 69
2.2
Secondary Objectives............................................................ 69
2.3
Exploratory Objectives........................................................... 69
3.
STUDY DESIGN......................................................................................... 70
3.1
Description of Study .............................................................. 70
3.1.1
Overview of Study Design ..................................................... 70
3.1.1.1
Part 1: Single-Ascending Dose (SAD) in Healthy 
Volunteers ............................................................................. 72
3.1.1.2
Part 2a/2b: Proof-of-Mechanism in CHB Infected 
Patients.................................................................................. 73
3.1.1.3
Part 2c: Extended Duration of RO7062931 Therapy 
in CHB Infected Patients .................................................................74
3.1.2
Dose-Review/Escalation Decisions ....................................... 75
3.1.2.1
Part 1 Dose- Escalation Decision Criteria.............................. 76
3.1.3
Dose-Escalation Stopping Criteria......................................... 76
3.1.3.1
Part 1..................................................................................... 76
3.1.3.2
Part 2..................................................................................... 77
3.1.4
Communication Strategy ....................................................... 77
3.1.5
End of Study.......................................................................... 78


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3.2
Rationale for Study Design.................................................... 78
3.2.1
Rationale for Dosage Selection ............................................. 78
3.2.2
Rationale for Study Population .............................................. 79
3.2.3
Rationale for Control Group................................................... 79
3.2.4
Rationale for Biomarker Assessments................................... 80
3.2.5
Rationale for Resistance Monitoring...................................... 81
3.3
Outcome Measures ............................................................... 81
3.3.1
Safety Outcome Measures .................................................... 81
3.3.2
Pharmacokinetic (PK) and Pharmacodynamic 
(PD) Outcome Measures....................................................... 82
3.3.2.1
Pharmacokinetic Outcome Measures.................................... 82
3.3.2.2
Pharmacodynamic Outcome Measures (Part 2 
only)....................................................................................... 82
3.3.3
Exploratory Outcome Measures ............................................ 83
4.
MATERIALS AND METHODS .................................................................... 84
4.1
Center.................................................................................... 84
4.2
Study Population ................................................................... 84
4.2.1
Recruitment Procedures........................................................ 84
4.2.2
Inclusion Criteria.................................................................... 84
4.2.2.1
Part 1 - Healthy volunteers only............................................. 84
4.2.2.2
Part 2a and Part 2b - CHB patients only................................ 85
4.2.2.3
Part 2c - CHB patients only ...................................................... 86
4.2.3
Exclusion Criteria................................................................... 87
4.2.3.1
Part 1 - Healthy volunteers only............................................. 87
4.2.3.2
Part 2a and Part 2b - CHB patients only................................ 88
4.2.3.3
Part 2c - CHB patients only ...................................................... 90
4.3
Method of Treatment Assignment and Blinding..................... 92
4.4
Study Treatment.................................................................... 94
4.4.1
Formulation, Packaging, and Handling.................................. 94
4.4.1.1
RO7062931 and Placebo ...................................................... 94
4.4.1.2
Standard of Care (NUC and PEG-IFN)...................................... 95
4.4.2
Dosage, Administration and Compliance............................... 95
4.4.2.1
RO7062931 and Placebo ...................................................... 95


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4.4.3
Investigational Medicinal Product Accountability ................... 97
4.4.4
Post-Trial Access to RO7062931 .......................................... 98
4.4.5
Post-Trial Access to NUC/PEG-IFN.......................................... 98
4.5
Concomitant Therapy and Food ............................................ 98
4.5.1
Permitted Therapy................................................................. 98
4.5.2
Prohibited Therapy ................................................................ 99
4.5.3
Prohibited Food ..................................................................... 99
4.6
Study Assessments ............................................................... 99
4.6.1
Description of Study Assessments ........................................ 99
4.6.1.1
Medical History and Demographic Data ................................ 99
4.6.1.2
Physical Examinations......................................................... 100
4.6.1.3
Vital Signs............................................................................ 100
4.6.1.4
Electrocardiograms.............................................................. 101
4.6.1.5
Laboratory Assessments ..................................................... 102
4.6.2
Timing of Study Assessments ............................................. 111
4.6.2.1
Screening and Pretreatment Assessments.......................... 111
4.6.2.2
Assessments during Treatment........................................... 112
4.6.2.3
Follow-Up Assessments and Study Completion.................. 112
4.7
Subject, Study and Site Discontinuation.............................. 112
4.7.1
Study Subject Discontinuation............................................. 112
4.7.1.1
Discontinuation from Study Drug......................................... 113
4.7.1.2
Withdrawal from Study......................................................... 114
4.7.2
Study and Site Discontinuation............................................ 114
5.
ASSESSMENT OF SAFETY..................................................................... 115
5.1
Safety Parameters and Definitions ...................................... 115
5.1.1
Adverse Events ................................................................... 115
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 116
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 117
5.2
Safety Plan .......................................................................... 117
5.2.1
Management of Specific Adverse Events ............................ 117
5.2.1.1
Potential Drug-Induced Liver Injury (DILI)............................. 117


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5.2.1.2
Alanine Transaminase (ALT) Elevations.................................. 118
5.2.1.3
Dose Modifications with PEG-IFN .......................................... 120
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 121
5.3.1
Adverse Event Reporting Period ......................................... 121
5.3.2
Eliciting Adverse Event Information..................................... 121
5.3.3
Assessment of Severity of Adverse Events ......................... 122
5.3.4
Assessment of Causality of Adverse Events ....................... 122
5.3.5
Procedures for Recording Adverse Events.......................... 122
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 123
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 123
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 124
5.3.5.4
Abnormal Laboratory Values ............................................... 124
5.3.5.5
Abnormal Vital Sign Value................................................... 125
5.3.5.6
Alanine and Aspartate Transaminases (ALT/AST)
Elevations ............................................................................. 125
5.3.5.7
Deaths ................................................................................. 126
5.3.5.8
Pre-Existing Medical Conditions.......................................... 126
5.3.5.9
Lack of Efficacy or Worsening of Chronic 
Hepatitis B Infection............................................................. 127
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 127
5.3.5.11
Overdoses ........................................................................... 128
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 128
5.4.1
Emergency Medical Contacts.............................................. 129
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 129
5.4.3
Reporting Requirements for Pregnancies............................ 130
5.4.3.1
Pregnancies in Female Patients.......................................... 130
5.4.3.2
Pregnancies in Female Partners of Male Study 
Subjects............................................................................... 130
5.4.3.3
Abortions ............................................................................. 130
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 131


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5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 131
5.5
Follow-Up of Patients after Adverse Events ........................ 131
5.5.1
Investigator Follow-Up......................................................... 131
5.5.2
Sponsor Follow-Up .............................................................. 131
5.6
Post-Study Adverse Events................................................. 131
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 132
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 132
6.1
Determination of Sample Size ............................................. 132
6.2
Summaries of Conduct of Study.......................................... 133
6.3
Analysis Populations ........................................................... 133
6.3.1
Safety Analysis Population .................................................. 133
6.3.2
Pharmacokinetic Analysis Population.................................. 133
6.4
Summaries of Treatment Group Comparability ................... 134
6.5
Safety Analyses................................................................... 134
6.5.1
Adverse Events ................................................................... 134
6.5.2
Clinical Laboratory Test Results.......................................... 134
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................. 135
6.5.2.2
Definition of Laboratory Abnormalities................................. 135
6.5.3
Vital Signs............................................................................ 135
6.5.4
ECG Data Analysis.............................................................. 135
6.5.5
Concomitant Medications .................................................... 136
6.6
Pharmacodynamic Analyses ............................................... 136
6.6.1
Viral Dynamic Response Analyses...................................... 136
6.6.2
PK/Viral Dynamic Response Analyses ................................ 136
6.6.3
Efficacy Analyses................................................................... 137
6.7
Pharmacokinetic Analyses................................................... 137
6.8
Exploratory Analyses........................................................... 137
6.8.1
Liver and Kidney Biomarker Data........................................ 137
6.9
Inflammatory Markers, Autoantibodies and ADA 
Data..................................................................................... 137


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6.10
Analysis to Support Dose-Selection .................................... 138
6.10.1.1
Part 1................................................................................... 138
6.10.1.2
Part 2b Dose Selection: First Two Cohorts.......................... 139
6.10.1.3
Part 2b Dose/ Regimen Selection: Exploratory 
Cohorts................................................................................ 139
6.11
Interim Analyses.................................................................... 140
7.
DATA COLLECTION AND MANAGEMENT ............................................. 140
7.1
Data Quality Assurance....................................................... 140
7.2
Electronic Case Report Forms............................................. 140
7.3
Source Data Documentation................................................ 141
7.4
Use of Computerized Systems ............................................ 141
7.5
Retention of Records........................................................... 142
8.
ETHICAL CONSIDERATIONS.................................................................. 142
8.1
Compliance with Laws and Regulations .............................. 142
8.2
Informed Consent................................................................ 142
8.3
Institutional Review Board or Ethics Committee.................. 143
8.4
Confidentiality...................................................................... 143
8.5
Financial Disclosure ............................................................ 144
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 144
9.1
Study Documentation .......................................................... 144
9.2
Site Inspections ................................................................... 144
9.3
Administrative Structure....................................................... 145
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 145
9.5
Protocol Amendments ......................................................... 145
10. REFERENCES ......................................................................................... 146
LIST OF TABLES
Table 1
PEG-IFN Hematological Dose Modifications Guidelines................. 120
Table 2
Adverse Event Severity Grading Scale ..................................... 122


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LIST OF FIGURES
Figure 1
Study Design: Parts 1, 2a, and 2b Short Treatment Durations ... 70
Figure 2
Study Design: Part 2c - Extended Treatment Durations ............. 71
LIST OF APPENDICES
Appendix 1
Schedule of Assessments – Part 1, SAD, Main Table .............. 148
Appendix 2
Schedule of Assessments – Part 1, SAD, Detailed Table......... 150
Appendix 3
Schedule of Assessments – Part 2a, PoM (2 Doses Q1M), 
Main Table ................................................................................ 151
Appendix 4
Schedule of Assessments – Part 2a, PoM (2 Doses Q1M), 
Detailed Table........................................................................... 154
Appendix 5
Schedule of Assessments – Part 2b, PoM (3 Doses Q2W), 
Main Table ................................................................................ 155
Appendix 6
Schedule of Assessments – Part 2b, PoM (3 Doses Q2W), 
Detailed Table........................................................................... 158
Appendix 7
Schedule of Assessments – Part 2b, PoM (4 Doses QW), 
Main Table ................................................................................ 159
Appendix 8
Schedule of Assessments – Part 2b, PoM (4 Doses QW), 
Detailed Table........................................................................... 162
Appendix 9
Schedule of Assessments – Part 2b, PoM (5 Doses QW), 
Main Table ................................................................................ 163
Appendix 10
Schedule of Assessments – Part 2b, PoM (5 Doses QW), 
Detailed Table........................................................................... 166
Appendix 11
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Main 
Table.......................................................................................... 167
Appendix 12
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, 
Detailed Table............................................................................. 171
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main 
Table.......................................................................................... 173
Appendix 14
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, 
Detailed Table............................................................................. 179
Appendix 15
Alcohol Unit Calculation - Examples ......................................... 181
Appendix 16
Child-Pugh Classification of Severity of Liver Disease.............. 183
Appendix 17
Toxicity Table for Grading Injection Reactions.......................... 184
Appendix 18
Division of AIDS (DAIDS) Table for Grading the Severity 
of Adverse Events (for Part 2c of the Study) ............................ 185


RO7062931—F. Hoffmann-La Roche Ltd
46/Protocol BP39405, Version 4
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, SPONSOR-OPEN, PLACEBO-CONTROLLED 
STUDY TO EVALUATE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS AND PHARMACODYNAMICS OF
SUBCUTANEOUS ADMINISTRATION OF RO7062931 WITH 
SINGLE ASCENDING DOSES IN HEALTHY VOLUNTEERS AND 
MULTIPLE DOSES AND MODIFIED REGIMENS IN 
VIROLOGICALLY SUPPRESSED PATIENTS WITH CHRONIC 
HEPATITIS B VIRUS INFECTION
PROTOCOL NUMBER:
BP39405
VERSION:
4
TEST PRODUCT:
RO7062931
PHASE:
I
SPONSOR:
F. Hoffmann-La Roche Ltd
–
OBJECTIVES
Primary Objective:
The primary objectives of this study are:

To assess the safety and tolerability of RO7062931 compared to placebo after 
single-ascending subcutaneous (SC) doses in healthy volunteers (HVs).

To assess the safety and tolerability of RO7062931 compared to placebo after multiple SC 
doses in chronic Hepatitis B (CHB) patients.
Secondary Objectives
The secondary objectives for this study are as follows:
For Part 1:

To assess plasma and urine pharmacokinetics (PK) of RO7062931, and if applicable 
metabolite(s), after single-ascending SC doses.
For Part 2:

To assess the plasma and urine PK of RO7062931 and if applicable metabolite(s), after 
multiple SC doses.

To study HBsAg dynamics after SC administration of RO7062931.
Exploratory Objectives
The exploratory objectives of this study are as follows:

Pharmacodynamics (PD) exploratory objectives:
-
For Part 2: to explore the effect of multiple doses of RO7062931 on viral and anti-viral 
parameters other than quantitative HBsAg during and after the end of treatment in CHB 
patients.




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Part 2c is an adaptive, open-label, non-controlled, multi-arm, multi-center, study to evaluate 
the efficacy and safety of RO7062931 following subcutaneous administration on top of 
Standard of Care (SoC) therapies (a nucleoside/nucleotide analogue[ NUC] with/without 
pegylated interferon [PEG-IFN]) in NUC-suppressed or treatment-naive CHB patients. Both 
HBeAg positive and negative patients will be enrolled. Cohort 9 will enroll NUC-suppressed 
CHB patients and patients will receive RO7062931 on top of a NUC for up to 24 weeks. 
Cohort 10 will enroll NUC-suppressed CHB patients and patients will receive RO7062931 on 
top of a NUC plus PEG-IFN for up to 48 weeks. For Cohorts 9 and 10, RO7062931 will be 
administered at a dose determined from study Parts 2a and 2b. Cohorts 11 and 12 (optional 
cohorts) may enroll treatment-naïve immune-active CHB patients and/or different treatment 
combinations or treatment duration.
NUMBER OF PATIENTS
In Part 1 of the study, up to 8 cohorts of 10 HVs are planned. HVs will at each dose level be 
randomized to either active treatment (eight HVs per cohort) or placebo (two HVs per cohort). 
For Parts 2a and 2b of the study, in CHB infected patients, a sample size of no more than 
80 patients with CHB was chosen (6 patients [Part 2a] and 8 patients [Part 2b] per dose cohort). 
For Part 2c, approximately 16 patients will be enrolled into the initial 2 cohorts (8 patients in 
each cohort). If utilized, approximately 8 patients will be enrolled to each of the Cohorts 11 
and 12.
Depending on evaluation of safety, tolerability and PK data from all previous cohorts of the 
study, one or more additional cohorts may be studied.
TARGET POPULATION
The target population consists of male and female HVs/ patients diagnosed with chronic 
hepatitis B infection, between the age of 18 and 65, inclusive.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria:
Study subjects must meet the below criteria for study entry.
Part 1 - Healthy volunteers only:
1.
Able to participate and willing to give written informed consent and to comply with the study 
restrictions.
2.
Healthy male and female (of non-childbearing potential) subjects. Health status is defined by 
absence 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.
3.
18 to 65 years of age, inclusive.
4.
A Body Mass Index (BMI) between 18 to 30 kg/m2 inclusive and a body weight of at least 
50 kg.
5.
Women should be of non-childbearing potential. A woman is considered to be of childbearing 
potential if she is post-menarcheal but has not reached a post-menopausal state 
(12 continuous months of amenorrhea with no identified cause other than menopause, 
confirmed by follicle-stimulating hormone [FSH], or amenorrhea for at least 24 months if on 
hormone replacement therapy), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agree to refrain from donating sperm, as defined below:


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With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and up to 105 days after 
the last dose to avoid exposing the embryo. Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the healthy volunteer. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
6.
Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1 
and agree to remain as non-smoker during the study.
Part 2a and Part 2b - CHB patients only:
1.
Ability and willingness of patient to provide written informed consent.
2.
Adult male and female (of non-childbearing potential) patients, aged 18-65 years (inclusive).
3.
A BMI between 18 to 32 kg/m2 inclusive.
4.
Chronic hepatitis B infection.
5.
Positive test for HBsAg for more than 6 months prior to randomization.
6.
HBsAg titer 103 IU/mL at screening.
7.
On entecavir, tenofovir, adefovir or telbivudine treatment for at least 6 months prior to 
randomization and will remain on stable treatment during the study.
8.
HBV DNA 90 IU/mL for at least the preceding 6 months.
9.
Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 56 days prior 
to first study treatment within normal ranges, with the exception of otherwise specified criteria 
or judged to be not clinically significant by Principal Investigator (PI) and Medical Monitor.
10. Alanine transaminase (ALT), aspartate aminotransferase (AST), -glutamyltransferase 
(GGT), and alkaline phosphatase (ALP) at screening 1.5 upper limit of normal (ULN); 
normal values for total bilirubin and prothrombin time (PT)/International Normalized Ratio 
(INR)/activated partial thromboplastin time (aPTT) tests at screening (except for patients with 
Gilbert’s syndrome TB 47 mol/L [2.75 mg/dL]).
11. Liver biopsy, Fibroscanor equivalent test obtained within the past 6 months demonstrating 
liver disease consistent with chronic HBV infection without evidence of bridging fibrosis or 
cirrhosis (Metavir 3, recommended cut-off for Fibroscan 8.5 kPa).
12. Women should be of non-childbearing potential. A woman is considered to be of childbearing 
potential if she is post-menarcheal but has not reached a post-menopausal state 
( 12 continuous months of amenorrhea with no identified cause other than menopause, 
confirmed by FSH, or amenorrhea for at least 24 months if on hormone replacement 
therapy), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 


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remain abstinent or use a condom during the treatment period and up to 105 days after 
the last dose to avoid exposing the embryo. Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Part 2c - CHB patients only
1.
Ability and willingness of patients to provide written informed consent
2.
Adult male and female patients, 18 to 65 years of age, inclusive.
3.
A BMI between 18 to 32 kg/m2 inclusive.
4.
CHB infection (HBsAg-positive for ≥ 6 months) 
5.
For Cohorts only enrolling NUC-suppressed CHB patients, patients must meet the 
following criteria: 
a.
Patients treated with a single NUC (entecavir, tenofovir alafenamide, or tenofovir 
disoproxil fumarate) for ≥12 months. Patients must be on the same NUC therapy for 
at least 3 months before screening. 
b.
HBV DNA <LLOQ at screening and in preceding 6 months (at least one 
measurement >30 days prior to screening).
c.
ALT ≤ 2 x ULN for >6 months prior to screening and confirmed at screening. Total 
bilirubin within normal range at screening, except for patients with Gilbert’s 
syndrome (TB ≤47 µmol/L [2.75 mg/dL]).
6.
For cohorts only enrolling treatment-naïve and immune-active patients (e.g., Cohort 11), 
patients must meet the following criteria:
a.
HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, or 2 x 103
IU/mL for HBeAg negative patients.
b.
Elevated serum ALT>2 ULN to ≤5 ULN, 2 values within 6 months, at least one of 
which is at screening and both results must be at least 14 days apart.  Total bilirubin 
within normal range at screening, except for patients with Gilbert’s syndrome 
(TB ≤47 µmol/L [2.75 mg/dL).
7.
Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 days 
prior to first study treatment within normal ranges, with the exception of otherwise 
specified criteria or judged to be not clinically significant by PI and Medical Monitor.
8.
Liver biopsy, Fibroscanor equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection without evidence of 
bridging fibrosis or cirrhosis ( Metavir 3, recommended cut-off for fibroscan 8.5 kPa).
9.
Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post-menarcheal but has not reached a post-menopausal 
state ( 12 continuous months of amenorrhea with no identified cause other than 
menopause, confirmed by follicle-stimulating hormone [FSH], or amenorrhea for at least 24 
months if on hormone replacement therapy), and has not undergone surgical sterilization 


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(removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom plus spermicide during the treatment period and up 
to 6 months after the last dose to avoid exposing the embryo. Men must refrain from 
donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
Exclusion criteria:
Study subjects who meet any of the below criteria will be excluded from study entry.
Part 1 - Healthy volunteers only:
1.
Women who are lactating.
2.
Any suspicion or history of alcohol and/or other substance abuse or dependence in the past 
6 months.
3.
Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone, 
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or positive 
cotinine test at screening or Day 1.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus 
(HIV) 1 and 2.
5.
Confirmed (e.g., two consecutive triplicate measurements) average systolic blood pressure 
(SBP) 140 or 90 mmHg, and diastolic blood pressure (DBP) 90 or 45 mmHg at 
Screening.
6.
Confirmed (e.g., two consecutive triplicate measurements) average resting pulse rate 
(PR) 90 or 45 beats per minute (bpm) at Screening.
7.
A personal history of unexplained blackouts or faints, or known risk factors for Torsade de 
Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal ECG, including 
arrhythmias or marked QT abnormalities (QTcF 300 msec or 450 msec at Screening).
8.
ECG morphology at screening that renders measurement of QT interval imprecise (e.g., 
neuromuscular artifact that cannot be readily eliminated, indistinct QRS onset, low amplitude 
T-wave, merged T- and U-waves, prominent U-waves, arrhythmias, etc.).
9.
Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right or left 
bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Any out of range findings in liver function tests, INR and renal function tests or any 
clinically significant abnormalities (as judged by the Investigator) in the physical examination 
and in the remaining laboratory test results (including hepatic and renal panels, complete 


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blood count, chemistry panel and urinalysis) at screening and on Day-1.
12. Participation in an investigational drug or device study within 90 days prior to screening or 
5 times the half-life of the investigational drug (whichever is longer).
13. Donation of blood over 500 mL within three months prior to screening.
14. Concomitant disease or condition (including allergic reactions against any drug, or multiple 
allergies) 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 
healthy volunteers in this study.
15. Any major illness within the one month preceding the Screening visit, or any febrile illness 
within the two weeks preceding the screening visit.
16. Alcohol consumption of more than 2 standard drinks per day on average; 1 standard drink 
equals 10 grams of alcohol (for further guidance please see Appendix 9).
17. Hypersensitivity to the excipients of the study drug.
18. Healthy volunteers under judicial supervision, guardianship or curatorship.
Part 2a and Part 2b - CHB patients only:
1.
Women who are lactating.
2.
History or other evidence of bleeding from esophageal varices.
3.
Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification [see
Appendix 10] or clinical evidence such as ascites or varices).
4.
History or other evidence of a medical condition associated with chronic liver disease other 
than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, 
toxin exposure, thalassemia, non-alcoholic steatohepatitis, etc.).
5.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
6.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, or HIV.
7.
Documented history of infection with hepatitis D virus.
8.
Expected to need systemic antiviral therapy other than that provided by the study at any time 
during their participation in the study, with the exception of oral/topical therapy for Herpes 
simplex virus (HSV) I or HSV II.
9.
History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) 13 ng/mL at 
Screening.
10. History of immunologically-mediated disease (e.g., inflammatory bowel disease, idiopathic 
thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, 
scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other 
autoimmune disease).
11. History of clinically significant and not adequately controlled cardiovascular, endocrine, 
gastrointestinal, renal, ocular, pulmonary, or neurological disease.
12. Evidence of an active or suspected cancer or a history of malignancy other than adequately 


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treated basal cell carcinoma.
13. History of having received (in the last 6 months) or currently receiving any systemic anti-
neoplastic (including radiation) or immune-modulatory treatment (including systemic 
corticosteroids).
14. History of organ transplantation.
15. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or 
multiple drug allergies (non-active hay fever is acceptable).
16. Significant acute infection (e.g., influenza, local infection) or any other clinically significant 
illness within 2 weeks of randomization.
17. Clinically relevant ECG abnormalities on screening ECG including arrhythmias or marked QT 
abnormalities (QTcF 300 msec or 450 msec) at Screening.
18. Any of the following laboratory parameters at screening:
a)
White blood cells (WBC) 3,000 cells/ mm3
b)
Neutrophil count 1500 cells/mm3
c)
Platelet count 140,000 cells/mm3
d)
aPTT 40 seconds, INR 1.2
e)
Hemoglobin (Hgb) 12 g/dL in females or 13 g/dL in males.
19. Abnormal renal function including serum creatinine ULN or calculated creatinine 
clearance 70 mL/min (using the Cockcroft Gault formula).
20. Participation in an investigational drug or device study within 30 days prior to randomization.
21. Donation or loss of blood over 500 mL within 3 months prior to starting study medication.
22. Administration of any blood product within 3 months of randomization.
23. History or evidence of alcohol abuse (consumption of more than 2 standard drinks per day 
on average; 1 standard drink equals 10 grams of alcohol, for further guidance please see 
Appendix 9) and/or drug abuse within one year of randomization; positive test result for 
drugs of abuse at Screening.
24. Patients under judicial supervision, guardianship or curatorship.
25. Medical or social conditions that would potentially interfere with the patient’s ability to comply 
with the study visit schedule or the study assessments.
Part 2c – CHB patients only
1.
Women who are lactating
2.
History or other evidence of bleeding from esophageal varices.
3.
Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal or 
gastric varices, splenomegaly, nodular liver, jaundice, hepatic encephalopathy, portal 
hypertension.
4.
One or more of the following laboratory abnormalities at screening:


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a)
Total serum bilirubin > ULN (exception Gilbert’s disease). 
b)
(INR >1.1 ULN.
c)
Serum albumin <3.5 g/dL (<35g/L).
d)
AFP >13 ng/mL (if >ULN, hepatic imaging must exclude hepatocellular carcinoma 
[HCC]).
e)
Positive results for anti-mitochondrial antibodies (AMA >1:80), anti-nuclear antibody 
(ANA) (>1:80), anti–smooth muscle antibody (ASMA >1:40), anti-thyroperoxidase 
antibodies (a-TPO), anti-thyroglobulin, or anti-platelet antibodies
f)
Thyroid stimulating hormone (TSH) within normal ranges.
g)
Platelet count <100,000 cells/mm3
h)
Hemoglobin <12 g/dL (females) or <13 g/dL (males).
i)
White blood cell count <2500 cell/mm3. 
j)
Neutrophil count <1500 cell/mm3 (<1200 cell/mm3 if considered a physiological 
variant in a patient of African descent).
5.
History or other evidence of a medical condition associated with chronic liver disease other 
than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, 
toxin exposure, thalassemia, nonalcoholic steatohepatitis, etc.).
6.
History of thyroid disease poorly controlled on prescribed medications or clinically 
relevant abnormal thyroid function tests (thyroid-stimulating hormone [TSH].
7.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
8.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C (quantitative anti-HCV), 
hepatitis D (total anti-HDV), hepatitis E (IgM and IgE anti-HEV), or human 
immunodeficiency virus (anti-HIV1/anti-HIV2).
9.
Expected to need systemic antiviral therapy other than that provided by the study at any 
time during their participation in the study, with the exception or oral therapy for HSV I 
or HSV II.
10.
History of significant gastrointestinal disease (including but not limited to gastric ulcers).
11.
History of clinically significant cardiovascular, endocrine, renal, ocular, pulmonary, 
psychiatric, or neurological disease.
12.
Evidence of an active or suspected cancer or a history of malignancy other than adequately 
treated basal cell carcinoma.
13.
History of organ transplantation.
14.
Participation in an investigational drug or device study within 30 days prior to screening 
or previous treatment with an investigational agent for HBV (6 months prior to screening)
15.
Taking any drugs or nutrients listed in prohibited medications and prohibited food 
sections.
16.
Significant acute infection (e.g., influenza, local infection) or any other clinically 


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significant illness within 2 weeks of randomization.
17.
ECG at screening with clinically significant abnormalities, including QTcF interval (QT 
corrected using Fridericia’s formula) ≥450 msec for males and ≥470 msec for females.
18.
Abnormal renal function including serum creatinine ULN or calculated creatinine 
clearance 70 mL/min (using the Cockcroft Gault formula).
19.
Donation or loss of blood over 500 mL within 3 months prior to randomization.
20.
Administration of any blood product within 3 months prior to randomization.
21.
History of alcohol abuse (consumption of more than 2 standard drinks per day on average; 
1 standard drink = 10 grams of alcohol) and/or drug abuse within one year of 
randomization; positive test result for drugs of abuse or alcohol breath test at screening.
22.
Subjects under judicial supervision, guardianship, or curatorship. 
23.
Medical or social conditions that would potentially interfere with the subject’s ability to 
comply with the study visit schedule or the study assessments.
LENGTH OF STUDY
The total duration of the study for each HV in Part 1 will be 16 weeks, and for each patient in 
Part 2 24 weeks (for Cohort 8, 23 weeks) , except for Part 2c where the total duration may 
be 52 weeks, divided as follows:
Screening: Up to 28 days (Part 1) and 56 days (Part 2a and 2b) and up to 28 days (Part 2c);
In Clinic period: 
-
Part 1 (1 dose): Days 1 to 3
-
Part 2a (2 doses Q1M): Optional for Days 1 to 2 and Days 29 to 30
-
Part 2b (3 doses, Q2W): Optional for Days 1 to 2 and Days 29 to 30
-
Part 2b (4 doses, QW): Optional for Days – 1 to 2 and Days 22 to 23
-
Part 2b (5 doses, QW): Optional for Days 1 to 2 and Days 29 to 30
Treatment period: 
-
Part 2c (QW): Up to 48 weeks
Safety Follow-up: up to at least 84 days after the last dose of study drug for Part 1, up to at least 
112 days after the last dose of the study drug for Part 2a (2 doses, Q1M) and Part 2b (3 doses, Q2W and 
5 doses QW), up to at least 105 days after the last dose of the study drug for Part 2b (4 doses, QW), and 
up to 24 weeks after the last dose of the study drug for Part 2c.
END OF STUDY
The end of the study is defined as the last patient last visit (LPLV) per protocol (includes the 
safety and follow-up visit) or the date at which the last data point from the last patient required 
for statistical analysis is received, whichever is the later date, unless the patient was 
pre-maturely discontinued.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events, including adverse events of special interest.

Incidence of laboratory abnormalities based on hematology, blood chemistry, coagulation 
and urinalysis test results.

ECGs.

Vital signs, including blood pressure, heart rate and temperature.










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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AAV
Adeno-associated virus
ADA
Anti-drug antibody
AE
Adverse events
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AMA
Anti-mitochondrial antibodies
ANA
Anti-nuclear antibody
ASMA
Anti-smooth muscle antibody
AST
Aspartate aminotransferase
a-TPO
Anti-thyroglobulin
AUC
Area under the curve
BP
Bpm
Blood pressure
Beats per minute
BUN
Blood urea nitrogen
cccDNA
Covalently closed circular DNA
CHB
CL
Chronic Hepatitis B
Clearance
CNS
Central nervous system
CRO
Contract research organization
DAIDS
Division of AIDS Table
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLE
Dose-limiting event
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
ESF
Eligibility screening form
EU
European Commission
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GalNAc
N-Acetylgalactosamine


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GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
HBcAg
Hepatitis B core antigen
HBcrAg
Hepatitis B core-related antigen
HBeAg
Hepatitis B envelope antigen
HBsAg
Hepatitis B surface antigen
HAV
Hepatitis A
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCG
Human Chorionic gonadotropin
HDL
High-density lipoproteins
HED
Human equivalent dose
HIV
Human immunodeficiency virus
HR
Heart rate
HSV
Herpes simplex virus
HV
Healthy volunteer
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IxRS
Interactive (voice/web) response system
LDL
Low-density lipoproteins
LFT
Liver function test
LNA
Locked nucleic acid
LPLV
Last patient, last visit
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MTD
Maximum tolerated dose
NIMP
Non-investigational medicinal product
NOAEL
No-observed-adverse-event level
NUC
Nucleoside/nucleotide analogue
OTC
Over-the-counter
PD
Pharmacodynamic
PEG-IFN
Pegylated interferon


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PK
Pharmacokinetic
PoM
Proof of mechanism
PT
Prothrombin time
qHBsAg
Quantitative HBsAg
Q1M
Once a month
QW
Once a week
Q2W
Once every two weeks
QRS
QRS complex
RBR
Research Biosample Repository
RNA
Ribonucleic acid
SAD
Single-ascending dose
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Saturation dose
SoA
Schedule of Assessments
SoC
Standard of Care
SSO
Single stranded oligonucleotide
SUSAR
Suspected unexpected serious adverse reactions
TK
Toxicokinetics
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell
WGS
Whole genome sequencing


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1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
Hepatitis B virus (HBV) infection is a major cause of both acute hepatitis and chronic 
liver diseases, including cirrhosis and hepatocellular carcinoma. Approximately two 
billion people worldwide have serological evidence of past or present HBV infection, and 
around 240 million people are chronic hepatitis B surface antigen (HBsAg) carriers. An 
estimated 686,000 people die each year due to the acute or chronic consequences of 
hepatitis B (WHO 2016; EASL 2012).
Antiviral therapy of CHB aims to improve quality of life and survival of the patients by 
preventing progression of liver damage to cirrhosis, decompensated liver disease, 
hepatocellular carcinoma, and death. Sustained suppression of HBV replication is 
associated with biochemical remission, histological improvement and delayed disease 
progression (EASL 2009).
Chronic HBV infection is a dynamic process with several stages, during which CHB may 
be present either as HBV e antigen (HBeAg)-positive or HBeAg-negative. Current 
guidelines specify the ideal endpoint of therapy for CHB patients as the loss of HBsAg 
with or without HBsAg seroconversion (EASL 2012). For HBeAg-positive patients, 
HBeAg seroconversion is indicative of better prognoses, including lower rates of 
cirrhosis and slower disease progression. Other clinically meaningful endpoints, 
irrespective of HBeAg status, are HBV DNA suppression and alanine aminotransferase 
(ALT) normalization, which indicate the virological and biochemical responses to 
therapies, respectively. 
Currently, there are two types of drugs available for the treatment of CHB: 
subcutaneously administered interferon preparations (IFN; conventional or pegylated 
IFN [PEG-IFN]) and orally administered nucleoside/nucleotide analogues (NUC), 
including adefovir, telbivudine, tenofovir, entecavir, and lamivudine. Although 
nucleos(t)ide treatment is highly effective at normalizing liver enzymes (biochemical 
response) and in lowering HBV DNA level to undetectable levels (virological response), 
chronic HBV infection cannot be completely eradicated with currently approved 
therapeutics due to the persistence of HBV covalently closed circular DNA (cccDNA) in 
the nucleus of infected hepatocytes (Lucifora et al 2014). Signs of infection return to pre-
treatment levels (relapse) if nucleos(t)ides are discontinued in the majority of cases. 
Therefore, few individuals achieve a functional or clinical cure with current therapies 
(sustained HBsAg and HBV DNA loss with or without HBsAg seroconversion occurs 
in15% after five years following treatment discontinuation) (EASL 2012). Moreover,
PEG-IFN is associated with significant safety and tolerability risks, while NUC analogues 
frequently require prolonged or indefinite therapy and some are associated with high risk 
of resistance.


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1.2
BACKGROUND ON RO7062931
RO7062931is 
 
 
, intended for the treatment of 
CHB infections. Chronicity in CHB is believed to be perpetuated, at least in part, by 
protein products expressed from the HBV genome which are derived from translation of 
four mRNA species transcribed from the cccDNA template located in the nucleus of 
actively infected hepatocytes. 
 
 
 
 
 
See the RO7062931 Investigator Brochure (IB) for details on non-clinical and clinical 
studies.
1.2.1
Previous Non-Clinical Studies
RO7062931 has shown potent antiviral activity through the inhibition of 
, 
. RO7062931 is 
 active in vitro against 
 
genotypes A, B, C, D and NUC analog-resistant HBV. In mice infected with a 
recombinant adeno-associated virus (AAV) carrying a replicable HBV genome 
(AAV-HBV), administration of RO7062931 reduced 
 
.
The pharmacokinetics (PK) and toxicokinetics (TK) of RO7062931 were studied in rats 
and cynomolgus monkeys following subcutaneous (SC) injections. Similar plasma PK 
characteristics were observed for RO7062931 across the species. 
 
 
 
 
 
 
 
 
 


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RO7062931 is not expected to interfere with the activity of cytochrome (CYP) P450 
enzymes and/or drug transporters. 
1.2.2
Previous Clinical Studies
This Phase I study (BP39405) is the first-in-human study with RO7062931. One further 
clinical study with RO7062931 in Chinese Healthy Volunteers is currently ongoing.
Preliminary data from BP39405 study indicates that RO7062931 is safe and well 
tolerated: 

In the BP39405 study Part 1, 60 healthy volunteers in total, in six SAD cohorts 
(0.1, 0.3, 1.0, 2.0, 4.0, and 3.0 mg/kg) received a single dose of RO7062931 or 
placebo. Blinded data review demonstrated no dose dependency in the incidence and 
intensity of AEs. A total of 78 non-serious AEs were reported in 40 out of 60 HVs; 
the majorities (74) of those AEs were mild in intensity and 4 were of moderate in 
intensity. 

In Part 2a and Part 2b of the BP39405 study, at the cut-off date of 22 November 
2018, 54 patients were enrolled. Part 2a enrolled 27 patients in four cohorts for 
monthly dosing (0.5, 1.5, 3.0 mg/kg of RO7062931 or placebo). Part 2b enrolled 
further 27 patients in three cohorts exploring 3 mg/kg weekly (QW) or bi-weekly 
dosing (Q2W) of RO7062931. There was no dose-dependent or regimen-dependent 
increase in the frequency or severity of AEs. A total of 82 AEs were reported in 32 
of the 54 CHB patients; most AEs were mild and had resolved, and five AEs 
observed in 4 CHB patients were moderate in intensity.


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
There were no severe or SAEs, AEs leading to treatment withdrawal, or AEs of 
special interest. No particular pattern or significant changes were observed for vital 
signs, ECGs parameters, laboratory safety test results, or urine microscopy. No 
patients discontinued study medication due to safety reasons.

In addition, proof-of-mechanism (PoM) in CHB patients has been demonstrated 
with dose-dependent declines in HBsAg observed in patients treated with 
RO7062931 compared to placebo. Similar HBsAg declines were observed regardless 
of HBeAg status.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.3.1
Study Rationale
Study BP39405 is the first clinical study of RO7062931, designed to assess: the safety, 
tolerability and pharmacokinetics (PK) of subcutaneously administered single-ascending 
doses (SAD) in healthy volunteers (HVs; Part 1); and safety, tolerability, PK, and 
pharmacodynamic (PD) effects of subcutaneously administered multiple doses to CHB 
patients for a short duration of treatment (Part 2a and Part 2b) and for an extended 
duration of treatment (Part 2c). In this protocol, both healthy volunteers and patients 
are referred to as study subjects.
 
 
 
 
 
 
 
 
 
  


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Parts 2a/2b will involve patients with CHB infection who have responded to standard 
treatment with NUC inhibitors of HBV reverse transcriptase.
 
 
 
However, the results from Parts 2a/2b will provide essential 
information for selecting doses for future clinical trials and for supporting the 
development of a new treatment for chronic HBV infection.


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Part 2c of the study will assess the efficacy and safety of RO7062931 when 
administered with Standard of Care (SoC; NUC with/without PEG-IFN) for up to 48 
weeks. Preliminary data from Part 2a/2b have demonstrated proof of mechanism (PoM)
and RO7062931 administration in CHB patients is associated with a good safety and 
tolerability profile following 4 weeks of treatment. Considering steady state exposure of 
RO7062931 in liver with QW dosing is anticipated to take about 13 weeks, longer 
treatment duration is needed to evaluate the maximum effect on HBsAg levels, at 
steady state and beyond. 
1.3.2
Benefit–Risk Assessment
Before initiation of this first-in-human study, no prior clinical experience with 
RO7062931 existed. The evaluation of the potential risks of treatment and the specific 
tests, observations, and precautions required for clinical studies with RO7062931 were
based on information from non-clinical toxicology and safety pharmacology studies as 
well as prior experience with other oligonucleotide therapeutics. Safety and tolerability 
will be carefully assessed, and study subjects (referring to both healthy volunteers and 
patients in the protocol) will be closely monitored. The RO7062931 Investigator Brochure, 
Section 6 summarizes the key risk management activities to consider when 
administering this novel compound to study subjects.
Based on the exposure multiple to the predicted human efficacious dose calculations, 
and the non-clinical toxicology data, the selected starting-dose of 0.1 mg/kg is 
considered to be safe (see Section 3.2.1). Equivalent human exposures anticipated from 
the target dose range between 0.1 and 4 mg/kg of RO7062931 proposed within this 
study and evaluated under a controlled setting, should provide a better understanding of 
clinical safety and tolerability to guide future clinical studies. The risks for an individual 
study subject due to ascending doses of RO7062931 or study-related procedures are 
considered to be minimal.
The good safety and tolerability observed to date in CHB patients, the preliminary 
encouraging dose dependent declines in HBsAg levels, and the favorable results from 
pre-clinical chronic toxicity studies, support an evaluation of RO7062931 treatment at 
a dose level of up to 4mg/kg/week and for up to 48 weeks treatment duration when 
administered with standard of care (SoC) therapies. Consistent with current guidelines 
(FDA 2018), non-clinical combination studies of RO7062931 with approved SoC 
therapies (i.e. NUC or PEG-IFN) were not conducted, as available nonclinical data does 
not suggest a potential for serious synergistic toxicity. 
For further information please refer to the latest RO7062931 Investigator Brochure.


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2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objective of this study is:

To assess the safety and tolerability of RO7062931 compared to placebo after 
single-ascending subcutaneous (SC) doses in HVs.

To assess the safety and tolerability of RO7062931 compared to placebo after 
multiple SC doses in CHB patients.
2.2
SECONDARY OBJECTIVES
The secondary objectives of this study are as follows:
For Part 1:

To assess plasma and urine PK of RO7062931, and if applicable metabolite(s), after 
single-ascending SC doses.
For Part 2:

To assess the plasma and urine PK of RO7062931 and if applicable metabolite(s), 
after multiple SC doses.

To study HBsAg dynamics after SC administration of RO7062931.
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives of this study are as follows:
–
PD exploratory objectives:
-
For Part 2: to explore the effect of multiple doses of RO7062931 on viral and 
anti-viral parameters other than quantitative HBsAg during and after the end of 
treatment in CHB patients.
-
To explore the effects of RO7062931 doses on further exploratory biomarkers
–
PK exploratory objective:
 


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
The study will be conducted in two parts, of which Part 1 will be in healthy volunteers 
and Part 2 will be in CHB patients (see Figure 1). Both parts of the study are randomized. 
Part 1 will evaluate the safety, tolerability and PK of RO7062931, and if applicable 
metabolite(s), following SC administration of single doses in healthy volunteers. Part 2 
will evaluate the safety, tolerability PK and PD (viral dynamics) following administration 
of multiple SC doses of RO7062931 in CHB patients over a short treatment duration 
(Figure 1) and extended treatment durations (Figure 2) (see Section 4.6).
Figure 1
Study Design: Parts 1, 2a, and 2b Short Treatment Durations


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Figure 2
Study Design: Part 2c - Extended Treatment Durations
The total duration of the study for each HV in Part 1 will be16 weeks.

Part 1 (1 dose) 
-
Screening: Up to 28 days;
-
In Clinic period: Days 1 to 3;
-
Safety Follow-up: up to at least Day 85.
The total duration of the study for each patient in Part 2 will be 24 weeks, except for 
Part 2c where the total duration may be 52 weeks.

Part 2a (2 doses, Q1M)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days 1 to 2 and Days 29 to 30;
-
Safety Follow-up: up to at least Day 113.

Part 2b (3 doses, Q2W)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days1 to 2 and Days 29 to 30;
-
Safety Follow-up: Up to at least Day 113.

Part 2b (4 doses, QW)
-
Screening: Up to 56 days;
-
In Clinic period (optional): Days 1 to 2 and Days 22 to 23;
-
Safety Follow-up: Up to at least Day 106.
HBV LNA+NUC
HBV LNA+ NUC + 
PEG-IFN
N ~ 8 (NUC suppressed 
CHB Pts)
24 wk
48 wk
72 wk
N ~ 8 (NUC suppressed CHB pts)
12 wk
Cohort 9
Cohort 10
Follow Up
HBV LNA+ NUC  ±
PEG-IFN
N ~ 8 ( e.g. Tx Naïve, active CHB pts)
Follow Up
Cohort 11
(optional)
Follow Up
HBV LNA + NUC
N ~ 8 (e.g. NUC suppressed CHB pts)
Cohort 12
(optional)
Follow Up
Sample size may be increased up to n=30 in each arm


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
Part 2b (5 doses, QW)
–
Screening: Up to 56 days;
–
In Clinic period (optional): Days 1 to 2 and Days 29 to 30;
–
Safety Follow-up: Up to at least Day 113.

Part 2c (QW)
–
Screening: Up to 28 days;
–
Treatment period: Up to 48 weeks;
–
Follow-up period: Up to 24 weeks.
3.1.1.1
Part 1: Single-Ascending Dose (SAD) in Healthy Volunteers
Part 1 is a randomized, Sponsor-open, Investigator-blinded, subject-blinded
placebo-controlled, adaptive SAD study with an adaptive dose-escalation schedule. The 
first cohort will receive a single dose of 0.1 mg/kg RO7062931 or placebo using a 4:1 
randomization scheme. 
 
 
 
 
 
. 
However, at this dose, AEs are expected to be mild and within this protocol higher doses 
may be evaluated if this dose is found to be safe and well tolerated.
 
 The use of a Bayesian analysis, specifically a continual reassessment method 
(CRM) analysis will be explored as a tool to help to guide the selection of these 
additional doses and is explained in further detail in the exploratory analysis 
(Section 6.8). There will be ongoing assessment of available safety, tolerability, and PK 
data prior to initiation of the next dose and cohort.
Eight HVs receiving RO7062931 and two receiving placebo are planned to be enrolled in 
each cohort of Part 1. The HVs will be admitted to the clinic on Day 1 and discharged 
on Day 3, following the morning assessments. Ambulatory visits will be performed as 
indicated in the SoA tables (see Appendix 1 to Appendix 2).The HVs of each cohort will 
receive sentinel dosing, where two subjects will be dosed on Day 1, at least one of which 
will receive RO7062931 to monitor acute reactions and the remaining 8 subjects can be 
dosed on the following day (24 hours afterwards) following satisfactory safety 
assessments of the first two subjects by the Investigator. Following the single dose of all 
HVs in a cohort, safety will be monitored for at least 28 days prior to escalation to the 
next dose cohort.


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3.1.1.2
Part 2a/2b: Proof-of-Mechanism in CHB Infected Patients
Part 2a/b is a multi-center randomized, Sponsor-open, Investigator-blinded, 
subject-blinded, placebo-controlled, adaptive, parallel multiple-dose study in chronically 
HBV infected patients, with the aim to study the safety, tolerability, PK of 
RO7062931(and if applicable metabolite[s]), and the relationship between RO7062931 
dose, dose regimen and viral dynamic response. 
 
 
 
 
 
In Part 2a, CHB patients will receive two monthly doses (Q1M) of RO7062931. Part 2a is 
planned to consist of 4 parallel cohorts of 3 RO7062931 dose levels and one placebo. 
 
 
 
 
 In addition to safety, PK will be evaluated in the 
first two patients of each dose cohort prior to subsequent randomization to confirm that 
RO7062931 exposure is comparable as found for the HVs. Cohort doses may be 
adjusted across the patient cohorts if plasma PK appears to significantly differ from the 
HVs. Each cohort in Part 2a will consist of 6 patients.
In Part 2b, a dose identified from the dose-response analysis of Part 2a (based on either 
HBsAg decline or maximum dose evaluated and well tolerated) will be tested in different 
dosing regimens administered weekly (QW) or bi-weekly (Q2W). The total dose of
400 mg per day will not be exceeded. The selection of dosing regimens will be 
guided by the analysis of safety, PK and PD data of all previous cohorts in Part 2.
In Part 2b, each patient will be randomized to active or placebo in each dose cohort/level 
in a 3:1 ratio. Each cohort in Part 2b will be comprised of 8 patients, six patients will 
receive RO7062931 and two will receive placebo. CHB patients will be followed up 
weekly for the first 28 days and then monthly up to at least 84 days after the last 
dose of RO7062931.


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There will be two optional overnight stay periods for the patients: between Day 1 and 
Day 2, and between Day 29 and Day 30 (exception: between Day 22 and Day 23 for the 
cohort with 4 doses given QW). If the Investigator agrees, the patients can leave the 
clinic after completing the last evening assessment and return the following morning 
prior to the first scheduled assessment. In Part 2b, where drug administration is given on 
days other than Day 1 and Day 29 (or Day 22 for the cohort with 4 doses given QW), the 
patients will be administered the drug in the clinic as an ambulatory visit. 
Visits and assessments will be performed as indicated in the SoA tables (see Appendix 
3 to Appendix 14). 
All doses in Part 2 will be lower than, or equal to, the doses studied and considered to 
be well-tolerated in Part 1. Subsequent doses and regimens for Part 2b/2c will be 
selected on the basis of the analysis of Part 2a data. Part 2b will be initiated once Part 
2a data have been analyzed. The total dose will not exceed 400 mg per day.
Due to the adaptive nature of this study, the actual number of dose levels and the 
number of study subjects/cohorts at each dose may be modified depending on emerging 
data. Planned doses may be adjusted (increased, decreased, or repeated) or dosing 
may be discontinued. After safety and PK data review (see Section 3.1.4), study 
subjects may be requested to return to the site for additional safety or PK assessments, 
upon agreement between subjects, Investigators and the Sponsor.
3.1.1.3
Part 2c: Extended Duration of RO7062931 Therapy in CHB 
Infected Patients
Part 2c is an adaptive, open-label, non-controlled, multi-arm, multi-center, study to 
evaluate the efficacy and safety of RO7062931 following subcutaneous administration 
on top of SoC therapies (a NUC with/without PEG-IFN) in NUC-suppressed or 
treatment- naïve CHB patients (Figure 2). Both HBeAg positive and negative patients 
will be enrolled. 

Cohort 9 will enroll NUC-suppressed CHB patients. Patients will receive 
RO7062931 on top of a NUC for up to 24 weeks. RO7062931 will be administered
at a dose determined from study Parts 2a and 2b.

Cohort 10 will enroll NUC-suppressed CHB patients. Patients will receive 
RO7062931 on top of a NUC plus PEG-IFN for up to 48 weeks. RO7062931 will be 
administered at a dose determined from study Parts 2a and 2b.

Cohort 11 and 12 (optional cohorts) may enroll treatment-naïve immune-active 
CHB patients and/or different treatment combinations or treatment duration.


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All cohorts will initially enroll approximately 8 CHB patients per cohort. Initially the 
enrollment will occur sequentially (Cohort 9 will be followed by Cohort 10, see 
Section 4.3). At the end of treatment (either 24 or 48 weeks depending on cohort), all 
study treatment (RO7062931 and PEG-IFN) will be discontinued and all patients will 
be followed up for at least 24 weeks post-treatment follow up. 
Based on emerging and accumulated PK, PD, efficacy and safety data from this study or 
other related studies, the initial cohorts may be expanded to enroll a total of 30 CHB 
patients. Enrollment of the expanded cohorts may be either sequential or parallel.
3.1.2
Dose-Review/Escalation Decisions
Dose-escalation/review meetings will be conducted by the Investigator, the Medical 
Monitor, and the Sponsor Clinical Team prior to each RO7062931 dose-escalation (see 
Section 3.1.4). The study will have an adaptive dosing design and the actual doses may 
be modified based on emerging safety, tolerability, PK and PD data, but with 
dose-escalation ratios not higher than currently projected (i.e., with more conservative 
escalations at higher dose levels). The decision to escalate to the next dose level, or add 
an additional cohort at a previously studied dose, will be made following the review of 
the following data from the completed cohort:
For Part 1

All available safety information, including AEs, ECGs, vital signs, clinical laboratory 
test results collected up to Day 29 visit. 

All available PK data collected over1 week post-dose to characterize the 
RO7062931, and if available, its metabolite(s) and predict exposure in the following 
cohort(s).
For Parts 2a/2b

All available safety information, including AEs, ECGs, vital signs, clinical laboratory 
test results collected up to Day 57 visit (exception: Day 50 for the cohort with 
4 doses given QW).

Adequate data over the first week in Part 2a to characterize the RO7062931 PK and 
predict exposure in cohorts with different regimens or doses used in Part 2b.

HBsAg levels at least by two weeks after the last dose. 
For Part 2c

Commencement of optional cohorts, or expansion of existing cohorts, will be 
determined based on accumulated safety, tolerability, PK, and PD data from this 
study. 


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3.1.2.1
Part 1 Dose Escalation Decision Criteria
Part 1 uses an adaptive dose-escalation schedule that may be modified if: 
 

Events emerge that the Sponsor and/or Investigator consider indicators that the 
planned dose-escalation step would result in unacceptable risks for the safety of the 
HVs.

The Sponsor and 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 3.1.3.1) but may exceed the proposed maximum dose level of 4 mg/kg only if 
anticipated to be safe and necessary to generate additional PK or PD data in support of 
dosing regimens for use in Part 2 of the study.
3.1.3
Dose-Escalation Stopping Criteria
3.1.3.1
Part 1
Dose-escalation in Part 1 will not be implemented as planned in healthy volunteers 
dosed with RO7062931, and dosing for a treatment arm/cohort in Part 2 will be 
discontinued, if one of the below criteria is fulfilled, unless it is obvious that the 
occurrence is not considered to be related to RO7062931. 
Dose-escalation will be stopped if at a dose level, more than 2 of 8 healthy volunteers 
receiving RO7062931 in Part 1 or, within a treatment arm/cohort in Part 2, more than 
2 of 6 patients experience:

Severe or clinically significant (as defined by the Investigator) RO7062931-related 
AEs of the same character, or

Significant RO7062931-related laboratory abnormality of the same character, or

Clinically significant RO7062931-related changes in vital signs or ECGs of the same 
character (e.g., QTcF 500 msec, or 60 msec longer than the pre-dose baseline, 
within the first 48 hours post-dose).

Within two consecutive dose cohorts, four occurrences of any of the above 
conditions in HVs receiving active drug.
Other findings (regardless of the incidence rates) that at the joint discretion of the 
Sponsor and the Investigator indicate that dose-escalation (in Part 1) or dosing (in Part 2) 
should be halted (see Section 4.7). 


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3.1.3.2
Part 2
In Part 2, in case a cohort is stopped, alternative regimens within a previously tolerated 
dose/monthly-exposure range could be further investigated or a regimen repeated in the 
subsequent cohorts by mutual agreement between the Sponsor and Investigator, in 
order to increase the amount of data within the tolerated dose/monthly-exposure range. 
Due to the exploratory nature of this clinical study, its conduct can be discontinued at 
any time at the discretion of the Sponsor.
3.1.4
Communication Strategy
After each subject receives RO7062931 (or placebo), the Investigator(s) must confirm to 
the Sponsor that the subject (HV or patient) has been dosed and provide a brief 
summary of the status of the subject in terms of safety and tolerability to 
RO7062931/placebo (this will be communicated by email and/or telephone). In Part 1 of 
the study, the Investigator(s) will provide a safety assessment feedback of the first two 
sentinel dosing HVs of each cohort.
In case of a safety concern, the Investigator will contact the Sponsor immediately to 
discuss study subject status and action taken/to be taken. In addition, after each cohort 
in Part 1 has been completed and after completion of Part 2a and Part 2b, the Sponsor 
will organize a teleconference with the investigators to discuss the safety and tolerability 
of RO7062931 and to discuss eventual next cohort(s) or continuation (Part 2a and 
Part 2b). The next recommended dose-level (supported by nCRM, if appropriate, for 
Parts 1 and 2b) will be discussed by Sponsor and investigators. During these 
teleconferences, adverse events (with severity assessed as given in Section 5.3.3, Table 
2) in addition to available safety laboratory results, vital signs, ECGs, will be discussed 
along with the results of the available PK data, and any other available data that may 
assist the dose-escalation decision process. The decision of these meetings will be 
documented in writing.
In addition to these communications, the Sponsor and investigators will be in regular 
contact throughout the study by email/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.


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3.1.5
End of Study
The end of the study is defined as the last patient last visit (LPLV) per protocol (includes 
the safety and follow-up visit) or the date at which the last data point from the last patient 
required for statistical analysis is received, whichever is the later date, unless the patient 
was prematurely discontinued.
3.2
RATIONALE FOR STUDY DESIGN
A two-part study design has been chosen to characterize RO7062931 in this clinical trial. 
In Part 1, safety and PK of single RO7062931 doses will be characterized in healthy 
volunteers to determine the best liver-targeted dose to be evaluated in CHB patients. In 
Part 2, safety, PK, HBsAg decline and other possible PD effects will be assessed 
following multiple RO7062931 doses in CHB patients and data will be obtained to further 
refine the dose and dosing regimen. Part 2c will evaluate the efficacy and safety of 
RO7062931 when administered with SoC for up to 48 weeks.
3.2.1
Rationale for Dosage Selection
A starting dose of 0.1 mg RO7062931 per kg has been selected for this first study in 
humans. 
 
 
 Therefore, the starting-dose 
of 0.1 mg/kg represents the lower end of the predicted therapeutic dose range in 
humans and would be expected to have little or no measureable pharmacodynamic 
effect if evaluated in CHB patients.
A two-pronged approach to the calculation of safety multiples was taken, in that
calculations were based, respectively, on plasma and liver levels. By applying the PK 
model for scaling to human PK, the expected AUC0-24h in plasma, and liver concentration 
at 168 hours post-dose, were derived and compared to the corresponding values 
obtained at the NOAEL in the GLP toxicity studies. 
 
 
 
 
 
For the calculations of safety margins, the anticipated efficacious dose level was 
conservatively 
, which is the upper part of the predicted range. While liver 
exposure is more relevant to the nature of the prevailing preclinical target organ (the 
liver), plasma exposure is expected to be more relevant to the other potential AEs (e.g., 
renal). 
 


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3.2.2
Rationale for Study Population
Part 1 will be conducted in healthy male 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 drug disposition and safety profile to be obtained.
Part 22a/2b will be conducted in nucleoside/nucleotide suppressed CHB infected 
patients. Only in this patient population can the pharmacodynamic effects of RO7062931 
in humans be tested. The PK and safety of RO7062931 will also be evaluated in this 
population. The results will provide essential information for supporting the future 
development, such as dose-selection for a Phase II study in CHB patients.
Part 2c of the study will be conducted in NUC-suppressed or potentially treatment-
naïve immune-active CHB patients, and will include both HBeAg positive and HBeAg 
negative patients. These patient populations are considered appropriate for trials of 
novel CHB therapeutics regimen, as highlighted in current guidelines (FDA 2018). 
3.2.3
Rationale for Control Group
This phase I study is designed to be adequate and well-controlled. In Part 1, 
randomization to RO7062931 or placebo will occur in a 4:1 ratio within each of the up to 
8 cohorts planned. This is considered sufficient to allow for comparisons of safety and 
tolerability of active to placebo both within and across cohorts.


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In Part 2a, randomization to 3 doses of active or placebo will occur in a 1:1:1:1 ratio. In 
Part 2b, randomization to active or placebo will be 3:1 (within cohorts). The assessment 
of dynamic changes of HBsAg in CHB patients, will allow estimating the effect of 
RO7062931 over placebo. The control patients will also allow for the comparisons of 
safety of active with placebo. 
It is not considered necessary to include controls within the cohorts of Part 2c. Part 2a 
and 2b have shown that placebo controls have negligible change in HBsAg levels over 
time. This information can be leveraged in Part 2c for interpretation of HBsAg
dynamics. The safety data from Part 2c will be compared qualitatively against Part 2a 
and Part 2b placebo data and against well-established historical safety profiles of SoC 
therapies.
3.2.4
Rationale for Biomarker Assessments
RO7062931 is a GalNAc-targeted LNA-containing single stranded 
oligodeoxyribonucleotide, complementary to HBV genome-derived mRNA species. With 
this, a rapid reduction of viral parameters like HBsAg, HBeAg, but also the 
corresponding mRNAs, is expected. Structural and functional differences between viral 
genotypes can influence the severity and response to treatment of hepatitis B virus
infection (Kramvis et al, 2005). Blood samples to monitor decline of viral parameters in 
correlation with administered dose and to establish the viral genotype will be taken at 
time-points, as indicated in the Schedule of Assessments tables (see Appendix 1 to
Appendix 14 ).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on nonclinical data (and class effect [Kynamro Solution for injection 189 mg, 
CHMP-EMA Assessment Report 2013]) RO7062931 is considered of to be low risk for 
acute reactions; however, cytokines and complement activation will be measured and 
sentinel dosing will be implemented.


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3.2.5
Rationale for Resistance Monitoring
Blood samples to monitor the potential for resistance emergence will be taken at 
time-points as indicated in the Schedule of Assessments (see Appendix 1 to Appendix 14
and Section 4.6.1.5.4).
3.3
OUTCOME MEASURES 
3.3.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events, including adverse events of special 
interest (see Section 5.3.1).

Incidence of laboratory abnormalities based on hematology, blood chemistry, 
coagulation and urinalysis test results (see Section 4.6.1.5).

ECGs (see Section 4.6.1.4 ).


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
Vital signs, including blood pressure, heart rate and temperature (see 
Section 4.6.1.3).
3.3.2
Pharmacokinetic (PK) and Pharmacodynamic (PD) Outcome 
Measures
3.3.2.1
Pharmacokinetic Outcome Measures
The PK evaluations for this study are as follows:
Blood and urine samples will be collected to evaluate the RO7062931 and if applicable 
metabolite(s) PK, as specified in the Schedule of Assessment tables (see Appendix 1 to
Appendix 14). Plasma and urine concentrations will be measured by specific validated 
methods.
The following plasma and urine PK parameters will be calculated for RO7062931 (and 
its metabolites, as appropriate), when possible, using non-compartmental methods:

Cmax: maximum plasma concentration.

tmax: time to reach the maximum plasma concentration.

AUC0-inf: area under the plasma concentration-time curve from time zero to infinity.

AUC0-last: area under the plasma concentration-time curve from time zero until the 
last quantifiable time-point.

Additional PK parameters may be calculated from available data including:

k (terminal elimination rate constant), 

t1/2 (terminal elimination half-life), 

CL (total clearance)

Vss (volume of distribution).

Urine PK parameters may be calculated with available data including:

Ae - cumulative amount of drug excreted in urine over a 24hour period or over 
defined time periods linked to the pools of urine collected.

In Part 2: sparse sampling for tenofovir (including tenofovir alafenamide, if approved 
for HBV and applicable), entecavir, adefovir and telbivudine will be made to 
determine patient compliance.
3.3.2.2
Pharmacodynamic Outcome Measures (Part 2 only)
In Part 2, blood samples for quantitative and qualitative determination of viral dynamic 
response measurements of, but not limited to, HBsAg, HBV DNA, HBV RNA, HBeAg, 
HBcrAg, anti-HBe, anti-HBc, and, anti-HBs and HBsAg/anti-HBs complex, will be 
collected at the time-points indicated in the Schedule of Assessment tables (see 
Appendix 3 to Appendix 14) and as detailed in Section 4.6.1.5.4.


RO7062931—F. Hoffmann-La Roche Ltd
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The PD outcome measure to support the secondary objective is the change in 
quantitative HBsAg over time. Derived endpoints of quantitative HBsAg will include:

Quantitative HBsAg (qHBsAg) (log10) and its change from baseline

Maximum change from baseline in quantitative HBsAg across all time-points

Rate of decrease for HBsAg at each time-point

Proportion of patients with undetectable qHBsAg (< 0.05 IU/mL)
All other PD outcome measures are considered exploratory (see Section 3.3.3).
3.3.3
Exploratory Outcome Measures
Exploratory PD outcome measures:
These will include but may not be limited to HBeAg, qualitative HBsAg, anti-HBs, 
anti-HBe, and maintenance of HBV DNA levels less than 90IU/mL (for Part 2c (for Part 
2c lower limit of quantification [LLOQ]).
Viral resistance monitoring will be performed in any patient who experiences viral 
breakthrough. Please see Section 4.6.1.5.4.
 
 
 
Exploratory safety outcome measures
 
Exploratory PK outcome measure:
 
 
 
 
 
 


RO7062931—F. Hoffmann-La Roche Ltd
84/Protocol BP39405, Version 4
 
 
 
4.
MATERIALS AND METHODS
4.1
CENTER
This is a multi-center study. Additional sites may be opened if necessary. Administrative 
and Contact Information, and List of Investigators are provided separately.
4.2
STUDY POPULATION
In this study, the target population consists of male and female HVs/ patients diagnosed 
with chronic hepatitis B infection, between the age of 18 and 65, inclusive. Study 
subjects must satisfy all inclusion and exclusion criteria to be enrolled into the study. 
Under no circumstances are subjects who enroll in this study permitted to be 
re-randomized to another cohort of this study.
Study subjects who drop out of the study for non-safety reasons may be replaced to 
ensure sufficient data to characterize the safety, tolerability, and PK and/or to make 
dose-escalation decisions. Study subjects who withdraw from the study due to poor 
tolerability or for study drug-related adverse events will not be replaced.
4.2.1
Recruitment Procedures 
Study subjects will be identified for potential recruitment using sites’ database, pre-
screening enrollment logs, IEC/IRB approved newspaper/radio/television/Social Network 
Service/campus poster advertisements, mailing lists and other distributable documents, 
prior to consenting to take place on this study.
4.2.2
Inclusion Criteria
Study subjects must meet the below criteria for study entry.
4.2.2.1
Part 1 - Healthy volunteers only:
1.
Able to participate and willing to give written informed consent and to comply with 
the study restrictions.
2.
Healthy male and female (of non-childbearing potential) subjects. Health status is 
defined by absence 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.
3.
18 to 65 years of age, inclusive.
4.
A Body Mass Index (BMI) between 18 to 30 kg/m2 inclusive and a body weight of at 
least 50 kg.


RO7062931—F. Hoffmann-La Roche Ltd
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5.
Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post-menarcheal but has not reached a 
post-menopausal state (12 continuous months of amenorrhea with no identified 
cause other than menopause, confirmed by follicle-stimulating hormone [FSH], or 
amenorrhea for at least 24 months if on hormone replacement therapy), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and up to 
105 days after the last dose to avoid exposing the embryo. Men must refrain 
from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the healthy 
volunteer. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
6.
Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on 
Day 1 and agree to remain as non-smoker during the study.
4.2.2.2
Part 2a and Part 2b - CHB patients only:
1.
Ability and willingness of patient to provide written informed consent.
2.
Adult male and female (of non-childbearing potential) patients, aged 18-65 years 
(inclusive).
3.
A BMI between 18 to 32 kg/m2 inclusive.
4.
Chronic hepatitis B infection.
5.
Positive test for HBsAg for more than 6 months prior to randomization.
6.
HBsAg titer103 IU/mL at screening.
7.
On entecavir, tenofovir, adefovir or telbivudine treatment for at least 6 months prior 
to randomization and will remain on stable treatment during the study.
8.
HBV DNA90 IU/mL for at least the preceding 6 months.
9.
Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 
56 days prior to first study treatment within normal ranges, with the exception of 
otherwise specified criteria or judged to be not clinically significant by Principal 
Investigator (PI) and Medical Monitor.
10. Alanine transaminase (ALT), aspartate aminotransferase (AST), 
-glutamyltransferase (GGT), and alkaline phosphatase (ALP) at 
screening 1.5upper limit of normal (ULN); normal values for total bilirubin and 
prothrombin time (PT)/International Normalized Ratio (INR)/activated partial 
thromboplastin time (aPTT) tests at screening (except for patients with Gilbert’s 
syndrome TB47 mol/L [2.75 mg/dL]).


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11. Liver biopsy, Fibroscanor equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection without evidence 
of bridging fibrosis or cirrhosis (Metavir 3, recommended cut-off for 
fibroscan 8.5 kPa).
12. Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post-menarcheal but has not reached a post-
menopausal state (12 continuous months of amenorrhea with no identified cause 
other than menopause, confirmed by follicle-stimulating hormone [FSH], or 
amenorrhea for at least 24 months if on hormone replacement therapy), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and up to 
105 days after the last dose to avoid exposing the embryo. Men must refrain 
from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
4.2.2.3
Part 2c - CHB patients only: 
1.
Ability and willingness of patients to provide written informed consent.
2.
Adult male and female patients, 18 to 65 years of age, inclusive.
3.
A BMI between 18 to 32 kg/m2 inclusive.
4.
CHB infection (HBsAg-positive for ≥ 6 months).
5.
For cohorts only enrolling NUC-suppressed CHB patients, patients must meet the 
following criteria: 
a.
Patients treated with a single NUC (entecavir, tenofovir alafenamide, or 
tenofovir disoproxil fumarate) for ≥12 months. Patients must be on the same 
NUC therapy for at least 3 months before screening. 
b. HBV DNA <LLOQ at screening and in preceding 6 months (at least one 
measurement >30 days prior to screening).
c.
ALT ≤ 2 x ULN for >6 months prior to screening and confirmed at screening. 
Total bilirubin within normal range at screening, except for patients with 
Gilbert’s syndrome (TB ≤47 µmol/L [2.75 mg/dL]).
6.
For cohorts only enrolling treatment-naïve and immune-active patients (e.g., 
Cohort 11), patients must meet the following criteria:
a.
HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, or 2 x 
103 IU/mL for HBeAg negative patients.


RO7062931—F. Hoffmann-La Roche Ltd
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b.
Elevated serum ALT >2 ULN to ≤5 ULN, 2 values within 6 months, at least 
one of which is at screening and both results must be at least 14 days apart.
Total bilirubin within normal range at screening, except for patients with 
Gilbert’s syndrome (TB ≤ 47 µmol/L [2.75 mg/dL]).
7.
Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 
days prior to first study treatment within normal ranges, with the exception of 
otherwise specified criteria or judged to be not clinically significant by PI and 
Medical Monitor.
8.
Liver biopsy, Fibroscanor equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection without 
evidence of bridging fibrosis or cirrhosis (Metavir 3, recommended cut-off for 
fibroscan 8.5 kPa).
9.
Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post-menarcheal but has not reached a post-
menopausal state ( 12 continuous months of amenorrhea with no identified cause 
other than menopause, confirmed by FSH, or amenorrhea for at least 24 months if 
on hormone replacement therapy), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom plus spermicide during the 
treatment period and up to 6 months after the last dose to avoid exposing the 
embryo. Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
4.2.3
Exclusion Criteria
Study subjects who meet any of the below criteria will be excluded from study entry.
4.2.3.1
Part 1 - Healthy volunteers only:
1.
Women who are lactating.
2.
Any suspicion or history of alcohol and/or other substance abuse or dependence in 
the past 6 months.
3.
Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone, 
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or 
positive cotinine test at Screening or Day1.


RO7062931—F. Hoffmann-La Roche Ltd
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4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency 
virus (HIV) 1 and 2.
5.
Confirmed (e.g., two consecutive triplicate measurements) average systolic blood 
pressure (SBP)140 or90 mmHg, and diastolic blood pressure (DBP)90
or45 mmHg at Screening.
6.
Confirmed (e.g., two consecutive triplicate measurements) average resting pulse 
rate (PR)90 or45 beats per minute (bpm) at Screening.
7.
A personal history of unexplained blackouts or faints, or known risk factors for 
Torsade de Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal 
ECG, including arrhythmias or marked QT abnormalities (QTcF300 msec 
or450 msec at Screening).
8.
ECG morphology at screening that renders measurement of QT interval imprecise 
(e.g., neuromuscular artifact that cannot be readily eliminated, indistinct QRS onset, 
low amplitude T-wave, merged T- and U-waves, prominent U-waves, arrhythmias, 
etc.).
9.
Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right 
or left bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Any out of range findings in liver function tests (LFTs), INR and renal 
function tests or any clinically significant abnormalities (as judged by the 
Investigator) in the physical examination and in the remaining laboratory test 
results (including hepatic and renal panels, complete blood count, chemistry panel 
and urinalysis) at Screening and on Day-1.
12. Participation in an investigational drug or device study within 90 days prior to 
screening or 5 times the half-life of the investigational drug (whichever is longer).
13. Donation of blood over 500 mL within three months prior to screening.
14. Concomitant disease or condition (including allergic reactions against any drug, or 
multiple allergies) 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 healthy volunteers in this study.
15. Any major illness within the one month preceding the Screening visit, or any febrile 
illness within the two weeks preceding the screening visit.
16. Alcohol consumption of more than 2 standard drinks per day on average; 1 standard 
drink equals 10 grams of alcohol (for further guidance please see Appendix 15). 
17. Hypersensitivity to the excipients of the study drug.
18. Healthy volunteers under judicial supervision, guardianship or curatorship.
4.2.3.2
Part 2a and Part 2b - CHB patients only:
1.
Women who are lactating.
2.
History or other evidence of bleeding from esophageal varices.


RO7062931—F. Hoffmann-La Roche Ltd
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3.
Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification 
[see Appendix 16] or clinical evidence such as ascites or varices).
4.
History or other evidence of a medical condition associated with chronic liver 
disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, 
alcoholic liver disease, toxin exposure, thalassemia, non-alcoholic steatohepatitis, 
etc.).
5.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
6.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, or HIV.
7.
Documented history of infection with hepatitis D virus.
8.
Expected to need systemic antiviral therapy other than that provided by the study at 
any time during their participation in the study, with the exception of oral/ topical 
therapy for Herpes simplex virus (HSV) I or HSV II.
9.
History of or suspicion of hepatocellular carcinoma or alpha fetoprotein 
(AFP)13 ng/mL at Screening.
10. History of immunologically-mediated disease (e.g., inflammatory bowel disease, 
idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic 
anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or 
any other autoimmune disease).
11. History of clinically significant and not adequately controlled cardiovascular, 
endocrine, gastrointestinal, renal, ocular, pulmonary, or neurological disease.
12. Evidence of an active or suspected cancer or a history of malignancy other than 
adequately treated basal cell carcinoma.
13. History of having received (in the last 6 months) or currently receiving any systemic 
anti-neoplastic (including radiation) or immune-modulatory treatment (including 
systemic corticosteroids).
14. History of organ transplantation.
15. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any 
drug, or multiple drug allergies (non-active hay fever is acceptable).
16. Significant acute infection (e.g., influenza, local infection) or any other clinically 
significant illness within 2 weeks of randomization.
17. Clinically relevant ECG abnormalities on screening ECG including arrhythmias or 
marked QT abnormalities (QTcF300 msec or450 msec) at Screening.
18. Any of the following laboratory parameters at screening:
a)
White blood cells (WBC)3,000 cells/ mm3
b)
Neutrophil count1500 cells/mm3
c)
Platelet count140,000 cells/mm3
d)
aPTT40 seconds, INR1.2
e)
Hemoglobin (Hgb)12 g/dL in females or13 g/dL in males.


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19. Abnormal renal function including serum creatinineULN or calculated creatinine 
clearance70 mL/min (using the Cockcroft Gault formula).
20. Participation in an investigational drug or device study within 30 days prior to 
randomization.
21. Donation or loss of blood over 500 mL within 3 months prior to starting study 
medication.
22. Administration of any blood product within 3 months of randomization.
23. History or evidence of alcohol abuse (consumption of more than 2 standard drinks 
per day on average; 1 standard drink equals 10 grams of alcohol, for further 
guidance please see Appendix 15) and/or drug abuse within one year of 
randomization; positive test result for drugs of abuse at Screening.
24. Patients under judicial supervision, guardianship or curatorship.
25. Medical or social conditions that would potentially interfere with the patient’s ability 
to comply with the study visit schedule or the study assessments.
4.2.3.3
Part 2c - CHB patients only: 
1.
Women who are lactating.
2.
History or other evidence of bleeding from esophageal varices.
3.
Evidence of liver cirrhosis or decompensated liver disease such as ascites, 
esophageal or gastric varices, splenomegaly, nodular liver, jaundice, hepatic 
encephalopathy, portal hypertension.
4.
One or more of the following laboratory abnormalities at screening:
a)
Total serum bilirubin > ULN (exception Gilbert’s disease). 
b) INR >1.1 ULN.
c)
Serum albumin <3.5 g/dL (<35g/L).
d) AFP >13 ng/mL (if >ULN, hepatic imaging must exclude hepatocellular 
carcinoma [HCC]).
e)
Positive results for anti-mitochondrial antibodies (AMA >1:80), anti-nuclear 
antibody (ANA) (>1:80), anti–smooth muscle antibody (ASMA >1:40), anti-
thyroperoxidase antibodies (a-TPO), anti-thyroglobulin, or anti-platelet 
antibodies
f)
Thyroid stimulating hormone (TSH) within normal ranges.
g) Platelet count <100,000 cells/mm3.
h) Hemoglobin <12 g/dL (females) or <13 g/dL (males).
i)
White blood cell count <2500 cells/mm3. 
j)
Neutrophil count <1500 celsl/mm3 (<1200 cell/mm3 if considered a 
physiological variant in a patient of African descent).


RO7062931—F. Hoffmann-La Roche Ltd
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5.
History or other evidence of a medical condition associated with chronic liver 
disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, 
alcoholic liver disease, toxin exposure, thalassemia, nonalcoholic steatohepatitis, 
etc.).
6.
History of thyroid disease poorly controlled on prescribed medications or clinically 
relevant abnormal thyroid function tests TSH.
7.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
8.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C (quantitative anti-HCV), 
hepatitis D (total anti-HDV), hepatitis E (IgM and IgE anti-HEV), or human 
immunodeficiency virus (anti-HIV1/anti-HIV2).
9.
Expected to need systemic antiviral therapy other than that provided by the study 
at any time during their participation in the study, with the exception or oral 
therapy for HSV I or HSV II.
10. History of significant gastrointestinal disease (including but not limited to gastric 
ulcers).
11. History of clinically significant cardiovascular, endocrine, renal, ocular, 
pulmonary, psychiatric, or neurological disease.
12. Evidence of an active or suspected cancer or a history of malignancy other than 
adequately treated basal cell carcinoma.
13. History of organ transplantation.
14. Participation in an investigational drug or device study within 30 days prior to 
screening or previous treatment with an investigational agent for HBV (6 months 
prior to screening).
15. Taking any drugs or nutrients listed in prohibited medications and prohibited food 
sections.
16. Significant acute infection (e.g., influenza, local infection) or any other clinically 
significant illness within 2 weeks of randomization.
17. ECG at screening with clinically significant abnormalities, including QTcF 
interval (QT corrected using Fridericia’s formula) ≥450 msec for males and 
≥470 msec for females.
18. Abnormal renal function including serum creatinine ULN or calculated 
creatinine clearance 70 mL/min (using the Cockcroft Gault formula).
19. Donation or loss of blood over 500 mL within 3 months prior to randomization.
20. Administration of any blood product within 3 months prior to randomization.
21. History of alcohol abuse (consumption of more than 2 standard drinks per day on 
average; 1 standard drink = 10 grams of alcohol) and/or drug abuse within one year 
of randomization; positive test result for drugs of abuse or alcohol breath test at 
screening.
22. Subjects under judicial supervision, guardianship, or curatorship. 


RO7062931—F. Hoffmann-La Roche Ltd
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23. Medical or social conditions that would potentially interfere with the subject’s 
ability to comply with the study visit schedule or the study assessments.
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Part 1, Part 2a, and Part 2b are Sponsor-open, Investigator-blinded, subject-blinded. 
This means that the study subjects will be blinded, the Investigator(s), site staff 
observing the subjects will be blinded and the Sponsor will be unblinded. Part 2c is 
open-label.
In Part 1, the site pharmacist and the study drug administrator will be unblinded. For 
Parts 2a and 2b, the site Pharmacist will be unblinded. Members of the Sponsor’s study 
team who do not have direct contact with the Investigator or study site staff will be 
unblinded. This does not include any CROs and any sponsor staff in direct contact with 
the investigators and the study sites, who will remain blinded. Part 2c of the study is a 
non-randomized, non-controlled, open-label study; therefore site staff observing the 
patients, patients, and the Sponsor will be unblinded.
Part 1
Ten healthy volunteers will be randomized to active or placebo treatment in each dose 
cohort/level in a 4:1 ratio. The randomization numbers will be generated by the Sponsor 
or its designee. The randomized treatment assignment will be allocated from the list 
sequentially to subjects in the order in which they are enrolled. For each dose cohort, the 
randomization will be designed such that of the first 2 subjects, one will receive active 
drug, and the other will receive placebo. The remaining 8 subjects in the cohort will be 
randomized such that 7 receive active drug and 1 receives placebo. The treatment 
allocation will be managed by the unblinded Pharmacist and will be based on the 
randomization assignment list. An unblinded study drug administrator will administer the 
drug to the subject. Drug administration of a subject will be performed in isolation of 
other subjects.  
To allow informed recommendations or decisions regarding the dose selection in Part 1, 
an integrated assessment of the safety, tolerability and available pharmacokinetics 
and/or pharmacodynamics will be made prior to each dose decision. If required, 
unblinded data (individual as well as at group level) may also be presented to the Drug 
Safety Committee or other experts of the Sponsor.
Part 2a 
Patients will be randomized to placebo or one of three active dose levels of RO7062931 
in a 1:1:1:1 ratio. The randomization numbers will be generated by an IxRS (Interactive 
voice/web response system) according to specifications provided by the sponsor to the 
external randomization vendor. The Sponsor may postpone or stop enrolment of 
certain patient subgroups, in order to evaluate pharmacodynamic parameters in 
different patient subgroups. Each cohort/arm will consist of 6 patients. These cohorts 
will be run in parallel. The treatment allocation will be managed by the unblinded 


RO7062931—F. Hoffmann-La Roche Ltd
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Pharmacist and will be based on the IxRS randomization assignment. The unblinded 
pharmacist will fix tape to the syringes to mask any potential color difference between 
syringes while still allowing visualization of dose volumes. 
The PK data from the first 8 patients of Part 2a (assuming 2 patients per cohort/arm), 
who have been randomized and have received their first dose will be reviewed by the 
project Clinical Pharmacologist prior to randomization of any further patients to ensure 
the exposure for patients is in the same range as for healthy volunteers. Should the 
ranges look different, dose levels for subsequent patients may be adjusted.
Part 2b
Similar to Part 1, each patient will be randomized to active treatment or placebo in each 
dose cohort/level in a 3:1 ratio. The randomization numbers will be generated by an 
IxRS (Interactive voice/web response system) according to specifications provided by 
the sponsor to the external randomization vendor. The Sponsor may postpone or stop 
enrolment of or only enroll certain patient subgroups, in order to evaluate 
pharmacodynamic parameters in different patient subgroups. Each cohort will be 
comprised of 8 patients, six patients will receive RO7062931 and two will receive 
placebo. The first two cohorts will be run in parallel; therefore, patients will also be 
randomized to a cohort. Any subsequent cohorts may be sequential or parallel. The 
treatment allocation will be managed by the unblinded Pharmacist and will be based on 
the IxRS randomization assignment. The method of tape masking as described for Part 
2a will be used in Part 2b to protect the blind. 
Part 2c
For Part 2c, the IxRS will be used to register patients to the open-label cohorts. 
Additionally, IxRS will be used to dispense RO7062931 and PEG-IFN for patients. The 
Sponsor may postpone or stop enrolment of, or only enroll certain patient subgroups, in 
order to evaluate pharmacodynamic parameters in different patient subgroups.  The 
initial 8 patients of cohort 9 will be enrolled prior to the enrollment of the initial 8 
patients in cohort 10. Either or both of these cohorts may be expanded up to a maximum 
of 30 patients in total. Assignment of patients at this expansion stage may be 
sequential or in parallel. Enrolment of subsequent cohorts 11 and 12 may be sequential 
or parallel. 
The treatment allocation will be managed by the Pharmacist and will be based on the 
IxRS assignment. 


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The Principal Investigator(s) will receive a set of sealed treatment codes for Part 1. 
These may have the form of sealed envelopes or scratch codes. If the identity of the test 
medication needs to be known in order to manage the study subject’s condition (in the 
case of a serious adverse event), the treatment code for that study subject may be 
broken. For Parts 2a and 2b, the Investigator(s) will be able to break the treatment code 
by contacting the IxRS. Treatment codes should not be broken except in emergency 
situations. 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).
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 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. As per health authority 
reporting requirements, the Sponsor will break the treatment code for all unexpected 
serious adverse events (see Section 5.1) that are considered by the Investigator to be 
related to study drug.
4.4
STUDY TREATMENT
4.4.1
Formulation, Packaging, and Handling
4.4.1.1
RO7062931 and Placebo
RO7062931 and placebo (IMP) to be used in the study will be provided by Roche.
 
 
 
 
 
 
 
 


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4.4.1.2
Standard of Care (NUC and PEG-IFN)
As NUCs (entecavir, tenofovir alafenamide or tenofovir disoproxil fumarate) are to be 
used as background SoC therapies, they are classed as non-investigational medicinal 
product (NIMP). Please see local prescribing information for additional information.
As PEG-IFN is not licensed for use in CHB patients receiving NUC therapy, it is thus 
classed as an IMP.
PEG-IFN is a clear and colourless to light yellow sterile liquid provided in prefilled 
syringes for single use. Each prefilled syringe of 0.5 mL solution contains 
180 µg peginterferon alfa-2a.
The list of excipients is as follows: sodium chloride, polysorbate 80, benzyl alcohol, 
sodium acetate, acetic acid, and water for injections.
The packaging and labeling of PEG-IFN will be in accordance with Roche standard and 
local regulations. Study drug packaging 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. Study drug should be stored under the 
recommended storage conditions (2 to 8°C, protected from light). For further details, 
see the packaging label.
Upon arrival of investigational products at the site, site personnel should check them 
for damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.
4.4.2
Dosage, Administration and Compliance
4.4.2.1
RO7062931 and Placebo
The qualified individual responsible for dispensing the study drug will be unblinded and 
will prepare the correct dose according to the randomization schedule. This individual 
will write the date dispensed, study subject number and initials on the study drug vial 
label and on the Drug Accountability Record. This individual will also record the study 
drug (e.g., batch number) received by each subject during the study.
SC doses will be administered at an appropriate site, for example the abdomen or upper 
thigh. For multiple doses, the administration site should be rotated so that the nature of 
any injection site reactions may be better understood (for details on dosing and dose 
regimen, see Section 3). All RO7062931 doses will be administered at the study clinic in 


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the morning by investigational staff and should be administered in the fasted state either 
two hours before or two hours after a morning meal. After SC administration of study 
drug, the Part 2 patients should remain at the site at least until the post-dose 
assessments are completed. The drug should be administered concomitantly with the 
nucleosides/nucleotides taken by the patient.
For Part 2c:
All RO7062931 administrations will be via the SC route utilizing sterile 
technique.RO7062931 doses will be administered SC once weekly for up to 24 weeks in 
Cohort 9 and for up to 48 weeks in Cohort 10. All RO7062931 doses will be 
administered at the study clinic in the morning by investigational staff and should be 
administered in the fasted state either two hours before or two hours after a morning 
meal.
For cohorts involving PEG-IFN, RO7062931 and PEG-IFN SC doses should be 
administered at different sites (e.g. left thigh and right thigh), and the administration 
sites should be rotated on a weekly basis between doses. This will allow to better 
characterize and minimize the risk of injection site reactions. For convenience, consider 
SC treatment administrations in the same morning as the NUC administration 
and PEG-IFN SC administration should be at least 1 hour after RO7062931 SC 
administration.
PEG-IFN administration
All PEG-IFN administrations will be administered via the SC route utilizing sterile 
technique. PEG-IFN at a dose of 180 µg will be administered once weekly for up to 
48 weeks. PEG-IFN will be administered weekly at study clinic. 
Specific guidelines for adjusting the doses of PEG-IFN for adverse event management 
are provided in Section 5.2.1.3. If PEG-IFN is interrupted or discontinued permanently, 
patients should continue treatment with RO7062931 and NUC until the end of the 
treatment period.
For further information on the PEG-IFN, please refer to the latest PEG-IFN
Investigator Brochure.
NUC administration
NUC will be administered per local label or as per prescribing information and should 
be taken in the morning of RO7062931 or RO7062931 and PEG-IFN administration. 
NUC administration during the study, including the follow-up period, should be 
captured in the site documentation and eCRF. This information should include 
information about any missing doses during treatment and follow-up period. 
For further information on the NUCs used in this study, please follow local prescribing 
information.


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4.4.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(RO7062931, placebo, and PEG-IFN) will be provided by the Sponsor. The 
investigational site will acknowledge receipt of IMPs, to confirm the shipment condition 
and content. Any damaged shipments will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the study subject to whom the study drug was dispensed (for 
example, subject initials and date of birth).

The date(s) and quantity of the study drug returned by the study subject.

All records and drug supplies must be available for inspection by the Roche Monitor 
at every monitoring visit.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure 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 
investigational medicinal product for safety reasons. In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Written documentation of destruction must contain the following:

Identity [e.g., batch number] of investigational product[s] destroyed

Quantity of investigational product[s] destroyed

Date of destruction

Method of destruction

Name and signature of responsible person [or company] who destroyed 
investigational product[s].
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.


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4.4.4
Post-Trial Access to RO7062931
Currently, the Sponsor does not have any plans to provide RO7062931 to study subjects 
after conclusion of the study.
4.4.5
Post-Trial Access to NUC/PEG-IFN
NUC or PEG-IFN are marketed drugs and commercially available. No post-study 
medication or drug reimbursement is provided as part of this protocol. The investigator 
is responsible for ensuring that consideration has been given to the post-study care of 
the patient’s medical condition.
4.5
CONCOMITANT THERAPY AND FOOD
There are no concomitant treatment restrictions at this time as no drug-drug interactions 
are foreseen for RO7062931. In Part 1, there are some restrictions for healthy 
volunteers that should be maintained.

Any prescribed or over-the-counter (OTC) medication, vitamins, fish oils, protein 
powders, including herbal remedies, taken within 2 weeks prior to first study drug 
administration with the exception of hormone replacement therapy (HRT) which is 
allowed throughout the study. Paracetamol (up to 1 g per day) will be allowed. 

However, in the event that a healthy volunteer requires additional medication during 
the course of the trial, this may be allowed after consultation with the Investigator 
and Sponsor. 

Herbal therapy or substances (e.g. tea)/supplements/traditional Chinese medicines, 
as well as OTC drugs, may affect patient laboratory values. Abnormal values may 
lead to screening failures or patient withdrawal from study treatment. As such, 
patients at screening should be carefully questioned regarding such practices/habits 
and should be advised to refrain from them, if deemed necessary.
It is unlikely that food will have an impact on the PK of RO7062931, however, for study 
subjects taking nucleosides/nucleotides food restrictions may apply. Therefore, it is 
suggested that both RO7062931 and the nucleosides/nucleotides be taken in the fasted 
state (2 hours before, or, 2 hours after a meal) during each clinic visit where RO7062931 
is administered. Taking RO7062931 in a fasted state will apply to healthy volunteers and 
patients.
4.5.1
Permitted Therapy 
Concomitant therapy 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. All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF).
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF.


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4.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be prohibited. All concomitant 
medications need be discussed with the Sponsor prior to enrolling study subjects.
For patients in Part 2c who take NUC or PEG-IFN during the study, please follow the 
prescribing information or the PEG-IFN Investigator Brochure, to guide as to whether 
concomitant medications are permitted or prohibited. 
In case of doubt, the Sponsor may be contacted regarding potential prohibited 
concomitant medications, which may be allowed if the rationale is discussed, agreed and 
documented between the Investigator and Sponsor Medical Monitor.
4.5.3
Prohibited Food
There are no prohibited foods for either healthy volunteers or patients.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the Schedule of 
Assessments tables as outlined in Appendix 1 to Appendix 14. At time-points when 
several assessments coincide, the following sequence should be followed with the PK 
blood sample to be taken first at the nominal time-point:

Urine collection

Vital signs

ECGs

PK, viral dynamic, safety blood sampling

Study drug administration
4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, i.e., surgeries, 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 the CHB patients, the detailed HBV history will be documented, which will include 
date of HBV diagnosis, mode of HBV infection (if known), HBV genotype (if documented), 
all previous HBV treatments and outcomes of treatments, occurrence of nucleos(t)ide 
analogue resistance (if any), previous evaluations of cirrhosis, dates/outcomes of liver 
biopsies (if any). 
Demographic data will include age, sex, and self-reported race/ethnicity.


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4.6.1.2
Physical Examinations
A complete physical examination should be performed at baseline 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. 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.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in healthy volunteer/patient’s notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
Body weight will be recorded at screening and during the study. Height will be recorded 
at the Screening visit only. BMI will be calculated at Screening.
4.6.1.3
Vital Signs
Vital signs will be obtained after the subject has been resting in a supine position for at 
least 10 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 Appendix 1 to
Appendix 14). 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).


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4.6.1.4
Electrocardiograms
ECGs will be collected after the study subject has been in a supine position for at least 
10 minutes prior to each ECG evaluation. At the specified time-points (see SoA tables, 
see Appendix 1 to Appendix 14), 12-lead ECGs will be obtained in triplicate, i.e., three 
consecutive interpretable 12-lead ECGs within a 3-5-minute interval, and recorded in the 
case report form (CRF). Triplicate recordings should be taken for any unscheduled ECG.
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 [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.
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic ECG tracings must be appropriately kept by the 
study center and must fulfill all applicable archiving requirements. The ECG intervals and 
interpretation will be recorded on the eCRF or may be sent electronically. If considered 
appropriate by Roche, ECGs may be analyzed retrospectively at a central laboratory.
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).


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10. If any QT/QTc values500 msec or increases from pre-dose on Day 1 QTc
60 msec (as provided by the machine), the site should repeat the ECG 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.
4.6.1.5
Laboratory Assessments
All laboratory assessments will be performed at one or more central laboratories. The 
subsections below provide additional details specific to the type of assessments being 
conducted. Applicable reference ranges for the study laboratory parameters must be 
supplied to the Sponsor before the study starts.
Residual laboratory samples may be used to repeat laboratory tests in the event of a 
problem with the original sample as outlined in the SoA. Additionally, the residual 
samples may be used for exploratory HBV biomarker analyses to further understand 
disease biology and treatment impact. This may include, but is not limited to, analysis of 
viral and host response factors (DNA and/or non-DNA) to infection and treatment, 
development/validation of HBV assays, and immunogenicity analyses.
The collected samples will be destroyed no later than 5 years after the final closure of 
the clinical database, unless specified otherwise in the subsections below or unless 
regulatory authorities require specimens to be maintained for a longer time period. For 
patients who consented to optional RBR sample collection and analyses, any unused 
residual samples will be used for RBR specimen storage (see Section 4.6.1.5.7).
4.6.1.5.1
Safety Laboratory Assessments
Laboratory safety tests shall be collected at time-points specified in the Schedule of 
Assessments (see Appendix 1 to Appendix 14). Handling of residual samples is 
described in Section 4.6.1.5. 
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 study subject 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. 
Additional blood and urine safety samples will also be collected at the time of a serious 
adverse event.


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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. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the central laboratory. 
The following blood and urine samples will be collected:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), mean 
corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration 
(MCHC).

Blood chemistry: ALT, AST, total and indirect bilirubin, ALP, blood urea nitrogen 
(BUN), gamma-glutamyl transferase (GGT) (at Screening only), glutamate 
dehydrogenase (GLDH), creatine phosphokinase (at Screening only), total protein, 
albumin, creatinine and calculated creatinine clearance (using the Cockcroft Gault 
formula), glomerular filtration rate (GFR) calculated (MDRD4 method), uric acid, 
cystatin c, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides, sodium, chloride, potassium, calcium, magnesium, phosphate and 
bicarbonate. 

Coagulation: prothrombin time (PT), International Normalized Ratio (INR), activated 
partial thromboplastin time (aPTT)

Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocytes, specific gravity and pH. Urine will be 
also sent to the laboratory to perform microscopy to examine urine sediment for 
casts and cells. If there is a clinically significant positive dipstick result, (i.e., 
confirmed by a positive repeated sample), urine will be sent to the laboratory for 
culture. If there is an explanation for the positive dipstick result, e.g., menses, it 
should be recorded. Urine color may be evaluated from urinalysis or urine PK 
samples if considered necessary.

Viral serology: Human immunodeficiency virus (HIV-1 Antibody, HIV-2 Antibody), 
hepatitis A virus (HAV IgM Antibody), hepatitis B virus (surface antigen, HBsAg), 
hepatitis C virus (quantitative HCV antibody), hepatitis D (total HDV antibody) 
(Part 2c), and hepatitis E virus (IgM and IgG HEV antibodies) (Part 2c).

Auto-antibodies at Screening: AMA, ANA, ASMA, a-TPO, anti-thyroglobulin, and 
anti-platelet antibodies (Part 2c).

Pregnancy test
For all women enrolled in the study: Blood sample for determining beta-human 
chorionic gonadotropin (-HCG) 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.

Alpha fetoprotein: At Screening only for HBV patients.

Thyroid function test: TSH (Part 2c).


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
Hormones: FSH (females only to confirm post-menopausal status, performed at 
Screening only).

Drugs of abuse (urine): Cannabinoids, amphetamines, methamphetamines, opiates, 
methadone, cocaine, benzodiazepines, and barbiturates.

Alcohol breath or blood test will be performed.
4.6.1.5.2
Pharmacokinetic Assessments
Blood and urine samples will be collected to evaluate the PK of RO7062931 and 
metabolites as specified in the SoA (see Appendix 1 to Appendix 14). When the PK 
assessment is scheduled for the same nominal time as another scheduled assessment, 
the PK blood samples should be taken as close as possible to the scheduled time.
Blood and urine samples will be collected from all healthy volunteer cohorts in Part 1 and 
from CHB patients in Part 2. The volume of each urine sample at each interval will be
measured by the site staff and recorded in CRF. The actual date and time of each blood 
sample collection, the start and end date and time for each urine sample collection will 
be recorded in CRF.
 
 
  
Sparse sampling for tenofovir (including tenofovir alafenamide, if approved for HBV and 
applicable), entecavir, adefovir and telbivudine will be collected for Parts 2a and 2b and 
entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate for Part 2c. 
A decision to stop PK sampling earlier or to collect more samples than currently 
proposed scheduled times will be based on the PK profile of the study drug. Timing of 
PK sampling may change based on emerging PK results after agreement with the 
Sponsor and the Investigator.
PK parameters will be estimated using standard non-compartmental methods for 
RO7062931.
PK samples will be stored for up to 2 years for the protocol assessments, unless 
otherwise indicated. Samples will be destroyed no later than 2 years after the date of 
final closure of the clinical database, unless regulatory authorities require specimens to 
be maintained for a longer time period. If required, the residual of the PK samples taken 
during the study (any time-point) can be used for additional analysis (including assay 
validations and immunogenicity analyses).
Additional PK samples will also be collected at the time of a serious adverse event. 


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Samples for laboratory tests as specified above will be sent to one or several central 
laboratories or to the Sponsor for analysis. For sampling procedures, storage conditions, 
and shipment instructions, see the separate laboratory manual.
4.6.1.5.3
Assessments for Inflammatory Markers, Autoantibodies and 
Anti-Drug Antibodies (ADA)
Samples for laboratory tests as specified below will be sent to one or several central 
laboratories or to the Sponsor for analysis. For sampling procedures, storage conditions, 
and shipment instructions, see the separate laboratory manual.
Handling of residual samples is described in Section 4.6.1.5. 
The following separate assessments will take place in this study: 

For inflammatory markers

For development of autoantibodies

For development of anti-drug antibodies (ADAs)
Inflammatory Markers
Blood samples for assessing inflammatory markers will be obtained for all study subjects 
at pre-specified time-points (see SoA, Appendix 1 to Appendix 14). In addition, in case an 
immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled 
sample will be collected as close to the onset of the AE as possible. Blood samples 
(both planned and unscheduled) will be taken to assess: complement, CRP, ESR, 
gamma globulin and other inflammatory biomarkers (such as, but not limited to, IL-6, 
IL-8, IL12, MCP1, TNF).
For patients in Part 2c, a baseline (Day 1, pre-dose) sample for inflammatory markers 
will be assessed. In case an immune AE/AE suggestive of immunological involvement 
occurs, the samples collected at the other time-points as well as an unscheduled sample 
collected as close to the onset of the AE as possible will be assessed.
Auto-antibodies
Blood samples for assessing autoantibodies will be obtained for all study subjects before 
dosing, at baseline (also see SoA, Appendix 1 to Appendix 14). In addition, in case of an 
autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an 
unscheduled sample will be collected as close to the onset of the AE as is possible. The 
panel of autoantibodies to be assessed will be: anti-nuclear antibodies, anti-ds-DNA
antibodies, anti-histone antibodies, anti-ssDNA antibodies, anti-neutrophil cytoplasmic 
antibody, anti-cardiolipin antibodies, and rheumatoid factor. 


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ADA Assessment
Blood samples will be collected from all subjects at each time-point as specified in the 
SoA tables (see Appendix 1 to Appendix 14). All ADA blood samples will be collected 
prior to dosing of investigational drug.
4.6.1.5.4
Pharmacodynamic Assessments
During the course of the study, PD sampling time-points may be modified on the basis of 
emerging data to ensure the pharmacodynamics of RO7062931 can be adequately 
characterized.
Blood samples for pharmacodynamics assessments will be collected as indicated in the 
SoA tables (see Appendix 1 to Appendix 14). Samples for laboratory tests as specified 
below will be sent to one or several central laboratories or to the Sponsor for analysis. 
For sampling procedures, storage conditions, and shipment instructions, see the 
separate laboratory manual.
In Part 2c, based on continuous analysis of the data in this study and other studies, any 
sample type not considered to be critical for PD evaluation may be stopped at any time 
if the data from the samples collected does not produce useful information.
Handling of residual samples is described in Section 4.6.1.5. 
HBV-Specific Viral Assessments
HBV-specific viral assessments will be performed only in patients in Part 2 of the study; 
also see viral dynamic outcome measures in Section 3.3.2.2. Monitoring of viral 
resistance will be performed in any patient that experiences breakthrough. 
Commercially available assays will be used for the assessment of viral parameters when 
available and applicable. For the parameters that do not have suitable commercial 
assays, validated research type assays will be used.
Blood samples for viral dynamic data and viral genotyping will be collected.


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Viral Resistance Monitoring
Blood samples will be collected at baseline (BL; Day 1 pre-dose) and throughout the 
study, as detailed in the SoA, to monitor for the development of drug resistance. 
Sequencing of the complete HBV genome will be performed for all viral resistance
monitoring samples at BL if viral load is1000 copies/mL. For patients whose BL sample 
contains1000 copies/mL and therefore, a BL sequence cannot be established, an 
archived sample should be provided with a reasonable effort if available in order to get a 
BL sequence. If a patient experiences an increase in serum HBV DNA level of more than 
1log10 (10-fold) over nadir (viral breakthrough) during the treatment period or follow-up 
period of the study, an ad hoc (unscheduled) blood sample will be taken to confirm the 
breakthrough. Samples from confirmed viral breakthrough and subsequent follow-up 
visits will be sent for population sequencing. Other sequencing analyses (e.g., ultra deep 
sequencing) and phenotypic analysis may be performed in addition.
Virological breakthrough should be reported as an adverse event.
4.6.1.5.5
Clinical Genotyping
A blood sample will be taken pre-dose on Day 1 for DNA extraction from all subjects. If, 
however, the genetic blood sample is not collected during the scheduled visit, it may be 
collected at any time during the conduct of the clinical study.
 
 
 
 
The sample collected for DNA extraction may be used for whole exome and/or whole 
genome sequencing and other genetic analysis and may be sent to one or more 
laboratories for analysis. These assessments will be performed if safety or scientific 
rationales develop.
Handling of residual samples is described in Section 4.6.1.5. 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4.
4.6.1.5.6
Other Assessments
A number of exploratory safety urinary kidney biomarkers will be analyzed from urine 
samples including but not limited to: α1-microglobulin, β2-microglobulin, and KIM-1.


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Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety evaluation may be stopped at any time if the 
data from the samples collected does not produce useful information.
Samples as specified above will be sent to one or several central laboratories or to the 
Sponsor for analysis. For sampling procedures, storage conditions, and shipment 
instructions, see the separate laboratory manual.
Handling of residual samples is described in Section 4.6.1.5. 
4.6.1.5.7
Optional Samples for Research Biosample Repository
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, peptides). 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.
Unused residual samples from the assessments described in Section 4.6.1.5.1 through 
to Section 4.6.1.5.6 will be retained as well as specimens will be collected from patients 
who give specific consent to participate in this optional Research Biosample Repository. 
Collected specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression.

To increase knowledge and understanding of disease biology.

To study drug 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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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.
Sample Collection
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers:

Leftover serum and plasma samples to assess protein biomarkers including, but not 
limited to proteomics.
The following samples will be collected for identification of genetic (inherited) biomarkers:

Blood for DNA extraction to assess for biomarkers, including but not limited to the 
following: single nucleotide polymorphisms (SNPs).
The samples collected for DNA extraction may be used for whole genome sequencing 
(WGS) and other genetic analysis and may be sent to one or more laboratories for 
analysis.
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
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 laboratory 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 Section 8.4).


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Confidentiality
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.
Study subject 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 study subject, unless permitted or required by law.
Data derived from RBR specimen analysis on individual study subject 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. Patients 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 patients 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.
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 study subject 
the objectives, methods, and potential hazards of participation in the RBR. Study 
subjects 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 study subject’s agreement to provide optional 
RBR specimens. Study subjects who decline to participate will not provide a separate 
signature.
The Investigator should document whether or not the study subject 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.


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Withdrawal from the Research Biosample Repository
Study subjects who give consent to provide specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a study subject wishes to 
withdraw consent to the testing of his or her specimens, the Investigator must inform the 
Medical Monitor in writing of the study subject’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 study subject will be provided with instructions on how to 
withdraw consent after the trial is closed. A study subject's withdrawal from Study 
BP39405 does not, by itself, constitute withdrawal of specimens from the RBR. Likewise, 
a study subject’s withdrawal from the RBR does not constitute withdrawal from Study 
BP39405. Data already generated before time of withdrawal of consent to RBR will still 
be used.
Monitoring and Oversight
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 study subject participation in Research 
Biosample Repository 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.
4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled study subjects and for study subjects 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 study subjects meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all study subjects screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened study subject with regard to the protocol’s inclusion and exclusion criteria is to 
be completed by the Investigator and kept at the investigational site.
For Part 2, documented liver biopsy or Fibroscan® or equivalent test results 
demonstrating chronic HBV infection with absence of cirrhosis and bridging fibrosis must 
be available within the 6 months. If no results are available, a Fibroscan® will be 
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If a subject fails an inclusion/exclusion criterion due to a transient and non-clinically 
significant condition at screening, the Investigator may repeat the relevant screening 
assessment(s) within the screening period (28 days for Part 1 and Part 2c and 56 days 
for Parts 2a and 2b). If the subject fails a second time, they will be classed as a screen 
failure and cannot be re-screened. Re-screening is allowed for subjects who were 
screened in the study and met study inclusion/exclusion criteria but failed to be 
randomized within 28 days after the start of the screening period for Part 1 and Part 2c 
or within 56 days after the start of the screening period for Part 2a and 2b. In order to 
re-screen such a subject, all inclusion and exclusion criteria should be re-evaluated and 
all applicable screening assessments repeated if done more than 28 days before 
randomization for Part 1 and Part 2c or more than 56 days before randomization for 
Parts 2a and 2b. There is no need to repeat alpha-fetoprotein test if done for the study in 
central laboratory within 6 months before re-screening.
4.6.2.2
Assessments during Treatment
Under no circumstances will study subjects who enroll in any part of this study and have 
completed treatment as specified, be permitted to be allocated a new randomization 
number and re-enroll in the study.
All assessments must be performed as per SoA tables (see Appendix 1 to Appendix 14).
4.6.2.3
Follow-Up Assessments and Study Completion
Study subjects who complete the study or discontinue from the study early will be asked 
to return to the clinic after the last dose of study drug for a follow-up visit.
All follow up assessments must be performed as per SoA tables (see Appendix 1 to
Appendix 14).
Adverse events should be followed as outlined in Section 5.5. 
4.7
SUBJECT, STUDY AND SITE DISCONTINUATION
4.7.1
Study Subject Discontinuation
Subjects will be treated until unacceptable toxicities or withdrawal of consent.
The Investigator has the right to discontinue a study subject from RO7062931 or 
withdraw a study subject from the study at any time. In addition, study subjects have the 
right to voluntarily discontinue study drug or withdraw from the study at any time for any 
reason. Reasons for discontinuation of study drug or withdrawal from the study may 
include, but are not limited to, the following:

Study subject withdrawal of consent at any time.

Any medical condition that the investigator or Sponsor determines may jeopardize 
the study subject’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the study subject.


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
Subject non-compliance.
4.7.1.1
Discontinuation from Study Drug
Study subjects must discontinue study drug if they experience any of the following:

Pregnancy

A serious adverse event (SAE) considered by the Investigator to be related to 
treatment with RO7062931.
Study subjects who discontinue study drug prematurely will be asked to return to the 
clinic for a study completion/early termination visit and may undergo follow-up
assessments. The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF. 
Study subjects who discontinue study drug prematurely for safety reasons will not be 
replaced. Study subjects who discontinue study drug prematurely for non-safety reasons 
may be replaced. The Sponsor should be informed of subjects’ discontinuations from the 
study or from the study drug.
Part 2: CHB Patients
Individual patients must discontinue RO7062931/placebo if they experience any of the 
following:

Safety and tolerability issues, e.g., acute reactions, not tolerable and not 
manageable with symptomatic treatment.

Grade 4 ALT (i.e.,≥10ULN) as defined by the Division of Acquired 
Immunodeficiency Syndrome (AIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE grading table) confirmed within 48-72 hours
(not for Part 2c).

Grade 3 ALT (i.e.,5x to < 10 ULN) combined with total bilirubin2ULN (of 
which35% is direct bilirubin), or Grade 3 ALT and INR1.5.

Any other confirmed (within 48-72h) Grade 4 laboratory abnormality deemed 
clinically significant (based on Investigator’s assessment).

Development of liver decompensation (ascites, varices, Child-Pugh Class B or C 
clinical classification).

Grade 3 renal adverse events defined as creatinine50% from baseline and/or 
eGFR <60 ml/min/1.73 m2.

Development of resistance in a CHB patient is suspected if the patient experiences 
an increase in serum HBV DNA of1 log10 (10-fold) over nadir during the treatment 
period, i.e., virological breakthrough.

NUC analogue discontinuation due to safety issues or resistance development.


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All prematurely discontinued patients will have assessments performed at the end of 
treatment with RO7062931/placebo listed in the SoAs tables. If a patient discontinues 
study drug between study visits, he/she should be called for an unscheduled visit to 
have these assessments performed.
All patients who discontinued the study treatment prematurely should complete the 
4-week follow-up period (starting from the date of the last dose taken) and continue 
safety follow up as per SoAs (see Appendix 1 to Appendix 14). The primary reason for 
premature study drug discontinuation should be documented on the appropriate eCRF.
4.7.1.2
Withdrawal from Study
Every effort should be made to obtain information on study subjects who withdraw from 
the study. The primary reason for withdrawal from the study should be documented on 
the appropriate eCRF.
Study subjects will not be followed for any reason after consent has been withdrawn.
When a patient voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless patient specifically 
requests for these to be discarded or local laws require their immediate destruction. A 
patient's withdrawal from Study BP39405 does not, by itself, constitute withdrawal of 
specimens donated to the RBR.
Study subjects who withdraw from the study for safety reasons will not be replaced. 
Study subjects who withdraw from the study for other reasons may be replaced.
4.7.2
Study and Site Discontinuation
The Sponsor has the right to 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 study subjects.

Clinically significant changes in safety parameters considered to be related to 
RO7062931 and not considered acceptable by the Investigator and/or Sponsor.
Study subject 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.


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The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events (SAEs) and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.1.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following:

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.

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline.

Any deterioration in a laboratory value 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 drug.

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).


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5.1.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death).

Life-threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death).
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10).

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the study subject’s ability to conduct normal life functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.

Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
study subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above).
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 (see Table 2); 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; see Section 5.4.2 for 
reporting instructions).


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5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions). Adverse events of special interest for 
this study include the following:

Cases of an isolated elevated ALT or AST ≥10 ULN (Section 5.2 and 5.3.5.6).

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6.

Suspected transmission of an infectious agent by the study drug, 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 drug is suspected.

Severe injection site reactions

Grade 3 renal adverse events defined as creatinine 50% from baseline and/or 
eGFR <60 mL/min/1.73 m2.
5.2
SAFETY PLAN
Measures will be taken to ensure the safety of the healthy volunteers/patients 
participating in this trial; in particular, the use of appropriate inclusion and exclusion 
criteria and close monitoring of the study subjects. HVs/ patients will be monitored by AE 
monitoring, vital sign monitoring, ECG monitoring, and hematology and clinical chemistry 
parameters.
The Investigator has the right to withdraw a HV/ patient for safety reasons at any time. 
Also, the Investigator and Sponsor may terminate a particular cohort or the study as 
whole at any time if considered warranted for safety reasons. For example, a particular 
cohort may be terminated in case of safety related drop-outs if the safety events were 
similar in nature.
5.2.1
Management of Specific Adverse Events 
5.2.1.1
Potential Drug-Induced Liver Injury (DILI)
Wherever possible, timely confirmation (within 48 to 72 hours) of initial liver-related 
laboratory abnormalities should occur prior to the reporting of a potential DILI event. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs, and discontinuation of all study medications (RO7062931, NUC, or PEG-IFN, 
where applicable) must be considered.


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In this study, potential DILI is defined as follows:

For healthy volunteers (Part 1): ALT > 3 ULN accompanied total 
bilirubin > 2 ULN

For CHB patients (Part 2): ALT > 3 baseline / ULN (whichever is higher) 
accompanied by total bilirubin >2 ULN
AND

No other immediately apparent possible causes of ALT elevation and 
hyperbilirubinemia, including, but not limited to acute viral hepatitis, cholestasis, 
pre-existing hepatic disease excluding HCV/HEV or the administration of other 
drug(s), herbal medications, or substances known to be hepatotoxic.
5.2.1.2
Alanine Transaminase (ALT) Elevations 
Abrupt elevation of serum ALT above normal is known to occur spontaneously in patients 
with CHB during the course of disease, and/or during anti-viral therapy. Transient 
ALT elevations are not always harmful and may be due to:

The underlying disease 

Immune clearance of infected hepatocytes 

Drug-induced immune-mediated hepatitis

DILI
Isolated ALT elevations of 2-3 times the baseline value that are self-limited may reflect a 
desirable treatment-related immunologic response rather than drug toxicity. However,
progressive increases or ALT elevations associated with increases in bilirubin without
alkaline phosphatase increase should primarily be considered adverse events, i.e. potential 
DILI.
In the event of ALT elevation > 5x ULN, more frequent monitoring of liver tests should 
be performed based on medical judgment and other causes of ALT elevations should be 
investigated. For patients with ALT > 5 ULN, the following management plan is 
recommended:


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ALT elevations during treatment

Isolated ALT elevation with preserved hepatic function (e.g. no significant changes in 
bilirubin, INR/PT, albumin, and ALP): 
-
Closely monitor liver function tests (LFTs) (i.e. ALT/AST, bilirubin, albumin, ALP and 
INR/PT): 
o
ALT 5 to 10 x ULN: Repeat LFTs every week. 
o
ALT >10 x ULN: Temporarily interrupt RO7062931 or RO7062931 and PEG-IFN 
treatment and repeat LFTs twice weekly until ALT level < 5 x ULN. Continue NUC 
treatment. Consider re-introducing RO7062931 or RO7062931 and PEG-IFN 
therapy following discussion with medical monitor based on subsequent laboratory
results.

ALT flare accompanied by declining liver synthetic and excretory functions (increased 
bilirubin >2 x ULN, or albumin decline >0.5 g/dL, or INR >1.5) or other signs of hepatic 
impairment (severe fatigue, nausea, vomiting, right upper quadrant pain):
-
RO7062931 or RO7062931 and PEG-IFN will be permanently discontinued, continue 
NUC treatment.
-
Closely monitor liver function tests: 
o
ALT 5 to 10 x ULN: Repeat LFTs every week.
o
ALT >10 x ULN: Repeat LFTs twice weekly until ALT level < 5 x ULN.
-
Investigate the participant for potential etiologies of the laboratory changes.
-
If alternative reasons/diagnoses cannot explain the laboratory changes, a 
potential DILI will be considered. 
If ALT elevations are associated with increased HBV DNA levels, virological breakthrough will 
be suspected (see Section 4.6.1.5.4).
ALT elevations during follow-up

Isolated ALT elevation with preserved hepatic function: 
-
ALT 5 to 10 x ULN: Repeat LFTs every week.  
-
ALT >10 x ULN: Repeat LFTs twice weekly until ALT level <5 x ULN. 

ALT elevation accompanied by declining liver synthetic and excretory functions:
-
ALT 5 to 10 x ULN: Repeat LFTs and ALT/AST every week.
-
ALT >10 x ULN: Repeat LFTs and ALT/AST twice weekly until ALT level < 5 x ULN. 
-
Investigate the CHB patient for potential etiologies of the laboratory changes.
-
If alternative reasons/diagnoses cannot explain the laboratory changes, a potentially
delayed DILI will be suspected and CHB patient will be monitored accordingly.


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In participants who have not discontinued NUC therapy if ALT elevations are associated with 
increased HBV DNA levels, virological breakthrough will be suspected (see Section 4.6.1.5.4). 
The Investigator should aim to exclude development of decompensated liver disease. 
Patients who develop signs of decompensated liver disease (e.g., ascites, variceal 
hemorrhage, Child-Pugh Class B or C clinical classification [Appendix 16]) should 
discontinue study treatment (Section 4.7.1.1). Patients who develop flares should be 
monitored more closely with additional unscheduled visits and laboratory assessments.
At the discretion of the Investigator, study treatment can be discontinued.
5.2.1.3
Dose Modifications with PEG-IFN
The intention of Part 2c of the protocol is that patients remain on PEG-IFN until the 
completion of the allocated treatment period. However, it is possible that some patients
will encounter transient or prolonged adverse effects or abnormal laboratory values at 
some juncture during their participation in the trial leading to potential need for 
adjustment of the PEG-IFN dosage.
If severe adverse reactions or laboratory abnormalities develop during PEG-IFN 
therapy, the dose should be modified until the adverse reactions abate. If intolerance 
persists after dose adjustment, PEG-IFN therapy should be discontinued. 
When dose modification of PEG-IFN is required for adverse reactions (clinical and/or 
laboratory), an initial dose reduction to 135 mcg (adjustment to the corresponding 
graduation mark for the prefilled syringes) is recommended. Dose reduction to 90 mcg 
(adjustment to the corresponding graduation mark for the prefilled syringes) may be 
needed if the adverse reaction persists or recurs. Following improvement of the adverse 
reaction, re-escalation of the dose may be considered. Table 1 provides guidelines for 
dose modifications and discontinuation of PEG-IFN for haematological laboratory 
abnormalities.
Table 1
PEG-IFN Hematological Dose Modifications Guidelines
Laboratory Values
Recommended Dose
ANC < 750 cells/mm³
ANC < 500 cells/mm³
Reduce to 135 mcg
Discontinue treatment until ANC values return to more 
than 1000 cells/mm3. Reinstitute at 90 mcg and monitor 
ANC.
Platelets < 50,000 cells/mm³
Platelets < 25,000 cells/mm³
Reduce to 90 mcg
Discontinue treatment 


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For patients who discontinue PEG-IFN early due to intolerability or if stopping criteria 
are met, then NUC and RO7062931 should be continued up to 48 weeks. The reasons 
for discontinuation of PEG-IFN and length of treatment duration will be recorded in 
the eCRF.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4-5.6. The 
Investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4).
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each study subject contact. All 
adverse events, whether reported by the study subject or noted by study personnel, will 
be recorded in the study subject’s medical record. Adverse events will then be reported 
on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, 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 drug, all adverse events, regardless of relationship to study 
drug, will be reported until the last follow-up visit.
After the last follow-up visit, investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be related to prior 
treatment with study drug (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all study subject evaluation time‑points. Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”


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5.3.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing adverse event severity in the study for Part 1 
and Parts 2a and 2b.
Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2).
For Part 2c, DAIDS toxicity grading scales (Appendix 18) will be used to assess 
adverse event severity.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the study subject, 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 drug, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study drug.

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug.

Known association of the event with the study drug or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the study subject or use of concomitant medications 
known to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For study subjects receiving combination therapy, causality will be assessed individually 
for each protocol mandated therapy.
5.3.5
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.


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5.3.5.1
Diagnosis versus Signs and Symptoms
Injection-Site Reactions
Adverse events that occur during or after study drug administration and are judged to be 
local and related to the SC study drug injection should be captured as a diagnosis (e.g., 
“injection site reaction" on the Adverse Event eCRF. If possible, avoid ambiguous terms 
such as "systemic reaction.") Associated signs and symptoms should be recorded on the 
dedicated Injection Reaction eCRF.
Grading of pre-defined injection site reaction symptoms is described in Appendix 17. If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Injection Reaction eCRF.
Other Adverse Events 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
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.


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5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
healthy volunteer/patient 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 patient evaluation time‑points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.3.5.4
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.


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5.3.5.5
Abnormal Vital Sign Value
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
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.
5.3.5.6
Alanine and Aspartate Transaminases (ALT/AST) Elevations 
For Part 1: 
The finding of an elevated ALT or AST (3ULN) 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 (Hy’s 
Law). Therefore, investigators must report as an adverse event the occurrence of either 
of the following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.


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For Part 2:
CHB patients may have elevated baseline ALT levels without an increase in bilirubin. 
However, the finding of an elevated ALT in combination with either an elevated total 
bilirubin or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of potential severe liver injury or 
worsening of disease. Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment- emergent ALT 3 Baseline and >3x ULN value in combination with
total bilirubin2ULN.

Treatment-emergent ALT3 Baseline and >3x ULN value in combination with 
clinical jaundice.
*For Part 2c (treatment- naïve and immune-active CHB patients), the threshold of 
ALT > 3 ULN baseline will be capped at 10 ULN.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
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 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). This 
includes death attributed to progression of chronic hepatitis B.
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. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable. 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.
5.3.5.8
Pre-Existing Medical Conditions
A pre-existing 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.


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A pre-existing 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”).
5.3.5.9
Lack of Efficacy or Worsening of Chronic Hepatitis B Infection
As this is the first study of RO7062931 in humans as well as in CHB patients and these 
patients are virologically suppressed, the effect on HBsAg is being explored as part of 
the secondary endpoints in this study. The short duration of treatment RO7062931 is not 
anticipated to provide the patients with therapeutic benefit, but rather to give evidence on 
the effect of multiple doses of RO7062931 on HBsAg.
Therefore, lack of RO7062931 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 (Section 4.6.1.5.3), and abnormal liver function tests (as 
defined in Section 5.3.5.6) should be reported as adverse events. Hepatic flares should 
be reported as adverse events of special interest (Section 5.1.3).
5.3.5.10
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 Section 5.1.2), except as outlined below.
The following hospitalization scenarios are not considered to be serious adverse events:

Hospitalization for respite care
–
Planned hospitalization required by the protocol.

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 study subject has not suffered an adverse event.
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events 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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5.3.5.11
Overdoses
Study drug (including IMP and NIMP) overdose is the accidental or intentional use of 
the drug in an amount higher than the dose being studied. An overdose or incorrect 
administration of study drug is not an adverse event unless it results in untoward medical 
effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).
5.4
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 drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies
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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5.4.1
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.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
After informed consent has been obtained but prior to initiation of study drug, 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 SAE responsible immediately 
(i.e., no more than 24 hours after learning of the event).
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3) that occur after initiation of study drug, investigators 
should record all case details that can be gathered on the Serious Adverse Reporting 
Form and forward this form to the SAE Responsible within 24 hours.
In the case of electronic reporting, investigators should record all case details that can 
be gathered immediately (i.e., within 24 hours after learning of the event) on the 
appropriate Serious Adverse Event / Adverse Event of Special Interest 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 SAE 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.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female subjects of childbearing potential will not be allowed to participate in this study. 
Although highly unlikely, female subjects will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 105 days after the last 
dose of study drug (Parts 2a and 2b) or within 6 months after last dose (Part 2c). A 
Clinical Trial Pregnancy Reporting Form should be completed by the Investigator and 
submitted to the sponsor within 24 hours after learning of the pregnancy. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of 
the pregnancy.
5.4.3.2
Pregnancies in Female Partners of Male Study Subjects
Male patients will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
105 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed by the Investigator and submitted to the Sponsor within 24 hours 
after learning of the pregnancy. Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male study subject 
exposed to study drug. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of the 
pregnancy. An Investigator who is contacted by the male study subject 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.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious adverse event (SAE; 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 5.4.2).
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 5.4.2).
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.


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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug 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 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
The Investigator must report all medical device complaints to the Sponsor. The 
Investigator should document as much information as possible on the Medical Device 
Complaint including the product number and expiration date. If the medical device 
complaint results in an adverse event, the adverse event must be reported on the 
Adverse Event eCRF. If the event is serious, the Adverse Event eCRF must be 
completed and reported to the Sponsor within 24 hours after learning of the event (see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the patient 
is lost to follow-up, or the patient withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug 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 patient’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 5.4.3.
5.5.2
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.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as after the last follow-up visit). 


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If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the adverse event reporting period, if the event is believed to be related to prior 
study drug treatment, the event should be reported directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the Serious Adverse Event 
Reporting Form using the fax number or email address provided to investigators. 
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest 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:

RO7062931 Investigator 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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Statistical summaries will be descriptive in nature and will be reported separately for 
each part of the study within the clinical study report. All study subjects who are 
randomized to receive placebo in Part 1 will be pooled as a respective placebo control 
group for Part 1. Placebo from Part 2b will be pooled with the placebo cohort from 
Part 2a. 
6.1
DETERMINATION OF SAMPLE SIZE
In Part 1 of the study, the adaptive SAD part, the planned sample size of 8 active per 
cohort was chosen not only to allow adequate assessment of safety and tolerability but 
also to increase the precision of the estimates of mean PK and urinary parameters,
 
Up to 80 HVs will be included in Part 1 of this study. Up to 8 cohorts of 10 HVs (8 on 
active and 2 on placebo per dose level) are planned but, based on the analysis of 
emerging PK and safety data, additional cohorts may be included or subsequent cohorts 
modified.


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For Parts 22a and 2b of the study, the PoM in CHB infected patients, a sample size of no 
more than 80 patients with CHB has been chosen (6 patients [Part 2a] and 8 patients 
[Part 2b] per dose cohort). It is anticipated that this sample size will allow 
characterization of the PK/PD (viral dynamic response) relationship, as well as safety 
and tolerability, in patients with CHB.
For Part 2c, approximately 16 patients will be enrolled into the initial 2 cohorts 
(8 patients in each cohort). If utilized, approximately 8 patients will be enrolled to each 
of the Cohorts 11 and 12. The sample size supports the assessment of response rate of 
undetectable qHBsAg at Week 24 follow-up in Cohorts 10, 11, and 12. 
A sample size of 8 ensures that the associated lower 90% confidence limit is above 10%, 
if the observed response rate is at least 38% (i.e. at least 3/8), assuming a binomial 
distribution. This sample size is also considered reasonable to support the safety and 
tolerability objectives of all cohorts, as well as to allow characterization of the qHBsAg 
profiles in Cohort 9.The cohorts may be expanded up to 30 subjects if warranted by 
emerging PD and/or safety data. A sample size of 30 ensures that the associated lower 
90% confidence limit is above 20%, if the observed response rate is at least 37% (i.e. at 
least 11/30).  
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations and discontinuations from the study will be 
summarized by treatment and dose level. The number of healthy volunteers or patients 
who were randomized, discontinued and completed the study will be summarized. 
Reasons for premature study withdrawal will be listed and summarized by treatment and 
dose level. Demographic and other baseline characteristics will be summarized with 
descriptive statistics.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
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.
6.3.2
Pharmacokinetic Analysis Population
Study subjects will be excluded from the pharmacokinetic analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol or if data are unavailable or incomplete which may influence the 
pharmacokinetic 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.


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6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Descriptive statistics will be generated for demographics, including sex, self-reported 
race, ethnicity, age and for Part 2 only: baseline disease characteristics including: HBV 
history (duration of HBV disease, mode of infection, HBV genotype, previous HBV 
treatments and outcomes, occurrence of NUC resistance). Baseline viral dynamics: 
HBsAg, HBV DNA and HBeAg will also be summarized. 
Data for study drug administration and concomitant medication will be listed. The 
number of subjects who were randomized, discontinued treatment period, completed 
treatment period, discontinued study and completed the study (including follow-up period) 
will be summarized.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
All study subjects who receive at least one dose of study drug will be included in the 
safety analysis. 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 will be flagged 
for laboratory data.
As appropriate, listings, summary tables and graphs (study subject plot and/or mean 
plots) will be provided for safety and tolerability assessments.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor by assigning preferred terms. Adverse events will be 
summarized by mapped term and appropriate thesaurus level.
AEs will be described by individual listings and frequency tables broken down by body 
system.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Study subject listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before
processing. Laboratory test values will be presented by listings and descriptive summary 
statistics.


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6.5.2.1
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.
6.5.2.2
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 study subject 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 study subject, the midpoint of the standard reference range will be used 
as the study subject baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the study subject
listings as “HH” for very high or “LL” for very low.
6.5.3
Vital Signs
Vital signs data will be presented by individual listings. In addition, tabular summaries 
will be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be as 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.


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6.5.5
Concomitant Medications
The original terms recorded on the study subjects’ 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.
6.6
PHARMACODYNAMIC ANALYSES
Pharmacodynamic parameters will be presented by listings and descriptive summary 
statistics separately by Part and/or cohorts.
6.6.1
Viral Dynamic Response Analyses
Summary descriptive statistics will be used to summarize the viral dynamic response 
outcome measure of quantitative HBsAg (log10), actual and change from baseline in 
quantitative HBsAg at each time-point by dose group. Rate of decrease in quantitative 
HBsAg will also be summarized using descriptive statistics. 
Plots of quantitative HBsAg (actual and change from baseline) over time will be utilized 
to compare the longitudinal profiles across doses. 
Mean (SD) of HBsAg (actual and change) will be calculated for each dose level and 
plotted on one plot, different line types and symbols used to differentiate the dose levels, 
In addition, individual patient data will be plotted over time, one plot for each dose level. 
Further exploration may include plots of quantitative HBsAg over time, grouped by 
baseline characteristics and/or demographics of interest. 
All other exploratory viral dynamic responses will be listed by time-points as a minimum. 
Further exploration of these exploratory responses for potential treatment effects may 
include longitudinal graphs and/or summaries.
6.6.2
PK/Viral Dynamic Response Analyses
The relationship between RO7062931 and dose, and metabolite(s) and dose if 
applicable, and the change of HBsAg at each time-point and rate of decrease will be 
explored by graphical analysis. The relationship between RO7062931 PK and urinary 
parameters and HBsAg will also be explored by graphical analysis. Assuming a 
monotonic relationship between HBsAg decrease and dose/plasma RO7062931, an 
appropriate exposure/dose-response model may be fitted to the data from Part 2a. This 
model may be used to guide dose selection for Part 2b, and will be further developed 
with data from Parts 2b and 2c.


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6.6.3
Efficacy Analyses
The proportion of patients with undetectable qHBsAg and associated 95% binomial confidence 
intervals will be calculated at 24 week after the end of treatment. Patients with missing 
HBsAg measures at 24 weeks visit after the end of treatment and thereafter will be treated as 
non-responders.
6.7
PHARMACOKINETIC ANALYSES
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Summary descriptive statistics of plasma PK parameters 
including Cmax, Tmax, AUCinf, AUClast, and t1/2 for RO7062931 and any metabolites when 
available will be presented by cohort/treatment arm including mean, standard deviation 
(SD), coefficient of variation (CV), medians and ranges. Note: the geometric or 
arithmetic mean and associated CV% will be used to describe Cmax, AUCinf, AUClast and
t1/2. Median values will be used to describe Tmax. Where appropriate, data may be pooled 
and analyzed, for example, all single dose data may be pooled. Listings, summary tables 
and graphs (individual plots and/or mean plots) by treatment group will be provided. 
Descriptive statistics of urine PK parameters for RO7062931 and any metabolites will be 
presented, where available. PK and PD data from this study may be used to develop a 
population PK/PD model.
Where appropriate, listings and summary tables of nucleoside/nucleotide-analogues, 
tenofovir, tenofovir, alafenamide, entecavir, adefovir, or telbivudine concentrations will 
be provided based on the sparse sampling throughout the study.
 
6.8
EXPLORATORY ANALYSES
6.8.1
Liver and Kidney Biomarker Data
The exploratory safety parameters (see Section 4.6.1.5.6), will be explored graphically. 
Plots will include longitudinal plots for both actual result and change from baseline. 
Longitudinal plots will include individual subject responses by dose, as well as 
mean/median plots. Box and whisker plots may also be used to detect outliers. 
6.9
INFLAMMATORY MARKERS, AUTOANTIBODIES AND ADA 
DATA
At minimum, any data that is collected as detailed in Section 4.6.1.5.3, and is available 
at the time of database closure will be listed and summarized using descriptive statistics. 
Data may also be explored graphically.




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The aim of such a dual endpoint approach would be to estimate an optimal dose level 
which represents an optimal trade-off between safety and biomarker response.
 
 
 
 
6.10.1.2
Part 2b Dose Selection: First Two Cohorts
A repeated measures dose-response model will be fitted to the data observed in Part 2a 
to model the relationship between quantitative HBsAg decline over time. The dose 
selected to be studied in different dosing regimens in the first two cohorts of Part 2b will 
be the lowest dose that yields the greatest decline at any time-point. Furthermore, a dual 
endpoint methodology described above for Part 1, modeling the quantitative HBsAg 
decline simultaneously with DLE in order to select a dose that maximizes the PD effect 
(HBsAg decline) whilst controlling on safety (DLE) will also be explored. 
The shape of the dose-response observed in Part 2a would determine the function that 
would be used to parameterize the HBsAg decline. The PD data and the safety data 
from Part 2a would be used to specify the priors.
6.10.1.3
Part 2b Dose/ Regimen Selection: Exploratory Cohorts
A response-adaptive approach will be explored to help guide the selection of the doses 
to be studied in the exploratory part of Part 2b using optimization criteria. Criterion that 
optimizes the dose-response parameters (D-optimality) as well as criterion that 
optimizes the target dose (TD-optimality) will be explored. 
The HBsAg decline at Day 29 will be modelled against cumulative dose using the most 
appropriate dose-response model. These parameter estimates would then be used as 
initial parameters for model selection. The efficiency of a set of models, where the doses 
and dose regimens to be further explored in the exploratory part of Part 2b are varied, 
will be compared using the R function (optDesign) within the (dose-finding) package 
(Bornkamp et al 2016).


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6.11
INTERIM ANALYSES
No interim analysis is planned for Part 1s 2a, and 2b of this study.
In Part 2c, administrative interim analyses will be conducted at Weeks 12 and 24 for 
the initial 8 enrolled in both Cohorts 9 and 10. Given the hypothesis-generating nature 
of this study, the Sponsor may choose to conduct additional administrative interim PD 
analyses. The decision to conduct additional interim analyses and the timing of the 
analyses will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis. The interim analysis will be performed and interpreted by Sponsor 
study team personnel.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system.
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Central laboratory data and 
electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line EDC system. The data collected in the 
source documents is entered onto the study eCRF. An audit trail will maintain a record of 
initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change. For each study subjects enrolled, an eCRF 
must be completed and electronically signed by the Principal Investigator or authorized 
delegate from the study staff. If a study subject withdraws from the study, the reason 
must be noted on the eCRF. If a study subject is withdrawn from the study because of a 
treatment‑limiting adverse event, thorough efforts should be made to clearly document 
the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports.


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eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient 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, patient-reported outcomes, 
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.
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 in Section 7.5.
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.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local Health Authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. No records may be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
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).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms or pregnant partner form, if applicable) will be provided to each site. If applicable, 
it will be provided in a certified translation of the local language. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms 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 patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient 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 patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for Health Authority submission purposes.


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Patients 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 patient 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 patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
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 patient 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 (see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local Health Authority and IRB/EC. 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.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study 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 patient, 
unless permitted or required by law.


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Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
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).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the Investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
Roche shall also submit a Development Safety Update Report (DSUR) once a year to 
the IEC and CAs according to local regulatory requirements and timelines of each 
country participating in the study.
It is the understanding of the Sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an Institutional Review Board (IRB). This board must operate in accordance with the 
current Federal Regulations. The Sponsor will be sent a letter or certificate of approval 
prior to initiation of the study, and also whenever subsequent amendments 
/modifications are made to the protocol. Roche shall also submit an IND Annual Report 
to FDA according to local regulatory requirements and timelines.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ 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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9.3
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for the 
study management, data management, statistical analysis and medical writing for the 
clinical study report.
The Sponsor is also responsible for managing CROs, the IxRS vendor and central 
laboratories used in the study.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
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 
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.
9.5
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.
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.


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10.
REFERENCES
Bornkamp B, Pinheiro J, Bretz F. Planning and Analyzing Dose Finding Experiments. 
2016. Version 0.9-15. 
(https://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf)
Committee for Medicinal Products for Human Use (CHMP). Assessment Report: 
Kynamro Solution for injection 189 mg. European Medicines Agency (EMA) 2013.
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events. Version 2, November 2014.(http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8)
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B. J Hepatol. 2009;50:227-242.
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–185.
 
 
Investigator’s Brochure PEG-Interferon.
Investigator’s Brochure RO7062931.
Kramvis A, Kew M, François G, Hepatitis B virus genotypes. Vaccine. 2005;23(19):2409-
23.
Lucifora J, Xia Y, Reisinger F. Specific and non-hepatotoxic degradation of nuclear 
hepatitis B virus cccDNA. Science. 2014; 343(6176):1221-1228.
 
 
Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood 
transfusion. N Engl J Med. 1966; 274(9): 473-81.
U.S. Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). Chronic Hepatitis B Virus Infection: Developing 
Drugs for Treatment. Guidance for Industry. Draft Guidance. November 2018. 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM624695.pdf)


RO7062931—F. Hoffmann-La Roche Ltd
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WHO Fact Sheet N°204, updated July 2016.
(http://www.who.int/mediacentre/factsheets/fs204/en/index.html)
 




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Appendix 1
Schedule of Assessments – Part 1, SAD, Main Table (cont.)
a)
Blood sample for PK and safety lab assessment will be collected in case of a SAE or at times of early 
termination.
b)
Blood beta-human chorionic gonadotropin (β-HCG) for pregnancy test at screening, urine on all other 
occasions.
c)
FSH only for females and to confirm post-menopausal status.
d)
Pre-dose.
e)
If necessary, subjects may be asked to return for additional follow-up visits.
f)
ADA samples will be stored and will only be analyzed in case an immune driven AE/AE suggestive of 
immunological involvement occurs, or in case of an atypical PK result.
g)
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled 
sample will be collected and analyzed.
h)
Complete physical examination is required at Screening and Day 1. At all other visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed at the discretion of 
the Investigator.
i)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If 
the sample is not collected at the scheduled time-point, it can be collected at any other time-point. Only 
one sample will be collected per patient.
j)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an 
unscheduled sample will be collected and analyzed.
k)
Urine collection periods [0-4], [4-8], [8-12] and [12-24] hours post-dose.








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Appendix 3
Schedule of Assessments – Part 2a, PoM (2 Doses Q1M), Main Table (cont.)
i)
ADA samples will be stored and will only be analyzed in case an auto-immune driven AE/AE suggestive of auto-immunological involvement occurs or in 
case of an atypical PK result.
j)
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and analyzed.
k)
Complete physical examination is required at screening and Day 1. At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled 
time-point, it can be collected at any other time-point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
* Keep left over sample for patients participating in the RBR program.








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Appendix 5
Schedule of Assessments – Part 2b, PoM (3 Doses Q2W), Main Table (cont.)
i)
ADA samples will be stored and will only be analyzed in case an auto-immune driven AE/AE suggestive of auto-immunological involvement occurs or 
in case of an atypical PK result.
j)
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and analyzed.
k)
Complete physical examination is required at screening and Day 1. At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled 
time-point, it can be collected at any other time-point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
* Keep left-over sample for patients participating in the RBR program.








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Appendix 7
Schedule of Assessments – Part 2b, PoM (4 Doses QW), Main Table (cont.)
a)
For those patients who do not have a liver biopsy, Fibroscan® or equivalent test within past 6 months from Screening.
b)
Pre-dose.
c)
Optional overnight stay in the clinic: On Day -1, Day 1 and Day 22 patients 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.
d)
Blood sample for PK and safety lab assessment will be collected at the event of SAE.
e)
Discontinuation visit: in case of early termination, a patient should be called for this visit and assessments should be performed as listed.
f)
Blood beta-human chorionic gonadotropin (ß-HCG) for pregnancy test at Screening, urine on all other occasions.
g)
FSH only for females and to confirm post-menopausal status.
h)
If necessary, subjects may be asked to return for additional follow-up visits.
i)
ADA samples will be stored and will only be analyzed in case an immune driven AE/AE suggestive of immunological, anti-drug, involvement occurs or in 
case of an atypical PK result.
j)
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and analyzed.
k)
Complete physical examination, is required at screening and Day -1. At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled time-
point, it can be collected at any other time-point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
* Keep left over sample for patients participating in the RBR program.








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Appendix 9
Schedule of Assessments – Part 2b, PoM (5 Doses QW), Main Table (cont.)
a)
For those patients who do not have a liver biopsy, Fibroscan® or equivalent test within the past 6 months from Screening.
b)
Pre-dose.
c)
Optional overnight stay in the clinic: On Day -1 and Day 1 as well as on Day 29 patients 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.
d)
Blood sample for RO7062931 PK and safety lab assessment will also be collected in the event of SAE.
e)
Discontinuation visit: in case of early termination, a patient should be called for this visit and assessments should be performed as listed.
f)
Blood beta-human chorionic gonadotropin (-HCG) for pregnancy test at screening, urine on all other occasions.
g)
FSH only for females and to confirm post-menopausal status.
h)
If necessary, the patients may be asked to return for additional follow-up visits.
i)
ADA samples will be stored and will only be analyzed in case an auto-immune driven AE/AE suggestive of auto-immunological involvement occurs or in 
case of an atypical PK result.
j)
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and analyzed.
k)
Complete physical examination, is required at screening and Day 1. At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled 
time-point, it can be collected at any other time-point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
* Keep left over sample for patients participating in the RBR program.


RO7062931—F. Hoffmann-La Roche Ltd
166/Protocol BP39405, Version 4
Appendix 10
Schedule of Assessments – Part 2b, PoM (5 Doses QW), Detailed Table
a) One sample to be taken at any point between 2-4 hours post-dose.
b) Urine collection periods [0-4] and [4-8] hours post-dose.
Period
Day
Scheduled Time (h)
Vital Signs ECG-12 lead Inflammatory 
Markers
Autoantibodies ADA Urine Kidney 
Biomarkers
Blood Liver 
Biomarker
PK Blood 
Sample
Urine PK 
Sample
b NUC PK 
Sample
HBsAg 
Quantitative
HBsAg, HBeAg Qualitative, 
HBcAg  HBsAg/Anti-HBs 
Complex  Anti 
HBe/AntiHBs/Anti HBc
HBV DNA, HBV TNA, 
Viral Resistance 
Monitoring
Screening
D-56 to D-2
x
x
x
x
x
Day -1
x
x
x
x
Predose
x
x
x
x
x
x
x
x
x
x
0
x
0.5
x
1
x
x
x
2
x
x
a
3
x
4
x
x
x
x
6
x
8
x
x
x
x
Day 2
24
x
x
x
x
x
x
x
Predose
x
x
x
x
x
x
x
x
x
2
x
x
x
Predose
x
x
x
x
x
x
x
x
x
x
x
2
x
x
x
Predose
x
x
x
x
x
x
x
x
x
2
x
x
x
Predose
x
x
x
x
x
x
x
x
x
x
x
x
0.5
x
1
x
x
x
2
x
x
a
4
x
x
x
x
6
x
8
x
x
x
Day 30
24
x
x
x
x
x
Discontinuation
x
x
x
x
x
x
x
x
Day 36
x
x
x
x
x
Day 43
x
x
x
x
x
x
Day 50
x
x
x
Day 57
x
x
x
x
x
x
x
x
x
x
Day 85
x
x
x
x
x
x
x
x
x
x
Day 113
x
x
x
x
x
x
x
x
x
x
Follow Up Visit
Period 1
Day 1
Day 8
Day 15
Day 22
Day 29


RO7062931—F. Hoffmann-La Roche Ltd
167/Protocol BP39405, Version 4
Appendix 11
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Main Table
Period
Discont-
inuatione
Follow Up 
Visit
Follow Up 
Visit
Follow  Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow  Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visith
Day
D-28 to D-4
Day -7 to -
4
Day 1
w eek 2
week 4
week 8
w eek 12
week 13
week 18
week 24
week 25
week 26
week 28
week 30
week 32
week 34
week 36
w eek 40
week 44
week 48
notime
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Fibroscan®a
x
Physical Examinationk
x
x
x
x
Vital Signsi
x
x
x
x
x
x
x
x
ECG-12 lead
x
x
x
x
Hematologyd
x
xb
xb
xb
xb
xb
xb
x
x
x
x
Blood Chemistryd
x
x
b
x
b
x
b
x
b
x
b
x
b
x
x
x
x
Urinalysisd
x
xb
xb
xb
xb
xb
xb
x
x
x
x
TSH
x
Viral Serologyn
x
Coagulationd
x
x
b
x
b
x
b
x
b
x
b
x
b
x
x
x
x
Inflammatory Markersj
x
x
x
x
x
x
x
x
Autoantibodies (screening)o
x
Autoantibodies (monitoring)m
xb
xb
xb
xb
xb
x
x
ADA
x
b
x
b
x
b
x
b
x
b
x
b
x
x
Alpha fetoprotein
x
RBR DNA
x
b
Pregnancy Testf
x
x
x
Screening
Treatment Period


RO7062931—F. Hoffmann-La Roche Ltd
168/Protocol BP39405, Version 4
Appendix 11
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Main Table (cont.)
Period
Discont-
inuatione
Follow Up 
Visit
Follow  Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visith
Day
D-28 to D-4
Day -7 to -
4
Day 1
week 2
w eek 4
week 8
week 12
week 13
week 18
week 24
week 25
week 26
week 28
week 30
week 32
week 34
week 36
week 40
week 44
week 48
notime
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
Assessments
FSHg
x
Substance Use
x
Medicationsc
PK Blood Sampleq
7
x
2
2
7
x
2
7
x
x
x
x
x
Urine PK Sampler
2
2
2
NUC PKs
2
HBsAg Quantitative
x
xb
xb
xb
xb
xb
xb
xb
xb
x
x
x
x
x
x
x
x
x
x
x
HBsAg, HBeAg Qualitative; 
HBsAg/Anti-HBs Complex; Anti 
Hbe; AntiHBs
x
x
b
x
b
x
b
x
b
x
b
x
b
x
x
x
x
x
x
x
x
Viral Genotypes
xb
,
sequencing
x
xb
xb
xb
xb
xb
xb
x
x
x
x
x
HBV RNA,  HBcrAg
xb
xb
xb
xb
xb
xb
x
x
x
x
x
Clinical Genotyping
x
l
Ambulatory Visit
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomisation
x
Adverse Events
x
x
x
x
x
x
x
x
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
x
x
x
x
x
x
x
x
Screening
Treatment Period
x


RO7062931—F. Hoffmann-La Roche Ltd
169/Protocol BP39405, Version 4
Appendix 11
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Main Table (cont.)
a)
For those patients who do not have a liver biopsy, Fibroscan® or equivalent test within the past 6 months from Screening.
b)
Pre‑dose.
c)
Daily administration of NUC and weekly clinic SC administration of RO7062931 
d)
Blood sample for RO7062931 PK and safety lab assessment will also be collected in the event of an SAE.
e)
Discontinuation visit: in case of early termination, a patient should be called for this visit and assessments should be performed as listed.
f)
Blood beta‑human chorionic gonadotropin (‑HCG) for pregnancy test at screening, other occasions, at any time a secondary amenorrhea of more than 1 week occurs.
g)
FSH only for females and to confirm post‑menopausal status.
h)
If necessary, the patients may be asked to return for additional follow-up visits.
i)
Body weight will be measured at each visit for dosing
j)
Baseline sample will be assessed and in case of an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and 
analyzed along with follow-up time-points.
k)
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.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled time‑point, it can be collected 
at any other time‑point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
n)
HAV, HCV, HDV, HEV, and HIV.
o)
ANA, AMA, ASMA, a-TPO, anti-thyroglobulin, anti-platelet
 
q)
Serial PK samples will be taken at pre-dose and 0.5, 1, 2, 4, 6 and 8 hours post-dose on Day 1 of Weeks 1, 12, 24, and 48. 
A Day 2 PK sample (24 hour time point) will be collected in Weeks 1, 12, 24, and 48. 
A pre-dose sample will be collected in Weeks 2, 13, and 25 representing 168 hours post the previous dose in Weeks 1, 12, and 24, respectively. An additional sample will be 
collected in Week 49 at 168 hours post the 48 week dose. 
Sparse PK sampling at pre-dose and within a range of 2-4 hours post-dose will be made on Day 1 of Weeks 4, 8, 18, 30, and 36.
One PK sample is required on the follow up visits in Weeks 50, 52, and 54, and one PK sample is required upon discontinuation. 


RO7062931—F. Hoffmann-La Roche Ltd
170/Protocol BP39405, Version 4
Appendix 11
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Main Table (cont.)
r)
All voided urine will be collected in two pools from 0-4 hours and 4-8 hours post dose on Day 1 of Weeks 1, 12 and 24.
s)
PK samples for NUC analysis on Day 1 of Week 1 pre- NUC dose and 2-4 hours post NUC dose. One sample collected if DNA rebound is detected. 
 
 
 


RO7062931—F. Hoffmann-La Roche Ltd
171/Protocol BP39405, Version 4
Appendix 12
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Detailed Table
Period
Week 
Day
Scheduled Time (h)
PK Blood Samplea
Urine PK Sampleb
NUC PK Samplec
Screening
-7 to -4
Predose
x
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
2
7
Predose
x
Predose
x
2
4
Predose
x
2
4
Predose
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
13
7
Predose
x
Predose
x
2
4
Predose
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
25
7
168
x
Follow up
26
1
NA
x
Follow up
28
1
NA
x
Follow up
30
1
NA
x
Discontinuation
x
DNA Rebound
x
1
1
1
1
1
1
Treatment Period
1
4
8
12
18
24
x
x
x
x
x
x
x
x
x
x


RO7062931—F. Hoffmann-La Roche Ltd
172/Protocol BP39405, Version 4
Appendix 12
Schedule of Assessments – Part 2c, QW Doses for 24 Weeks, Detailed Table (cont.)
a)
Serial PK samples will be taken at pre-dose and 0.5, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Weeks 1, 12 and 24.
A day 2 PK sample (24-hour time point) will be collected in Weeks 1, 12, and 24.
A pre-dose sample will be collected in Weeks 2 and 13, representing 168 hours post the previous dose in Weeks 1 and 12, respectively.  An additional sample will be collected 
in week 25 at 168 hours post the 24-week dose.
Sparse PK sampling at pre-dose and within a range of 2-4 hours post dose will be made on day 1 of Weeks 4, 8, and 18.
One PK sample is required on the follow up visits in Weeks 26, 28 and 30 and upon discontinuation.
b)
All voided urine will be collected in two pools from 0-4 hours and 4-8 hours post dose on day 1 of Weeks 1, 12 and 24.
c)
PK samples for NUC analysis on Day 1 of Week 1 pre-NUC dose and 2-4 hours post NUC dose. One sample will be collected if DNA rebound is detected.
 
 
 


RO7062931—F. Hoffmann-La Roche Ltd
173/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table
Period
Day
D-28 to D-4
Day -7 to -
4
Day 1
week 2
week 4
week 8
week 12
week 13
week 18
week 24
week 25
week 30
Week 36
Week 42
week 48
week 49
notime
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Fibroscan®a
x
Physical Examinationk
x
x
Vital Signsi
x
x
x
x
x
x
ECG-12 lead
x
x
Hematologyd
x
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
Blood Chemistryd
x
xb
xb
xb
xb
xb
xb
xb
xb
xb
xb
Urinalysisd
x
xb
xb
xb
xb
xb
xb
xb
xb
xb
xb
TSH
x
Viral Serologyn
x
Coagulationd
x
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
Inflammatory Markersj
x
x
x
x
x
x
x
Autoantibodies (screening)o
x
Autoantibodies (monitoring)m
x
b
x
b
x
b
x
b
x
b
x
b
ADA
xb
xb
xb
xb
xb
xb
xb
xb
xb
xb
Alpha fetoprotein
x
RBR DNA
xb
Pregnancy Testf
x
Screening
Treatment Period


RO7062931—F. Hoffmann-La Roche Ltd
174/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table (cont.)
Period
Discont-
inuatione
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visith
Day
week 50
week 52
week 54
week 56
week 58 
week 60
week 64
week 68
week 72
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
Assessments
Informed Consent
Eligibility
Demography
Medical History
Fibroscan®a
Physical Examinationk
x
x
Vital Signsi
x
x
ECG-12 lead
x
x
Hematologyd
x
x
x
x
Blood Chemistryd
x
x
x
x
Urinalysisd
x
x
x
x
TSH
Viral Serologyn
Coagulationd
x
x
x
x
Inflammatory Markersj
x
x
Autoantibodies (screening)o
Autoantibodies (monitoring)m
x
x
ADA
x
x
Alpha fetoprotein
RBR DNA
Urine Kidney Biomarkersp
x
x
Pregnancy Testf
x
x


RO7062931—F. Hoffmann-La Roche Ltd
175/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table (cont.)
Period
Day
D-28 to D-4
Day -7 to -
4
Day 1
week 2
week 4
week 8
week 12
week 13
week 18
week 24
week 25
week 30
Week 36
Week 42
week 48
week 49
notime
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Assessments
FSHg
x
Substance Use
x
Medicationsc
PK Blood Sampleq
7
x
2
2
7
x
2
7
x
2
2
7
x
Urine PK Sampler
2
2
2
2
2
NUC PKs
2
HBsAg Quantitative
x
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
b
x
HBsAg, HBeAg Qualitative; 
HBsAg/Anti-HBs Complex; Anti 
Hbe; AntiHBs
x
xb
xb
xb
xb
xb
xb
xb
Viral Genotypes
xb
HBV DNA, Viral Resistance 
sequencing
x
xb
xb
xb
xb
xb
xb
xb
HBV RNA,  HBcrAg
xb
xb
xb
xb
xb
xb
xb
Clinical Genotyping
x
l
Ambulatory Visit
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomisation
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Screening
Treatment Period
x


RO7062931—F. Hoffmann-La Roche Ltd
176/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table (cont.)
Period
Discont-
inuatione
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visit
Follow Up 
Visith
Day
week 50
week 52
week 54
week 56
week 58 
week 60
week 64
week 68
week 72
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
Assessments
FSHg
Substance Use
Medicationsc
PK Blood Sampleq
x
x
x
x
Urine PK Sampler
NUC PKs
HBsAg Quantitative
x
x
x
x
x
x
x
x
x
x
HBsAg, HBeAg Qualitative; 
HBsAg/Anti-HBs Complex; Anti 
Hbe; AntiHBs
x
x
x
x
x
x
x
x
Viral Genotypes
HBV DNA, Viral Resistance 
sequencing
x
x
x
x
x
HBV RNA,  HBcrAg
x
x
x
x
x
Clinical Genotyping
Ambulatory Visit
x
x
x
x
x
x
x
x
x
x
Randomisation
Adverse Events
x
x
x
x
x
x
x
x
x
x
Previous and Concomitant 
Treatments
x
x
x
x
x
x
x
x
x
x


RO7062931—F. Hoffmann-La Roche Ltd
177/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table (cont.)
a)
For those patients who do not have a liver biopsy, Fibroscan® or equivalent test within the past 6 months from Screening.
b)
Pre‑dose.
c)
Daily administration of NUC and weekly clinic SC administration of RO7062931 or RO7062931 and PEG-IFN
d)
Blood sample for RO7062931 PK and safety laboratory assessment will also be collected in the event of an SAE.
e)
Discontinuation visit: in case of early termination, a patient should be called for this visit and assessments should be performed as listed.
f)
Blood beta‑human chorionic gonadotropin (‑HCG) for pregnancy test at screening, other occasions, at any time a secondary amenorrhea of more than 1 week occurs.
g)
FSH only for females and to confirm post‑menopausal status.
h)
If necessary, the patients may be asked to return for additional follow-up visits.
i)
Body weight will be measured at each visit for dosing
j)
Baseline sample will be assessed and in case of an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and 
analyzed along with follow-up time-points.
k)
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.
l)
One single whole blood sample to be collected for genetic analysis at any time after randomization. If the sample is not collected at the scheduled time‑point, it can be collected 
at any other time‑point. Only one sample will be collected per patient.
m)
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analyzed.
n)
HAV, HCV, HDV, HEV, and HIV.
o)
ANA, AMA, ASMA, a-TPO, anti-thyroglobulin, anti-platelet.
 
q)
Serial PK samples will be taken at pre-dose and 0.5, 1, 2, 4, 6 and 8 hours post-dose on Day 1 of Weeks 1, 12, 24, and 48. 
A Day 2 PK sample (24 hour time point) will be collected in Weeks 1, 12, 24, and 48. 
A pre-dose sample will be collected in Weeks 2, 13, and 25 representing 168 hours post the previous dose in Weeks 1, 12, and 24, respectively. An additional sample will be 
collected in Week 49 at 168 hours post the 48 week dose. 
Sparse PK sampling at pre-dose and within a range of 2-4 hours post-dose will be made on Day 1 of Weeks 4, 8, 18, 30, and 36.
One PK sample is required on the follow up visits in Weeks 50, 52, and 54, and one PK sample is required upon discontinuation. 


RO7062931—F. Hoffmann-La Roche Ltd
178/Protocol BP39405, Version 4
Appendix 13
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Main Table (cont.)
r)
All voided urine will be collected in two pools from 0-4 hours and 4-8 hours post-dose on Day 1 of Weeks 1, 12, 24, and 48.
s)
PK samples for NUC analysis on Day 1 of Week 1 pre-NUC dose and 2-4 hours post-NUC dose. One sample collected if DNA rebound is detected. 
 
 
*
Keep all left over sample for patients participating in the RBR program.


RO7062931—F. Hoffmann-La Roche Ltd
179/Protocol BP39405, Version 4
Appendix 14
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Detailed
Table
Period
Week 
Day
Scheduled Time (h)
PK Blood Samplea
Urine PK Sampleb
NUC PK Samplec
Screening
-7 to -4
Predose
x
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
2
7
Predose
x
Predose
x
2
4
Predose
x
2
4
Predose
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
13
7
Predose
x
Predose
x
2
4
Predose
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
25
1
Predose
x
Predose
x
2
4
Predose
x
2
4
Predose
x
0.5
x
1
x
2
x
4
x
6
x
8
x
2
24
x
49
7
168
x
Follow up
50
1
NA
x
Follow up
52
1
NA
x
Follow up
54
1
NA
x
Discontinuation
x
DNA Rebound
x
1
1
1
1
1
1
1
x
x
x
x
Treatment Period
1
4
8
12
18
24
30
36
48
1
1
x
x
x
x
x
x
x
x
x
x


RO7062931—F. Hoffmann-La Roche Ltd
180/Protocol BP39405, Version 4
Appendix 14
Schedule of Assessments – Part 2c, QW Doses for 48 Weeks, Detailed
Table (cont.)
a)
Serial PK samples will be taken at pre-dose and 0.5, 1, 2, 4, 6 and 8 hours post-dose on Day 1 of Weeks 1, 12, 24, 
and 48.
A Day 2 PK sample (24-hour time point) will be collected in Weeks 1, 12, 24, and 48.
A pre-dose sample will be collected in Weeks 2, 13, and 25 representing 168 hours post the previous dose in 
Weeks 1, 12, and 24 respectively. An additional sample will be collected in Week 49 at 168 hours post the 48 
week dose.
Sparse PK sampling at pre-dose and within a range of 2-4 hours post-dose will be made on Day 1 of Weeks 4, 8, 
18, 30, and 36.
One PK sample is required on the follow up visits in Weeks 50, 52, and 54, and upon discontinuation.
b)
All voided urine will be collected in two pools from 0-4 hours and 4-8 hours post-dose on Day 1 of Weeks 1, 12, 
24, and 48.
c)
PK samples for NUC analysis on Day 1 of Week 1 pre-NUC dose and 2-4 hours post-NUC dose. One sample 
collected if DNA rebound is detected.
  
 
 
 


RO7062931—F. Hoffmann-La Roche Ltd
181/Protocol BP39405, Version 4
Appendix 15
Alcohol Unit Calculation - Examples
From Australian Department of Health (Population Health Division)
http://www.alcohol.gov.au/internet/alcohol/publishing.nsf/Content/standard


RO7062931—F. Hoffmann-La Roche Ltd
182/Protocol BP39405, Version 4
Appendix 15
Alcohol Unit Calculation - Examples (cont.)


RO7062931—F. Hoffmann-La Roche Ltd
183/Protocol BP39405, Version 4
Appendix 16
Child-Pugh Classification of Severity of Liver Disease
Points Scored for Increasing Abnormality
Clinical and Biochemical Measurements
1
2
3
Encephalopathy (grade)*
None
1 and 2
3 and 4
Ascites
Absent
Slight
Moderate
Bilirubin (mg per 100 mL)
1 - 2
2 - 3
> 3
Albumin (g per 100 mL)
3.5
2.8 - 3.5
< 2.8
Prothrombin time (sec. prolonged)
1 - 4
4 - 6
> 6
* According to grading of Trey, Burns and Saunders (1966)
1, 2 or 3 points are scored for increasing abnormality of each of the 5 parameters 
measured.
Grade A: 5 or 6
Grade B: 7 to 9
Grade C: 10 to 15


RO7062931—F. Hoffmann-La Roche Ltd
184/Protocol BP39405, Version 4
Appendix 17
Toxicity Table for Grading Injection Reactions
Parameter
Grade 1
Grade 2
Grade 3
Pain 
Mild 
tenderness at 
injection site
Moderate pain 
without 
limitation of 
usual 
activities
Severe pain 
requiring 
prescription non 
topical 
analgesics or 
limiting usual 
activities
Erythema 
average 
diameter 
(mm) of skin 
redness at 
the site of 
injection
Present but < 
25mm
≥ 25 mm but < 
50 mm
≥ 50 mm
Swelling, 
(same 
grading as 
erythema)
Present but < 
25mm
≥ 25 mm but < 
50 mm
≥ 50 mm 
Pruritus
Mild, not 
requiring any 
treatment
Requiring 
topical 
treatment
Refractory to 
topical 
treatment, OR 
requiring oral or 
parenteral 
treatment