Conditions: Hepatitis B, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 192
Healthy volunteers: yes

Brief summary:
This study is a multicenter, three-part study. Parts 1 and 2 are randomized, investigator- and participant-blinded, placebo-control, single-ascending dose (SAD) and multiple-ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7049389 following oral administration in healthy volunteers and chronic HBV infected participants. Part 3 is a non-randomized, non-controlled, open-label part to assess the efficacy and safety of RO7049389 when administered in combination with standard-of-care therapies for up to 48 weeks in nucleos(t)ide (NUC)-suppressed and treatment-naive chronic hepatitis B (CHB) participants.

Detailed description:

Arms:
arm 1: In Part 1a, participants will receive a single oral dose of placebo matching to RO7049389 film coated tablet on Day 1. In Part 1b, minimum 8 participants from Part 1a will be selected and 2 of whom will receive another single dose of placebo matching to RO7049389 on Day 16 after eating the standard United States - Food and Drug Administration (US FDA)-recommended high-fat and high-calorie breakfast. arm 2: In Part 1a, participants will receive a single oral dose of RO7049389 film coated tablet on Day 1 in dose-escalation cohorts with a starting dose of 150 milligrams (mg). The doses for subsequent cohorts will be defined by an adaptive approach based on the safety and PK data in previously-dosed healthy volunteers. In Part 1b, minimum 8 participants from Part 1a will be selected and 6 of whom will receive another single dose of RO7049389 on Day 16 after eating the standard US FDA-recommended high-fat and high-calorie breakfast. arm 3: Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 13 (either once a day \[QD\] or twice a day \[BID\]) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 micrograms \[mcg\]) on Day -1 and Day 14. arm 4: Participants will receive RO7049389 film coated tablet from Days 1 to 13 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 mcg) on Day -1 and Day 14. arm 5: Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 27 (either QD or BID) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 28. arm 6: Participants will receive RO7049389 film coated tablet from Days 1 to 27 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 28. arm 7: Participants will receive RO7049389 on top of a NUC for 48 weeks at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines. arm 8: Participants will receive RO7049389 for 4 weeks, followed by RO7049389 with an added NUC for 44 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines. arm 9: Participants will receive RO7049389 + NUC + Pegylated-Interferon (Peg-IFN) for 48 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC and Peg-IFN therapy will be administered per local label or guidelines.

Interventions: intervention 1: Midazolam intervention 2: Placebo intervention 3: RO7049389
Intervention descriptions: intervention 1: Single dose of 100 mcg midazolam solution will be administered orally, before (Day -1) and after (Day 14) the treatment with RO7049389 or matching placebo intervention 2: Placebo matching to RO7049389 will be administered as per schedule described in individual arm. intervention 3: RO7049389 will be administered as per schedule described in individual arm.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Safety,Tolerability, Pharmacokinetics And Efficacy Study Of Ro7049389 In: 
(1) Single- (With Or Without Food) And Multiple- (With Midazolam) Ascending 
Doses In Healthy Volunteers; (2) Patients Chronically Infected With Hepatitis 
B Virus (3) Patients With Chronic Hepatitis B 
NCT Number: NCT02952924 
Document Date: Protocol version 6: 21-May-2020 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F.Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7049389 —F. Hoffmann-La Roche Ltd
Protocol YP39364, Version 6
PROTOCOL
TITLE:
A SAFETY, TOLERABILITY, PHARMACOKINETICS 
AND EFFICACY STUDY OF RO7049389 IN: (1) 
SINGLE- (WITH OR WITHOUT FOOD) AND 
MULTIPLE- (WITH MIDAZOLAM) ASCENDING 
DOSES IN HEALTHY VOLUNTEERS; (2) PATIENTS 
CHRONICALLY INFECTED WITH HEPATITIS B 
VIRUS (3) PATIENTS WITH CHRONIC HEPATITIS B
PROTOCOL NUMBER:
YP39364
VERSION:
6
TEST PRODUCT:
RO7049389
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
DATE AMENDED:
Version 1: 23 September 2016
Version 2: 12 January 2017
Version 3: 16 August 2017
Version 4: 02 January 2019
Version 5: 21 June 2019
Version 6: See electronic date stamp below
 
21-May-2020 02:04:25
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7049389 —F. Hoffmann-La Roche Ltd
2/Protocol YP39364, Version 6
PROTOCOL ACCEPTANCE FORM
TITLE:
A SAFETY, TOLERABILITY, PHARMACOKINETICS 
AND EFFICACY STUDY OF RO7049389 IN: (1) 
SINGLE- (WITH OR WITHOUT FOOD) AND 
MULTIPLE- (WITH MIDAZOLAM) ASCENDING 
DOSES IN HEALTHY VOLUNTEERS; (2) PATIENTS 
CHRONICALLY INFECTED WITH HEPATITIS B 
VIRUS (3) PATIENTS WITH CHRONIC HEPATITIS B
PROTOCOL NUMBER:
YP39364
VERSION NUMBER:
6
TEST PRODUCT:
RO7049389
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.


RO7049389 —F. Hoffmann-La Roche Ltd
3/Protocol YP39364, Version 6
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE
Protocol YP39364 Version 5 has been amended to incorporate the following changes in 
Part 3: 

For patients not meeting the NUC Stopping Criteria (HBsAg 100 IU/mL and HBV 
DNA 20 IU/mL) at end of study treatment, the frequency of post-treatment 
follow-up visits has been reduced to every 8 weeks (Section 3.1.1.5., Table 5)
because NUC therapy is expected to be continued in these patients, which poses no 
need for close monitoring every 2 or 4 weeks.
As patients who do not meet NUC Stopping Criteria will continue with NUC therapy 
during follow-up, NUC will be provided or reimbursed by the Sponsor until 24 weeks 
post-treatment.

The exclusion criterion 1 of Part 3 (Section 4.1.3.3.) has been adjusted to remove the 
text on male subjects with partners who are pregnant because the risk of drug 
exposure to a pregnant woman whose male partner is enrolled in this study became 
extremely low and negligible when the male study participant uses contraceptive 
measures as required by the inclusion criterion 9 (Section 4.1.2.3).

The prohibited therapy and prohibited food sections (Sections 4.4.2. and 4.4.3.) have 
been updated for better clarity, and the examples of prohibited medicines have been 
listed in Appendix 16.

It has been clarified in Section 3.1.1. (including Figure 2) and Sections 4.1. and 6.1. 
that Cohort C can be expanded to 30 patients based on emerging efficacy/safety 
data. 

Retreatment criteria for dose interruption due to hepatitis flares have been modified 
to take the baseline alanine transaminase (ALT) level and the decline of viral 
markers into consideration (Section 5.2.1.2.).

Triplicate 12-lead ECG measurements have been changed to a single interpretable 
measurement per time-point (Section 4.5.1.4. and Appendix 7).

Sample collection time points have been updated from HCV Ab or HCV RNA to 
include both HCV Ab and HCV RNA samplings at screening for eligibility assessment 
(Section 4.5.1.5. and Appendix 7).

Collection time points for the following samples: HBV viral genotypes based on HBV 
RNA, HBV viral genotypes based on HBV DNA, viral resistance monitoring, HBV 
RNA, HBcrAg, and anti-HBc have been updated to Day 1 instead of during 
screening as these are not needed for the eligibility assessment (Appendix 7).


RO7049389 —F. Hoffmann-La Roche Ltd
4/Protocol YP39364, Version 6

Optional hospitalization for the Week 24 intensive PK has been included (Appendix 
7).

Guidance on how the study visits may be conducted to ensure subjects’ safety while 
continuing to participate in the study during COVID-19, or similar epidemic, has been 
added as Appendix 17.
Additional minor changes have been made to improve clarity and consistency, including 
update of background sections of the protocol in line with recent changes to the 
Investigator Brochure.
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RO7049389 —F. Hoffmann-La Roche Ltd
5/Protocol YP39364, Version 6
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL AMENDMENT, VERSION 6: RATIONALE...................................... 3
PROTOCOL SYNOPSIS .................................................................................... 13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 31
1.
BACKGROUND AND RATIONALE ............................................................ 34
1.1
Background on Hepatitis B Virus Infection............................. 34
1.2
Background on RO7049389 .................................................. 35
1.2.1
Previous Non-Clinical Studies ............................................... 35
1.2.2
Previous Clinical Studies ....................................................... 38
1.2.2.1
Preliminary results of study YP39364.................................... 38
1.2.2.2
Results from Study YP39406................................................. 39
1.2.2.3
Results from Study YP40218................................................. 40
1.3
Background on Midazolam .................................................... 40
1.4
Study Rationale and Benefit–Risk Assessment..................... 40
1.4.1
Study Rationale ..................................................................... 40
1.4.2
Benefit–Risk Assessment...................................................... 42
2.
OBJECTIVES.............................................................................................. 43
2.1
Objectives for Part 1 .............................................................. 43
2.2
Objectives for Part 2 .............................................................. 43
2.3
Objectives for Part 3 .............................................................. 44
3.
STUDY DESIGN......................................................................................... 45
3.1
Description of Study .............................................................. 45
3.1.1
Overview of Study Design ..................................................... 45
3.1.1.1
Part 1a: Single-Ascending Dose (SAD) in Healthy 
Subjects................................................................................. 47
3.1.1.2
Part 1b: Food Effect in Healthy Subjects ............................... 48
3.1.1.3
Part 1c: Multiple-Ascending Dose (MAD) in 
Healthy Subjects.................................................................... 49
3.1.1.4
Part 2: Proof-of-Mechanism (POM) in Patients 
with Chronic HBV Infection.................................................... 50


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6/Protocol YP39364, Version 6
3.1.1.5
Part 3: Proof-of-Mechanism (POM) in Patients 
with Chronic Hepatitis B......................................................... 50
3.1.2
Dose-Related Decision Criteria ............................................. 52
3.1.2.1
Part 1a: SAD.......................................................................... 53
3.1.2.2
Part 1c: MAD ......................................................................... 53
3.1.2.3
Part 2: POM........................................................................... 53
3.1.2.4
Part 3: POM........................................................................... 54
3.1.3
Dose-Escalation Stopping Criteria......................................... 54
3.1.4
End of Study.......................................................................... 55
3.2
Rationale for Study Design.................................................... 55
3.2.1
Rationale for Dosage Selection ............................................. 55
3.2.1.1
Part 1a: SAD.......................................................................... 55
3.2.1.2
Part 1b: Food Effect............................................................... 56
3.2.1.3
Part 1c: MAD ......................................................................... 56
3.2.1.4
Part 2: POM........................................................................... 56
3.2.1.5
Part 3: POM........................................................................... 56
3.2.2
Rationale for Assessing Midazolam 
Pharmacokinetics .................................................................. 57
3.2.3
Rationale for Measuring 4-
Hydroxycholesterol/Cholesterol Ratio.................................... 58
3.2.4
Rationale for Study Population .............................................. 58
3.2.4.1
Part 1: SAD and MAD in Healthy Volunteers......................... 58
3.2.4.2
Part 2: Patients with Chronic HBV infection........................... 58
3.2.4.3
Part 3: Patients with Chronic Hepatitis B ............................... 59
3.2.5
Rationale for Biomarker Assessments................................... 59
3.3
Outcome Measures ............................................................... 59
3.3.1
Safety Outcome Measures .................................................... 59
3.3.2
Pharmacokinetic Outcome Measures.................................... 60
3.3.3
Viral Dynamic Response Measures....................................... 61
3.3.4
Exploratory Outcome Measures ............................................ 62
4.
MATERIALS AND METHODS .................................................................... 62
4.1
Study Population ................................................................... 62
4.1.1
Recruitment Procedures........................................................ 63


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7/Protocol YP39364, Version 6
4.1.2
Inclusion Criteria.................................................................... 63
4.1.2.1
Part 1 – Healthy Volunteers only: .......................................... 63
4.1.2.2
Part 2 – Chronic HBV-Infected Patients only:........................ 63
4.1.2.3
Part 3 – Chronic Hepatitis B Patients only:............................ 64
4.1.3
Exclusion Criteria................................................................... 66
4.1.3.1
Part 1 – Healthy Volunteers only: .......................................... 66
4.1.3.2
Part 2 – Chronic HBV-Infected Patients only:........................ 68
4.1.3.3
Part 3 - Chronic Hepatitis B Patients only:............................. 70
4.2
Method of Treatment Assignment and Blinding..................... 71
4.3
Study Treatment.................................................................... 73
4.3.1
Formulation, Packaging, and Handling.................................. 73
4.3.1.1
RO7049389 and Placebo ...................................................... 73
4.3.1.2
Midazolam (Part 1 only)......................................................... 74
4.3.1.3
SoC (NUC and Peg-IFN) ....................................................... 74
4.3.2
Dosage, Administration and Compliance............................... 74
4.3.2.1
Part 1a: SAD.......................................................................... 75
4.3.2.2
Part 1b: Food Effect............................................................... 75
4.3.2.3
Part 1c: MAD ......................................................................... 75
4.3.2.4
Part 2: POM........................................................................... 76
4.3.2.5
Part 3 of the study ................................................................. 76
4.3.3
Investigational Medicinal Product Accountability ................... 78
4.3.4
Non-Investigational Medicinal Product 
Accountability ........................................................................ 79
4.3.5
Post-Trial Access to RO7049389 .......................................... 79
4.3.6
Post-Trial Access to SoC....................................................... 79
4.4
Concomitant Therapy and Food ............................................ 79
4.4.1
Permitted Therapy................................................................. 79
4.4.1.1
Healthy Volunteers ................................................................ 79
4.4.1.2
Chronically HBV-Infected Patients in Part 2 and 
Chronic Hepatitis B Patients in Part 3.................................... 80
4.4.2
Prohibited Therapy ................................................................ 80
4.4.2.1
Healthy Volunteers ................................................................ 80
4.4.2.2
Chronic HBV-infected Patients in Part 2 and 
Chronic Hepatitis B Patients in Part 3.................................... 80


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4.4.3
Prohibited Food ..................................................................... 82
4.4.4
Dietary and Special Requirements ........................................ 82
4.5
Study Assessments ............................................................... 82
4.5.1
Description of Study Assessments ........................................ 82
4.5.1.1
Medical History and Demographic Data ................................ 83
4.5.1.2
Physical Examinations........................................................... 83
4.5.1.3
Vital Signs.............................................................................. 84
4.5.1.4
Electrocardiograms................................................................ 84
4.5.1.5
Laboratory Assessments ....................................................... 86
4.5.1.6
Liver Imaging Assessments................................................... 87
4.5.1.7
Pharmacokinetic Assessments.............................................. 87
4.5.1.8
Exploratory Assessments ...................................................... 88
4.5.1.9
HBV-Specific Viral Assessments........................................... 89
4.5.1.10
Viral Resistance Monitoring................................................... 89
4.5.1.11
Clinical Genotyping (Drug Metabolizing Enzymes 
and Transporters).................................................................. 90
4.5.1.12
Samples for Research Biosample Repository ....................... 90
4.5.2
Timing of Study Assessments ............................................... 93
4.5.2.1
Screening and Pretreatment Assessments............................ 93
4.5.2.2
Assessments During Treatment ............................................ 94
4.5.2.3
Follow-Up Assessments ........................................................ 94
4.5.2.4
Assessments at Unscheduled Visits and Early 
Termination............................................................................ 94
4.6
Healthy Volunteer/Patient, Study, and Site 
Discontinuation...................................................................... 95
4.6.1
Healthy Volunteer/Patient Discontinuation............................. 95
4.6.1.1
Discontinuation from Study Drug........................................... 95
4.6.1.2
Withdrawal from Study........................................................... 97
4.6.2
Study and Site Discontinuation.............................................. 97
5.
ASSESSMENT OF SAFETY....................................................................... 97
5.1
Safety Parameters and Definitions ........................................ 97
5.1.1
Adverse Events ..................................................................... 98
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 98


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9/Protocol YP39364, Version 6
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 99
5.2
Safety Plan ............................................................................ 99
5.2.1
Management of Specific Adverse Events .............................. 99
5.2.1.1
Potential Drug-Induced Liver Injury (DILI).............................. 99
5.2.1.2
Hepatitis flare....................................................................... 100
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 102
5.3.1
Adverse Event Reporting Period ......................................... 102
5.3.2
Eliciting Adverse Event Information..................................... 103
5.3.3
Assessment of Severity of Adverse Events ......................... 103
5.3.4
Assessment of Causality of Adverse Events ....................... 103
5.3.5
Procedures for Recording Adverse Events.......................... 104
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 104
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 104
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 104
5.3.5.4
Abnormal Laboratory Values ............................................... 105
5.3.5.5
Abnormal Vital Sign Values ................................................. 106
5.3.5.6
Abnormal Liver Tests........................................................... 106
5.3.5.7
Deaths ................................................................................. 107
5.3.5.8
Preexisting Medical Conditions............................................ 107
5.3.5.9
Lack of Efficacy or Worsening of Chronic HBV 
Infection............................................................................... 108
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 108
5.3.5.11
Overdoses ........................................................................... 109
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 109
5.4.1
Emergency Medical Contacts.............................................. 110
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 110
5.4.3
Reporting Requirements for Pregnancies............................ 110
5.4.3.1
Pregnancies in Female Patients.......................................... 110


RO7049389 —F. Hoffmann-La Roche Ltd
10/Protocol YP39364, Version 6
5.4.3.2
Pregnancies in Female Partners of Male 
Subjects............................................................................... 110
5.4.3.3
Abortions ............................................................................. 111
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 111
5.5
Follow-Up of Patients after Adverse Events ........................ 111
5.5.1
Investigator Follow-Up......................................................... 111
5.5.2
Sponsor Follow-Up .............................................................. 111
5.6
Post-Study Adverse Events................................................. 112
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 112
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 112
6.1
Determination of Sample Size ............................................. 113
6.2
Summaries of Conduct of Study.......................................... 113
6.3
Analysis Populations ........................................................... 114
6.3.1
Safety Analysis Population .................................................. 114
6.3.2
Pharmacokinetic Analysis Population.................................. 114
6.3.3
Efficacy Analysis Population................................................ 114
6.4
Summaries of Treatment Group Comparability ................... 114
6.5
Safety Analyses................................................................... 114
6.5.1
Adverse Events ................................................................... 114
6.5.2
Clinical Laboratory Test Results.......................................... 115
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................. 115
6.5.2.2
Definition of Laboratory Abnormalities................................. 115
6.5.3
Vital Signs............................................................................ 116
6.5.4
ECG Data Analysis.............................................................. 116
6.5.5
Concomitant Medications .................................................... 117
6.6
Efficacy Analyses ................................................................ 117
6.6.1
Primary Efficacy Analyses ................................................... 117
6.6.2
Secondary Efficacy Analyses .............................................. 117
6.6.3
Exploratory Efficacy Analyses ............................................. 117
6.7
Pharmacokinetic Analyses................................................... 118


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6.8
Analysis to Support Dose-Escalation Decision 
and Dose Selection ............................................................. 119
6.9
Exploratory Analyses........................................................... 120
6.10
Interim Analyses .................................................................. 121
7.
DATA COLLECTION AND MANAGEMENT ............................................. 121
7.1
Data Quality Assurance....................................................... 121
7.2
Electronic Case Report Forms............................................. 121
7.3
Source Data Documentation................................................ 122
7.4
Use of Computerized Systems ............................................ 123
7.5
Retention of Records........................................................... 123
8.
ETHICAL CONSIDERATIONS.................................................................. 123
8.1
Compliance with Laws and Regulations .............................. 123
8.2
Informed Consent................................................................ 123
8.3
Institutional Review Board or Ethics Committee.................. 124
8.4
Confidentiality...................................................................... 125
8.5
Financial Disclosure ............................................................ 125
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 125
9.1
Study Documentation .......................................................... 125
9.2
Site Inspections ................................................................... 126
9.3
Administrative Structure....................................................... 126
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 126
9.5
Protocol Amendments ......................................................... 126
10. REFERENCES ......................................................................................... 128
LIST OF TABLES
Table 1
High-level Overview of Study Procedure: Part 1a (SAD) ............ 48
Table 2
High-level Overview of Study Procedure: Part 1b (FE)............... 49
Table 3
High-level Overview of Study Procedure: Part 1c (MAD)............ 49
Table 4
High-level Overview of Study Procedure: Part 2 (POM) ............. 50
Table 5
High-level Overview of Study Procedure: Part 3 (POM) ............. 52


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12/Protocol YP39364, Version 6
Table 6
Adverse Event Severity Grading Scale (For Part 1 and Part 2)
.................................................................................................. 103
LIST OF FIGURES
Figure 1
Study Design (Parts 1 & 2).......................................................... 46
Figure 2
Study Design (Part 3).................................................................. 46
Figure 3
Probability of DLE versus Dose of RO7049389 ........................ 120
LIST OF APPENDICES
Appendix 1
Schedule of Assessments: Parts 1a (SAD) and 1b (FE) –
Main Table ................................................................................ 130
Appendix 2
Schedule of Assessments: Parts 1a (SAD) and 1b (FE) –
Detailed Table........................................................................... 132
Appendix 3
Schedule of Assessments: Part 1c (MAD) – Main Table .......... 134
Appendix 4
Schedule of Assessments: Part 1c (MAD) – Detailed Table ..... 136
Appendix 5
Schedule of Assessments: Part 2 (POM) – Main Table ............ 138
Appendix 6
Schedule of Assessments: Part 2 (POM) – Detailed Table....... 140
Appendix 7
Schedule of Assessments: Part 3 (POM) – Main Table ............ 141
Appendix 8
Schedule of Assessments: Part 3 (POM) – Detailed Table....... 145
Appendix 9
High-Fat Breakfast for the Food Effect Cohort.......................... 147
Appendix 10
Cockcroft Gault Equation for Calculation CrCl and eGFR 
Equation for eGFR.................................................................... 148
Appendix 11
Child-Pugh Classification of Severity of Liver Disease.............. 149
Appendix 12
Simulation of the Operating Characteristics of the Planned 
SAD Design (Part 1a) ............................................................... 150
Appendix 13
Correction Formulas for QTc Intervals ...................................... 156
Appendix 14
Alcohol Volume Calculation ...................................................... 157
Appendix 15
Division of AIDS (DAIDS) Table for Grading the Severity of 
Adverse Events (For Part 3 of the study) .................................. 159
Appendix 16
List of Inducers, Inhibitors and Substrates of 
Drug-Metabolizing Enzymes and Transporters......................... 160
Appendix 17
Alternative Study Visits and Study Drug (IMP and non-IMP) 
Dispensing during COVID-19 or Similar Epidemic.................... 161


RO7049389 —F. Hoffmann-La Roche Ltd
13/Protocol YP39364, Version 6
PROTOCOL SYNOPSIS
TITLE:
A SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
EFFICACY STUDY OF RO7049389 IN: (1) SINGLE- (WITH OR 
WITHOUT FOOD) AND MULTIPLE- (WITH MIDAZOLAM) 
ASCENDING DOSES IN HEALTHY VOLUNTEERS; (2) PATIENTS 
CHRONICALLY INFECTED WITH HEPATITIS B VIRUS (3) 
PATIENTS WITH CHRONIC HEPATITIS B
PROTOCOL NUMBER:
YP39364
VERSION:
6
TEST PRODUCT:
RO7049389
PHASE:
I/II
INDICATION:
HBV
SPONSOR:
F. Hoffmann-La Roche Ltd


RO7049389 —F. Hoffmann-La Roche Ltd
14/Protocol YP39364, Version 6
OBJECTIVES
Objectives for Part 1
The primary objectives of Part 1 (healthy volunteers) of this study are as follows:

To assess the safety and tolerability of single and multiple doses of RO7049389.

To characterize the pharmacokinetics (PK) of RO7049389.
The secondary objectives of Part 1 of this study are as follows:

To evaluate the effect of food on the PK of RO7049389 after a single dose administration.

To evaluate the effect of multiple oral dosing of RO7049389 on CYP3A4 activity assessed 
by the PK of a single oral micro-dose of midazolam.
The exploratory objectives of Part 1 of this study are as follows:

To screen for the presence of metabolites of RO7049389 in selected plasma and urine 
samples.

To evaluate the effect of multiple oral dosing of RO7049389 on CYP3A4 activity assessed 
by plasma 4β-hydroxycholesterol/cholesterol ratio.
Objectives for Part 2
The primary objectives of Part 2 (patients chronically infected with HBV) of this study are as 
follows:

To assess the safety and tolerability of 4 weeks of treatment with RO7049389.

To investigate the antiviral effect (quantitative HBV DNA level) of 4 weeks of treatment 
with RO7049389.
The secondary objective of Part 2 of this study is:

To investigate the plasma PK of RO7049389.
The exploratory objectives of Part 2 of this study are as follows:

To investigate the response relationship between RO7049389 exposure and HBV DNA.

To explore other viral response outcomes (e.g., quantitative HBeAg, loss of HBeAg, 
HBeAg seroconversion, quantitative HBsAg, loss of HBsAg, HBsAg seroconversion) after
4 weeks of treatment with RO7049389.

Exploratory liver biomarkers will be examined.

To investigate metabolites of RO7049389 in selected plasma samples.
Objectives for Part 3
The primary objective of Part 3 (patients with chronic hepatitis B) of this study is:

To evaluate anti viral effect (functional cure) of treatment with RO7049389 on top of 
Standard of Care (SoC).

Functional cure is defined as HBV DNA < lower limit of quantification (LLOQ, 20
IU/mL) with HBsAg loss (<0.05 IU/mL) at 24 weeks post-treatment.
The secondary objectives of Part 3 of this study are as follows:

To further characterize the efficacy profile of RO7049389 on top of SoC over time, 
including HBsAg loss, HBsAg seroconversion, quantitative HBsAg change from baseline, 
HBeAg loss, HBeAg seroconversion, quantitative HBeAg change from baseline, HBV DNA 
< LLOQ, HBV DNA change from baseline in different proof of mechanism (POM) cohorts 
of Part 3 and in subgroups of baseline HBeAg +/- patients, or of baseline high / low HBsAg 
level patients.


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
To assess other viral response outcomes (including HBV core-related antigen levels, anti-
HBc antibody, quantitative HBV RNA, etc.) over time.

To assess the ALT normalization in patients with baseline ALT elevation.

To characterize the plasma PK profiles of RO7049389 and its metabolites.

To assess the long-term safety and tolerability of RO7049389 on top of SoC (a NUC with 
or without Peg-IFN).

To assess the PK interaction between NUCs and RO7049389.

To assess HBV genotypic resistant variants associated with virologic failure.
The exploratory objectives of Part 3 of this study are as follows:

To explore other viral response outcomes (i.e., total HBsAg) over time.

To explore relationship between exposure and efficacy/safety response (e.g., HBsAg, 
HBV DNA, etc.).

To explore safety, PK, and antiviral activities of RO7049389 in different ethnic 
subpopulations (e.g., Caucasian versus Asian). 

To assess effect of treatment on liver stiffness.

To explore relationship between baseline disease characteristics (e.g., HBeAg status, viral 
load, HBV genotype based on DNA or RNA or historical data, etc.) and efficacy/safety 
response.

To explore the effect of the genetic polymorphism of CYP3A4, UGT1A3 and OATP1B on 
the PK of RO7049389 by clinical genotyping.

To explore the PK interaction among NUCs, Peg-INF and RO7049389.
STUDY DESIGN
Description of Study
Study YP39364 is a first-in-human study conducted in three parts. Parts 1 and 2 of the study 
are randomized sponsor-open, investigator-blinded, subject-blinded. Part 3 of the study is a 
non-randomized, non-controlled, open-label study. 
Part 1 of the study will evaluate safety, tolerability, and PK of RO7049389 following oral 
administration of single (Parts 1a and 1b) or multiple (Part 1c) doses in healthy volunteers. 
The effect of food on the PK of RO7049389 will be evaluated within one of the SAD cohorts 
(Part 1b). Drug interaction with micro-dose midazolam will be assessed in all MAD cohorts 
(Part 1c). There will be no midazolam dosing in SAD cohorts (Part 1a and 1b). In Part 1 of the 
study, approximately 93 healthy volunteers will be enrolled. A Bayesian adaptive approach, 
i.e., Continuous Reassessment Method (CRM) will be used, alongside scientific and clinical 
judgment, to inform decisions about the dose of RO7049389 to be given to the next cohort 
during dose-escalation, as well as to identify the maximum tolerated dose (MTD).
Part 2 of the study will evaluate the safety, tolerability, PK and PD of RO7049389 following 
oral administration in patients chronically infected with HBV. In Part 2 of the study, 
approximately 35 patients will be enrolled.
Part 3 of the study is an open label, adaptive, multi-arm trial designed to evaluate safety, 
tolerability, PK, PD, and efficacy of RO7049389 following oral administration on top of SoC (a 
NUC with/without Peg-IFN) in NUC-suppressed or treatment-naive chronic hepatitis B (CHB) 
patients. Initially, approximately 55 patients will be enrolled in the first three cohorts of Part 
3. This part of the study is designed to be adaptive based on emerging data to enable the 
increase of the sample size of any cohort, and to open additional treatment cohorts to explore 
different treatment durations, dose regimens, or different combinations.


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NUMBER OF STUDY SUBJECTS
The study may enroll up to a total of 93 healthy volunteers. Due to the adaptive nature of this 
study, the actual number of patients to be enrolled will be determined during the study:

Up to 53 healthy volunteers in Part 1a of the study. The initial cohort will be of 5 healthy 
volunteers, with up to 6 subsequent cohorts of 8 healthy volunteers.

Eight subjects in a dose-level in Part 1a will be asked to return for Part 1b of the study.

Up to 40 healthy volunteers in Part 1c of the study. There will be up to 5 cohorts with 
8 healthy volunteers in each.

Up to 35 patients in Part 2. There will be up to 5 cohorts with 7 patients in each.

Initially, approximately 55 patients will be enrolled in the first 3 cohorts in Part 3 with 
approximately 30 patients in POM Cohort A, 10 patients in POM Cohort B, and 15 
patients in POM Cohort C. Based on emerging efficacy/safety data, the sample size in
Cohort C can be increased to approximately 30 patients. In addition, additional treatment 
cohorts may be opened to explore different treatment durations, dose regimens, or 
different combinations. 
Healthy volunteers or patients who drop out of the study for non-safety reasons may be 
replaced to ensure sufficient data to characterize the safety and PK profile, and to make a 
dose-escalation decision. Healthy volunteers or patients who withdraw from the study due to 
poor tolerability or due to study drug-related adverse events will not be replaced.
TARGET POPULATION
Part 1: SAD, Food Effect, and MAD in Healthy Volunteers
The study population consists of healthy male and female subjects, aged 18 to 60 years, 
inclusive.
Part 2: Chronic HBV-infected patients
The study population consists of male and female patients chronically infected with HBV, aged 
18 to 60 years, inclusive, who are currently not on anti-HBV treatment (never treated or have 
not been on treatment within 6 months prior to randomization).
Part 3: Chronic Hepatitis B (CHB) patients
The study population consists of male and female NUC-suppressed or anti-HBV treatment-
naïve CHB patients, aged 18 to 60 years, inclusive. Both HBeAg positive and negative 
patients will be enrolled, and at least 30% of patients enrolled in each cohort will be HBeAg 
positive. In order to evaluate PK, PD, and safety in different major ethnic subgroups (e.g., 
Caucasian versus Asian) in some cohorts, the Sponsor may postpone or stop enrolment of 
certain patient subgroups according to the actual enrollment situation to achieve suitable 
balance across the groups.
INCLUSION/EXCLUSION CRITERIA
Inclusion Criteria
Healthy volunteers/patients with HBV must meet the following criteria for study entry:
Part 1 – Healthy Volunteers only:
1.
Healthy male and female subjects, 18 to 60 years of age, inclusive. Healthy status is 
defined by absence of evidence of any active or chronic disease following a detailed 
medical and surgical history, a complete physical examination including vital signs, 12-
lead ECG, hematology, blood chemistry, serology and urinalysis.


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2.
A body mass index (BMI) between 18 to 30 kg/m2 inclusive. 
3.
Female subjects must be either surgically sterile (by means of hysterectomy and/or 
bilateral oophorectomy) or post-menopausal for at least one year (defined as amenorrhea 
≥12 consecutive months without another cause, and confirmed by follicle stimulating 
hormone level >35 mIU/mL).
4.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
a.
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 28 days after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
5.
Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) in 
accordance with institutional and regulatory requirements.
Part 2 – Chronic HBV-Infected Patients only:
1.
Adult male and female patients, 18 to 60 years of age, inclusive.
2.
A BMI between 18 to 30 kg/m2 inclusive.
3.
Chronic hepatitis B infection, defined as positive test for HBsAg for more than 6 months 
prior to randomization.
4.
HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, or 2 103 IU/mL for 
HBeAg negative patients.
5.
ALT at screening ≤5 x upper limit of normal (ULN; both immune-tolerant and immune-
active patients).
6.
Screening laboratory values (hematology, chemistry [other than liver function test], 
urinalysis) obtained up to 28 days prior to first study treatment within acceptable range or 
judged to be not clinically significant by the Investigator and the Sponsor.
7.
Liver biopsy, fibroscan or equivalent test obtained within the past 6 months demonstrating 
liver disease consistent with chronic HBV infection with absence of extensive bridging 
fibrosis and absence of cirrhosis (cutoff for fibroscan is liver stiffness measurement ≤8.5 
kPa or Metavir fibrotic Stage <3, or other equivalent staging systems).
8.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
a.
Men must remain abstinent or use a condom during the treatment period and for 
at least 28 days after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 


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acceptable methods of contraception.
9.
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods that result in a 
failure rate of <1% per year during the treatment period and for at least 3 months after the 
last dose of study drug
a.
A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year 
include male sterilization, and copper intrauterine devices.
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.
10. Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) in 
accordance with institutional and regulatory requirements.
Part 3 – Chronic Hepatitis B Patients only:
1.
Adult male and female patients, 18 to 60 years of age (inclusive) at the time of signing the 
informed consent form (ICF).
2.
A BMI between 18 to 32 kg/m2 inclusive.
3.
Chronic hepatitis B infection, defined as positive test for HBsAg or HBV DNA (including 
qualitative, quantitative, and genotype testing) or positive HBeAg for more than 6 months 
prior to screening.
4.
HBsAg >250 IU/mL at screening. 
5.
For Cohorts only enrolling NUC-suppressed CHB patients (e.g., POM Cohort A), patients 
must qualify for 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.
At least one result showed HBV DNA <60 IU/mL at least 6 months prior to 
screening; and HBV DNA <20 IU/mL at screening by Roche Cobas assay.
c.
ALT ≤2 x ULN at screening and at Day -1 (can be checked by local lab result).
6.
For Cohorts only enrolling anti-HBV treatment-naïve and immune-active patients (e.g., 
POM Cohort B and Cohort C), patients must qualify for the following criteria:
a.
Previous anti-HBV treatments for <30 days in total, and did not receive any anti-
HBV treatments within 3 months prior to the first study dose.
b.
HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, 
or 2 103 IU/mL for HBeAg negative patients.
c.
ALT at screening between 1–5 (exclusive) x ULN and ALT <5 x ULN at Day -1 


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(can be checked by local lab result).
7.
Screening laboratory values (hematology, chemistry [other than liver function test], 
urinalysis) obtained up to 28 days prior to first study treatment within acceptable range or 
judged to be not clinically significant by the Investigator and the Medical Monitor.
8.
Liver biopsy, Fibroscan, or equivalent test obtained within the past 6 months demonstrating 
liver disease consistent with chronic HBV infection with absence of extensive bridging 
fibrosis and absence of cirrhosis (cutoff for Fibroscan is liver stiffness measurement ≤8.5 
kPa for treatment-naïve patients and ≤7.4 kPa for NUC-suppressed CHB patients, or 
Metavir fibrotic Stage <3, or other equivalent staging systems).
9.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or agree to 
use contraceptive measures, and agree to refrain from donating sperm, as defined below:
a.
Men must remain abstinent or use a condom during the treatment period and for 
at least 6 months after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
10. For women of childbearing potential: agree to use two methods of contraception, with at 
least one method considered as highly effective during the study and for at least 6 months 
after the last dose of study drug.
a.
A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
b.
Contraceptive methods considered as highly effective (failure rate <1% per year 
when used consistently and correctly): 
- Combined (estrogen- and progestogen-containing) or progestogen-only 
hormonal contraception associated with inhibition of ovulation
- intrauterine device (IUD)
- intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- vasectomized partner
- sexual abstinence*
* Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire 
period of study treatment and at least 6 months after the last dose of 
study drug. In such case, there is no need to use two contraceptive 
methods. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not 


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acceptable methods of contraception.
c.
Contraceptive methods NOT considered as highly effective (failure rate >1% per 
year):
- Progestogen-only oral hormonal contraception (where inhibition of ovulation is 
not the primary mode of action)
- Male or female condoms with or without spermicide
- Cap, diaphragm, or sponge with spermicide
11. Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) in 
accordance with institutional and regulatory requirements.
Exclusion Criteria
Healthy volunteers/patients with HBV who meet any of the following criteria will be excluded 
from study entry:
Part 1 – Healthy Volunteers only:
1.
Pregnant (positive pregnancy test) or lactating women, and male subjects with partners 
who are pregnant or lactating.
2.
History or symptoms of any clinically significant gastrointestinal, renal, hepatic, broncho-
pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, hematological or 
allergic disease, metabolic disorder, cancer, or cirrhosis.
3.
Personal history or family history of congenital long QT syndrome and/or cardiac sudden 
death.
4.
History of Gilbert’s syndrome.
5.
History of having received or currently receiving any systemic anti-neoplastic (including 
radiation) or immune-modulatory treatment (including systemic oral or inhaled 
corticosteroids) 6 months prior to the first dose of study drug or the expectation that such 
treatment will be needed at any time during the study.
6.
Subjects who have had significant acute infection, e.g., influenza, local infection, acute 
gastrointestinal symptoms, or any other clinically significant illness within two weeks of 
screening.
7.
Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or 
multiple drug allergies (non-active hay fever is acceptable).
8.
Any clinically significant concomitant diseases or condition that could interfere with, or 
treatment of which might interfere with, the conduct of the study, or that would, in the 
opinion of the Investigator, pose an unacceptable risk to the subject in this study.
9.
Confirmed (based on the average of 3 separate resting blood pressure measurements, 
properly measured with well-maintained equipment, after at least 10 minutes rest) systolic 
Blood Pressure greater than 140 or less than 90 mmHg, and diastolic BP greater than 90 
or less than 50 mmHg at screening.
10. Clinically relevant ECG abnormalities on screening ECG e.g.:
a.
QTcF 450 msec or 300 msec


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b.
Notable resting bradycardia (HR 45 bpm), or HR 90 bpm
c.
ECGs with documented machine errors in the interval duration assessments.
d.
Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-
Parkinson-White Syndrome, or cardiac pacemaker.
11. ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT 
measurement (e.g., neuromuscular artifact that cannot be readily eliminated, arrhythmias, 
indistinct QRS onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves).
12. Creatinine Clearance (CrCl) 70 mL/min (using the Cockcroft-Gault formula).
13. Positive test at screening of any of the following: Hepatitis A (HAV IgM Ab), Hepatitis B 
(HBsAg), Hepatitis C (HCV RNA or HCV Ab) or human immunodeficiency virus (HIV Ab).
14. Any other clinically significant abnormalities in laboratory test results at screening. In the 
case of uncertain or questionable results, tests performed during screening may be 
repeated before randomization to confirm eligibility.
15. Participation in an investigational drug or device study within 90 days prior to screening or 
more than 4 times per year.
16. Donation or loss of blood over 500 mL within 3 months prior to screening.
17. Positive test for drugs of abuse (including recreational drugs) and/or positive alcohol test at 
screening or on Day -1.
18. History of drug and/or alcohol abuse or addiction.
19. History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks 
per day on average (1 standard drink 10 grams of alcohol). Alcohol consumption will be 
prohibited at least 48 hours before screening, 48 hours before and 48 hours after each 
dose, and 48 hours before each scheduled visit.
20. Use of 5 cigarettes or equivalent nicotine-containing product per day.
21. Taking any prescribed or over-the-counter (OTC) medications (including vitamins or herbal 
remedies) within 2 weeks of first dosing or within 5 times the elimination half-life of the 
medication prior to first dosing (whichever is longer). Occasional 
acetaminophen/paracetamol is allowed. Exceptions may be made on a case-by-case basis 
following discussion and agreement between the Investigator and the Sponsor.
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.
24. History of hypersensitivity to benzodiazepines or its formulation ingredients (for MAD-
midazolam cohorts)
25. Acute narrow-angle glaucoma (for MAD-midazolam cohorts).
Part 2 – Chronic HBV-Infected Patients only:
1.
Pregnant (positive pregnancy test) or lactating women, and male subjects with partners 
who are pregnant or 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 


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gastric varices, splenomegaly, nodular liver, jaundice, hepatic encephalopathy.
4.
One or more of the following laboratory abnormalities at screening:
a.
Total serum bilirubin 2.5 mg/dL ( 42.75 mol/L). For patients with 
documented Gilbert’s syndrome total bilirubin 2.75 mg/dL ( 47 mol/L).
b.
International normalized ratio (INR) 1.5.
c.
Serum albumin 3.0 g/dL ( 30 g/L).
d.
Platelet count 140,000 cells/mm3.
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.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
7.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, or human 
immunodeficiency 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 or oral therapy for HSV I or 
HSV II.
9.
History of or suspicion of hepatocellular carcinoma or alpha-fetoprotein ULN at 
screening.
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. Previous or concurrent HBV treatments in the past 6 months.
15. History of capsid modulators treatment, including treatment in investigative trials
16. Participation in an investigational drug or device study within 30 days prior to 
randomization.
17. Taking any drugs or nutrients listed in prohibited medications and prohibited food sections.
18. Significant acute infection (e.g., influenza, local infection) or any other clinically significant 
illness within 2 weeks of randomization.
19. Clinically relevant ECG abnormalities on screening ECG.
20. Abnormal renal function including serum or plasma creatinine ULN or calculated 
creatinine clearance 70 mL/min using the Cockcroft Gault formula.
21. Donation or loss of blood over 500 mL within 3 months prior to randomization.
22. Administration of any blood product within 3 months prior to randomization.
23. 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.


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24. Subjects under judicial supervision, guardianship or curatorship.
25. Medical or social conditions that would potentially interfere with the subject’s ability to 
comply with the study visit schedule or the study assessments.
Part 3 – Chronic Hepatitis B Patients only:
1.
Pregnant (positive pregnancy test) or lactating women.
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.
4.
One or more of the following laboratory abnormalities at screening:
a.
Total serum bilirubin > ULN (exception Gilbert’s disease). 
b.
International normalized ratio (INR) >1.1 ULN.
c.
Serum albumin <3.0 g/dL (<30 g/L).
d.
Platelet count <140,000 cells/mm3
e.
Hemoglobin <12 g/dL (females) or <13 g/dL (males).
f.
White blood cell count <2500 cell/mm3. 
g.
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], free triiodothyronine 
[FT3], free thyroxin [FT4] at screening.
7.
Documented history or other evidence of metabolic liver disease within one year of 
screening.
8.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, HEV or human 
immunodeficiency virus (HIV).
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 of oral therapy for HSV I or 
HSV II.
10. Diagnosed or suspected hepatocellular carcinoma as evidenced by screening alpha-
fetoprotein (AFP) ≥100 ng/mL. If AFP >ULN, absence of mass/findings suspicious for HCC 
must be demonstrated by ultrasound or CT or MRI within the screening period.
11. History of significant gastrointestinal disease (including but not limited to gastric ulcers).
12. History of clinically significant cardiovascular, endocrine, renal, ocular, pulmonary, 
psychiatric, or neurological disease.
13. Evidence of an active or suspected cancer or a history of malignancy other than 
adequately treated basal cell carcinoma.
14. History of organ transplantation.
15. Participation in an investigational drug or device study within 30 days prior to screening.


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16. Taking any drugs or nutrients listed in prohibited medications and prohibited food sections.
17. Significant acute infection (e.g., influenza, local infection) or any other clinically significant 
illness within 2 weeks of screening.
18. 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.
19. Abnormal renal function including serum or plasma creatinine ULN or glomerular filtration 
rate (eGFR; using CDK-Epi equation) <60 mL/min.
20. Donation or loss of blood over 500 mL within 3 months prior to screening.
21. Administration of any blood product within 3 months prior to screening.
22. 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.
23. Subjects under judicial supervision, guardianship, or curatorship. 
24. 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 Part 1a (SAD) of the study will be approximately 8 weeks divided as 
follows:

Screening: Up to 4 weeks.

In Clinic period: Days –2 to 3 (may be extended at the discretion of the Investigator or at the 
request of the Sponsor based safety and emerging PK and/or PD data).

Ambulatory visits: Days 4, 5

Safety Follow-up: Days 8 1 day and 29 3 days.
The total duration of Part 1b (FE) of the study will be approximately 10 weeks divided as 
follows:

Screening: Up to 4 weeks.

In Clinic period: Days –2 to 3 and Days 15 to 18 (may be extended at the discretion of the 
Investigator or at the request of the Sponsor based safety and emerging PK and/or PD 
data).

Ambulatory visits: Days 4, 5, 19, and 20.

Safety Follow-up: Days 23 1 day, and 44 3 days.
The total duration of Part 1c (MAD) of the study will be approximately 10 weeks divided as 
follows:

Screening: Up to 4 weeks.

In Clinic period: Day -2 to Day 16 (may be extended at the discretion of the Investigator or 
at the request of the Sponsor based safety and emerging PK and/or PD data).

Safety Follow-up: Days 21 1 day and 42 3 days.
The total duration of Part 2 (POM) of the study will be approximately 20 weeks divided as 
follows:

Screening: Up to 4 weeks.

Treatment period: 4 weeks. 


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
In Clinic period (optional): Day -1 to Day 2 and Day 27 to Day 29 (may be extended at the 
discretion of the Investigator or at the request of the Sponsor based safety and emerging 
PK and/or PD data).

Ambulatory visits: Days -1, 1, 2, 3, 4, 8, 15, 22, 28, and 29.

Safety Follow-up (Ambulatory): Days 35 (1 day), 56 (3 days), 84 (2 weeks), and 112 
(2 weeks).
The total duration of Part 3 (POM) of the study will be approximately 76 weeks divided as 
follows:

Screening: Up to 4 weeks.

Treatment period: Up to 48 weeks, ambulatory visits:
-
0–4 weeks: every 2 weeks.
-
4–48 weeks: every 4 weeks.

Post-treatment follow-up for 24 weeks, ambulatory visits:
For patients who meet NUC Stopping Criteria (HBsAg 100 IU/mL and HBV DNA 20 
IU/mL) at end-of-treatment (EOT) visit:
-
Post-EOT 0–12 weeks: every 2 weeks.
-
Post-EOT 12–24 weeks: every 4 weeks.
For patients who do NOT meet NUC Stopping Criteria at EOT visit:
-
Post-EOT 0-24 weeks: every 8 weeks.
END OF STUDY
The end of the study is defined as the date when the last study subject last observation (LSLO) 
occurs. LSLO is expected to occur 24 weeks after the last dose is administered in Part 3.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events.

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, coagulation, 
and urinalysis test results, etc.

ECGs.

Vital signs including blood pressure, pulse rate and body temperature.


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PHARMACOKINETIC OUTCOME MEASURES
The pharmacokinetic outcome measures for this study are as follows:
RO7049389 and its metabolites (M5, M6 and M11, if applicable) parameters in Parts 1a (SAD) 
and RO7049389 parameters in Part 1b (SAD and Food Effect):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-last: area under the plasma concentration versus time curve up to the last measurable 
concentration.

AUC0-∞: Area under the plasma concentration versus time curve extrapolated to infinity;

T1/2: Apparent terminal phase half-life.

CL/F: Apparent clearance after oral administration.

Ae (Cumulative amount excreted unchanged in the urine) and CLR (Renal clearance, 
computed as Ae/AUC), if warranted.
RO7049389 and its metabolites (M5, M6 and M11, if applicable) parameters in Part 1c (MAD):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-: Area under the plasma concentration-time curve for a dosing interval.

Ctrough: Trough plasma concentration.

T1/2: Apparent terminal phase half-life.

Accumulation index of RO7049389 and its metabolites.

Ae and CLR, if warranted.
Midazolam parameters in Part 1c (MAD):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-last: area under the plasma concentration versus time curve up to the last measurable 
concentration.

AUC0-∞: Area under the plasma concentration versus time curve extrapolated to infinity.

AUC0-6h: Area under the plasma concentration versus time curve up to 6 hours post-dose.

T1/2: Apparent terminal phase half-life.

CL/F: Apparent clearance after oral administration.
RO7049389 and its metabolites (M5, M6 and M11) parameters in Part 2 [POM] and Part 3 
[RO7049389 on top of SoC]:

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-: Area under the plasma concentration-time curve for a dosing interval, if applicable.

Ctrough: Trough plasma concentration.

T1/2: Apparent terminal phase half-life, if applicable.

Accumulation index of RO7049389 and its metabolites, if applicable.
NUC and Peg-IFN parameters in Part 3 (RO7049389 on top of SoC):

Ctrough: Trough plasma concentration.


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PHARMACODYNAMIC OUTCOME MEASURES
Viral dynamic response outcomes will be measured in Part 2 and Part 3 of the study, and will 
include, but will not be limited to the following:

Quantitative HBV DNA level (actual and change from baseline).

HBsAg (qualitative and quantitative).

HBeAg (qualitative and semi-quantitative).

Anti-HBs antibody status (quantitative).

Anti-HBe antibody status (qualitative).

Anti-HBc antibody (qualitative).

Quantitative Hepatitis B core related antigen (HBcrAg).

Quantitative HBV RNA.
Outcomes of antiviral response will include:

Quantitative HBsAg decline, loss of HBsAg, development of anti-HBs, HBsAg 
seroconversion (loss of HBsAg and presence of anti-HBs).

Quantitative HBeAg decline, loss of HBeAg, development of anti-HBe, HBeAg 
seroconversion (loss of HBeAg and presence of anti-HBe).

Quantitative HBV DNA decline, HBV DNA <LLOQ.

Viral resistance will be monitored from Day 1 through follow-up.
EXPLORATORY OUTCOME MEASURES
Since the following measures are set to be exploratory, in some circumstances, these measures 
will only be tested in a subset of the patients or part of the visits:
In Part 1, endogenous substances levels will be investigated to assess the effect of multiple oral 
dosing or RO7049389 on CYP3A4 activity. Analysis will include plasma 
4-hydroxycholesterol/cholesterol ratio.
In Part 3:

Changes of total HBsAg from baseline.

Change of liver stiffness measurement by Fibroscan.
RESEARCH BIOSAMPLE REPOSITORY (RBR) SAMPLE COLLECTION
Specimens will be collected from study subjects who give specific consent to participate in this 
optional Research Biosample Repository.


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INVESTIGATIONAL MEDICINAL PRODUCT(S)
Part 1 and Part 2:
All IMPs required for completion of this study (RO7049389 and matching placebo) will be 
provided by the Sponsor. Midazolam solution will be prepared by the site. 
Part 3:
The IMPs required for completion of this study (RO7049389) will be provided by the Sponsor. 
NON IMPs
All patients in Part 3 of the study will also be treated with SoC therapy (a NUC with or without 
Peg-IFN): 

NUC: For NUC-suppressed patients who have been on a NUC before entering the study, 
they should continue to take the same NUC per local label. If patients were taking generic 
NUC, they will be recommended to switch to the original drug after enrolling in the study.
For anti-HBV treatment-naïve patients, the choice of entecavir, tenofovir alafenamide, or 
tenofovir disoproxil fumarate is at the discretion of treating physician and per local label. 
NUC will be provided or reimbursed by the Sponsor until 24 weeks post treatment.

Peg-IFN (Pegylated interferon alfa): Patients who are required to use Peg-IFN, e.g., in POM 
Cohort C, will either be provided or reimbursed by the Sponsor for the duration of the study.
PROCEDURES
Schedules of Assessments (SoA) are provided in Appendices 1 – 8.
STATISTICAL METHODS
SAFETY ANALYSES
All healthy volunteers (Part 1) and patients (Parts 2 and 3) who have received at least one dose 
of the study drug, whether prematurely withdrawn from the study or not, will be included in the 
safety analysis.
PHARMACOKINETIC ANALYSES
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.
PHARMACODYNAMIC ANALYSES
The analyses of viral dynamic response in Part 2 of the study will include all patients who were 
randomized and received at least one dose of study drug (RO7049389 or placebo). Patients will 
be analyzed according to the treatment group to which they were randomized.
The analyses of viral dynamic response in Part 3 of the study will include all patients who 
received at least one dose of RO7049389.
SAMPLE SIZE JUSTIFICATION
For Part 1 of the study, up to 93 healthy volunteers will be enrolled. This comprises up to 53 for 
Parts 1a and 1b, and up to 40 for Part 1c. For Part 2 of the study, up to 35 patients with chronic 
HBV-infection will be enrolled.
The number of study subjects to be randomized was chosen based on practical considerations 
and complies with standard safety review rules. With six study subjects receiving active drug at 
a dose level, there is an 82% chance to observe at least one adverse event that has an 
incidence rate of 25% in the population. The total sample size may increase adaptively based 
on the study findings for safety, PK or viral dynamic outcomes. 
This sample size for POM (Part 2) is to support the assessment of viral dynamic response to the 
study drug treatment. When the sample size is 6, a one-sided 90% confidence interval for the 


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mean change from baseline of HBV DNA (Log10 IU/mL) will have an interval that extends no 
more than 0.904 from the observed mean assuming that the standard deviation is 1.5 and that 
the confidence interval is based on the t-statistic.
Initially, approximately 55 patients with Chronic Hepatitis B will be enrolled in the first 3 
cohorts of Part 3 with approximately 30 patients in POM Cohort A, 10 patients in POM Cohort 
B, and 15 patients in POM Cohort C. Based on emerging efficacy/safety data, the sample size 
in Cohort C can be increased to approximately 30 patients. In addition, additional treatment 
cohorts may be opened to explore different treatment durations, dose regimens, or different 
combinations.
The sample size for Part 3 is intended to support the assessment of response rate of HBV DNA 
<LLOQ and HBsAg loss at 24 weeks after EOT. A sample size of 10, 15, or 30 would ensure 
that the lower 95% CI is above 5%, 9%, or 14%, respectively, if the underlying response rate is 
30%, assuming binomial distribution.
INTERIM ANALYSIS
No interim analysis is planned for Part 1 and Part 2 of this study. Given the hypothesis-
generating nature of this study, the Sponsor may choose to conduct interim efficacy analyses 
for Part 3 of the study. The decision to conduct an optional interim analysis and the timing of the 
analysis 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.
LIST OF PROHIBITED MEDICATIONS
Healthy Volunteers
All medications (prescription and OTC) taken within 30 days of study screening will be recorded 
on the appropriate eCRF. 
As a general rule, no concomitant medication will be permitted within 14 days prior to the first 
dosing or within 5 half-lives of the medication prior to the first dosing (whichever is longer), until 
the follow up visit (Day 8 for Part 1a, Day 23 for Part 1b, and Day 21 for Part 1c), with the 
exception of the cases listed as the Permitted Therapy.
Exceptions may be made on a case-by-case basis following discussion and agreement between 
the investigator and the sponsor after unless the rationale for exception is discussed and clearly 
documented. 
Chronic HBV-infected patients in Part 2 and Chronic Hepatitis B Patients in Part 3
For all patients, the following are prohibited:

Any systemic antiviral therapy other than that provided by the study at any time from 14 
days before starting the study drug until the end of follow-up period, with the exception of 
oral therapy for HSV I or HSV II. Investigational drugs or herbal and other remedies being 
taken by the patient for possible or perceived effects against HBV are prohibited.

Inducers of CYP3A enzyme (including but not limited to efavirenz, nevirapine, pioglitazone, 
rifampin, rifabutin, troglitazone, phenobarbital, phenytoin, carbamazepine, and St. John’s 
wort) within 14 days or 5 half-lives, (whichever is longer) before the first administration of 
RO7049389 and while on study treatment. 

Inhibitors of CYP3A enzyme (including but not limited to indinavir, nelfinavir, clarithromycin, 
itraconazole, ketoconazole, nefazodone, ketoconazole, verapamil, suboxone, diltiazem, 
cimetidine, amiodarone, fluvoxamine, troleandomycin, voriconazole) within 7 days or 5 half-
lives (whichever is longer) before the first administration of RO7049389 and while on 
treatment with RO7049389. 

Inducers of UDP-glucuronosyltransferase (UGT) enzymes (including but not limited to 
carbamazepine, nicotine) within 14 days or 5 half-lives, (whichever is longer) before the first 
administration of RO7049389 and while on study treatment.

Inhibitors of UGT enzymes (including but not limited to atazanavir, gemfibrozil, indinavir, 
ketoconazole) within 7 days or 5 half-lives (whichever is longer) before the first 
administration of RO7049389 and while on treatment with RO7049389. 


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
Inhibitors of OATP transporters (including but not limited to cyclosporine, rifampicin, 
eltrombopag, lapatinib, lopinavir, ritonavir) within 7 days before the first administration of 
RO7049389 and while on treatment with RO7049389. 

Inhibitors of breast cancer resistance protein (BCRP) transporter (including but not limited 
to cyclosporine, elacridar, eltrombopag, gefitinib) within 7 days before the first 
administration of RO7049389 and while on treatment with RO7049389. 

The total daily dose of acetaminophen (paracetamol) should not exceed 1 g/day. 

Patients who have been on stable hormone replacement therapy for a period of at least 2 
months prior to Screening will not be excluded from the study. 

Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents, radiation 
therapy, anti-arrhythmics, ergot derivatives, oral/parenteral corticosteroids, or topical Class 
1 and 2 steroids, probenecid, and bile acid binding resins while on study treatment. 

Any hormonal methods of contraception during the study treatment period and 28 days 
afterwards (only for patients enrolled into part 2).

Midazolam data from part 1c indicated mild but not clinically significant inhibition of CYP3A 
enzyme by RO7049389. CYP3A4 substrates with narrow therapeutic range (including but 
not limited to alfentanil, cyclosporine, diegotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus) may need to be used with caution in Parts 2 and 3 of the 
study.

For substrates of OATP1B (including but not limited to atrasentan, bosentan, ezetimibe, 
irinotecan, statins (e.g., atorvastatin, rosuvastatin, simvastatin, pitavastatin, pravastatin), 
repaglinide, rifampin, valsartan, olmesartan), the co-administration of RO7049389 is 
expected to result in mild (< 2 fold) increase in blood concentrations of the substrates. 
Therefore, use the lowest necessary dose, titrate the dose carefully, and monitor closely for 
substrate-associated adverse reactions.
Prohibited Food
Use of the following is prohibited during the study:

Alcohol consumption is to be strongly discouraged in patients with chronic HBV infection 14 
days before starting the study drug until 24 weeks after the last dose. During the study, 
patients should not consume more than 20 g of alcohol per day (or on average 
approximately 140 g of alcohol per week). 

In healthy volunteers, alcohol must not be consumed from 48 hours before screening, 48 
hours before admission until completion of follow-up visit.

Any nutrients known to modulate activity of CYP enzymes (e.g., grapefruit juice or Seville 
orange juice) will be prohibited within 3 days before Day -1 through the last dose of 
RO7049389.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AASLD
American Association for the Study of Liver 
Diseases
AE
Adverse event
Ae
Cumulative amount excreted unchanged in the 
urine
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APASL
Asian Pacific Association for the Study of the 
Liver
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-
Area under the plasma concentration-time curve 
for a dosing interval
BMI
Body mass index
BP
Blood Pressure
cccDNA
Covalently closed circular DNA
CHB
Chronic Hepatitis B
CL
Clearance
CL/F
Apparent clearance
CRM
Continuous reassessment method
CYP
Cytochrome P450
DAIDS
Division of AIDS
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DRF
Dose range finding
EASL
European Association for the Study of the Liver
EC
Ethics Committee
ECG
Electrocardiograms
eCRF
Electronic Case Report Form
EFD
Embryofetal development
EOT
End of Treatment
FDA
Food and Drug Administration
FT3
Free triiodothyronine
FT4
Free thyroxine
GLDH
Glutamate dehydrogenase


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Abbreviation
Definition
GLP
Good Laboratory Practice
HAV
Hepatitis A virus
HBcrAg
Hepatitis B core-related antigen
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
hERG
human ether-à-go-go–related gene
HDV
Hepatitis D virus
HDL
High density lipoproteins
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IM
Immunomodulatory
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
LLOQ
lower limit of quantification
LPLV
Last patient, last visit
LSLO
Last study subject, last observation
MAD
Multiple-ascending Doses
MDR
Multi-drug resistance
MTD
Maximal tolerated dose
NOAEL
No observed adverse effect level
NUCs
Nucleos(t)ide analogues
OTC
Over the counter
PCR
Polymerase chain reaction 
PD
Pharmacodynamic
Peg-IFN
Pegylated interferon
POM
Proof of mechanism


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Abbreviation
Definition
PK
Pharmacokinetic
PT
Prothrombin time
QD
Once per day
QRS
QRS Complex
QT
QT Interval
QTc
QT corrected for heart rate
QTca
Rate corrected QT interval
QTcaT
Rate- and temperature-corrected QT interval
QTcF
QT corrected for heart rate using the Fridericia 
correction factor
RBC
Red Blood Cell
RBR
Research Biosample Repository
RNA
Ribonucleic acid
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SoA
Schedule of Assessments
SoC
Standard of care
TSH
Thyroid-stimulating hormone
UGT
UDP glucuronosyltransferase
ULN
Upper limit of normal
US
United States
V
Volume
WBC
White Blood Cell


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1.
BACKGROUND AND RATIONALE
RO7049389, an inhibitor of hepatitis B virus (HBV) capsid assembly, is being developed 
for the treatment of patients with chronic HBV infection. 
1.1
BACKGROUND ON HEPATITIS B VIRUS INFECTION
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. An 
estimated 887,000 deaths each year were caused by the acute or chronic consequences 
of hepatitis B (WHO 2019).
Chronic HBV infection can be characterized by the persistence of high levels of HBV 
antigens (including hepatitis B e antigen [HBeAg] and hepatitis B surface antigen 
[HBsAg]). Disease progression is a dynamic process with several stages, during which 
chronic hepatitis B may be presented either as HBeAg-positive or HBeAg-negative 
hepatitis.
Persistence of HBV infection is a consequence of the presence of covalently closed 
circular DNA (cccDNA) in the nuclei of infected hepatocytes. Despite the advancement 
in the understanding of HBV disease biology, eradication of cccDNA (defined as 
‘disease cure’) may not be achievable for the foreseeable future. Nevertheless, the 
sustained clearance of HBsAg has been shown to be protective against disease 
progression and development of HBV complications including cirrhosis, liver failure and 
hepatocellular carcinoma. Accordingly, sustained HBsAg loss with or without 
seroconversion has been defined as ‘functional cure’, and is specified by current 
treatment guidelines as the optimal treatment endpoint. Achieving functional cure allows 
treatment cessation (EASL 2017) with low likelihood of virological relapse. 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. For HBeAg-positive patients, HBeAg 
seroconversion is indicative of a better prognosis, including lower rates of cirrhosis and 
slower disease progression. For both HBeAg-positive and -negative CHB, sustained 
suppression of HBV replication is associated with biochemical remission, histological 
improvement and delayed disease progression. However, virological relapse is a major 
limitation of the currently approved therapies as they rarely result in functional cure
(HBsAg loss).
Currently, there are two classes of standard of care (SoC) drugs available for the 
treatment of chronic hepatitis B (CHB): subcutaneously administered interferon (IFN) 
preparations and orally administered nucleos(t)ide analogues (NUCs). Although both 
SoC therapies can induce the loss of HBeAg with development of anti-HBe antibody 
(serological response) and the suppression of HBV DNA to an undetectable level by 
sensitive polymerase chain reaction (PCR) methods (virological response), and are able 


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to normalize liver transaminases levels (biochemical response), neither treatment 
achieves a high rate of functional cure. HBsAg loss only occurs in approximately 3% of 
patients after one year of treatment and in 15% after one to five years follow-up 
(EASL 2017). In addition, IFN-based therapies are associated with many side-effects, 
while NUCs frequently require prolonged or possibly life-long therapy, and some are 
associated with a high risk of viral resistance.
1.2
BACKGROUND ON RO7049389
RO7049389 is an inhibitor of HBV capsid assembly and belongs to the well-studied 
class of heteroaryldihydropyrimidine (HAP) compounds. This class of compounds 
induces formation of abnormal HBV core protein aggregates, which are subsequently 
recognized and depleted. Depleting functional core protein results in interruption of viral 
assembly and inhibition of HBV replication.
The HBV core protein is involved in multiple steps of the viral life cycle such as 
encapsidation of pre-genomic ribonucleic acid (pgRNA), subsequent initiation of reverse 
transcription, and is an important component of cccDNA mini-chromosome. Furthermore, 
literature suggests that the HBV core protein may play a role in suppressing host innate 
immune responses (Twu et al 1988; Fernandez et al 2003; Gruffaz et al 2013). Depletion 
of functional core protein may therefore facilitate host immune restoration. RO7049389
can therefore potentially provide anti-HBV benefits by both direct inhibition of viral 
replication and augmentation of host immune responses against the virus.
1.2.1
Previous Non-Clinical Studies
RO7049389 has shown potent antiviral activity through the induction of HBV core protein 
misassembly and subsequent degradation, and has a high degree of selectivity against 
HBV. RO7049389 demonstrated activity against most prevalent HBV genotypes (A, B, C, 
D) and against a panel of nucleos(t)ide analogue-resistant HBV variants tested in vitro. 
RO7049389 showed additive or minor-to-moderate synergism in in vitro combination 
analyses with each of the following: entecavir, tenofovir, and IFN-α-2a (Roferon-A). In 
recombinant AAV-HBV-infected mice, orally administered RO7049389 was shown to 
reduce serum levels of HBV DNA, HBsAg, and HBeAg. Combination treatment of 
RO7049389 with the Roche TLR7 agonist RO7020531 in AAV-HBV mice resulted in 
HBsAg reduction to below the lower limit of quantification (LLOQ) in 5 of 7 animals by 
the end of the 6-week treatment. This reduction was sustained through the off-treatment 
follow-up period. Anti-hepatitis B surface antibody (anti-HBs) was detected in 3 of 7 mice
treated with this combination. The anti-viral efficacy of RO7049389, either alone or in 
combination with Peg-IFN, was also demonstrated in an additional animal model of 
HBV-infected human liver chimeric mice.
Pharmacokinetic (PK) studies in rats, monkeys and mini-pigs showed a moderate plasma
clearance (~50% liver blood flow), moderate distribution (~body water volume) and 


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relatively short half-life 2 hours. Plasma exposures following oral administration at 
pharmacodynamic (PD) dose levels are moderate with ~20% oral bioavailability; at 
higher dose levels in 28-day toxicity studies, overall oral exposures were high, with 
male/female area under the curve (AUC) of 181000/362000 ng h/mL at 250 mg/kg 
once per day (QD) in the rat and 111000/124000 ng h/mL at 350 mg/kg QD in the 
mini-pig. 
RO7049389 is stable in plasma of all species tested (including human) with unbound 
fraction in all species in the range of 4 to 12% unbound fraction with no excessive 
binding to erythrocytes. 
Metabolism studies showed the disposition of RO7049389 to be mediated mainly by liver 
metabolism (oxidative via CYP3A4 as major and direct glucuronidation via UGT1A3 
likely as minor); however, further contribution of biliary clearance cannot be excluded.
RO7049389 showed little or no induction potential for enzymes such as major 
cytochrome P450 (CYP) isoforms or UDP glucuronosyltransferases (UGTs) as well as 
various transporters, however, RO7049389 is a substrate of human multi-drug 
resistance (MDR)1 (P-glycoprotein [P-gp]) and of human liver organic anion-transporting 
polypeptide 1B1 (OATP1B1) and OATP1B3. RO7049389 shows little or no inhibition for 
all CYP isoforms, carboxyl esterases and aldehyde oxidase but it inhibited to various 
degrees MDR1, OAT3, BSEP, OATP1B3 and especially OATP1B1. Therefore, in vivo 
drug-drug interactions due to co-administration of respective transporter substrates 
cannot be excluded.
RO7049389 demonstrated no potential to cause time-dependent inhibition of all 
cytochrome P450 isoforms except for CYP3A4 where a mild inhibition was observed. 
Therefore, in vivo drug-drug interactions (DDIs) with co-administered drugs that are 
CYP3A4 substrates cannot be excluded.
Three metabolites of RO7049389 have been identified in human plasma that each exceed 
10% of total drug-related material (M5, M6 and M11) based on steady state exposures. 
Metabolite M5 exceeds exposures of RO7049389. Based on the available PK evaluation 
of M5 and preliminary data for M6 and M11, accumulation of these metabolites is 
limited with twice daily or once daily repeated dosing. All three metabolites have been 
characterized for the inhibitory potential on drug metabolizing enzymes and do not 
appear to pose a concern for potential DDI.
There were no adverse test article-related effects in rats, monkeys or mini-pigs up to 
1000 mg/kg/day in the single-ascending dose or the repeat-dose toxicity studies. The 
no-observed-adverse-effect level (NOAEL) was determined as the highest dose tested in 
each study: 14-day study 1000 mg/kg/day (AUC0-24 546 µg h/mL), 4-week study 250 
mg/kg/day (AUC0-24 272 µg h/mL), and 26 week study 120 mg/kg/day (AUC0-24
117 µg h/mL) in rats; 15-day study 1000 mg/kg/day (AUC0-24 575 µg h/mL), 4-week 


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study 350 mg/kg/day (AUC0-24 118 µg h/mL), and 39-week study 250 mg/kg/day (AUC0-
24 73.4 µg h/mL) in mini-pigs. 
RO7049389 was neither mutagenic nor clastogenic in vitro or in vivo. 
In definitive Good Laboratory Practice (GLP) reproductive and developmental toxicity 
studies, no adverse effects on embryofetal development (EFD) were observed in the rat 
at doses up to 75 mg/kg/day (AUC0-24 70.2 µg hr/mL) or in rabbits at the highest tested 
dose of 300 mg/kg/day (AUC0-24 23.5 µg hr/mL). In rats, increased early embryonic 
death and an increase in transient skeletal variations (bent scapulae and/or wavy ribs) 
were noted at 150 mg/kg/day (AUC0-24 325 µg hr/mL). Thus, the NOAEL for EFD was 
75 mg/kg/day in the rat and 300 mg/kg/day in the rabbit. In a definitive (GLP) fertility 
study in male and female rats, no adverse effects on mating performance, fertility, or 
early embryonic development were noted up to the highest tested dose of 250 
mg/kg/day.
Cardiovascular function was assessed in conscious telemetered minipigs in a pilot non-
GLP study at doses of 100–1000 mg/kg and in a pivotal GLP-compliant study at 75, 150, 
and 250 mg/kg. In the pilot study, administration of 1000 mg/kg RO7049389 caused a 
core body temperature decrease of approximately 1.5C and individually rate-corrected 
QT interval (QTca) increases of 40 ms. After rate and temperature correction, the rate-
and temperature-corrected QT interval (QTcaT) increase was approximately 15–20 ms. 
The NOEL for cardiovascular parameters in the non-GLP pilot study was 300 mg/kg and 
in the pivotal GLP telemetry study was the highest dose evaluated of 250 mg/kg. 
Systemic concentrations at 4 hours after dosing were around 7 µg/mL in both sexes with 
corresponding free concentrations of around 800 ng/mL, which is more than 10-fold 
lower than the human ether-à-go-go–related gene (hERG) IC20. The hERG IC20 is about 
20-fold higher than the maximum concentration of unbound RO7049389 at the Cmax of 
the potential highest dose in clinical studies (600 mg BID).
RO7049389 had no effect on neurobehavioral and respiratory function in rats at dose 
levels of up to 150 mg/kg.
An in vitro study indicated that RO7049389 had no phototoxicity potential.
Separate studies were performed with the major human metabolites M5, M6, and M11. 
In vitro genotoxicity studies of M5, M6, and M11, and hERG assays of M5 did not reveal 
any new preclinical safety signals.
In a 2-week dose range finding (DRF) study with M5 administered to the rats, dose 
levels at ≥1000 mg/kg/day resulted in early mortalities and effects on body weight. The 
dose of 750 mg/kg/day was NOAEL (AUC0-24 58.2 h µg/mL). 


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A DRF EFD study in rats showed that administration of 375 or 750 mg/kg/day of M5 
led to maternal toxicity leading to lower dose level selection for a subsequent 
GLP-compliant study. In the definitive GLP EFD study in rats, administration of M5 
at 180 mg/kg/day led to failed implantation and/or early embryonic death and
pregnancy failure in the majority of rats. The NOAEL for maternal and embryo fetal 
toxicity was 60 mg/kg/day (unbound M5 AUC0-24 0.28 µg• h/mL, total M5 AUC0-24 4.9 
µg• h/mL). The exposure of unbound M5 is 3x and total M5 is 0.2x of those in humans 
given the recommended dose of RO7049389 (600 mg QD). There were no indications of 
teratogenicity at any dose level. The unbound (free) M5 exposure is considered more 
relevant for risk assessment in human as generally pharmacological effects (on-target or 
off-target) are mediated by the unbound drug levels in plasma or tissue, and for M5 
significant differences in plasma protein binding exists between species (FDA 2020).
See the RO7049389 Investigator’s Brochure for further details on non-clinical studies.
1.2.2
Previous Clinical Studies
This study (YP39364) is the first-in-human study with RO7049389. At present, Parts 1 
and 2 have been completed and the Part 3 is ongoing. Two other Phase I clinical studies 
with RO7049389: YP39406 and YP40218 have also been completed.
Overall, RO7049389 was safe and well tolerated across three studies in both HVs and 
patients. The safety profiles were consistent between HVs and patients, as well as 
between Asian and non-Asian HVs/patients. Additionally, there were no safety signals or 
dose-related trends in the ECGs, vital signs, or laboratory safety data (except for ALT 
elevations, which were only observed in patients).
1.2.2.1
Preliminary results of study YP39364
Preliminary results of Parts 1 and 2 of study YP39364 are as follows:
Part 1 of YP39364: Healthy Volunteers

Forty-one healthy volunteers in the SAD part of the study received RO7049389 at 
dose levels ranging from 150 to 2500 mg or matching placebo. Forty two healthy 
volunteers in the MAD part of the study were treated with twice-daily RO7049389 
(dose ranging from 200 mg to 600 mg) for 14 days or 800 mg BID with a standard 
meal for 3 days (the cohort was prematurely terminated due to non-safety related 
reasons). 

Safety data review showed that both single doses and BID dosing were well 
tolerated in all healthy volunteers. Fifty-nine adverse events (AEs) were reported,
with 44 AEs in 30 of 62 HVs who received RO7049389 and 15 AEs in 9 of 21 HVs 
who received placebo. The majority of AEs were of mild intensity and considered as 
not related to study drug. All AEs resolved or were resolving. The most common AE 
was headache in both the SAD and MAD treatment-active arms. No severe AEs or 
serious adverse events (SAEs) were observed in any cohort and no AEs leading to 


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drug discontinuation were reported. There were no clinically significant changes in 
ECG parameters, vital signs, or laboratory safety test results.
Part 2 of YP39364: Patients with Chronic HBV infection

In Part 2 of the study, 37 patients with chronic HBV infection received RO7049389 
or matching placebo at doses of 200 or 400 mg BID with a standard meal, 600 mg 
QD,1000 mg QD or 200 mg QD fasted for 28 days in one of the five proof of 
mechanism (POM) Cohorts. Of these 37 patients, two patients (one in POM Cohort 
2 and the other in POM Cohort 4) were discontinued due to non-safety reasons and 
were replaced. 

A total of 75 AEs were reported with 69 AEs in 19 of 31 patients who received 
RO7049389 and 6 AEs in 3 of 6 patients who received placebo. The majority of AEs 
in the treatment-active arms were of mild intensity with headache, ALT increased, 
AST increased, upper respiratory tract infection (URTI), and diarrhea being the 
most common AEs. All of the AEs resolved or were resolving at the time the data 
were extracted. Transient lab abnormalities (Grade 2-4 ALT/AST elevations) were 
observed in 6 of 31 patients who received RO7049389. There were no safety 
signals or dose related trends in the ECG parameters, vital signs, or laboratory 
safety data other than ALT/AST. No severe AEs or SAEs were reported in patients 
who received RO7049389. One pre-dose SAE (worsening of ALT/AST elevation) 
was reported in the placebo arm, and the patient was replaced. 

Preliminary efficacy data from the 35 patients (30 active: 5 placebo) who completed 
28 days of treatment in Part 2 of the study showed robust declines in plasma HBV 
DNA in both HBeAg positive and negative patients with a median decline of 2.7, 3.2, 
2.9, 3.2, and 3.0 log10 IU/mL from baseline in the five POM cohorts, respectively. 
Viral breakthrough was not observed during dosing; however, HBV DNA levels 
returned towards the baseline by 4 weeks post-treatment.
1.2.2.2
Results from Study YP39406 

YP39406 is a randomized, sponsor-open, investigator-blinded, subject-blinded, 
placebo-controlled, SAD and MAD study to investigate the safety, tolerability, and 
PK of RO7049389 in healthy Chinese volunteers. Safety data review showed that 
both single doses and BID dosing were well tolerated in all healthy volunteers. No
SAEs or AEs leading to discontinuation were reported. No clinically significant 
changes in ECG parameters, vital signs, or laboratory safety test results were 
observed.

Twenty-eight healthy volunteers in the SAD part of the study received RO7049389 
or placebo at doses of 200 mg fasted, 400 mg fasted, and 600 mg fasted. Nine AEs 
were reported with 8 AEs in 4 of 22 HVs in the active arms and 1 AE in 1 of 6 
HVs in the placebo arm. All AEs were of mild intensity and none of these AEs were 
considered to be related to study drug. All of these AEs resolved without treatment.

Twenty-four healthy volunteers in the MAD part of the study received RO7049389 or 
placebo at a dose of 200mg BID and 400mg BID. There were 21 subjects who 
participated in both SAD and MAD parts of the study. Twenty-three AEs were 


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reported with 19 AEs in 15 of 20 HVs who received RO7049389 and 4 AEs in 2 of 
4 HVs who received placebo. All AEs were of mild intensity. Thirteen AEs of lip dry 
(xerocheilia) with 2 cases from the placebo arm and 11 cases from the active arm
were considered to be related to study drug by the investigator. All AEs resolved 
without treatment.
1.2.2.3
Results from Study YP40218

Study YP40218 is an open-label, fixed-sequence, two-period study to investigate 
the effect of RO7049389 on the pharmacokinetics of pitavastatin in healthy 
volunteers. Pitavastatin was administered orally to participants on Day 1 of Period 1 
and Day 4 of Period 2. RO7049389 was administered at a dose of 800 mg BID for 6 
days in Period 2. 

Eighteen healthy volunteers were enrolled in the study. Twelve AEs were reported 
in 7 out of 18 healthy volunteers. All AEs were of mild intensity except for one AE of 
vomiting, which also led to the discontinuation of the subject from the study. Nine 
AEs were considered related to the study treatment by the investigator. One AE of 
headache was considered to be related to both RO704389 and pitavastatin, while 
the remaining 8 AEs were considered related only to RO704389. All AEs resolved 
without treatment. No severe AEs or SAEs were observed. There were no clinically 
significant changes in ECG parameters, vital signs, or laboratory safety test results. 
1.3
BACKGROUND ON MIDAZOLAM
As described in Section 1.2.1, preclinical studies conducted with RO7049389 could not 
exclude in vivo drug-drug interactions (DDIs) between the study drug and CYP3A4 
substrates. Therefore, micro-doses of a clinically validated probe substrate of CYP3A4, 
Midazolam, will be used in this study to evaluate the DDIs of RO7049389 on CYP3A4 
activity (EMA 2012). Midazolam is approved for use as a short-acting benzodiazepine 
and central nervous system depressant. For additional background, see the PI 
(Midazolam, DRUGDEX).
1.4
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.4.1
Study Rationale
This is the first clinical study of RO7049389. The study comprises three parts. 
Part 1 will be conducted in healthy volunteers to assess the safety, tolerability, and 
pharmacokinetics (PK) of orally administered single- and multiple-ascending doses (SAD 
and MAD). The solubility of RO7049389 in bio-relevant media is low and pH-dependent. 
However, physiologically-based pharmacokinetic (PBPK) modeling indicates that the 
absorption of RO7049389 is unlikely to be affected by food at the predicted therapeutic 
dose of 400 mg BID. To confirm this expectation and provide guidance with regard to 
food restriction for subsequent clinical trials, the effect of food on the PK of RO7049389 
will be evaluated in one of the SAD cohorts. 


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In addition, the effect of multiple dosing of RO7049389 on the PK of a single oral 
micro-dose of midazolam (MDZ) will be evaluated in MAD cohorts. Micro-dosing of MDZ 
has been shown to be a safe and an effective means to probe the modulation effect of a 
compound on CYP3A4 activity (EMA 2012). It is being incorporated in this study to 
investigate the weak in vitro signal of time-dependent CYP3A4 inhibition observed with 
RO7049389. Studying a wide range of RO7049389 dose levels will provide a 
comprehensive understanding on the relationship between dose versus CYP3A4 activity 
and help to define the optimal dose-range for Phase II studies from the DDI perspective.
In the MAD cohorts, 4-hydroxycholesterol/cholesterol ratio in plasma will be measured 
as an endogenous marker for hepatic CYP3A4 activity. The correlation between 
midazolam clearance and endogenous substances ratios will be explored in this study.
Part 2 of this study is a proof-of-mechanism (POM) evaluation investigating the 
relationship between systemic RO7049389 exposure and viral PD response in 
chronically HBV-infected patients who will receive study treatment for 28 days. In the
Part 2 POM cohorts, antiviral effect of RO7049389 will be measured by the reduction of 
HBV DNA. 
RO7049389 causes formation of abnormal capsid structure which is subsequently 
degraded, resulting in core protein depletion. Interference of capsid structure directly 
inhibits viral replication process. Therefore, HBV DNA reduction provides evidence of the 
mode-of-action (MoA) of a capsid inhibitor. In studies using mouse models of chronic 
HBV infection, significant reduction of HBV DNA (2-3 logs within 2 weeks) appeared to 
correlate with HBsAg and HBeAg decline at a later time-point. The first-in-patient, 28-
days treatment in Part 2 is not expected to demonstrate HBsAg reduction within the 
planned 4-week dosing, and it is still unclear how the reduction in HBV DNA will be 
correlated with HBsAg reduction in patients with longer treatment duration. Nevertheless, 
it is hypothesized that in human, suppression of HBV DNA will also be the initial efficacy 
marker, followed by reduction in viral antigens. The aim of Part 2 of this study is to select 
a safe and effective dose as the basis for Part 3 of this study and future studies.
Part 3 of the study will assess the efficacy/safety of RO7049389 when administered in 
combination with SoC therapies (a NUC with/without Peg-IFN), for up to 48 weeks. The 
primary objective of Part 3 is to assess HBV DNA <LLOQ with HBsAg loss at 24 weeks 
post-treatment (i.e., rates of functional cure). 
Currently two classes of SoC therapies have been approved for treatment of hepatitis B: 
Peg-IFN and NUCs. Current treatments reduce the risk of CHB sequelae but are 
associated with very low rates of functional cure (HBsAg loss rates generally not 
exceeding 3% after one year of therapy). Combinations of antiviral therapy that target 
different steps in the HBV life cycle to suppress viral replication with immune modulatory 
therapy to restore immune responses to HBV are more likely to be efficacious than 


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monotherapy to achieve sustained loss of HBsAg (functional cure). Thus, administration 
of RO7049389 in combination with NUC with/without Peg-IFN for 48 weeks may provide 
higher rates of functional cure than is observed with SoC therapies alone.
Interim data from Part 2 of this study has demonstrated that RO7049389 administration 
in HBV-infected patients is associated with a good safety and tolerability profile, as well 
as declines in HBV DNA levels (i.e., positive POM). The pre-clinical data in mice 
demonstrated that HBsAg and HBeAg reduction occurred only after maximal DNA 
suppression, which suggests the effect of RO7049389 on viral antigens requires a
longer treatment duration than the 4 weeks explored in Part 2. Thus, Part 3 aims to 
evaluate the effect of RO7049389 after longer treatment duration of up to 48 weeks.
1.4.2
Benefit–Risk Assessment
Part 1 will be conducted in healthy volunteers, and no therapeutic benefit is anticipated 
for these subjects. Part 2 will involve patients chronically infected with HBV. The 
short-term nature of the proposed treatment is not expected to result in functional cure, 
as defined by HBsAg loss. However, the results from Part 2 will provide essential 
information for selecting suitable doses for future studies. Part 3 of the study will also 
involve CHB patients. The longer-duration treatment in combination with SoC aims to 
result in therapeutic benefit for participating subjects, including possibly higher functional 
cure rates than observed currently with SoC therapies (monotherapy with a NUC or Peg-
IFN, or combination therapy with a NUC plus Peg-IFN).  
Before initiation of Part 1, no prior clinical experience with RO7049389 existed. The 
evaluation of the potential risks of treatment and the specific tests, observations, and 
precautions required for clinical studies with RO7049389 were based on information 
from non-clinical toxicology and safety pharmacology studies. Safety and tolerability will 
be carefully assessed, and study subjects (referring to both healthy volunteers and 
patients in the protocol) will be closely monitored. Section 6 of the Investigator’s 
Brochure (Guidance to the Investigator) summarizes key risk management activities to 
consider when dosing this novel compound.
Based on (i) the calculation of a safe starting-dose for the first-in-human study as 
recommended in the Food and Drug Administration (FDA) guidance (FDA 2005), and on 
(ii) exposure multiple calculations, the selected starting-dose of 150 mg is considered to 
be safe (please refer to Section 3.2.1 for details). The target exposure range of 
RO7049389 proposed within this study has been shown to be safe and well-tolerated in 
pre-clinical studies, and 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 RO7049389 or study-related 
procedures are considered to be minimal.


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RO7049389 has shown to be safe and well tolerated when dosed for up to 4 weeks 
treatment in 30 CHB patients in Part 2 of this study. To support the long-term treatment 
(up to 48 weeks) of RO7049389 in Part 3, chronic toxicology studies including a 26-week 
study (120 mg/kg/day [AUC0-24 117 µg h/mL]) in rats and a 39-week study (250 
mg/kg/day [AUC0-24 73.4 µg h/mL]) in mini-pigs have been completed. RO7049389 was 
neither mutagenic nor clastogenic in vitro or in vivo. 
In Part 3 of the study, RO7049389 will be administered on top of SoC. According to the 
draft FDA guidance (FDA 2018), non-clinical combination studies of an investigational 
drug plus an approved drug are not recommended. Therefore, there is no combination 
toxicity study of RO7049389 on top of SoC therapy. However, long-term treatment with 
SoC therapies have shown a highly favorable safety profile. Safety and tolerability will be 
carefully assessed during the study by close monitoring.
2.
OBJECTIVES
2.1
OBJECTIVES FOR PART 1
The primary objectives of Part 1 (healthy volunteers) of this study are as follows:

To assess the safety and tolerability of single and multiple doses of RO7049389.

To characterize the PK of RO7049389.
The secondary objectives of Part 1 of this study are as follows:

To evaluate the effect of food on the PK of RO7049389 after a single dose 
administration.

To evaluate the effect of multiple oral dosing of RO7049389 on CYP3A4 activity 
assessed by the PK of a single oral micro-dose of midazolam.
The exploratory objectives of Part 1 of this study are as follows:

To screen for the presence of metabolites of RO7049389 in selected plasma and 
urine samples.

To evaluate the effect of multiple oral dosing of RO7049389 on CYP3A4 activity 
assessed by plasma 4β-hydroxycholesterol/cholesterol ratio.
2.2
OBJECTIVES FOR PART 2
The primary objectives of Part 2 (patients chronically infected with HBV) of this study 
are as follows:

To assess the safety and tolerability of 4 weeks of treatment with RO7049389.

To investigate the antiviral effect (quantitative HBV DNA level) of 4 weeks of 
treatment with RO7049389.


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The secondary objective of Part 2 of this study is:

To investigate the plasma PK of RO7049389. 
The exploratory objectives of Part 2 of this study are as follows:

To investigate the response relationship between RO7049389 exposure and HBV 
DNA

To explore other viral response outcomes (e.g., quantitative HBeAg, loss of HBeAg, 
HBeAg seroconversion, quantitative HBsAg, loss of HBsAg, HBsAg seroconversion) 
after 4 weeks of treatment with RO7049389.

Exploratory liver biomarkers will be examined.

To investigate metabolites of RO7049389 in selected plasma samples.
2.3
OBJECTIVES FOR PART 3
The primary objective of Part 3 (patients with chronic hepatitis B) of this study is:

To evaluate anti-viral effect (functional cure) of treatment with RO7049389 on top of 
Standard of Care (SoC). 
o
Functional cure is defined as HBV DNA < lower limit of quantification 
(LLOQ, 20 IU/mL) with HBsAg loss (<0.05 IU/mL) at 24 weeks post-
treatment.
The secondary objectives of Part 3 of this study are as follows:

To further characterize the efficacy profile of RO7049389 on top of SoC over time, 
including HBsAg loss, HBsAg seroconversion, quantitative HBsAg change from 
baseline, HBeAg loss, HBeAg seroconversion, quantitative HBeAg change from 
baseline, HBV DNA < LLOQ, HBV DNA change from baseline in different proof of 
mechanism (POM) cohorts of Part 3 and in subgroups of baseline HBeAg +/-
patients, or of baseline high / low HBsAg level patients.

To assess other viral response outcomes (including HBV core-related antigen levels, 
anti-HBc antibody, quantitative HBV RNA, etc.) over time.

To assess the ALT normalization in patients with baseline ALT elevation.

To characterize the plasma PK profiles of RO7049389 and its metabolites.

To assess the long-term safety and tolerability of RO7049389 on top of SoC (a NUC 
with or without Peg-IFN).

To assess the PK interaction between NUCs and RO7049389.

To assess HBV genotypic resistant variants associated with virologic failure.
The exploratory objectives of Part 3 of this study are as follows:

To explore other viral response outcomes (i.e., total HBsAg) over time.


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
To explore relationship between exposure and efficacy/safety response (e.g., 
HBsAg, HBV DNA, etc.).

To explore safety, PK, and antiviral activities of RO7049389 in different ethnic 
subpopulations (e.g., Caucasian versus Asian).

To assess effect of treatment on liver stiffness.

To explore relationship between baseline disease characteristics (e.g., HBeAg 
status, viral load, HBV genotype based on DNA or RNA or historical data, etc.) and 
efficacy/safety response.

To explore the effect of the genetic polymorphism of CYP3A4, UGT1A3 and 
OATP1B on the PK of RO7049389 by clinical genotyping.

To explore the PK interaction among NUCs, Peg-INF and RO7049389.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
Study YP39364 is a first-in-human study comprised of three parts. 
Part 1 of the study will evaluate safety, tolerability, and PK of RO7049389 following oral 
administration of single (Parts 1a and 1b, Figure 1) or multiple (Part 1c) doses in healthy 
volunteers. The effect of food on the PK of RO7049389 will be evaluated within one of 
the SAD cohorts (Part 1b). Drug interaction with micro-dose midazolam will be assessed 
in all MAD cohorts (Part 1c). There will be no midazolam dosing in SAD cohorts (Part 1a 
and 1b). In Part 1 of the study, approximately 93 healthy volunteers will be enrolled. A 
Bayesian adaptive approach, i.e., Continuous Reassessment Method (CRM) will be 
used, alongside scientific and clinical judgment, to inform decisions about the dose of 
RO7049389 to be given to the next cohort during dose-escalation, as well as to identify 
the maximum tolerated dose (MTD).
Part 2 of the study will evaluate the safety, tolerability, PK and PD of RO7049389 
following oral administration in patients chronically infected with HBV (Figure 1). In Part 
2 of the study, approximately 35 patients will be enrolled.
Part 3 of the study will evaluate the safety, tolerability, PK, PD, and efficacy of 
RO7049389 following oral administration on top of SoC therapies (a NUC with/without 
Peg-IFN) in NUC-suppressed or treatment-naive CHB patients (Figure 2). Initially, 
approximately 55 patients are planned in the first three cohorts of Part 3. Based on 
emerging efficacy/safety data, the sample size in Cohort C can be increased to 
approximately 30 patients. In addition, additional treatment cohorts may be opened to 
explore different treatment durations, dose regimens, or different combinations.


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Figure 1
Study Design (Parts 1 & 2)
Figure 2
     Study Design (Part 3)
If there are no safety and PK concerns during the dose-escalation, the planned study 
procedures are as follows:

Cohort 1 in the SAD arm of the study (Part 1a) will receive a single-dose of 150 mg 
(see Section 3.1.2 for rationale). Doses for subsequent cohorts will be defined by an 
adaptive approach based on the safety and PK data in previously-dosed healthy 
subjects (refer to Section 3.2.1 for details).

The effect of food on the PK of RO7049389 will be evaluated within one of the SAD 
cohorts (Part 1b). The food-effect cohort will be selected such that the expected 
exposure of RO7049389 will be efficacious, based on the safety and PK data from 
previous SAD cohorts, and estimated efficacious target from non-clinical data.


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
Cohort 1 in the MAD arm of the study (Part 1c) will start when exposure in the SAD 
dose level has reached 0.5-fold or higher of the predicted efficacious exposure. The 
starting dose of the MAD arm of the study will be chosen such that the expected 
steady-state exposure of RO7049389 will be 0.5-fold of the expected efficacious 
exposure or higher, but less than, or equal to, the exposure that has been explored 
and well-tolerated in previous SAD cohort(s).

Cohort 1 in Part 2 of the study will start when steady-state exposure in the MAD 
dose level has reached 0.5-fold or higher of the projected efficacious exposure. The 
starting dose of Part 2 of the study will be chosen such that the expected 
steady-state exposure of RO7049389 will be less than, or equal to, the exposure 
that has been explored and well-tolerated in the previous MAD cohort(s).

If MTD in SAD part of the study is reached at an exposure level which is lower than 
0.5 -fold of the estimated efficacious exposure, MAD will start at a dose level less 
than MTD in SAD. 

If MTD in MAD part of the study is reached at an exposure level which is lower than 
0.5-fold of the estimated efficacious exposure, POM will start at a dose level less 
than or equal to MTD in MAD. 

Doses and dosing regimens in the cohorts of Part 3 will be selected based on 
accumulated PK, PD, efficacy and safety data from this study or other related 
studies, as well as exposure and safety data from chronic GLP tox studies. 
If any safety or PK concerns emerge during the study, the planned cohorts may be 
adjusted. Details are described in the relevant sections of the protocol. Details on 
efficacious target from non-clinical data are described in Section 3.2.1.
3.1.1.1
Part 1a: Single-Ascending Dose (SAD) in Healthy Subjects
Part 1a is a randomized, sponsor-open, investigator-blinded, subject-blinded, placebo-
controlled, adaptive single-ascending dose study. This part of the study consists of 
approximately 5 planned dose levels with four or five healthy volunteers in each. An 
additional 1-2 cohorts may be enrolled to evaluate additional doses as needed based on 
emerging data. Up to two back-up subjects can undergo the preparatory activities in 
order to replace participants who withdraw from the study for non-safety reasons.
The first cohort of the SAD arm of the study will be split into two groups. Initially, two 
healthy volunteers will be dosed, one with RO7049389, and one with placebo. Following 
acceptable safety assessment of the first two healthy volunteers by the Investigator, and 
at least 24 hours after the initial administration, three more healthy volunteers will be 
dosed, two with RO7049389, and one with placebo. 
For subsequent cohorts in Part 1a, a minimum of 4 HVs will be enrolled in a 3:1 ratio to 
receive RO7049389 and placebo. The sample size may be increased to 8, with 6 
volunteers receiving RO7049389 and 2 receiving placebo at dose levels at or above the 
projected efficacious exposure.


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The doses in this part will be administered under fasted condition (see Section 4.3.2 for 
detail).
Healthy volunteers enrolling for Part 1a of the study, and who do not go on to participate 
in Part 1b, will be in the study for approximately 8 weeks, as follows (and in Table 1):
Eight healthy volunteers from Part 1a will go on to participate in Part 1b of the study, 
described below.
Table 1
High-level Overview of Study Procedure: Part 1a (SAD)
3.1.1.2
Part 1b: Food Effect in Healthy Subjects
Part 1b is a sponsor-open, investigator-blinded, subject-blinded, placebo-controlled, two-
period (fasted, fed) sequential food-effect study in healthy volunteers. Part 1b will include 
a minimum of 8 healthy volunteers from one of the dose levels of Part 1a, 6 of whom will 
have received RO7049389, and 2 of whom will have received placebo. In the first period 
of the Part 1b, up to 2 back-up subjects can undergo the preparatory activities in order to 
replace participants who withdraw from the study for non-safety reasons. The dose at 
which food-effect will be assessed is that which is projected to be efficacious based on 
emerging PK data from previous cohort. The fed dose will occur when:

The safety and available PK data through 24 hours post-dose from the fasted 
dosing were reviewed.

The fasted dose was considered well-tolerated and there is agreement to continue 
to the next dose escalation.

The selected dose level is agreed by both the Sponsor and the Investigator.

The allocation of RO7049389 or placebo and the dose administered will be the 
same as that which was administered in the fasted state.

The eight healthy volunteers from Part 1a will be asked to return to the study unit on 
Day 15 after the initial dose of RO7049389.
Volunteers will be administered a single-dose of RO7049389, or placebo, on Day 16 in 
the fed state. ‘Fed state’ will be after eating the standard US FDA-recommended high-fat 
and high-calorie breakfast. Specific details on the content of the high-fat meal are 
provided in Appendix 9.


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Healthy volunteers enrolling for Part 1b of the study will be in the study for approximately 
10 weeks, from screening in Part 1a, through study completion in Part 1b, as follows 
(and in Table 2):
Table 2
High-level Overview of Study Procedure: Part 1b (FE)
3.1.1.3
Part 1c: Multiple-Ascending Dose (MAD) in Healthy Subjects
Part 1c is a randomized, sponsor-open, investigator-blinded, subject-blinded, placebo-
controlled, adaptive, multiple-ascending dose study. Up to 5 cohorts of 8 healthy 
volunteers will be enrolled. In each cohort, 6 healthy volunteers will be randomized to 
receive RO7049389, and 2 will be randomized to receive placebo. The dose and dosing 
regimen of MAD cohort 1 would be determined based on PK and safety data from 
available SAD cohorts. Based on emerging PK and safety evaluation from initial cohorts, 
additional cohorts may be enrolled to receive a higher or lower dose, or a different 
regimen. Up to 2 back-up subjects can undergo the preparatory activities in order to 
replace participants who withdraw from the study for non-safety reasons. Potential drug 
interaction with micro-dose midazolam will be assessed in all MAD cohorts.
Healthy volunteers in the first MAD cohort will be dosed with RO7049389 for 13 days 
(QD or BID regimen, depending on available PK and safety data). On Day 14, only one 
dose in the morning will be given regardless of the dosing regimen. A single oral dose of 
midazolam solution (100 g) will be administered on Day -1 and Day 14 (see 
Section 4.3.1.2).
Healthy volunteers enrolling for Part 1c of the study will be in the study for approximately 
10 weeks from screening through to study completion as follows (see also Table 3):
Table 3
High-level Overview of Study Procedure: Part 1c (MAD)
Ambulatory Visit
↓
↓
19 20
 15     16     17    18
Activities
Day
Study Drug
23 (±1)
44 (±3)
Screening
In-Clinic Period
Follow-up Visit
Follow-up Call
N/A
           ▲
-28
-3
-2
-1
1
2
…
13
14
15
16
42 (±3)
△
△
▲
▲…
▲
▲
▲
▲…
▲
a If PK data from SAD cohorts support QD regimen, subjects will be dosed for two weeks once daily
In-Clinic Period
Day
21 (±1)
Midazolam
Study Druga
Activities
Screening
Follow-up 
Visit
Follow-up 
Call


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3.1.1.4
Part 2: Proof-of-Mechanism (POM) in Patients with Chronic 
HBV Infection
Part 2 is a multi-center randomized, sponsor-open, investigator-blinded, subject-blinded, 
placebo-controlled, adaptive multiple-dose study in chronically HBV-infected patients. 
Five cohorts are planned. In each cohort, six patients will be randomized to receive 
RO7040389, and one will be randomized to receive placebo. Based on emerging PK 
and safety evaluation from previous cohorts, additional cohorts may be enrolled based 
on emerging data and development needs. Due to the adaptive nature of the study, the 
actual number of dose levels will be determined during the study. Up to two back-up 
subjects can undergo the preparatory activities in order to replace participants who 
withdraw from the study for non-safety reasons.
Patients will be dosed twice daily with RO7049389 for 27 days. On Day 28, only one 
dose in the morning will be given. Depending on the PK and safety evaluation from 
available data, a QD regimen may be used instead of BID dosing. Patients will have the 
option of two brief in-clinic stays, as described in the SoA (see Appendix 5).
Patients enrolling for Part 2 of the study will be in the study for approximately 20 weeks 
from screening through to study completion as follows (see also Table 4):
Table 4
High-level Overview of Study Procedure: Part 2 (POM)
a. If PK data from previous dose cohorts support QD regimen, subjects will be dosed for 28 days 
once daily
b. Patients will have an option to be housed in the clinical unit for two nights from Day -1 to Day 2 
and for three nights from Day 27 to Day 30.
3.1.1.5
Part 3: Proof-of-Mechanism (POM) in Patients with Chronic 
Hepatitis B 
Part 3 is a multi-center, open-label, non-controlled, adaptive, multi-arm study in CHB 
patients. Initially, three cohorts (A-C) are planned to enroll approximately 30 patients in 
POM Cohort A, 10 patients in POM Cohort B, and 15 to 30 patients in POM Cohort C
to receive RO7049389 on top of SoC therapies. 
Both HBeAg positive and negative patients will be enrolled, and at least 30% of patients 
enrolled in each cohort will be HBeAg positive. In order to evaluate pharmacokinetics, 
pharmacodynamics and safety in different ethnic subgroups, the Sponsor may postpone 
or stop enrolment of certain patient subgroups to achieve suitable balance across the
groups. 
Activities
Day
-28
-2
-1
1
2
3
4
…
8
…
15
…
22
…
28
29
84 
(±2 Weeks)
112 
(±2 Weeks)
Study Druga
▲
▲
▲
▲
…
▲
…
▲
…
▲
…
▲
▲
▲
▲
▲
…
▲
…
▲
…
▲
…
35 
(±1 Day)
56 
(±3 Days)
Screening
Ambulatory Visitb
Follow-up Visits


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Due to the adaptive and exploratory nature of the study, the sample size of existing 
cohorts can be increased and additional cohorts of different treatment regimens or 
treatment durations can be started, based on emerging clinical data. 

POM Cohort A will enroll NUC-suppressed CHB patients. Patients will receive 
RO7049389 on top of a NUC for 48 weeks. RO7049389 will be administered at a 
dose determined from study Part 2. NUC therapy (entecavir, tenofovir alafenamide, 
or tenofovir disoproxil fumarate as per investigators decision) will be administrated 
as per local label or guidelines.

POM Cohort B will enroll treatment-naïve immune-active CHB patients. Patients will 
first receive RO7049389 only for 4 weeks to compare PK, safety, and its effect on 
HBV DNA declining in different ethnic subgroups when RO7049389 is used alone. 
Then a NUC will be added on for another 44 weeks. RO7049389 will be 
administered at a dose determined from study Part 2. NUC therapy (entecavir, 
tenofovir alafenamide, or tenofovir disoproxil fumarate as per investigators decision) 
will be administered as per local label or guidelines. 

POM Cohort C will enroll treatment-naïve immune-active CHB patients. Patients will 
receive RO7049389 + NUC + Peg-IFN therapy for 48 weeks. RO7049389 will be 
administered at a dose regimen determined from study Part 2. NUC (entecavir, 
tenofovir alafenamide, or tenofovir disoproxil fumarate as per investigators decision) 
and Peg-IFN therapy will be administered as per local label or guidelines. For Peg-
IFN therapy, there are stopping rules recommended in major guidelines 
(2018 AASLD, 2017 EASL, 2015 APASL guidelines). These criteria were developed 
based on Peg-IFN monotherapy data and may or may not be applicable to this 
investigational combination (NUC + RO7049389 + Peg-IFN). Investigators may refer 
to these stopping rules to individualize Peg-IFN treatment duration in this study. For 
patients who stop Peg-IFN early due to intolerability or meeting some stopping 
criteria, NUC and RO7049389 should be continued till 48 weeks. The reasons of 
stopping Peg-IFN and length of treatment duration should be clearly recorded on 
CRF.
At the end of study treatment (EOT) visit, stop RO7049389 and Peg-IFN (if used), but 
NUC therapy is expected to be continued as Standard of Care (SoC) with the exception 
of patients who achieve NUC Stopping Criteria: HBsAg < 100 IU/mL and HBV DNA < 
LLOQ (20 IU/mL) at EOT visit. NUC should be continued until central lab results from 
EOT visit become available and NUC Stopping Criteria are met.
The sample size of individual cohorts range from 10 to 30, and may be increased to 30 
subjects if considered warranted by emerging efficacy/safety data. In addition, based on 
emerging clinical data, additional cohorts may be enrolled to explore alternative 
combination regimens (e.g., shorter treatment duration of 12 or 24 weeks).
Patients enrolling for Part 3 of the study will be in the study for approximately 76 weeks 
from screening to study treatment and follow up as shown in Table 5. The screening 


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period will be up to 4 weeks. The treatment period will be for a maximum of 48 weeks 
followed by 24 weeks Follow-up period.
Table 5
High-level Overview of Study Procedure: Part 3 (POM)
Screening
Treatment period
Follow-up period
Early 
Termination/
Study Drug 
Discontinuation
Protocol Activity
Day 
-28 to -
2
Day 
-1
Day
1
2w
±3d
4w
±3d
8-48w
±6d
(Every 4 
weeks)
56 72w ±6d
(Every 8 weeks)
50-60w±3d
(Every 2 
weeks) a
64-72w±6d
(Every 4 
weeks) a
Dispense 
RO7049389 and/or 
provide SoC
x
x
x
Safety evaluation
x
x
x
x
x
x
x
Efficacy 
assessment 
x
x
x
x
x
x
x
a. Only applicable to participants who meet NUC Stopping Criteria at the EOT visit.
3.1.2
Dose-Related Decision Criteria
Dose-related decisions will be made jointly by the Sponsor’s Clinical Team and the 
Investigator(s). Doses may be repeated, reduced or escalated based on emerging safety, 
tolerability, PK data and/or observations on viral dynamic response (Part 2 only) at each 
dose-level. The dose-escalation decision will be submitted to Ethics Committee (EC) 
and/or Health Authorities (HA) per local requirement.
The decision to escalate to the next dose-level or to add an additional cohort at a 
previously-studied dose will be based primarily on safety and tolerability data, and 
secondarily on available PK data, at the previous dosage level. In addition, all available 
safety, tolerability, and PK data from the previous dose-level(s) will be reviewed.
The decision to escalate to the next dose level will be made following review of the 
following data from the completed cohort: 

All available safety information, including adverse events (AEs), electrocardiograms 
(ECGs), vital signs, clinical laboratory test results collected up to 48 hours post-dose 
(Part 1a) or post-last dose (Part 1c and Part 2).

Adequate PK data over at least 24 hours post-dose (Part 1a) or at steady-state (Part 
1c and Part 2) to characterize the PK and predict exposure in the following cohort(s).

Pre-clinical data suggest above-proportional increases in exposure. 
Hence, PK data is needed for dose escalation.

Available viral dynamic response data will also be considered in dose-decisions in 
Part 2 of the study.
Dose-escalation will continue according to the protocol until the MTD is identified, or the 
systemic exposure reaches the exposures observed at the NOAEL in mini-pig from the 
GLP toxicity studies (AUCss of 117,000 ng h/mL and Cmax of 18588 ng/mL). Potential 


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exploration of exposure beyond the NOAEL in the mini-pig will not occur unless 
approval is received from the Ethics Committees of the study sites.
Safety and tolerability data from all 5 subjects in SAD Cohort 1 will be required for the 
dose-escalation decision of Cohort 2. Except for SAD Cohort 1, evaluable safety and 
tolerability data from a minimum of 4 subjects in SAD cohorts, 6 subjects in MAD cohorts, 
and 5 patients in POM cohorts will be required in order to make the decision to escalate 
to the next dose.
3.1.2.1
Part 1a: SAD
A dose may not be escalated to more than 3-fold increase in AUC0-∞ from one cohort to 
the next, except in the case where the observed exposure of SAD Cohort 1 in Part 1a of 
the study is substantially below the predicted values. Given the uncertainty of the 
predicted exposure of RO7049389, PK data from SAD Cohort 1 will be examined after 
completion of dosing of all subjects from the cohort. In case the observed exposure of 
this cohort is substantially below the predicted values, the dose-level for SAD Cohort 2 
may be adjusted to reach the originally-expected exposure level for the starting-dose. 
The dose-escalation thereafter will follow an adaptive approach. This procedure will limit 
the number of subjects going through the study procedures at a non-informative 
low-dose.
3.1.2.2
Part 1c: MAD
The dose-range and dosing regimen in MAD cohorts in Part 1c of the study will be 
determined based on available safety, tolerability, and PK data from the available SAD 
cohorts. The mean predicted steady-state AUC0-τ and Cmax values of the highest MAD 
dose will not substantially exceed the mean AUC0-∞ and Cmax values for the highest safe 
and well-tolerated single-dose studied in the SAD cohorts.
A dose may not be escalated to more than 3-fold increase in AUC0-from one cohort to 
the next. Dose-escalation will continue according to the study design until the MTD is 
identified or the systemic exposure reaches the exposure which is around 10-fold above 
the projected efficacious exposure or the exposure attained at NOAEL in the mini-pig. 
The MTD is defined by the incidence of dose-limiting events (DLEs). A DLE will be 
defined as any treatment-related adverse reaction per investigators assessment (e.g., 
adverse event, laboratory abnormality, change in vital signs, ECG) that would prevent 
another drug administration at the same dose level in a given study subject.
3.1.2.3
Part 2: POM
Doses and dosing regimen in Part 2 of the study will be determined based on available 
safety, tolerability, and PK data and also guided by adaptive approach with consideration 
of predictive models for safety and viral dynamic response as a function of exposure. 
Based on the PK and safety evaluation of the initial and previous dose cohorts, 


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subsequent cohorts may be enrolled to receive a higher or lower dose or different 
regimen.
3.1.2.4
Part 3: POM
Doses and dosing regimens in Part 3 of the study will be determined based on 
accumulated safety, tolerability, PK, and PD data from this study, as well as the other 
related studies. The total daily dose will not exceed 800 mg while 1000 mg QD and 400 
mg BID have been demonstrated to be safe and well tolerated in Part 2. For parent drug, 
the projected mean unbound exposure in Part 3 should not be higher (safety margin 
≥1.0) than the NOAEL mean unbound exposure in animals (including the 39-week study 
in mini-pigs). For the metabolites, the projected mean unbound exposure in Part 3 
should not be substantially higher (metabolites safety margin ≥ 0.7) than the NOAEL 
mean unbound exposure in animals (including the 39-week study in mini-pigs). 
3.1.3
Dose-Escalation Stopping Criteria
Planned dose-escalation will be stopped if one of the following circumstances occurs in 
healthy volunteers or patients treated with RO7049389, unless it is obvious that the 
occurrence is not related to the administration of study drug. 
At a given dose-level, more than one third of subjects on active drug experience:

Severe or clinically significant (as defined by the Investigator) RO7049389-related 
AEs of the same character.

Clinically significant RO7049389-related laboratory abnormality of the same 
character.

Clinically significant RO7049389-related changes in vital signs or ECGs of the same 
character (e.g., QT corrected for heart rate using the Fridericia correction factor 
(QTcF) 500 msec, or 60 msec longer than the pre-dose baseline, within the first
48 hours post-dose).

It is predicted that further dose-escalation will not result in a further increase in 
plasma exposure.

Systemic exposure (AUC or Cmax) reaches the NOAEL after single-dose or at 
steady-state after repeated dosing. Potential exploration of exposure beyond the 
NOAEL in mini-pig will not occur unless approval is received from the Ethics 
Committees.

Other findings (regardless of the incidence rates) that, at the joint discretion of the 
Sponsor and the Investigator, indicate dose-escalation should be halted.
In case the dose-escalation is stopped, lower doses could be investigated, or a dose 
could be repeated in the subsequent cohorts by mutual agreement between the Sponsor 
and Investigator.
For discontinuation from study drug for an individual study subject, see Section 4.6.1.


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3.1.4
End of Study
The end of the study is defined as the date when the last study subject last observation 
(LSLO) occurs. LSLO is expected to occur 24 weeks after the last dose is administered 
in Part 3.
3.2
RATIONALE FOR STUDY DESIGN
The rationale for the design of study YP39364 is given in Section 1.4.1.
3.2.1
Rationale for Dosage Selection
Dose selection in all parts of the study will be guided by adaptive approach. A continual 
re-assessment method (CRM), with control for the probability of over-dosing, based on 
occurrence of dose-limiting event (DLE) will be used to inform the decision about the 
dose of RO7049389 to be given to the next cohort during dose escalation.
3.2.1.1
Part 1a: SAD
Starting-dose selection is pharmacology-driven and supported by non-clinical safety 
data. Caverage of 290 ng/mL total plasma concentration is considered efficacious and 
projected to provide two-log DNA reduction based on mouse models of chronic HBV 
infection. The proposed starting dose of 150 mg is predicted to provide total plasma 
Caverage concentration of 55 ng/mL, which is around one-fifth of that which is expected to 
be efficacious in humans.
The 4-week GLP-toxicology studies defined the NOAEL as 250 mg/kg/day and 
350 mg/kg/day in rats and mini-pigs, respectively. These doses convert to human 
equivalent doses (HED) of 40 mg/kg and 318 mg/kg, respectively. Using the lowest HED 
of 40 mg/kg from the rats NOAEL calculation and a safety factor of 10, the maximum 
recommended starting-dose (MRSD) for a 60 kg individual is 240 mg. The starting-dose 
of 150 mg proposed in this study is approximately 1.6-fold lower than the MRSD and is 
one fifth of the expected efficacious target (400 mg BID).
The human PK of RO7049389 was predicted using physiologically-based 
pharmacokinetic modelling. Based on hepatocytes data, hepatic metabolic plasma 
clearance in human was predicted to be 7.6 mL/min/kg. The prediction of RO7049389 
absorption was based on solubility, permeability, and pH solubility profile. The volume of 
distribution in man was estimated to be 0.9 L/kg. Based on a predicted human clearance 
of 7.6 mL/min/kg, volume of distribution of 0.9 L/kg, and a bioavailability of 28%, a 
single-dose of 150 mg is expected to lead to a AUC0-∞ of 1331 ng h/mL and Cmax of 
169 ng/mL. These predicted exposures are approximately 88- and 110-times lower than 
the systemic exposures observed at NOAEL in mini-pig from GLP toxicity study (AUCss
of 117,000 ng h/mL and Cmax of 18588 ng/mL).
In summary, a single-dose of 150 mg is considered to be a safe starting-dose for this 
entry-into-human (EIH) study. The dose-range proposed for this part of the study is 


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150 mg to MTD, or until the systemic exposure reaches the exposure attained at NOAEL 
in mini-pig.
3.2.1.2
Part 1b: Food Effect
The purpose of Part 1b of the study is to determine dosing instructions with regard to 
food for Part 1c and Part 2 of the study, as well as the future clinical studies. A dose in 
the middle of the planned dose-range will be selected in attempt to generate data that 
can reasonably cover the entire dose-range, including potential dose-levels in Part 1c 
and Part 2.
3.2.1.3
Part 1c: MAD
Based on single-dose RO7049389 safety and PK data, dose-range and dosing regimen 
for Part 1c cohorts will be determined. The dose-range in MAD cohorts in Part 1c of the 
study will be determined based on available safety, tolerability, and PK data from the 
SAD cohorts in Part 1a. The mean predicted steady-state AUC0-τ and Cmax values of the 
highest MAD dose will not substantially exceed the mean AUC0-∞ and Cmax values for the 
highest safe and well-tolerated single-dose studied in the SAD cohorts.
3.2.1.4
Part 2: POM
In addition to PK and tolerability in chronically-infected patients, Part 2 of the study will 
investigate the short-term effect of RO7049389 on the viral dynamics in humans during 
4 weeks of treatment at different dose-levels. The response profiles and the relationship 
between the viral dynamics and the exposure of RO7049389 will be characterized. 
These findings, in combination with the tolerability and safety observations in patients, 
will be used to support further clinical studies, such as dose-selection for subsequent 
clinical studies.
The starting-dose of Part 2 (POM study) will be a dose that has been studied and 
considered to be well-tolerated in Part 1c (MAD). Subsequent doses can be higher or 
lower than the starting-dose, and will be selected using PK, tolerability/safety, and viral 
dynamic response data.
The highest dose level for this study will not markedly exceed the observed mean 
exposures of RO7049389 from the highest dose level considered to be well-tolerated in 
healthy subjects. Predictions on the drug exposure will be based on the PK of 
RO7049389 from the cumulative data and analyses through the study.
3.2.1.5
Part 3: POM
Part 3 of the study will investigate the efficacy/safety of RO7049389 when administered 
on top of SoC therapies for up to 48 weeks. The doses and dosing regimen in Part 3 will 
be determined based on accumulated data from this study and related studies, but the 
total daily dose will not exceed 800 mg while 1000 mg QD and 400 mg BID have been 
demonstrated to be safe and well tolerated in Part 2. For parent drug, the projected 
mean unbound exposure in Part 3 should not be higher (safety margin ≥1.0) than the 


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NOAEL mean unbound exposure in animals (including the 39-week study in mini-pigs). 
For the metabolites, the projected mean unbound exposure in Part 3 should not be 
substantially higher (metabolites safety margin ≥0.7) than the NOAEL mean unbound 
exposure in animals (including the 39-week study in mini-pigs). Based on the PK, 
efficacy, and safety evaluation of the initial cohorts (A-C), subsequent cohorts may be 
added to receive a higher or lower dose or different regimen.
3.2.2
Rationale for Assessing Midazolam Pharmacokinetics
An important aspect of drug development is to predict clinically-relevant drug-drug 
interactions. Based on in vitro data, RO7049389 is a weak CYP3A time-dependent 
inhibitor. This study will assess the effect of RO7049389 on CYP3A4 inhibition as 
measured by midazolam systemic exposure at all the dose levels tested in the MAD 
cohorts. At the early stage of drug development, it is often challenging to choose a 
therapeutically-relevant dose to assess drug interaction potentials. Studying a wide 
range of RO7049389 dose levels will provide a comprehensive understanding on the 
dose versus CYP3A4 inhibition relationship and help to define the optimal dose-range 
for Phase II studies from the DDI perspective.
Midazolam is a short-acting drug in the benzodiazepine class. It is selected because it is 
exclusively metabolized by CYP3A4, it is not a substrate of P-glycoprotein and it has 
been validated in a number of studies. It is a recommended ‘sensitive’ model substrate 
for CYP3A4 by Regulatory Agencies and is the most widely-used CYP3A4 probe 
substrate across the literature (EMA, 2012). As the majority of co-medications in the 
targeted patient population are administered by the oral route, the oral administration of 
midazolam is selected, which will reveal the net effect of possible intestine and liver 
CYP3A4 inhibition.
In humans, it has been shown that oral midazolam PK is linear in a range of 0.1 g to 
3 mg (30,000-fold). Therefore, PK from nano- and microgram doses of midazolam can 
reliably predict its PK at milligrams dose-level, which are often used in clinical drug 
interaction studies (Halama et al., 2013). Also, it is reported that the folds of CYP3A4 
inhibition detected by micro-dose of midazolam were similar to those by therapeutic 
dose of midazolam, suggesting this unobstructive micro-dose approach can be used to 
assess CYP3A4 activity as an alternative to the regular approach with milligrams dose 
level of midazolam. 
The recommended oral dose of midazolam for pre-operative sedation, anxiolysis, and 
amnesia in pediatric patients is 0.25 to 0.5 mg/kg with a maximum dose of 20 mg 
(Midazolam, DRUGDEX). The dose-selection for midazolam in this study (100 g) is far 
lower than the therapeutic dose-levels and considered micro-dose according to the ICH 
guidance (ICH guideline M3).


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Giving 100 µg of midazolam to the study participant is not expected to affect the safety 
assessment of RO7049389 when given together on Day 14. The estimate of average 
CYP3A4 half-life ranges from 26 to 140 hours (Yang et al., 2008). The 14-day treatment 
duration of RO7049389 allows the achievement of approximate steady-state of CYP3A4 
induction and maximizes the possibility of demonstrating an interaction with a CYP3A4 
substrate.
3.2.3
Rationale for Measuring 4-Hydroxycholesterol/Cholesterol 
Ratio
In the MAD cohorts, in Part 1c of the study, 4-hydroxycholesterol/cholesterol ratio in 
plasma will be measured as an endogenous marker for hepatic CYP3A4 inhibition. 
4-hydroxycholesterol is a metabolite formed by CYP3A4 and CYP3A5-catalyzed 
metabolism of cholesterol (Björkhem-Bergman et al., 2013).
The ratio of metabolite to parent will be calculated to adjust for between-subject 
differences in cholesterol levels. This ratio has been used to assess CYP3A4 activity in 
humans and has been shown to have concordance with the midazolam method. Unlike 
midazolam, which is extensively metabolized by the intestinal and liver CYP3A4, the 
metabolism of cholesterol in the intestine is not expected to be significant. Hence, the 
magnitude of the induction determined by oral midazolam can be greater than by 
4β-hydroxycholesterol/cholesterol as it mostly reflects liver CYP3A4 only.
Correlation between midazolam clearance and endogenous substances ratios will be 
explored in this study. If CYP3A4 activity needs be monitored for future RO7049389 
clinical studies, the 4-hydroxycholesterol/cholesterol ratio, instead of midazolam, can 
be conveniently employed in such studies.
3.2.4
Rationale for Study Population
3.2.4.1
Part 1: SAD and MAD in Healthy Volunteers
The Part 1 section of the study will be conducted in healthy male and female volunteers 
of non-childbearing potential, 18 to 60 years of age. The absence of confounding 
diseases and co-medications in healthy volunteers allows for a clearer and more 
consistent assessment of drug disposition and safety profile.
3.2.4.2
Part 2: Patients with Chronic HBV infection
Part 2 (POM) of the study will be conducted in patients with chronic HBV infection, who 
are HBV treatment-naïve, or have stopped HBV treatment for more than 6 months. Both 
HBeAg-positive (immune-tolerant/immune-active) and HBeAg-negative patients can be 
enrolled in the study. All the enrolled patients will have a HBV DNA level at 
minimal2104 IU/mL for HBeAg positive patients, or 2103 IU/mL for 
HBeAg-negative patients. This will allow for the detection of antiviral activity, given that 
HBV DNA reduction is the direct evidence of primary MoA of RO7049389. The dynamics 
of HBV DNA readout will be used for dose-selection for a Phase II study in patients with 


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chronic HBV infection. The PK and safety of RO7049389 will also be evaluated in this 
population.
3.2.4.3
Part 3: Patients with Chronic Hepatitis B
Part 3 of the study will be conducted in both NUC-suppressed and treatment-naïve CHB 
patients and will include both HBeAg positive and negative CHB patients. 
It was shown that minimizing the HBV viral load by antivirals increases the 
responsiveness of HBV specific T-cells which are hypo-responsive in cases of persistent
HBV infection, and that HBV DNA suppression is an essential requirement for the 
functional reconstitution of anti-HBV T cell responses (both CD4 and CD8) (Boni et al 
1998; Boni et al 2001; Boni et al 2003). RO7049389 will contribute to combination 
regimens with one or more antiviral agents with different mode of actions or immune-
enhancer (e.g., IFN), with the aim of inducing a functional cure. Therefore, treatment 
with NUCs should provide a good basis for addition of RO7049389 and increase the 
possibility of functional cure. 
POM Cohort B and C will enroll treatment-naïve and immune-active CHB patients. 
These patients are indicated to initiate SoC antiviral therapy according to the current 
major HBV guideline (2018 AASLD, 2017 EASL, 2015 APASL guidelines). Elevated ALT 
and HBV DNA levels will allow for the characterization of antiviral activity (on both HBV 
DNA and HBsAg) of RO7049389 on top of SoC. In addition, in the immune-active phase, 
the host immune response to HBV is increased. HBeAg/HBsAg seroconversion may 
occur in this phase. Therefore, an exploration of antiviral effects in treatment naïve and 
immune-active patients will bring value in scientific understanding of RO7049389 on top 
of SoC.
3.2.5
Rationale for Biomarker Assessments
RO7049389 is an inhibitor of HBV capsid assembly. The molecule induces formation of 
abnormal HBV core protein aggregates, which are subsequently recognized and 
depleted. Depleting functional core protein results in interruption of viral assembly, 
inhibition of HBV replication, and reduction of HBV DNA. Blood samples for quantitative 
or qualitative determination of HBV DNA and other viral parameters will be collected at 
the time-points indicated in the SoA.
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.

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, 
coagulation, and urinalysis test results, etc.

ECGs.


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
Vital signs including blood pressure (BP), pulse rate and body temperature.
3.3.2
Pharmacokinetic Outcome Measures
Blood and urine samples will be collected to evaluate the PK, as specified in the SoA. 
RO7049389 plasma and urine concentrations will be measured by specific validated 
methods. PK parameters will be estimated using standard non-compartmental methods 
for RO7049389.
RO7049389 and its metabolites (M5, M6 and M11, if applicable) parameters in Parts 1a 
(SAD) and RO7049389 parameters in Part 1b (SAD and Food Effect):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-last: area under the plasma concentration versus time curve up to the last 
measurable concentration.

AUC0-∞: Area under the plasma concentration versus time curve extrapolated to 
infinity.

T1/2: Apparent terminal phase half-life.

CL/F: Apparent clearance after oral administration.

Ae (Cumulative amount excreted unchanged in the urine) and CLR (Renal 
clearance, computed as Ae/AUC), if warranted.
RO7049389 and its metabolites (M5, M6 and M11, if applicable) parameters in Part 1c 
(MAD):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-τ: Area under the plasma concentration-time curve for a dosing interval.

Ctrough: Trough plasma concentration.

T1/2: Apparent terminal phase half-life.

Accumulation index of RO7049389 and its metabolites.

Ae and CLR, if warranted.
Midazolam parameters in Part 1c (MAD):

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-last: area under the plasma concentration versus time curve up to the last 
measurable concentration.

AUC0-∞: Area under the plasma concentration versus time curve extrapolated to 
infinity.


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
AUC0-6h: Area under the plasma concentration versus time curve up to 6 hours 
post-dose.

T1/2: Apparent terminal phase half-life.

CL/F: Apparent clearance after oral administration.
RO7049389 and its metabolites (M5, M6 and M11) parameters in Part 2 (POM) and Part 
3 [RO7049389 on top of SoC]:

Cmax: Maximum observed plasma concentration.

Tmax: Time to maximum observed plasma concentration.

AUC0-τ: Area under the plasma concentration-time curve for a dosing interval, if 
applicable.

Ctrough: Trough plasma concentration.

T1/2: Apparent terminal phase half-life, if applicable.

Accumulation index of RO7049389 and its metabolites, if applicable.
NUC and Peg-IFN parameters in Part 3 (RO7049389 on top of SoC):

Ctrough: Trough plasma concentration.
3.3.3
Viral Dynamic Response Measures
Blood samples for quantitative and qualitative determination of viral dynamic response 
measurements will be collected at the time-points indicated in the Schedule of 
Assessment tables and as detailed in Section 4.5.1.9. Viral dynamic response measures 
will be measured only in Part 2 and Part 3 of the study, and will include, but will not be 
limited to the following:

Quantitative HBV DNA level (actual and change from baseline).

HBsAg (qualitative and quantitative).

HBeAg (qualitative and semi-quantitative).

Anti-HBs antibody status (quantitative).

Anti-HBe antibody status (qualitative).

Anti-HBc antibody (qualitative).

Quantitative Hepatitis B core related antigen (HBcrAg).

Quantitative HBV RNA.

Quantitative HBsAg decline, loss of HBsAg, development of anti-HBs, HBsAg 
seroconversion (loss of HBsAg and presence of anti-HBs).

Quantitative HBeAg decline, loss of HBeAg, development of anti-HBe, HBeAg 
seroconversion (loss of HBeAg and presence of anti-HBe).

Quantitative HBV DNA decline, HBV DNA <LLOQ.


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
Viral resistance will be monitored from Day 1 through follow-up, see 
Section 4.5.1.10.
3.3.4
Exploratory Outcome Measures
Since the following measures are set to be exploratory, in some circumstances, these 
measures will only be tested in a subset of the patients or part of the visits:
In Part 1, endogenous substances levels will be investigated to assess the effect of 
multiple oral dosing or RO7049389 on CYP3A4 activity. Analysis will include plasma 
4-hydroxycholesterol/cholesterol ratio.
In Part 3:

Changes of total HBsAg from baseline.

Change of liver stiffness measurement by Fibroscan.
4.
MATERIALS AND METHODS
4.1
STUDY POPULATION
The study may enroll up to a total of 93 healthy volunteers. Due to the adaptive and 
exploratory nature of this study, the actual number of patients will be determined during 
the study: 

Up to 53 healthy volunteers in Part 1a of the study. The initial cohort will be of 
5 healthy volunteers, with up to 6 subsequent cohorts of 8 healthy volunteers.

Eight subjects in a dose-level in Part 1a will be asked to return for Part 1b of the 
study.

Up to 40 healthy volunteers in Part 1c of the study. There will be up to 5 cohorts with 
8 healthy volunteers in each.

Up to 35 patients in Part 2. There will be up to 5 cohorts with 7 patients in each.

Initially, approximately 55 patients will be enrolled in the first 3 cohorts in Part 3 
with approximately 30 patients in POM Cohort A, 10 patients in POM Cohort B, 
and 15 patients in POM Cohort C. Based on emerging efficacy/safety data, the 
sample size in Cohort C can be increased to approximately 30 patients. In addition, 
additional treatment cohorts may be opened to explore different treatment durations, 
dose regimens, or different combinations.
Healthy volunteers or patients who drop out of the study treatment for non-safety 
reasons may be replaced to ensure sufficient data to characterize the safety and PK 
profile, and to make a dose-escalation decision. Healthy volunteers or patients who 
withdraw from the study due to poor tolerability or due to study drug-related adverse 
events will not be replaced.


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4.1.1
Recruitment Procedures
Healthy volunteers and patients will be identified for potential recruitment using 
pre-screening enrollment logs, Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) approved newspaper/radio/television/Social Network Service/campus poster 
advertisements, mailing lists and other distributable documents, prior to consenting to 
take part in this study.
4.1.2
Inclusion Criteria
Healthy volunteers/patients with HBV must meet the following criteria for study entry:
4.1.2.1
Part 1 – Healthy Volunteers only:
1. Healthy male and female subjects, 18 to 60 years of age, inclusive. Healthy status is 
defined by absence of evidence of any active or chronic disease following a detailed 
medical and surgical history, a complete physical examination including vital signs, 
12-lead ECG, hematology, blood chemistry, serology and urinalysis.
2. A body mass index (BMI) between 18 to 30 kg/m2 inclusive.
3. Female subjects must be either surgically sterile (by means of hysterectomy and/or 
bilateral oophorectomy) or post-menopausal for at least one year (defined as 
amenorrhea 12 consecutive months without another cause, and confirmed by 
follicle-stimulating hormone level 35 mIU/mL).
4. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
a. With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 28 days after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
5. Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) 
in accordance with institutional and regulatory requirements.
4.1.2.2
Part 2 – Chronic HBV-Infected Patients only:
1.
Adult male and female patients, 18 to 60 years of age, inclusive.
2.
A BMI between 18 to 30 kg/m2 inclusive.
3.
Chronic hepatitis B infection, defined as positive test for HBsAg for more than 
6 months prior to randomization.
4.
HBV DNA at screening 2 104 IU/mL for HBeAg positive patients, 
or 2103 IU/mL for HBeAg negative patients.


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5.
ALT at screening 5upper limit of normal (ULN; both-immune tolerant and 
immune-active patients).
6.
Screening laboratory values (hematology, chemistry [other than liver function test],
urinalysis) obtained up to 28 days prior to first study treatment within acceptable 
range or judged to be not clinically significant by the Investigator and the Sponsor.
7.
Liver biopsy, fibroscan or equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection with absence of 
extensive bridging fibrosis and absence of cirrhosis (cutoff for fibroscan is liver 
stiffness measurement ≤8.5 kPa or Metavir fibrotic Stage <3, or other equivalent 
staging systems).
8.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
a. Men must remain abstinent or use a condom during the treatment period and for 
at least 28 days after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
9.
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods that result in 
a failure rate of 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.
a. A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1% per 
year include male sterilization, and copper intrauterine devices.
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.
10. Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) 
in accordance with institutional and regulatory requirements.
4.1.2.3
Part 3 – Chronic Hepatitis B Patients only:
1.
Adult male and female patients, 18 to 60 years of age (inclusive) at the time of 
signing the informed consent form (ICF).
2.
A BMI between 18 to 32 kg/m2 inclusive.


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3.
Chronic hepatitis B infection, defined as positive test for HBsAg or HBV DNA 
(including qualitative, quantitative, and genotype testing) or positive HBeAg for more 
than 6 months prior to screening.
4.
HBsAg >250 IU/mL at screening. 
5.
For Cohorts only enrolling NUC-suppressed CHB patients (e.g., POM Cohort A), 
patients must qualify for 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.
At least one result showed HBV DNA <60 IU/mL at least 6 months prior to 
screening; and HBV DNA <20 IU/mL at screening by Roche Cobas assay.
c.
ALT ≤2 x ULN at screening and at Day -1 (can be checked by local lab result).
6.
For Cohorts only enrolling anti-HBV treatment-naïve and immune-active patients 
(e.g., POM Cohort B and Cohort C), patients must qualify for the following criteria:
a. Previous anti-HBV treatments for <30 days in total, and did not receive any anti-
HBV treatments within 3 months prior to the first study dose.
b. HBV DNA at screening ≥2 x 104 IU/mL for HBeAg positive patients, or 2 x 103
IU/mL for HBeAg negative patients.
c.
ALT at screening between 1–5 (exclusive) x ULN and ALT <5 x ULN at Day -1 
(can be checked by local lab result).
7.
Screening laboratory values (hematology, chemistry [other than liver function test], 
urinalysis) obtained up to 28 days prior to first study treatment within acceptable 
range or judged to be not clinically significant by the Investigator and the Medical 
Monitor.
8.
Liver biopsy, Fibroscan, or equivalent test obtained within the past 6 months 
demonstrating liver disease consistent with chronic HBV infection with absence of 
extensive bridging fibrosis and absence of cirrhosis (cutoff for Fibroscan is liver 
stiffness measurement ≤8.5 kPa for treatment-naïve patients and ≤7.4 kPa for NUC-
suppressed CHB patients, or Metavir fibrotic Stage <3, or other equivalent staging 
systems).
9.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
agree to use contraceptive measures, and agree to refrain from donating sperm, as 
defined below:
a. Men must remain abstinent or use a condom during the treatment period and for 
at least 6 months after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.


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10. For women of childbearing potential: agree to use two methods of contraception, 
with at least one method considered as highly effective during the study and for at 
least 6 months after the last dose of study drug.
a. A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
b. Contraceptive methods considered as highly effective (failure rate <1% per year 
when used consistently and correctly):
- Combined (estrogen- and progestogen-containing) or progestogen-
only hormonal contraception associated with inhibition of ovulation
- intrauterine device (IUD)
- intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- vasectomized partner
- sexual abstinence*
* Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire 
period of study treatment and at least 6 months after the last dose of 
study drug. In such case, there is no need to use two contraceptive 
methods. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
c.
Contraceptive methods NOT considered as highly effective (failure rate >1% per 
year):
- Progestogen-only oral hormonal contraception (where inhibition of 
ovulation is not the primary mode of action)
- Male or female condoms with or without spermicide
- Cap, diaphragm, or sponge with spermicide
11. Informed of, willing and able to comply with all of the protocol requirements and the 
investigational nature of the study, and have signed an informed consent form (ICF) 
in accordance with institutional and regulatory requirements.
4.1.3
Exclusion Criteria
Healthy volunteers/patients with HBV who meet any of the following criteria will be 
excluded from study entry:
4.1.3.1
Part 1 – Healthy Volunteers only:
1.
Pregnant (positive pregnancy test) or lactating women, and male subjects with 
partners who are pregnant or lactating.


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2.
History or symptoms of any clinically significant gastrointestinal, renal, hepatic, 
broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, 
hematological or allergic disease, metabolic disorder, cancer, or cirrhosis.
3.
Personal history or family history of congenital long QT syndrome and/or cardiac 
sudden death.
4.
History of Gilbert’s syndrome.
5.
History of having received or currently receiving any systemic anti-neoplastic 
(including radiation) or immune-modulatory treatment (including systemic oral or 
inhaled corticosteroids) 6 months prior to the first dose of study drug or the 
expectation that such treatment will be needed at any time during the study.
6.
Subjects who have had significant acute infection, e.g., influenza, local infection, 
acute gastrointestinal symptoms, or any other clinically significant illness within two 
weeks of dose administration.
7.
Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any 
drug, or multiple drug allergies (non-active hay fever is acceptable).
8.
Any clinically significant concomitant diseases or condition that could interfere with, 
or treatment of which might interfere with, the conduct of the study, or that would, in 
the opinion of the Investigator, pose an unacceptable risk to the subject in this study.
9.
Confirmed (based on the average of 3 separate resting blood pressure 
measurements, properly measured with well-maintained equipment, after at least 
10 minutes rest) systolic Blood Pressure greater than 140 or less than 90 mmHg, 
and diastolic BP greater than 90 or less than 50 mmHg at screening.
10. Clinically relevant ECG abnormalities on screening ECG e.g.:
a. QTcF 450 msec or 300 msec
b. Notable resting bradycardia (HR 45 bpm), or HR 90 bpm
c. ECGs with documented machine errors in the interval duration assessments.
d. Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-
Parkinson-White Syndrome, or cardiac pacemaker.
11. ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate 
QT measurement (e.g., neuromuscular artifact that cannot be readily eliminated, 
arrhythmias, indistinct QRS onset, low amplitude T-wave, merged T- and U-waves, 
prominent U-waves).
12. Creatinine Clearance (CrCl)70 mL/min (using the Cockcroft-Gault formula 
[Appendix 10]).
13. Positive test at screening of any of the following: Hepatitis A (HAV IgM Ab), 
Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab) or human 
immunodeficiency virus (HIV Ab).
14. Any other clinically significant abnormalities in laboratory test results at screening. In 
the case of uncertain or questionable results, tests performed during screening may 
be repeated before randomization to confirm eligibility.


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15. Participation in an investigational drug or device study within 90 days prior to 
screening or more than 4 times per year.
16. Donation or loss of blood over 500 mL within 3 months prior to screening.
17. Positive test for drugs of abuse (including recreational drugs) and/or positive alcohol 
test at screening or on Day -1.
18. History of drug and/or alcohol abuse or addiction.
19. History (within 3 months of screening) of alcohol consumption exceeding 2 standard 
drinks per day on average (1 standard drink10 grams of alcohol). Alcohol 
consumption will be prohibited at least 48 hours before screening, 48 hours before 
and 48 hours after each dose, and 48 hours before each scheduled visit.
20. Use of5 cigarettes or equivalent nicotine-containing product per day.
21. Taking any prescribed or over-the-counter (OTC) medications (including vitamins or 
herbal remedies) within 2 weeks of first dosing or within 5 times the elimination 
half-life of the medication prior to first dosing (whichever is longer; see also 
Section 4.4.2). Occasional acetaminophen/paracetamol is allowed (see also 
Section 4.4.1). Exceptions may be made on a case-by-case basis following 
discussion and agreement between the Investigator and the Sponsor.
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.
24. History of hypersensitivity to benzodiazepines or its formulation ingredients (for 
MAD-midazolam cohorts)
25. Acute narrow-angle glaucoma (for MAD-midazolam cohorts).
4.1.3.2
Part 2 – Chronic HBV-Infected Patients only:
1.
Pregnant (positive pregnancy test) or lactating women, and male subjects with 
partners who are pregnant or 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.
4.
One or more of the following laboratory abnormalities at screening:
a.
Total serum bilirubin 2.5 mg/dL ( 42.75 mol/L). For patients with 
documented Gilbert’s syndrome total bilirubin 2.75 mg/dL ( 47 mol/L).
b.
International normalized ratio (INR) 1.5.
c.
Serum albumin 3.0 g/dL ( 30 g/L).
d.
Platelet count 140,000 cells/mm3.
5.
History or other evidence of a medical condition associated with chronic liver 
disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, 


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alcoholic liver disease, toxin exposure, thalassemia, nonalcoholic steatohepatitis, 
etc.).
6.
Documented history or other evidence of metabolic liver disease within one year of 
randomization.
7.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, or human 
immunodeficiency 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 or oral therapy for 
HSV I or HSV II.
9.
History of or suspicion of hepatocellular carcinoma or alpha-fetoprotein ULN at 
screening.
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. Previous or concurrent HBV treatments in the past 6 months.
15. History of capsid modulators treatment, including treatment in investigative trials
16. Participation in an investigational drug or device study within 30 days prior to 
randomization.
17. Taking any drugs or nutrients listed in prohibited medications and prohibited food 
sections (see also Section 4.4.3).
18. Significant acute infection (e.g., influenza, local infection) or any other clinically 
significant illness within 2 weeks of randomization.
19. Clinically relevant ECG abnormalities on screening ECG.
20. Abnormal renal function including serum or plasma creatinine > ULN or calculated 
creatinine clearance70 mL/min using the Cockcroft Gault formula (Appendix 10).
21. Donation or loss of blood over 500 mL within 3 months prior to randomization.
22. Administration of any blood product within 3 months prior to randomization.
23. 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.
24. Subjects under judicial supervision, guardianship or curatorship.
25. Medical or social conditions that would potentially interfere with the subject’s ability 
to comply with the study visit schedule or the study assessments.


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4.1.3.3
Part 3 - Chronic Hepatitis B Patients only:
1.
Pregnant (positive pregnancy test) or lactating women.
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.
4.
One or more of the following laboratory abnormalities at screening:
a.
Total serum bilirubin > ULN (exception Gilbert’s disease). 
b.
International normalized ratio (INR) >1.1 ULN.
c.
Serum albumin <3.0 g/dL (<30 g/L).
d.
Platelet count <140,000 cells/mm3
e.
Hemoglobin <12 g/dL (females) or <13 g/dL (males).
f.
White blood cell count <2500 cell/mm3. 
g.
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], free 
triiodothyronine [FT3], free thyroxin [FT4] at screening.
7.
Documented history or other evidence of metabolic liver disease within one year of 
screening.
8.
Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, HEV or human 
immunodeficiency virus (HIV).
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 of oral therapy for 
HSV I or HSV II.
10. Diagnosed or suspected hepatocellular carcinoma as evidenced by screening 
alpha-fetoprotein (AFP) ≥100 ng/mL. If AFP >ULN, absence of mass/findings 
suspicious for HCC must be demonstrated by ultrasound or CT or MRI within the 
screening period.
11. History of significant gastrointestinal disease (including but not limited to gastric 
ulcers).
12. History of clinically significant cardiovascular, endocrine, renal, ocular, pulmonary, 
psychiatric, or neurological disease.
13. Evidence of an active or suspected cancer or a history of malignancy other than 
adequately treated basal cell carcinoma.


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14. History of organ transplantation.
15. Participation in an investigational drug or device study within 30 days prior to 
screening.
16. Taking any drugs or nutrients listed in prohibited medications and prohibited food 
sections.
17. Significant acute infection (e.g., influenza, local infection) or any other clinically 
significant illness within 2 weeks of screening.
18. 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.
19. Abnormal renal function including serum or plasma creatinine > ULN or glomerular 
filtration rate (eGFR; using CKD-Epi equation) <60 mL/min (Appendix 10).
20. Donation or loss of blood over 500 mL within 3 months prior to screening.
21. Administration of any blood product within 3 months prior to screening.
22. 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.
23. Subjects under judicial supervision, guardianship, or curatorship. 
24. Medical or social conditions that would potentially interfere with the subject’s ability 
to comply with the study visit schedule or the study assessments.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Randomization numbers for healthy volunteers will be generated by independent 
representatives of the Sponsor, or its designee, for Part 1 of the study. The patient 
randomization numbers for Part 2 (POM) will be generated by the IxRS 
(Interactive voice/web response system), according to specifications provided by the 
Sponsor to the external randomization vendor. Part 3 of the study is a non-randomized, 
non-controlled, open-label study.
Parts 1 and 2 of the study are investigator-blinded and subject-blinded. In order to 
minimize bias in reporting, collecting, and interpreting safety data, healthy volunteers, 
patients, Investigator(s), and all individuals in direct contact with study subjects at the 
investigative site will remain blinded until the completion of the study, except the 
pharmacist handling the study drug distribution in Part 1.
Part 1 and Part 2 of this study are sponsor-open. At the Sponsor side, the Clinical 
Pharmacologists, the Study Pharmacometrician, the Study Clinical Pharmacology 
Scientist, the Study Biostatistician, the Statistical Programmer/Data Acquisition 
Specialist/Clinical Data Programmer, the IxRS service provider, the individuals 
responsible for metabolite identification, and the individual responsible for PK sample 


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bioanalysis will be unblinded to treatment assignment for each of Parts 1a (SAD), 1c 
(MAD) and Part 2 (POM) of the study. Other members of the sponsor staff may be 
unblinded at the Clinical Pharmacologist’s discretion, if this is considered necessary to 
optimize data analysis and dose-escalation decision-making.
Before each of the dose-escalation decisions, the individual safety, tolerability, available 
PK data, and viral dynamic response (Part 2 only) will be reviewed in a blinded fashion 
by the Investigator and the Sponsor’s clinical team. The Investigator may also be 
unblinded in mutual agreement with the Clinical Pharmacologist if treatment assignment 
knowledge is considered critical to allow study progression, and/or is deemed important 
to define future risk management activities. Unblinding can occur as soon as the 
Investigator(s) and the responsible Roche scientists have reviewed the data, even if the 
data have not been entered onto the Case Report Forms (CRFs). 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.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (SAE; see Section 5.1.2) that are 
considered by the Investigator to be related to study drug.
The Principal Investigator will receive a set of sealed treatment codes for Parts 1a (SAD) 
and 1c (MAD). These will 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 subject’s 
condition (e.g., in the case of a serious adverse event), the treatment code for that 
subject may be broken. 
At the final monitoring visit, the unused code labels will be counted and checked and a 
statement to the effect that all are intact (or not as the case may be) will be made by the 
Monitor; this statement will be included or referred to in the final study report. All code 
labels will be returned to Roche.
For Part 2 (POM), the Investigator 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.


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For Part 3, the IxRS is used to register patients to one of the three open label cohorts. 
Additionally, IxRS is used to dispense RO7049389 for patients to provide them with 
sufficient tablets for that time until the next visit. NUC and Peg-IFN will be provided or 
reimbursed as non-IMP by the Sponsor.
4.3
STUDY TREATMENT
The following drugs which will be used in the study are marketed drugs and will not be 
considered as IMPs, midazolam; entecavir, tenofovir alafenamide, or tenofovir disoproxil 
fumarate; and peginterferon alfa (Peg-IFN).
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
RO7049389 and Placebo
RO7049389 and matching placebo (IMP, Placebo only in Parts 1 and 2) to be used in 
the study will be provided by the Sponsor. 
The clinical formulation is a film-coated tablet for oral administration. 
Two different formulations have been developed to date:
The first formulation is a reddish-brown film-coated tablet consisting of RO7049389 and 
the inactive ingredients hypromellose, microcrystalline cellulose, croscarmellose sodium, 
silicon dioxide, mannitol, sodium stearylfumarate. The coating mixture consists of 
hypromellose, lactose monohydrate, macrogol, red iron oxide, titanium dioxide, black 
iron oxide, and yellow iron oxide. All excipients used in the formulation are compendial 
(Ph. Eur. and/or USP/NF) grade.
The film-coated tablets are available containing 50 mg, 100 mg, 200 mg, and 500 mg of 
RO7049389. A matching-placebo, in terms of size, shape and color, has also been 
developed for clinical usage. Placebo film-coated tablets have been manufactured 
containing the inactive ingredients isomalt, microcrystalline cellulose, sodium 
stearylfumarate, croscarmellose sodium, and the same coating mixture, but no active 
substance.
This clinical formulation of RO7049389 should be stored under the recommended 
storage conditions: “Store at 2-8C, protect from light and moisture.” 
The second formulation has been manufactured as a white film-coated tablet consisting 
of RO7049389 with dose strength 200 mg and the inactive ingredients hypromellose, 
microcrystalline cellulose, croscarmellose sodium, silicon dioxide, mannitol, and sodium 
stearylfumarate. The coating mixture consists of hypromellose, lactose monohydrate, 
macrogol and titanium dioxide. All excipients used in the formulation are compendial 
(Ph. Eur. and/or USP) grade.


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This clinical formulation of RO7049389 should be stored under the recommended 
storage conditions: “Do not store above 25C, protect from light and moisture.”  
For information on the shelf life of RO7049389 film-coated tablets and the matching 
placebo, see the packaging.
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. The packaging and labeling of the study drug will be in 
accordance with Roche standard and local regulations.
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.
For further details, see the Investigator’s Brochure.
4.3.1.2
Midazolam (Part 1 only)
The study site pharmacy will prepare a midazolam stock solution of 50 g/mL from 
commercially-available midazolam. Two mL of 50 g/mL stock solution will be 
administered to subjects in the MAD part of study giving a dose of 100 g of midazolam.
4.3.1.3
SoC (NUC and Peg-IFN)
NUC (entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate) and Peg-IFN will 
be used in Part 3 of the study for an authorized indication, and follow the general 
warnings and precautions as per local label. Both NUC and Peg-IFN are marketed drugs 
and will not be considered as investigational medicinal products (IMPs). Peg-IFN and 
NUC will be provided or reimbursed by the Sponsor until 24 weeks post-treatment.
4.3.2
Dosage, Administration and Compliance
Active or placebo (placebo in Parts 1 and 2 only) doses will be administered orally to the 
study subjects with approximately 240 mL of still water at room temperature. An 
additional amount of water up to 100 mL could be given to assist dose administration 
only if needed. For Parts 1 and 2, the dose in mg, the date and time of dosing, and the 
exact volume of water should be recorded on the eCRF (the exact volume of water 
will only be recorded during the in-clinic period). For Part 3, the daily dose in mg, 
the start and end dates of dosing, plus the date and time of the most recent dosing prior 
to PK sample collection should be recorded on the eCRF. The starting-dose of 150 mg 
will be administered as three 50 mg tablets. All other doses will be administered as the 
appropriate combination of 50 mg, 100 mg, 200 mg, and 500 mg tablets.
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose according to the randomization schedule. This individual will write the date 
dispensed and study subject’s number and initials on the study drug vial label and on the 


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Drug Accountability Record. This individual will also record the study drug batch or lot 
number received by each study subject during the study.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Sections 3.1.2, 3.1.3, and 4.6.1.1.
4.3.2.1
Part 1a: SAD
RO7049389, or matching-placebo, will be administered orally to healthy volunteers by 
investigational staff during the morning of Day 1, after an overnight fast of at least 
8 hours. Healthy volunteers will not eat for at least 4 hours after the dose is administered. 
Water will be allowed until one hour prior to dosing, and from one hour post-dosing. 
Approximately 4-5 hours after dosing, healthy subjects will be served lunch.
4.3.2.2
Part 1b: Food Effect
Healthy volunteers will fast overnight for at least 8 hours prior to Day 16. On the morning 
of Day 16, a high-fat breakfast (see Appendix 9) will be served to healthy volunteers, 
which should be consumed within 30 minutes. RO7049389 or placebo will then be 
administered at the same dose as Day 1 in Part 1a of the study.
4.3.2.3
Part 1c: MAD
RO7049389, or matching-placebo, will be administered orally to healthy volunteers by 
investigational staff from Day 1 to Day 13 twice daily, and on Day 14 once in the morning. 
A light breakfast will be served 30 minutes after morning dosing. Lunch will be served 
approximately 4-5 hours post-morning-dose. The second daily dose will be administered 
in the evening, approximately 12 hours after the morning dose. Food will be restricted 
2 hours prior to, and 1 hour post, the evening dosing.
If QD dosing is required, RO7049389, or matching-placebo, will be administered orally in 
the morning, and a light breakfast will be served 30 minutes after dosing.
Timing of meals relative to dosing may be changed by the results of the food effect 
investigation. For example, if food has a marked negative effect on absorption of 
RO7049389, then, for the morning dose healthy volunteers must fast overnight (at least 
8 hours) and will not eat for 2 hours after the morning dose is administered. If food has 
no marked effect on bioavailability, then the morning dose will be administered with a 
light breakfast and the evening dose 12 hours later with, or shortly after, dinner. An 
optional evening snack will be allowed, provided that the fasting period is ensured before 
the following morning assessments.
The dose-range for RO7049389 MAD cohorts will be determined based on available PK, 
safety and tolerability data from the SAD arm of the study (Part 1a).


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Midazolam
In MAD cohorts, a single oral dose of 100 g midazolam solution will be administered 
orally to all subjects on Day -1 and Day 14. The Day -1 dosing will occur at least 
24 hours prior to the first dose event of RO7049389 on Day 1. The fasting requirement 
prior to dosing on Day -1 and Day 14 will be the same as for RO7049389. The Day 14 
dosing will occur at the same time when subjects take the last dose of RO7049389. 
When administered alone, midazolam will be taken with 240 mL of water. When 
co-administration occurs, midazolam will be taken with ~100 mL of water, whereupon 
RO7049389 will be taken with the rest of 140 mL of water. Lunch will be given 
approximately 4-5 hours after dosing.
4.3.2.4
Part 2: POM
If BID dosing is required, RO7049389, or matching-placebo, will be administered twice 
daily from Day 1 to Day 27, and once on Day 28 in the morning. The second daily dose 
will be administered in the evening, approximately 12 hours after the morning dose. 
During the in-house study periods (optional) and ambulatory visits, study drug will be 
administered by investigational staff. During out-patient study periods, study drug will be 
self-administered by patients following the guidance provided by investigational staff. 
During the in-house period, a light breakfast will be served 30 minutes before the 
morning dosing. Lunch will be served approximately 4-5 hours post-dose. Dinner will be 
served 30 minutes before evening dosing if BID. 
During the out-patient period, the medication is recommended to be taken within 30 min 
of completing a meal. Patients will be advised to take evening dose 12 hours apart from 
the morning dose and to avoid high fat meal. 
If QD dosing is required, RO7049389, or matching-placebo, will be administered orally in 
the morning, and a light breakfast will be served 30 minutes before dosing during the in-
house period. During the out-patient period, the medication is recommended to be taken 
within 30 min of completing a meal.
Food restrictions may be changed based on the results from the food effect arm of the 
study (Part 1b) study. If it is determined that food significantly affects RO7049389 
absorption, other dietary instructions (e.g., meals 2 hours prior to, and 1 hour post, both 
morning and evening doses) may be implemented.
4.3.2.5
Part 3 of the study
RO7049389 administration
RO7049389 will be administered orally to patients every day from Day 1 to the actual 
EOT visit at week 48. The dosing regimen will be defined prior to dosing of the first 
patient in each cohort.


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If BID dosing is required, the first dose will be administered in the morning and the 
second dose will be administered in the evening. If QD dosing is required, RO7049389 
will be administered once daily. RO7049389 should be administered at approximately 
the same time of each day. Dietary instructions may be implemented, fasted state is 
defined as at least 2 hours after a meal and 2 hours before the next meal; with meal is 
defined as within 30 minutes of completing a meal.
RO7049389 can be given together with NUC or separately.
During the in-house study periods (optional) and ambulatory visits, study drug will be 
administered by investigational staff. During out-patient study periods, study drug will be 
self-administered by patients following the guidance provided by investigational staff.
Patients will be asked to record their intake of RO7049389 at home via the patient diary.
NUC administration
NUC will be administered per local label (see the local prescribing information for 
entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate for more details). NUC 
will be provided or reimbursed by Sponsor. NUC administration during the study, 
including the follow-up period, should be captured in the site documentation and eCRF. 
This should include information about any missing doses during treatment and follow-up 
period. Patients will be asked to record their intake of NUCs at home via the patient diary.
For further information on the NUCs used in this study, please follow local prescribing 
information.
Peg-IFN administration
Peg-IFN (Peginterferon alfa) will be administered in POM Cohort C for 48 weeks per 
local label. Peg-IFN will either be provided or reimbursed by the Sponsor for the duration 
of the study. For patients who are unable to tolerate the dosing scheme of Peg-IFN, 
dose adjustments and interruptions are permitted in order to keep the patient on study 
treatment. It is highly recommended that dose reductions/interruptions and side-effect 
management per local labels or guidelines should be implemented in the study. However, 
in the short-term management of an individual patient, investigators may use their 
medical judgments in the best interest of the patient. These changes and adverse events 
must be recorded on eCRF. If Peg-IFN was interrupted or discontinued permanently, 
patients can continue to be treated with RO7049389 and NUC until the end of the 
treatment period. Patients will be asked to record their weekly Peg-IFN self-injection at 
home via the patient diary.
For further information on the Peg-IFN, please follow local prescription information.


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4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(RO7049389 or matching placebo) will be provided by the Sponsor. In Part 1, midazolam 
solution is prepared by the site.
The investigational site will acknowledge receipt of IMPs, to confirm the shipment 
condition and content. Any damaged shipments will be replaced.
The Investigator(s) 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 study subject initials and date of birth).

The date(s), quantity of the study drug dispensed to the study subject.

The identification of the person who dispensed the drug.

All records and drug supplies must be available for inspection by the Clinical Trial 
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 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].


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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.
4.3.4
Non-Investigational Medicinal Product Accountability
NUC and Peg-IFN are considered Non-IMP. NUC or Peg-IFN required for completion of 
this study will be provided or reimbursed by Sponsor. 
The Investigator is responsible for providing and checking compliance of NUC and Peg-
IFN during the study. The Drug Prescribe/Dispensing Log must be kept current and 
should contain the following information:

The identification of the study subject to whom the NUC or Peg-IFN was prescribed 
(for example study subject initials and date of birth).

The date(s), quantity of the NIMP prescribed or dispensed to the study subject.

The identification of the person who prescribed or dispensed the drug.

All records and drug supplies must be available for inspection by the Clinical Trial 
Monitor at every monitoring visit.
4.3.5
Post-Trial Access to RO7049389
Currently, the Sponsor does not have any plans to provide RO7049389 to the patients 
after the end of the study, or when patients discontinue or have been withdrawn from the 
study. The Sponsor will evaluate whether to continue providing RO7049389 to patients 
after the main study is over, in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.3.6
Post-Trial Access to SoC
NUC or Peg-IFN are marketed drugs and commercially available. After completion of 
study participation, no SoC 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.
4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted Therapy
4.4.1.1
Healthy Volunteers
As a general rule, no concomitant medication (including herbal products and vitamins) 
(see exclusion criteria) will be permitted, unless the rationale for exception is discussed 
and clearly documented between the Investigator(s), the Medical and Safety Monitor, 
and the Roche Clinical Pharmacologist. 
The following medications are permitted:


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
Medications used to treat AEs may only be prescribed after consultation with the 
Sponsor (with the exception of acetaminophen/paracetamol), unless there is a 
medical need to ensure the well-being of the subject that should not be delayed. All 
therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF.

Hormone replacement therapy (HRT): permitted if initiated at least 2 months prior to 
study start.

Occasional use of acetaminophen (up to 1 g per day, not to exceed 3 g/5 days) or 
ibuprofen (up to 400 mg per day) will be permitted. During the period of confinement 
to the clinical research unit, subjects will be restricted from the use of 
acetaminophen/paracetamol and other non-prescription medications beginning 4 
hours prior to dosing through 4 hours after dosing unless deemed necessary to treat 
an Adverse Event (AE) by the Investigator.
4.4.1.2
Chronically HBV-Infected Patients in Part 2 and Chronic 
Hepatitis B Patients in Part 3
Concomitant therapy includes any medication, e.g., prescription drugs, OTC drugs, 
approved dietary and herbal supplements, nutritional supplements and any 
non-medication interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) used by a patient from 
4 weeks prior to the first dosing through the study completion. All concomitant 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications eCRF.
4.4.2
Prohibited Therapy
4.4.2.1
Healthy Volunteers
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF. 
As a general rule, no concomitant medication will be permitted within 14 days prior to the 
first dosing or within 5 half-lives of the medication prior to the first dosing (whichever is 
longer), until the follow up visit (Day 8 for Part 1a, Day 23 for Part 1b, and Day 21 for 
Part 1c), with the exception of the cases listed in Section 4.4.1. 
Exceptions may be made on a case-by-case basis following discussion and agreement 
between the investigator and the sponsor after unless the rationale for exception is 
discussed and clearly documented. 
4.4.2.2
Chronic HBV-infected Patients in Part 2 and Chronic Hepatitis 
B Patients in Part 3
For patients who take NUC or Peg-IFN during the study, please follow the local 
prescription information to guide co-administration drug or prohibited therapy, if 
applicable. For all patients, the following are prohibited (for examples of drugs, see
Appendix 16):


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
Any systemic antiviral therapy other than that provided by the study at any time from 
14 days before starting the study drug until the end of follow-up period, with the 
exception of oral therapy for HSV I or HSV II. Investigational drugs or herbal and 
other remedies being taken by the patient for possible or perceived effects against 
HBV are prohibited.

Inducers of CYP3A enzyme within 14 days or 5 half-lives (whichever is longer) 
before the first administration of RO7049389 and while on study treatment with
RO7049389. 

Inhibitors of CYP3A enzyme within 7 days or 5 half-lives (whichever is longer) 
before the first administration of RO7049389 and while on treatment with 
RO7049389. 

Inducers of UDP-glucuronosyltransferase (UGT) enzymes within 14 days or 5 half-
lives (whichever is longer) before the first administration of RO7049389 and while 
on study treatment.

Inhibitors of UGT enzymes within 7 days or 5 half-lives (whichever is longer) before 
the first administration of RO7049389 and while on treatment with RO7049389. 

Inhibitors of OATP transporters within 7 days before the first administration of 
RO7049389 and while on treatment with RO7049389. 

Inhibitors of breast cancer resistance protein (BCRP) transporter within 7 days 
before the first administration of RO7049389 and while on treatment with 
RO7049389. 

The total daily dose of acetaminophen (paracetamol) should not exceed 1 g/day. 

Patients who have been on stable hormone replacement therapy for a period of at 
least 2 months prior to Screening will not be excluded from the study. 

Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents, 
radiation therapy anti-arrhythmics, ergot derivatives, oral/parenteral corticosteroids, 
or topical Class 1 and 2 steroids, probenecid, and bile acid binding resins while on 
study treatment. 

Any hormonal methods of contraception during the study treatment period and 
28 days afterwards (only for patients enrolled into part 2).

Midazolam data from part 1c indicated mild but not clinically significant inhibition of 
CYP3A enzyme by RO7049389. CYP3A4 substrates with narrow therapeutic range
may need to be used with caution in Parts 2 and 3 of the study.

For substrates of OATP1B, the co-administration of RO7049389 is expected to 
result in mild (< 2 fold) increase in blood concentrations of the substrates. Therefore, 
use the lowest necessary dose, titrate the dose carefully, and monitor closely for 
substrate-associated adverse reactions.
Exceptions to the above-mentioned concomitant medications will be made if the 
rationale is discussed and documented between the Investigator and the Medical 
Monitors.


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4.4.3
Prohibited Food
Use of the following is prohibited: 

Alcohol consumption is to be strongly discouraged in patients with chronic HBV 
infection 14 days before starting the study drug until 24 weeks after the last dose.
During the study, patients should not consume more than 20 g of alcohol per day (or 
on average approximately 140 g of alcohol per week; 1 standard drink = 10 grams 
of alcohol, for further guidance see Appendix 14). Patients will be queried on a 
regular basis concerning their alcohol consumption and appropriate comments 
concerning this intake will be recorded on the eCRF.

In healthy volunteers, alcohol must not be consumed from 48 hours before 
screening, 48 hours before admission until completion of follow-up visit.

Any nutrients known to modulate activity of CYP enzymes (e.g., grapefruit juice or 
Seville orange juice) will be prohibited within 3 days before Day -1 through the last 
dose of RO7049389.
4.4.4
Dietary and Special Requirements
In addition to the meal restrictions described in Section 4.4.3, the following requirements 
will also be applied in all substudies: 

Laboratory safety assessments should be conducted after study subjects have been 
fasted for a minimum of 8 hours (4h for screening and follow-up).

The excessive consumption of fluids (greater than 3 liters per day) should be 
avoided (only for Part 1).

On the days of a study visit caffeine (i.e., beverage, chocolate, or supplements) 
should not be consumed from 48 hours prior to study drug administration until 
discharge from the clinic (only for Part 1). 

No strenuous exercise is permitted during the study from 96 hours before admission 
until completion of the follow-up visit (only for Part 1).
Meals will be similar in composition and time of administration across all cohorts during 
the in-house period in Part 1 with the exception of those healthy subjects participating in 
the food effect substudy, where breakfast on Day 16 will be a meal with a high-fat 
breakfast. 
The use of tobacco is not permitted during the study for healthy subjects.
4.5
STUDY ASSESSMENTS
4.5.1
Description of Study Assessments
All examinations listed below will be performed according to the schedule of 
assessments outlined in Appendix 1 to Appendix 8.


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All time-points when several assessments coincide, the following sequence should be 
followed with the PK blood sample to be taken at the nominal time-point:

Urine collection

ECG recordings

Vital signs

PK, viral dynamic, safety blood sampling

Administer meal (Part 1b only)

Study drug administration
4.5.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, 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 
subjects within 30 days prior to the screening visit.
For the patients with chronic HBV infection, the detailed HBV history will be documented, 
which will include date of HBV diagnosis, mode of HBV infection (if known), HBV 
genotype (if known), all previous HBV treatments and outcomes of treatments (if any), 
occurrence of nucleos(t)ide analogue resistance (if any), previous evaluations for 
cirrhosis, dates/outcomes of liver biopsies (if any).
Demographic data will include age, sex, and self‑reported race/ethnicity.
4.5.1.2
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems. A genitourinary 
examination may be performed in case of evocative symptoms at the Investigator 
discretion.
Any abnormality identified at baseline (prior to dosing) 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 at the discretion of the Investigator. Changes from 
baseline abnormalities should be recorded in study subject’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 study. Height will only be recorded 
at screening. BMI will be calculated at screening.


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4.5.1.3
Vital Signs
Blood pressure, pulse rate and body temperature (tympanic or oral) will be recorded at 
the time points‑specified in Overall Schedule of Assessments (Part 1a and 1b 
Appendix 1, Part 1c Appendix 3, Part 2 Appendix 5, and Part 3 Appendix 7) and Detailed 
Schedule of Assessments (Part 1a and 1b Appendix 2, Part 1c Appendix 4, Part 2 
Appendix 6, and Part 3 Appendix 8).
Blood pressure and pulse rate should be obtained in a quiet room at a comfortable 
temperature, with the study subject's arm unconstrained by clothing or other material. 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. 
Blood pressure and pulse rate will be performed in triplicate (interval between 
measurements can be as short as 20 sec to 1 min) after the subject has rested in a 
supine position for at least 5 minutes. The mean of three consecutive replicates will be 
used as the value for the defined time-point.
4.5.1.4
Electrocardiograms
12-Lead ECG
ECGs will be collected after the study subject has been in a supine position for at least 
10 minutes. At the specified time-points, 12-lead ECGs will be obtained in triplicate, i.e., 
three consecutive interpretable 12-lead ECGs within a 3-5-minute interval, for Parts 1 
and 2. For Part 3, a single interpretable 12-lead ECG will be taken. Recordings should 
be taken for any unscheduled ECG. All ECG measurements should be recorded in the 
eCRF.
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 HR will be captured or 
calculated, and the changes in T-wave and U-wave morphology will be documented. 
T-wave information will be captured as normal or abnormal, U-wave information will be 
captured in two categories: absent/normal or abnormal.
For safety monitoring purposes, the Investigator must review, sign and date all ECG 
tracings either by wet signature or electronically. 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.


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2.
Tripilcate/One useful recording(s) 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 (TV, 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 if possible (it is accepted that this 
is not possible after the breakfast and lunch for some relevant cohorts).
5.
Strictly match timing and conditions of ECG recording to baseline. Conditions to be 
standardized include food intake, activity level, stressors, and room temperature.
6.
If possible, the same machine, brand and model, should be used for the same study 
subject throughout the study.
7.
ECGs should be 12-lead, recorded at 25 mm/sec for at least 10 seconds.
8.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper 
lead placement as contributing to the ECG abnormality.
9.
ECG machines should have periodic calibration and service records (minimum once 
a year).
10. If any QT / QT corrected for heart rate (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.
ECG Holter
Continuous 12-lead ECG recordings (Holter Monitor) will be obtained as specified in the 
SoA in Part 1a (SAD) and Part 1c (MAD) only (see SoAs; Appendix 1 to Appendix 4). A 
central ECG laboratory will extract triplicate ECG measurements from the continuous 
recordings within10 minutes of the pre-defined ECG time-points, specified in the SoA, 
to evaluate heart rate, ECG intervals and wave form analysis. The results of these 
analyses will be available prior to dose-escalation.
Healthy subjects should be at rest and in a supine position for10 minutes prior to and 
remain in a supine position for10 minutes after the specified ECG extraction 
time-points. Other time-points may also be retrospectively assessed in the event of 
clinical observations or findings which require further investigation.
While the healthy subjects are on Holter ECG monitoring, the absence of any 
environmental distractions (e.g., television, radio, conversation, or phone calls) during 
the pre- and post-ECG rest period, and at every ECG time-point must be emphasized. In 
particular, activities known to cause changes in heart rate should be avoided.


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The timings of assessments may be amended or the number of assessments increased 
during study conduct on the basis of emerging data in order to allow for optimal 
characterization of the effect profile.
4.5.1.5
Laboratory Assessments
The samples listed below will be collected at the time-points indicated in the SoA.

Hematology: Hemoglobin, hematocrit, total white blood cell (WBC) count, differential 
WBC count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils), 
platelet count, erythrocytes count (RBC), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC) and reticulocyte counts.

Coagulation: prothrombin time (PT), international normalized ratio (INR), activated 
partial thromboplastin time (aPTT).

Blood Chemistry: Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total and indirect bilirubin, alkaline phosphatase (ALP), gamma glutamyl 
transferase (GGT) (at screening only), creatinine phosphokinase (at screening only), 
total protein, albumin, urea, creatinine, CrCl (at screening only, using the Cockcroft-
Gault formula in Part 1 and Part 2 of the study), eGFR (CKD-EPI formula in Part 3 of 
the study [Appendix 10]), uric acid, total cholesterol, low density lipoproteins (LDL)
cholesterol, high density lipoproteins (HDL) cholesterol, triglycerides, fasting glucose, 
sodium, chloride, potassium, calcium, phosphorus, bile acids.

Urinalysis: A midstream, clean-catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leucocyte esterase, and pH. If the dipstick result 
is 2+ or greater for blood, protein or leukocytes, urine will be sent to the laboratory 
for microscopy. If there is an explanation for the positive dipstick result, e.g., 
menses, it should be recorded, and there is no need to perform microscopy. Urine 
color may be evaluated from urinalysis or urine PK samples if considered necessary.

Drugs of abuse will be measured in urine: cannabinoids, amphetamines, 
methamphetamines, opiates, methadone, cocaine, benzodiazepines, and 
barbiturates.

Alcohol: Alcohol Breath test.

Viral markers: 

Healthy subjects: Hepatitis A (HAV IgM Ab), Hepatitis B (HBsAg), 
Hepatitis C (HCV RNA or HCV Ab), human immunodeficiency virus (HIV-
1 and HIV-2 Ab). 

Patients with chronic HBV infection: Hepatitis A (HAV IgM Ab), Hepatitis C 
(HCV RNA and HCV Ab), Hepatitis E (HEV IgM Ab and IgG Ab), human 
immunodeficiency virus (HIV-1 and HIV-2 Ab), Hepatitis D (HDV Ab). For 
HBV-specific viral assessment in patients, please refer to Section 4.5.1.9.

Pregnancy Test: Serum or plasma beta-human chorionic gonadotropin (-HCG) at 
screening, urine on all other occasions (females only).


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
Hormones: Follicle-stimulating hormone (females only to confirm post-menopausal 
status, performed at screening only).

Alpha fetoprotein (at screening only for patients with chronic HBV infection).

Thyroid function test: FT3, FT4, TSH (Part 3).

Potential early liver injury biomarkers including, but not limited to glutamate 
dehydrogenase (GLDH) (Part 1c, Part 2, and Part 3).
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points specified 
in the Schedule of Assessments (Part 1a and 1b Appendix 1, Part 1c Appendix 3, Part 2 
Appendix 5, and Part 3 Appendix 7).
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’s 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.
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 local (Part 1) or central (Part 2) 
laboratory.
4.5.1.6
Liver Imaging Assessments
FibroScans will be conducted during Part 3 of the study at the time points indicated in 
Appendix 7 to monitor the change in liver stiffness. Liver stiffness measure using 
FibroScan has been widely accepted in the assessment and staging of liver fibrosis.
Abdominal hepatic ultrasound will be conducted during Part 3 of the study at the time 
points indicated in Appendix 7. Patients with chronic hepatitis B are at risk of disease 
progression to liver cirrhosis or developing HCC. Abdominal hepatic ultrasound is 
current practice to monitor disease progress and HCC surveillance in patients with 
chronic hepatitis B.
4.5.1.7
Pharmacokinetic Assessments
Blood and urine samples will be collected to evaluate the PK as specified in the SoA 
(see ‑ Overall Schedule of Assessments (Part 1a and 1b Appendix 1, Part 1c 
Appendix 3, Part 2 Appendix 5, and Part 3 Appendix 7) and Detailed Schedule of 


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Assessments (Part 1a and 1b Appendix 2, Part 1c Appendix 4, Part 2 Appendix 6, and 
Part 3 Appendix 8).
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 samples will be collected from all cohorts. Urine samples will be collected from all 
cohorts in Part 1a and Part 1c. No urine PK samples will be collected during the food 
effect dosing period (Part 1b), Part 2 or Part 3. Aliquots of the urine sample will be 
collected and stored for analysis. 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.
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.
A PK sample will also be collected following occurrence of a dose-limiting event or 
serious adverse event.
Plasma and urine concentrations of RO7049389 will be measured by specific and 
validated liquid chromatography tandem mass chromatography (LC-MS/MS) methods 
conducted in a GLP compliance environment.
PK parameters will be estimated using standard non-compartmental methods for 
RO7049389.
PK 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.
For sampling procedures, storage conditions, and shipment instructions, see the 
separate laboratory manual.
4.5.1.8
Exploratory Assessments
In Part 1, urine and plasma samples collected will be qualitatively and/or quantitatively 
analyzed for some of the metabolites of RO7049389 with the use of non-validated or 
validated methods. Endogenous substances levels will be investigated to assess the 
effect of multiple oral dosing of RO7049389 on CYP3A4 activity. Analysis will include 
plasma 4-hydroxycholesterol/cholesterol ratio.


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In Part 3, in order to avoid a potential loss of sensitivity of HBsAg detection due to the 
formation of HBsAg/anti-HBs complexes, an assay is being developed by the Sponsor to 
measure total HBsAg independently of the putative formation of complexes.
To explore relationship between baseline disease characteristics (e.g., HBeAg status,
viral load, HBV genotype) and efficacy /safety response, for NUC-suppressed patients 
(e.g., in POM Cohort A), HBV genotyping will be attempted based on HBV RNA.
To explore the effect of the genetic polymorphism of CYP3A4, UGT1A3 and OATP1B on 
the PK of RO7049389, clinical genotyping will be performed.
These samples will be destroyed no later than 5 years after the date of final closure of 
the clinical database, unless regulatory authorities require specimens to be maintained 
for a longer time period.
4.5.1.9
HBV-Specific Viral Assessments
HBV-specific viral assessments will be performed only in patients in Part 2 and Part 3 of 
the study.
Blood sample collection time-points are provided in the SoA; also see viral dynamic 
response measures in Section 3.3.3. Samples for laboratory tests as specified below will 
be sent to one or several central laboratories or to the Sponsor for analysis. Instruction 
manuals and supply kits will be provided for all central laboratory assessments. 
The collected samples will be destroyed no later than 5 years after the date of final 
closure of the clinical database, unless regulatory authorities require specimens to be 
maintained for a longer time period.
Blood samples for quantitative and qualitative determination of viral dynamic response 
including HBV DNA, HBsAg, HBeAg, anti-HBs, anti-HBe, HBV RNA, HBcrAg, anti-HBc, 
as well as viral resistance monitoring, viral genotypes based on DNA or RNA, and total 
HBsAg, etc. will be collected as detailed in the SoA.
4.5.1.10
Viral Resistance Monitoring
Blood samples will be collected as detailed in the SoA to monitor for the development of 
drug resistance. Sequencing (e.g., ultra-deep sequencing) of the HBV genome for viral 
resistance monitoring may be performed on all patients with HBV DNA LLOQ at 
baseline, and on those patients who experienced sub-optimal response or confirmed 
virological breakthrough (defined as a confirmed quantifiable HBV DNA level in patients 
who previously achieved HBV DNA below the LLOQ or a confirmed increase in HBV 
DNA level of more than one log10 [10-fold] over nadir while receiving RO7049389). 
Subjects, who did not experience virological breakthrough while receiving RO7049389 
and/or NUC, but showed a quantifiable HBV DNA level at or post the end of dosing may 
also be included in resistance testing. 


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Resistance testing may be done at baseline (Day -1), at the end of treatment (or at 
Study Drug Discontinuation/Early Termination) and at the end of the follow-up period, as 
well as at other visits, e.g., in the case that emerging mutations potentially linked to 
resistance will be found in the HBV genome.
These samples will be destroyed no later than 5 years after the date of final closure of 
the clinical database, unless regulatory authorities require specimens to be maintained 
for a longer time period.
4.5.1.11
Clinical Genotyping (Drug Metabolizing Enzymes and 
Transporters)
A blood sample will be taken as detailed in the SoA for DNA extraction from all subjects
if feasible. 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 clinical 
genotyping DNA samples are collected to explore whether genetic polymorphism of drug 
metabolizing enzymes (e.g., but not limited to UGT, CYP3A) and drug transporters 
(e.g., but not limited to OATP) can be related to the PK profile of RO7049389. For Part 3, 
only the genetic polymorphism of CYP3A4, UGT1A3, and OATP1B will be analyzed.
The specimen will be destroyed immediately after analysis and the results checked. 
Data arising from clinical genotyping will be subjected to the confidentiality standards 
described in Section 8.4.
4.5.1.12
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.
Specimens will be collected from study subjects 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 (only for Part 1 and Part 2).

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays (only for Part 1 and Part 2).


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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:

Serum to assess protein biomarkers including, but not limited to proteomics.

Plasma to assess viral nucleic acids including, but not limited to sequencing, splice 
variants.

Whole blood for RNA extraction to assess biomarkers including, but not limited to 
gene expression profiling.
The following samples will be collected for identification of genetic (inherited) biomarkers:

Whole blood for DNA extraction to assess biomarkers including, but not limited to 
single-nucleotide polymorphisms (SNPs).
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).
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’s 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.


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Data derived from RBR specimen analysis on individual study subject’s 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 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 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.
Withdrawal from the Research Biosample Repository
Study subject 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 Research Biosample 
Repository 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 YP39364 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 YP39364. Data already generated before time of withdrawal of 
consent to Research Biosample Repository will still be used.


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Monitoring and Oversight
Specimens collected for the Research Biosample Repository 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.
4.5.2
Timing of Study Assessments
4.5.2.1
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 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.
Screening assessments will be performed within 28 days prior to dosing, unless 
otherwise specified. 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 28-day screening period. 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 dosing within 28 days after the start of 
screening period because the recruitment into a cohort was suspended, or a stratum cap 
in a cohort was reached. 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 dosing. There is no need to repeat alpha-fetoprotein test 
if done for the study in central laboratory within 6 months before re-screening.


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4.5.2.2
Assessments During Treatment
Under no circumstances will study subjects who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the same part of the study.
All assessments must be performed as per SoA (see ‑ Overall Schedule of 
Assessments (Part 1a and 1b Appendix 1, Part 1c Appendix 3, Part 2 Appendix 5, and 
Part 3 Appendix 7) and Detailed Schedule of Assessments (Part 1a and 1b Appendix 2, 
Part 1c Appendix 4, Part 2 Appendix 6, and Part 3 Appendix 8).
4.5.2.3
Follow-Up Assessments 
All study subjects who complete the last dose administration or discontinue from the 
study treatment early will be asked to return to the clinic and complete follow-up 
assessments as specified in the SoA unless the study subjects refuse to do so. The
follow-up visit at 112 days post-first dose (for Part 2) or 72 weeks post-first dose (for 
Part 3) will be reported as the study completion visit in eCRF.
4.5.2.4
Assessments at Unscheduled Visits and Early Termination
If an unscheduled visit is required to ensure safety of study subjects, necessary 
assessments will be undertaken at the discretion of the Investigator. All unscheduled 
assessments should be reported in eCRF.
Unscheduled local laboratory tests may be ordered per Investigator’s discretion and may 
be used for the individual management of the HV/patient. A duplicate sample is 
recommended to simultaneously be sent to the central laboratory for analysis.
In case of early termination of a subject in Part 1c, a blood sample for PK assessment of 
RO7049389 should be collected at the time of discontinuation. In case of premature 
study drug discontinuation in Part 2 and Part 3, a patient should be called to complete an 
“early termination” visit within 7 days after the last dose of study drug or at the 
earliest possible time after “early termination” occurs, and assessments should be 
performed as listed in the SoA (Part 2 Appendix 5 and Part 3 Appendix 7) under “Early 
Termination/Study Drug Discontinuation”, including physical examination, vital signs, 
ECG, safety labs, HBV parameters, and RO7049389 PK assessment, etc.


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4.6
HEALTHY VOLUNTEER/PATIENT, STUDY, AND SITE 
DISCONTINUATION
4.6.1
Healthy Volunteer/Patient Discontinuation
The Investigator has the right to discontinue a study subject from RO7049389 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.

Patient non-compliance.
4.6.1.1
Discontinuation from Study Drug
4.6.1.1.1
Discontinuation of Study Treatment(s) Because of Safety 
Issues
All study subjects: individual study subjects must discontinue RO7049389/placebo if 
they experience any of the following:

Clinically significant RO7049389-related changes in safety parameters that are 
considered not acceptable by the Investigator and/or the Sponsor

Poor gastrointestinal (GI) tolerability that is considered to affect the study subject’s 
well-being and/or the PK evaluation.

In cases of suspected DILI, please follow the management plan in Section 5.2.1.1.
Part 2 (Patients with chronic HBV infection) and Part 3 (Patients with Chronic 
Hepatitis B): 
If patients experience a Hepatitis flare, please follow the management plan in Section 
5.2.1.2. Other than hepatitis flare, individual patients must discontinue 
RO7049389/placebo if they experience any of the following:

Any other confirmed (within 48-72 hours) Grade 4 laboratory abnormality, including 
Grade 4 hematology, deemed clinically significant (based on Investigator’s 
assessment).

Any sign of development of liver cirrhosis (or liver imaging indicating cirrhosis) or
decompensation (e.g., ascites, variceal hemorrhage, Child-Pugh Class B or C 
clinical classification).
After the initial event, subsequent monitoring and treatment plan should be discussed 
with the Medical Monitor.


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4.6.1.1.2
Discontinuation of Study Treatment(s) Because of Virological 
Breakthrough
For both Part 2 and Part 3, virological breakthrough will be defined as either a) a 
confirmed quantifiable HBV DNA level in a patient who previously achieved HBV DNA 
suppression below the assay LLOQ, or b) a confirmed increase in HBV DNA of more 
than 1 log10 (10-fold) IU/mL over the nadir achieved during the study treatment period. 
Blood samples taken at the time of virological breakthrough will be tested for evidence of 
treatment-emergent drug resistance. 
A timely confirmation of the initial HBV DNA (>LLOQ) result will be sought to meet the 
definition of virological breakthrough: the patient will be recalled for retesting, aiming to 
complete the confirmation visit within 2 weeks of the initial sample whenever possible. 
During the confirmation visit, there will be a thorough evaluation of adherence and 
factors that may be affecting compliance with treatment, and support for improved 
adherence will be offered as per routine clinical practice. At this visit, a blood sample will 
be collected to test for HBV DNA and plasma drug levels. If the HBV DNA load is 
confirmed, the sample will also be tested for antiviral drug resistance using genotypic 
and where feasible phenotypic testing.
The results of these assessments and investigations will be used to guide management. 
The general approach in cases of confirmed virological breakthrough while on CpAM 
treatment and not caused by poor compliance with treatment will be to discontinue the 
investigational study medications. NUC therapy is expected to be continued with any 
adjustment to be informed by the patient’s treatment history and assessment of 
adherence, HBV DNA levels, and any available result of drug resistance testing.
4.6.1.1.3
Other Causes of Discontinuation of Study Treatment(s)
All healthy volunteers and patients have the right to withdraw from the study at any time 
for any reason. 
The investigators have the right to withdraw study subject from the study in the event of 
intercurrent illness, adverse events, for administrative or other reasons. The Sponsor 
should be informed of study subjects’ discontinuations from the study or from the study 
drug.
Healthy volunteers or patients who withdraw from the study prematurely will be asked to 
return to the clinic for an “early termination” visit within 7 days after the last dose of 
study drug or at the earliest possible time after “early termination” occurs (see section 
4.5.2.4). The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF.


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4.6.1.2
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.
Healthy volunteers and patients 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 YP39364 does not, by itself, constitute withdrawal of 
specimens donated to the Research Biosample Repository.
Healthy volunteers and patients who withdraw from the study for safety reasons will not 
be replaced. Healthy volunteers and patients who withdraw from the study for other 
reasons will be replaced (see section 4.1).
4.6.2
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.

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.
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 and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 


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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).
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 healthy volunteer/patient’s ability to conduct 
normal life functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.


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
Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
healthy volunteer/patient 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 Grade 1-5 according to a pre-
defined grading criteria (see Section 5.3.3); 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).
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 elevated ALT or AST in combination with either 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.
5.2
SAFETY PLAN
5.2.1
Management of Specific Adverse Events
5.2.1.1
Potential Drug-Induced Liver Injury (DILI)
Wherever possible, timely confirmation 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 considered to be reported as SAEs, and 
discontinuation of all study medications (RO7049389/placebo, NUC, or Peg-IFN, where 
applicable) must be considered.


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In this study, potential drug-induced liver injury is defined as follows:
For healthy volunteers (Part 1): ALT >3 ULN accompanied by total bilirubin >2 ULN
For CHB patients (Part 2 and Part 3): ALT >3   baseline* AND >3 ULN, accompanied 
by total bilirubin >2 ULN
*The threshold of ALT >3 baseline will be capped at 10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
Hepatitis flare
Hepatitis flares (abrupt elevation of serum ALT above normal) are known to occur 
spontaneously in patients with CHB during the course of disease, and/or during anti-viral 
therapy. Transient hepatitis flares are not always harmful and may portend immune 
clearance of infected hepatocytes. Hepatitis flares may be due to direct DILI, drug-
induced immune-mediated hepatitis, the underlying disease (incomplete viral 
suppression), or immune clearance of infected hepatocytes (successful viral suppression 
and accompanying restitution of the host immune response). 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, 
increases inconsistent with the time course of a “flare” or ALT elevations associated with 
increases in bilirubin with or without alkaline phosphatase rise may primarily be 
considered adverse. 
There is no consistent definition of the ALT threshold for hepatitis flares. In this study, for 
all on-treatment or off-treatment ALT/AST elevation cases, more frequent monitoring of 
liver tests should be performed based on medical judgment. Other causes of ALT 
elevations should be investigated. For patients with ALT >5 ULN, the following 
management plan is recommended:
Confirmation and investigation of reasons

Schedule the patient to return to the clinic as soon as possible (ideally within 3 days 
after initial laboratory results were drawn). 

During the visit, a thorough clinical assessment of the subject will be performed. 

The following liver tests should be conducted: including but not limited to, serum 
ALT and AST, alkaline phosphatase (ALP), total and indirect bilirubin, International 
Normalized Ratio [INR]/prothrombin time [PT], serum albumin and liver ultrasound.

A PK sample (unscheduled) for RO7049389 should also be collected.


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
Investigate the patient for potential etiologies of the laboratory changes. At the 
discretion of investigators, the following testing can be conducted, such as plasma 
HBV DNA, serology for HBV, HDV, HAV IgM, HCV and HEV.
Monitoring frequency during on-treatment and off-treatment periods

ALT >10 ULN (or rise rapidly i.e., >2-fold increase within 48 hours): Repeat liver 
test twice weekly until ALT <10 ULN. 

ALT 5–10 ULN: Repeat liver test every week until ALT returns to below 5 ULN. 
Management during on-treatment period

Hepatitis flare with increasing HBV DNA: please follow Section 4.6.1.1.2
“Discontinuation of Study Treatment(s) Because of Virological Breakthrough”.

Isolated ALT >5 ULN with preserved hepatic function (e.g., no clinically significant 
changes in ALP, total and direct bilirubin, INR/PT, and albumin): 
1. ALT 5-10 ULN: Continue study treatment and keep monitoring; after up 
to 8 weeks monitoring, if ALT has not returned to <2 ULN or to the 
baseline level, and there is no decline of viral markers (e.g., HBsAg, 
HBeAg, HBcrAg etc.), consider to discontinue RO7049389 and Peg-IFN
permanently. NUC therapy can be continued or changed at the discretion 
of the investigator and applicable CHB guideline. 
2. ALT >10 ULN (or rise rapidly i.e., >2-fold increase within 48 hours): 
Consider interruption of RO7049389 and/or Peg-IFN; after up to 8 weeks 
interruption, if ALT has not returned to < 2 ULN or to the baseline level, 
and there is no decline of viral markers (e.g., HBsAg, HBeAg, HBcrAg 
etc.), consider to discontinue RO7049389 and Peg-IFN permanently.
NUC therapy can be continued or changed at the discretion of the 
investigator and applicable CHB guideline. If ALT returns to <2 ULN, re-
introduce RO7049389 from 200 mg QD, and gradually increase to the 
determined dose regimen for the respective cohort at the investigator’s 
discretion.  

ALT >5 ULN accompanied by declining liver synthetic and excretory functions 
(total bilirubin >2 ULN, or albumin <3.0 g/dL, or INR >1.5) or other signs of hepatic 
impairment (severe fatigue, nausea, vomiting, right upper quadrant pain):
1. RO7049389 and Peg-IFN will be permanently discontinued.
2. NUC therapy can be continued or changed at the discretion of the 
investigator and applicable CHB guideline.
Management during off-treatment period

If ALT>2 ULN is accompanied by confirmed virological relapse (HBV DNA >2,000 
IU/mL in HBeAg negative patients, or HBV DNA >20,000 IU/mL in HBeAg positive 
patients). NUC treatment may be restarted at the discretion of the investigator and 
applicable CHB guideline. 


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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 11]) should 
discontinue study treatment (Section 4.6.1.1). Patients who develop flares should be 
monitored more closely with additional unscheduled visits and laboratory assessments.
No dose modification of RO7049389/placebo for safety reasons is expected in the study. 
At the discretion of the Investigator, study treatment can be discontinued.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1.1 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, 5.5, and 5.6.
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 84 days in Part 2 of the study or until 24 weeks after the last 
dose of study drug in Part 3 of the study.
After a period of 84 days (Part 2) or 24 weeks from the last dose of study drug (Part 
3), 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).


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all healthy volunteer/patient 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?”
5.3.3
Assessment of Severity of Adverse Events
Table 6 provides guidance for assessing adverse event severity in Part 1 and Part 2.
Table 6
Adverse Event Severity Grading Scale (For Part 1 and Part 2)
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 3, DAIDS toxicity grading scales (Appendix 15) 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, or reintroduction 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.


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For healthy volunteers 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.
5.3.5.1
Diagnosis versus Signs and Symptoms
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.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
study subject evaluation time-points. Such events should only be recorded once on the 


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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 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 Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
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
Abnormal Liver Tests
For Healthy Volunteers:
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 patients with chronic HBV infection:
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 >3 ULN in combination with total 
bilirubin >2 ULN.

Treatment-emergent ALT >3 baseline* AND >3 ULN in combination with clinical 
jaundice. 
* The threshold of ALT >3   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).
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 one 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
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”).
5.3.5.9
Lack of Efficacy or Worsening of Chronic HBV Infection
As this is the first study of RO7049389 in patients with chronic HBV infection, the effects 
on viral parameters are being assessed as part of study endpoints in this study. Lack of 
RO7049389 efficacy in terms of changes in HBeAg and HBsAg do not qualify for 
adverse events in this study.
Medical occurrences or symptoms of deterioration in a course of chronic HBV infection 
should be recorded as an adverse event if judged by the Investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study. 
For virological breakthrough, see Section 4.6.1.1.2 and for hepatitis flares, see 
Section 5.3.5.6. Each of these should be reported as adverse events.
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 (e.g., for study drug administration 
and intensive PK sampling).

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
o
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.
o
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 Non-IMP) 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. Details will be available separately.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3), 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
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female healthy subjects of childbearing potential will not be allowed to participate in this 
study. Female patients of childbearing potential will be allowed to participate in this 
study, but they should avoid becoming pregnant during the study treatment and for at 
least 6 months post the last dose of study treatment as described in Inclusion Criteria. 
All female subjects will be instructed to immediately inform the Investigator if they 
become pregnant during the study, or within 6 months 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. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel the subject, 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 Subjects
Male study subjects will be instructed through the Informed Consent Form to 
immediately inform the Investigator if their partner becomes pregnant during the study 
and during the follow-up period, until 21 days in Part 1, or 28 days in Part 2, or 6 months 
in Part 3 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 


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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 (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.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female study subject 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).
5.5
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 


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(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 (Section 5.3.1). 
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 through use of the reference safety information in 
the document listed below:
Drug
Document
RO7049389
RO7049389 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary objective of Part 1 of this study is to characterize safety and tolerability, and 
PK profile, associated with a single-dose and multiple-doses of RO7049389 in healthy 
subjects. The primary objective of Part 2 and Part 3 of this study is to characterize safety, 
tolerability, and antiviral effect of multiple-doses of RO7049389 in patients with chronic 
HBV infection. Statistical summaries will be descriptive in nature and will be reported 
separately for each part of the study. All study subjects who are randomized to receive 


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placebo will be pooled as respective placebo control groups, according to each part of 
the study.
6.1
DETERMINATION OF SAMPLE SIZE
For Part 1 of the study, up to 93 healthy volunteers will be enrolled. This comprises up to
53 for Parts 1a and 1b, and up to 40 for Part 1c. For Part 2 of the study, up to 
35 patients with chronic HBV infection will be enrolled. 
The number of study subjects to be randomized in Parts 1 and 2 was chosen based on 
practical considerations and complies with standard safety review rules. With six study 
subjects receiving active drug at a dose-level, there is an 82% chance to observe at 
least one adverse event that has an incidence rate of 25% in the population. The total 
sample size may increase adaptively based on the study findings for safety, PK or viral 
dynamic outcomes. Good operating characteristics for the model-based predictions of 
MTD with control for overdosing are shown in Appendix 12 for a variety of dose-
response profiles.
This sample size for POM (Part 2) is to support the assessment of viral dynamic 
response to the study drug treatment. When the sample size is 6, a one-sided 90% 
confidence interval for the mean change from baseline of HBV DNA (Log10 IU/mL) will 
have an interval that extends no more than 0.904 from the observed mean assuming 
that the standard deviation is 1.5 and that the confidence interval is based on the 
t-statistic. 
Initially, approximately 55 patients with chronic hepatitis B will be enrolled in the first
three cohorts of Part 3 with approximately 30 patients in POM Cohort A, 10 patients in 
POM Cohort B, and 15 patients in POM Cohort C. Based on emerging efficacy/safety 
data, the sample size in Cohort C can be increased to approximately 30 patients. In 
addition, additional treatment cohorts may be opened to explore different treatment 
durations, dose regimens, or different combinations.
The sample size for Part 3 of the study is to support the assessment of response rate of 
HBV DNA <LLOQ with HBsAg loss at 24-weeks post-treatment. A sample size of 10, 15,
or 30 would ensure that the lower 95% CI is above 5%, 9%, or 14%, respectively, if the 
observed response rate is 30% assuming binomial distribution. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of study subjects who enroll, discontinue, or complete the study will be 
summarized by treatment and dose level. Reasons for premature study withdrawal will 
be listed and summarized by treatment and dose-level. Protocol deviations will be listed 
and evaluated for their potential impact on interpretation of study results. Study drug 
administration will be summarized by treatment. Descriptive statistics will be used in 
evaluating the conduct of the study.


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6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All healthy volunteers (Part 1) and patients (Parts 2 and Part 3) who have received at 
least one dose of the study drug, 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.
6.3.3
Efficacy Analysis Population
The analyses of viral dynamic response in Part 2 of the study will include all patients 
who were randomized and received at least one dose of study drug (RO7049389 or 
placebo). Patients will be analyzed according to the treatment group to which they were 
randomized. 
The analyses of viral dynamic response in Part 3 of the study will include all patients 
who received at least one dose of RO7049389.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Descriptive statistics will be used for demographic and baseline disease characteristics 
as applicable for each part of the study and will include sex, race, ethnicity, origin (Asian 
and non-Asian, Chinese among Asian), age, weight, height, body mass index, HBV DNA 
and HBsAg levels, HBV history (duration of HBV disease, previous HBV treatments, 
length of time on nucleos(t)ides), and viral genotype.
For continuous variables, mean, standard deviation, median, and minimum and 
maximum values will be presented. For categorical data, the proportion of study subjects 
in each category will be summarized.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor. Adverse events will be summarized by MedDRA mapped 
term and appropriate thesaurus level.


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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 subjects’ 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 individual listings with flagging of values 
outside the normal ranges.
The proportion of study subjects with laboratory abnormalities will be summarized, by 
treatment. Additionally, the value and change from baseline for each laboratory test will 
be summarized by treatment and visit using descriptive statistics.
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’s 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.


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6.5.3
Vital Signs
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. Summary descriptive statistics for 
the actual values and changes from baseline will be tabulated by nominal time for HR, 
QRS duration, PR and QTcF (as calculated per Appendix 15). 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. 
In addition, an exposure-response relationship may be developed using the ECG data 
extracted from the Holter monitoring in both of Parts 1a (SAD) and 1c (MAD). The 
primary ECG analysis will be based on a mixed effects repeated measures model with 
change-from-time-matched baseline (i.e., QTcF) as the dependent variable, drug 
plasma concentration as a continuous independent variable, time-point as a fixed effect, 
and an unstructured variance-covariance matrix. The absence of hysteresis will be 
checked graphically. If there is a delay in maximal change in placebo and baseline 
corrected QTcF compared to the peak plasma concentrations of the study drug, a PK 
model with an effect compartment will be explored to replace the direct effect model 
described above. The appropriateness of a linear model will be assessed by inspection 
of relevant goodness of fit plots. If there is an indication that a linear model is 
inappropriate, the non-linearity detected will be taken into account by an appropriate 
transformation of the concentration values. 
From the model, the slope of the exposure versus response curve will be estimated 
along with the corresponding two-sided 90% confidence intervals (CIs). The model will 
be used to evaluate the average difference from the RO7049389 treatment at 
pre-determined plasma concentrations, with bootstrapping methods used to estimate the 
two-sided 90% CIs of the average difference. The upper bound of these two-sided 
90% CIs will be compared to pre-specified thresholds (i.e., 10 msec).
The exposure-response (QTcF) analysis results will be reported in a separated 
document.


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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
EFFICACY ANALYSES
Efficacy analyses are only applicable to Parts 2 and 3 of the study. 
Plasma/serum samples for viral dynamic data (HBV DNA, HBsAg, HBeAg, anti-HBs,
anti-HBe, HBV RNA, HBcrAg, anti HBc, and viral genotypes) will be collected as 
detailed in the SoA.
6.6.1
Primary Efficacy Analyses
The primary efficacy endpoint in Part 2 will be mean change from baseline in quantitative 
HBV DNA levels. 
Summary descriptive statistics will be used to summarize HBV DNA levels, including 
actual and change from baseline (absolute and percentage) and maximum change from 
baseline (absolute and percentage) at each time-point. 
The primary efficacy endpoint in Part 3 will be proportion of patients achieving functional 
cure (HBV DNA <LLOQ (20 IU/mL) with HBsAg loss at 24 weeks post-treatment). 
Response rate and 95% CI will be calculated using Clopper-Pearson method at week 
12, 24, 36, 48 (EOT), and 24 weeks after EOT. Patients who cannot stop NUC therapy 
after week 48 because their HBV DNA have never been below LLOQ during the whole 
study period will be treated as not achieving functional cure. Patients with missing 
HBsAg or HBV DNA measures at 24 weeks visit after EOT and thereafter will be treated 
as not achieving functional cure.
6.6.2
Secondary Efficacy Analyses
Summary descriptive statistics will be used to summarize secondary efficacy outcome 
measures (HBV DNA, HBsAg, HBeAg, HBV RNA, and HBcrAg), including actual and
change from baseline and maximum change from baseline at each time point. In 
addition, the rate of loss of HBeAg, HBeAg seroconversion (loss of HBeAg and presence 
of anti-HBe), loss of HBsAg, HBsAg seroconversion (loss of HBsAg and presence of 
anti-HBs), HBV DNA levels less than 20 IU/mL, HBV RNA levels less than LLOQ/LOD,
and HBcrAg levels below LLOQ/LOD will also be summarized at each time-point.
6.6.3
Exploratory Efficacy Analyses
Dynamics of HBV viral markers as described below:


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The relationship between PK parameters and the viral response measures will be 
explored by graphical analysis. Further analysis of this relationship may be performed 
depending upon the findings in the graphical analysis. 
Summary descriptive statistics will be used to summarize the exploratory outcome 
measures, including actual and change from baseline and maximum change from 
baseline at each time-point. Exploratory efficacy analyses may be performed including, 
but not limited to total HBsAg and liver stiffness measurement by Fibroscan (see section 
3.3.4).
The findings from the resistance analyses will be listed for each patient selected for 
analysis, and report separately. Exploratory analysis may also be performed to identify 
markers and/or marker panels correlating with and/or potentially predictive of an in vivo 
PD response, the occurrence of certain AEs (to be defined) and/or changes in viral 
parameters.
6.7
PHARMACOKINETIC ANALYSES
Non-compartmental analysis will be employed for estimation of PK parameters. 
Individual plasma concentrations at each sampling time-point for RO7049389 of each 
cohort will be presented by listings and appropriate descriptive summary statistics, 
including means, medians, geometric means, ranges, standard deviations and 
coefficients of variation. Individual and mean plasma concentration of each cohort 
versus time data will be plotted on semi-logarithmic scales.
All PK parameters will be presented by individual listings and summary statistics for 
each cohort including means, geometric means, medians, ranges, standard deviations 
and coefficients of variation.
The relationship of selected PK parameters from Day 1 with dose will be evaluated 
graphically to establish dose-linearity. Dose-proportionality may be assessed by 
estimating the slope of the linear regression of logarithmically transformed variables 
Cmax, AUClast and AUC0-∞ versus the logarithmically transformed dose. A 95% confidence 
interval for the slope which includes the value 1 would be consistent with 
dose-proportionality.
To assess the effect of food, the logarithmically transformed variables Cmax, AUClast and 
AUC0-∞ will be subjected to an ANOVA (factors fasted/fed state and subject) for which 
measurements are available for healthy subjects in both the fasted and fed state. Ninety 
percent confidence intervals for the ratio of geometric means will be calculated using the 
fasting state as the reference.
A population PK model development and analysis may be performed. The Population 
PK results will be reported in a separated document.


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6.8
ANALYSIS TO SUPPORT DOSE-ESCALATION DECISION AND 
DOSE SELECTION 
A continual re-assessment method (CRM), with control for the probability of over-dosing, 
based on occurrence of dose-limiting event (DLE) will be used to inform decision about 
the dose of RO7049389 to be given to the next cohort during dose-escalation. A DLE will 
be defined as any treatment-related adverse reaction per investigator assessment (e.g., 
adverse event, laboratory abnormality, change in vital signs, ECG) that would prevent 
another drug administration at the same dose-level in a given study subject.
Details on the model/algorithm are given below. The relationship between the dose and 
the probability of observing a DLE will be described by the following two-parameter 
logistic regression model:
where is the probability of observing a DLE at a given dose, is the log of the odds for 
at the reference dose (ref, here equal to 450 mg) and is the change in the log odds 
for an e1-fold increase in dose (detailed discussion about this model parameterization 
can be found in Neuenschwander et al 2008).
Since the model will be estimated using a Bayesian framework, priors need to be 
specified for and . The following bivariate normal distribution will be used for and   
for the SAD Part 1a. For Part 1c (MAD) and Part 2 (POM), data from the already 
completed cohorts of the previous study parts may be used as prior information on the 
model. 
A visual representation of this prior (translated into the prior for the probability of DLE) is 
provided in Figure 3, showing the mean and 95% credible interval for the probability of 
DLE (y-axis) across different doses of RO7049389 (x-axis). This prior was built on the 
assumption that the starting-dose (150 mg) is safe with a 5% probability of observing a 
proportion of DLEs above 35% and that there is a 5% probability of observing a 
proportion of DLEs below 20% at the 6000 mg level. This information is conveyed into a 
‘minimally informative prior’, as described in Neuenschwander et al 2008, which would 
allow to model different possible dose-toxicity profiles.


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Figure 3
Probability of DLE versus Dose of RO7049389
After each cohort of study subjects completes dosing, the model will be updated with the 
DLE–observed occurrence and a new MTD will be defined as the dose such that:

The probability of being within the target safety interval (of 20% to 35% DLE rate) is 
maximized and

The probability of being within the excessive toxicity interval (above 35% DLE rate) 
is below 30%.

However, clinical judgment will always override model estimates in the 
dose-selection process.
Details about the operating characteristics of this Bayesian model-based approach for 
the planned study design for Part 1a are presented in Appendix 11.
It is expected that for the Part 1c (MAD) and Part 2 (POM) designs, good operating 
characteristics would be obtained for the dose-levels to be examined. For Part 2 (POM), 
a Bayesian dose-escalation approach may be applied to identify the dose giving an 
optimal trade-off between safety and viral response. Viral response (e.g., Week 4 HBV 
DNA change from baseline) would be modeled as a linear log-log function of dose and a 
gain function applied to select the next best dose (Yeung et al 2015).
6.9
EXPLORATORY ANALYSES
Urine and plasma samples collected in the study will be qualitatively analyzed for the 
presence of metabolites of RO7049389 with the use of non-validated methods.


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Endogenous substances levels will be investigated to assess the effect of multiple oral 
dosing of RO7049389 on CYP3A4 activity. Individual ratio (before and after 2 weeks of 
RO7049389 treatment in MAD cohorts) of plasma 4-hydroxycholesterol/cholesterol will 
be listed and summarized using descriptive statistics. Geometric mean ratio of after 
RO7049389 treatment relative to before RO7049389 treatment and the 90% confidence 
intervals will be computed.
The relationship between dose or exposure and efficacy response (e.g., HBV DNA, 
HBsAg) in patients will be assessed by modelling approach.
For exploratory analyses for Part 2 and Part 3 of the study, please see Section 6.6.3.
6.10
INTERIM ANALYSES
No interim analysis is planned for Parts 1 and 2 of this study.
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct interim efficacy analyses in Part 3. The decision to conduct an optional interim 
analysis and the timing of the analysis 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 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. Laboratory 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 


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name of person authorizing entry or change. For each healthy volunteer/patient enrolled, 
an eCRF must be completed and electronically signed by the Principal Investigator or 
authorized delegate from the study staff. If a healthy volunteer/patient withdraws from 
the study, the reason must be noted on the eCRF. If a healthy volunteer/patient 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 in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
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.


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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.
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 (U.S.) 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 such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. 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 


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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 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.
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. 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.


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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.
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 


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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.
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.
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.


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Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.


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10.
REFERENCES
Björkhem-Bergman L, Bäckström T, Nylén H, et al. Comparison of endogenous 
4-hydroxycholesterol with midazolam as markers for CYP3A4 induction by 
rifampicin. Drug Metab Dispos. 2013;41(8):1488-1493.
Boni C, Bertoletti A, Penna A, et al. Lamivudine treatment can restore T cell 
responsiveness in chronic hepatitis B. J Clin Invest. 1998;102(5):968-975.
Boni C, Penna A, Ogg GS, et al. Lamivudine treatment can overcome cytotoxic T-cell 
hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. 
Hepatology. 2001;33(4):963-971.
Boni C, Penna A, Bertoletti A, et al. Transient restoration of anti-viral T cell responses 
induced by lamivudine therapy in chronic hepatitis B. J Hepatol. 2003;39(4):595-
605.
Chalasani N, Regev A. Drug-Induced liver injury in patients with preexisting chronic liver 
disease in drug development: how to identify and manage? Gastroenterology. 
2016;151:1046–1051.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines 
on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-398.
FDA Guidance for Industry - Estimating the Maximum Safe Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers (2005). Retrieved from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf
FDA Guidance for Industry - In Vitro Drug Interaction Studies-Cytochrome P450 
Enzyme- and Transporter-Mediated Drug Interactions (2020). Retrieved from: 
https://www.fda.gov/media/134582/downloadFDA Guidance for Industry(draft) –
Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment (2018). 
Retrieved from: https://www.fda.gov/media/117977/download
Fernández M, Quiroga JA, Carreño V. Hepatitis B virus downregulates the human 
interferon-inducible MxA promoter through direct interaction of precore/core 
proteins. J Gen Virol. 2003;84(Pt 8):2073-2082.
Gruffaz M, Testoni B, Luangsay S, et al. Hepatitis B core protein is a key and very early 
negative regulator of Interferon response. J Hepatol. 2013;58:S155-S156.
Guideline on the Investigation of Drug Interactions (EMA). Retrieved from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
2/07/WC500129606.pdf
Halama B, Hohmann N, Burhenne J. A nanogram dose of the CYP3A probe substrate 
midazolam to evaluate drug interactions. Clin Pharmacol Ther. 2013;93(6):564-571.
ICH guideline M3 (R2). Retrieved from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidiscip
linary/M3_R2/Step4/M3_R2__Guideline.pdf


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Investigator’s Brochure, RO7049389. 
Midazolam. In: DRUGDEX System (Micromedex 2.0). Greenwood Village, CO:
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008;27(13):2420-2439.
Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the 
management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98.
Seto WK, Wong DK, Fung J, et al. Serum hepatitis B surface antigen(HBsAg) kinetics in 
hepatitis B e antigen (HBsAg)-negative chronic hepatitis B. Hepatol Int. 2013;7: 
119-126.
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and 
treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 
2018;67:1560-1599.
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http://www.micromedexsolutions.com/micromedex2/librarian# Accessed August 
11,2014.
Twu JS, Lee CH, Lin PM, et al. Hepatitis B virus suppresses expression of human beta-
interferon. Proc Natl Acad Sci USA. 1988;85(1):252-256.
WHO Fact Sheet N°204, updated July 2019. Retrieved from: 
http://www.who.int/mediacentre/factsheets/fs204/en/
Yang J, Liao M, Shou M. Cytochrome p450 turnover: regulation of synthesis and 
degradation, methods for determining rates, and implications for the prediction of 
drug interactions. Curr Drug Metab. 2008;9(5):384-394.
Yeung W, Whitehead J, Reigner B, et al. Bayesian adaptive dose-escalation procedures 
for binary and continuous responses utilizing a gain function. Pharm Statist. 
2015;14:479-487.


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Appendix 1 Schedule of Assessments: Parts 1a (SAD) and 1b (FE) – Main Table
Protocol Activity
Screening
Follow Up 
callk
Follow Up call 
(FE)k
Early Termination/ 
Study Drug 
Discontinuationl
Day
D-28 to D-3
Day -2 Day -1 Day 1 Day 2 Day 3 Day 4 Day 5
Follow-
up Day 8j Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
Follow-
up Day 23j
Day 29
Day 44
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
x
Vital Signsb
x
4
8
x
x
x
x
x
x
8
x
x
x
x
x
x
ECG-12 leadc
x
x
3
x
x
x
3
x
x
x
ECG-Holter Startd
x
x
ECG-Holter Endd
x
x
ECG-Holter Extractiond
6
7
x
Hematologye
x
x
x
x
x
x
x
x
Blood Chemistrye
x
x
x
x
x
x
x
x
Coagulatione
x
x
x
x
x
x
x
x
Urinalysise
x
x
x
x
x
x
x
x
Viral markersf
x
Substance Use
x
x
x
Pregnancy Testg
x
x
x
x
Follicle Stimulating Hormoneh
x
Randomisation
x
High-fat, high calorie meal
x
Administration of Study Medication
x
x
Plasma PK
12
2
x
x
x
12
2
x
x
x
x
Urine PK Sample
5
x
Clinical Genotypingi
x
In-Clinic Stay
x
x
x
x
x
x
x
Discharge
x
x
Ambulatory Visit
x
x
x
x
Adverse Events
Previous and Concomitant Treatments
All SAD cohorts
Food Effect (FE) Cohort Only
<---------------------------------------------------------------------------------------------------x--------------------------------------------------------------------------------------->
<---------------------------------------------------------------------------------------------------x--------------------------------------------------------------------------------------->


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Appendix 1 Schedule of Assessments: Parts 1a (SAD) and 1b (FE) – Main Table (cont.)
a.
A full physical exam is required at screening and follow-up. At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator. Height will only be recorded at screening. BMI will be calculated at 
screening.
b.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature.
c.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3 – 5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
d.
Triplicate ECG measurements from the continuous recordings within ± 10 minutes of the time points will be extracted. Subject should be in a 
supine position for at least 10 minutes prior to and remain in a supine position for at least 10 minutes after the ECG extraction time-point. ECG 
intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be 
documented. The absence of any environmental distractions (e.g., television, radio, conversation, or phone calls) during the pre- and post-
ECG rest period, and at every ECG time point specified in the SoA must be emphasized. In particular, activities known to cause changes in 
heart rate should be avoided.
e.
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) should be collected in the morning of Days 2 and 17 
approximately the same time as the 24 hour post-dose PK samples are collected. At all other time points these samples should be taken at 
the most appropriate time.
f.
Hepatitis A (HAV IgM Ab), Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab), human immunodeficiency virus (HIV-1 and HIV-2 Ab).
g.
Serum or plasma beta-human chronic gonadotropic (β-HCG) at screening, urine on all other occasions (females only).
h.
Follicle stimulating hormone (females only to confirm post-menopausal status).
i.
If the genetic blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
j.
A follow up visit to be completed in 7 days (±1) after the last dose of study medication. Subjects who participate in Part 1b (FE) will not have 
follow-up on Day 8.
k.
A follow up call to be completed in 28 days (±3) after the last dose of study medication. Subjects who participate in Part1a will have a follow 
up call on Day 29 only. Subjects who participate in both Part1a and Part 1b (FE) will have a follow-up call on Day 44 only.
l.
In case of early termination or study drug discontinuation, a subject should be called for an unscheduled visit and assessments should be 
performed as listed in the table.


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Appendix 2 Schedule of Assessments: Parts 1a (SAD) and 1b (FE) – Detailed Table
Protocol Activity
Day
Day 3 Day 4 Day 5
Scheduled Time (h)
0
1
2
3
4
6
12 Predose 0
0.25 0.5 1
1.5 2
3
4
0-4 6
8
4-8 10 12 8-12 12-24 24 36 24-48 48
72
96
Vital Signsa
X X
X
X
X
X
X
X X X
X
X
X
X
X
X
ECG-12 leadb
X
X
X
X
X
ECG-Holter Start
X
X
ECG-Holter End
X
X
ECG-Holter Extractionc
X X X X X X
X
X
X X X
X
X
X
Randomisation
X
Administration of 
Study Medication
X
Plasma PK
X
X
X
X
X
X X X
X X
X X
X X
X
X
X
Urine PK Sampled
X
X
X
X
X
X
All SAD cohorts
Day -1
Day 1
Day 2
Protocol Activity
Day
Day 18 Day 19 Day 20
Scheduled Time (h)
Predose 0
0.25 0.5 1
1.5 2
3
4
6
8
10 12 24 36 48
72
96
Vital Signsa
X
X
X
X X
X X
X
X
X
X
X
ECG-12 leadb
X
X
X
X
ECG-Holter Start
ECG-Holter End
ECG-Holter Extractionc
Randomisation
Administration of 
Study Medication
X
Plasma PK
X
X
X
X
X
X X
X X
X X
X
X
X
X
X
X
Urine PK Sampled
Food Effect (FE) Cohort Only
Day 16
Day 17


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Appendix 2 Schedule of Assessments: Parts 1a (SAD) and 1b (FE) – Detailed Table (cont.)
a.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature.
b.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3- 5 minute interval) after the subject has 
been in a supine position for a least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
c.
Triplicate ECG measurements from the continuous recordings within ± 10 minutes of the time points will be extracted. Subject should be in a 
supine position for at least 10 minutes prior to and remain in a supine position for at least 10 minutes after the ECG extraction time-point. 
ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be 
documented. The absence of any environmental distractions (e.g., television, radio, conversation, or phone calls) during the pre- and post-
ECG rest period, and at every ECG extraction time point specified in the SoA must be emphasized. In particular, activities known to cause 
changes in heart rate should be avoided. Holter extractions will not be collected in period 2 of FE cohort (Day 16 and beyond).
d.
Urine samples will be collected at pre-dose, 0-4, 4-8, 8-12, 12-24, 24-48 hours post-dose. Urine samples will not be collected in period 2 of 
FE cohort (Day 16 and beyond). 


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Appendix 3 Schedule of Assessments: Part 1c (MAD) – Main Table
Protocol Activity
Screening
Follow 
Up Visitj
Follow 
Up callk
Early Termination/ Study 
Drug Discontinuationl
Day
D-28 to D-3
Day -2 Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16
Day 21
Day 42
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
Vital Signsb
x
4
7
x
x
x
x
x
x
x
x
x
x
x
x
7
x
x
x
x
ECG-12 leadc
x
x
3
x
x
x
3
x
x
x
ECG-Holter Startd
x
x
x
ECG-Holter Endd
x
x
x
ECG-Holter Extractiond
6
7
x
7
x
Hematologye
x
x
x
x
x
x
x
Blood Chemistrye
x
x
x
x
x
x
x
Coagulatione
x
x
x
x
x
x
x
Urinalysise
x
x
x
x
x
x
x
Exploratory liver biomarkers
x
x
x
x
x
x
Viral markersf
x
Substance Use
x
x
Pregnancy Testg
x
x
x
x
Follicle Stimulating Hormoneh
x
Randomisation
x
Administration of Study Medication
2
2
2
2
2
2
2
2
2
2
2
2
2
x
Plasma PK
12
x
x
x
x
x
12
2
x
x
Urine PK Sample
5
5
Blood Sample for 4 
betahydroxycholesterol/cholesterol
x
x
Midazolam Microdosing
x
x
Midazolam PK sample
10
x
10
x
Clinical Genotypingi
x
In-Clinic Stay
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Discharge
x
Adverse Events
Previous and Concomitant Treatments
Week 2
Week 3
Week 1
<------------------------------------------------------------x-------------------------------------------------------->
<-----------------------------------------------------------x------------------------------------------------------->


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Appendix 3 Schedule of Assessments: Part 1c (MAD) – Main Table (cont.)
a.
A full physical exam is required at screening and follow-up. At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator. Height will only be recorded at screening. BMI will be calculated at 
screening.
b.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature.
c.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3 – 5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
d.
Triplicate ECG measurements from the continuous recordings within ± 10 minutes of the time points will be extracted. Subject should be in a 
supine position for at least 10 minutes prior to and remain in a supine position for at least 10 minutes after the ECG extraction time-point. 
ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be 
documented. The absence of any environmental distractions (e.g., television, radio, conversation, or phone calls) during the pre- and post-
ECG rest period, and at every ECG time point specified in the SoA must be emphasized. In particular, activities known to cause changes in 
heart rate should be avoided.
e.
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) should be collected in the morning of Days 3, 7, and 14 
approximately the same time before the morning dose (i.e., pre-dose). At all other time points these samples should be taken at the most 
appropriate time. 
f.
Hepatitis A (HAV IgM Ab), Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab), human immunodeficiency virus (HIV-1 and HIV-2 Ab).
g.
Serum or plasma beta-human chronic gonadotropic (β-HCG) at screening, urine on all other occasions (females only).
h.
Follicle stimulating hormone (females only to confirm post-menopausal status, performed at screening only).
i.
If the genetic blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
j.
A follow up visit to be completed in 7 days (±1) after the last dose of study medication.
k.
A follow up call to be completed in 28 days (±3) after the last dose of study medication.
l.
In case of early termination or study drug discontinuation, a subject should be called for an unscheduled visit and assessments should be 
performed as listed in the table.


RO7049389 —F. Hoffmann-La Roche Ltd
136/Protocol YP39364, Version 6
Appendix 4 Schedule of Assessments: Part 1c (MAD) – Detailed Table
Day
Scheduled Time (h)
Predose 0
0.25 0.5
1
2
3
4
6
8
10
12
Predose 0
0.25 0.5
1
1.5
2
3
4
0-4
6
8
4-8
10
12
8-12 12-24
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
ECG-12 leadb
x
x
x
x
ECG-Holter Start
x
x
ECG-Holter End
x
ECG-Holter Extraction
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomisation
x
Administration of Study 
Medicationc
x
x
Plasma PKd
x
x
x
x
x
x
x
x
x
x
x
x
Urine PK Samplee
x
x
x
x
x
Blood Sample for 4 
betahydroxycholesterol
/cholesterol
x
Midazolam Microdosing
x
Midazolam PK sample
x
x
x
x
x
x
x
x
x
x
x
Day -1
Day 1
Day
Day 2
Day 3
Day 4
Day 5
Day 7
Day 16
Scheduled Time (h)
Predose Predose Predose Predose Predose Predose
0
0.25
0.5
1
1.5
2
3
4
0-4
6
8
4-8
10
12
8-12 12-24
24
36
48
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG-12 leadb
x
x
x
x
x
x
x
ECG-Holter Start
x
ECG-Holter End
x
x
ECG-Holter Extraction
x
x
x
x
x
x
x
x
x
Randomisation
Administration of Study 
Medicationc
x
Plasma PKd
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine PK Samplee
x
x
x
x
x
Blood Sample for 4 
betahydroxycholesterol
/cholesterol
x
Midazolam Microdosing
x
Midazolam PK sample
x
x
x
x
x
x
x
x
x
x
x
Day 14
 Day 15


RO7049389 —F. Hoffmann-La Roche Ltd
137/Protocol YP39364, Version 6
Appendix 4 Schedule of Assessments: Part 1c (MAD) – Detailed Table (cont.)
a.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature
b.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3 – 5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
c.
BID dosing (12 hours apart) except for Day 14, where only one dose in the morning will be given. If PK data from SAD cohorts support QD 
regimen, subjects will be dosed for two weeks once daily.
d.
Plasma samples will be collected at pre-dose, 0.25,0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after the first dose (Day 1); and pre-dose, 0.25, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after the last morning dose (Day 14). Trough samples will be collected on Days 2, 3, 4, 5 
and 7 before the morning dose (i.e., pre-dose). 
e.
Urine samples will be collected at pre-dose, 0-4, 4-8, 8-12,12-24 hours post-morning dose on Days 1 and 14.


RO7049389 —F. Hoffmann-La Roche Ltd
138/Protocol YP39364, Version 6
Appendix 5 Schedule of Assessments: Part 2 (POM) – Main Table
Day
D-28 to D-2
Day -1
Day 1 Day 2 Day 3 Day 4 Day 5-7 Day 8 Day 9-14 Day 15
Day 16-
21
Day 22
Day 23-
26
Day 27 Day 28
Day 29
Day 35
(+/- 1 day)
Day 56
(+/- 3 days)
Day84
(+/- 2 weeks)
Day112
(+/- 2 weeks)
Assessments
Informed Consent
x
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
Vital Signsb
x
x
5
x
x
x
x
x
x
5
x
x
x
x
x
x
ECG-12 leadc
x
x
3
x
x
3
x
x
x
Hematologyd
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Chemistryd
x
x
x
x
x
x
x
x
x
x
x
x
x
Exploratory liver biomarkers
x
x
x
x
x
x
x
x
x
x
x
Coagulationd
x
x
x
x
x
x
x
x
x
x
x
Urinalysisd
x
x
x
x
x
x
x
x
x
x
x
Liver Biopsy/Fibroscane
x
Alpha-fetoprotein
x
Viral markers (HAV, HCV, HDV, 
HIV)f
x
RBR DNA
x
x
x
x
x
x
RBR RNA
x
x
x
x
x
x
RBR serum
x
x
x
x
x
x
RBR plasma
x
HBV DNA HBV total nucleic acid, 
Viral resistance monitoring
x
x
x
x
x
x
x
x
x
x
x
HBsAg quantitative
x
x
x
x
x
x
x
x
x
x
x
HBcAg
x
x
x
x
x
x
x
x
x
x
x
HBsAg, HBeAg qualitative
x
x
x
x
x
x
x
x
x
x
x
HBsAg/anti-HBsAg complex
x
x
x
x
x
x
x
x
x
x
x
anti-HBs, anti-HBe, anti-HBc
x
x
x
x
x
x
x
x
x
x
x
HBV Viral genotypes
x
Substance Use
x
x
Pregnancy Test g
x
x
x
x
FSHh
x
Randomisation
x
Administration of Study 
Medication
2
2
2
2
2
2
2
2
2
2
2
2
x
Plasma PK Samplei
7
x
x
x
x
x
x
7
x
x
Clinical Genotyping
x
Admission (optional)
x
x
Discharge (optional)
x
x
Ambulatory Visit
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events
Previous and Concomitant 
Treatments
Treatment period
Protocol Activity
Week 1
Screening
Week 2
Week 3
Week 4
Follow Up Visitm
Follow  Up Visitn
Early Termination/ 
Study Drug 
Discontinuationl
<-----------------------------------------------------------------------------------------------------------------x----------------------------------------------------------------------------------------------------->
<-----------------------------------------------------------------------------------------------------------------x----------------------------------------------------------------------------------------------------->
Week 5
Follow Up 
Visitj
Follow Up 
Visitk


RO7049389 —F. Hoffmann-La Roche Ltd
139/Protocol YP39364, Version 6
Appendix 5 Schedule of Assessments: Part 2 (POM) – Main Table (cont.)
a.
A full physical exam is required at screening and follow-up. At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator. Height will only be recorded at screening. BMI will be calculated at 
screening.
b.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature.
c.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3 – 5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
d.
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) should be collected in the morning of Days 2, 4, 8, 15, 22 
and 28 approximately the same time pre-dose (i.e., before the morning dose). At all other time points, samples should be taken at the most 
appropriate time.
e.
Screening biopsy, Fibroscan or equivalent documented within 6 months of randomization.
f.
Hepatitis A (HAV IgM Ab), Hepatitis C (HCV RNA or HCV Ab), Hepatitis D virus (total anti-HDV), human immunodeficiency virus (HIV-1 and 
HIV-2 Ab).
g.
Plasma or Serum beta-human chronic gonadotropic (β-HCG) at screening, urine on all other occasions (females only).
h.
Follicle stimulating hormone (females only to confirm post-menopausal status, performed at screening only).
i.
Plasma samples on Days 2, 3, 4, 8, 15, and 22 will be collected before the morning dose (i.e., pre-dose).
j.
A follow up visit to be completed in 7 days (±1) after the last dose of study medication.
k.
A follow up visit to be completed in 28 days (±3) after the last dose of study medication.
l.
In case of early termination or study drug discontinuation, a subject should be called for an unscheduled visit and assessments should be 
performed as listed in the table.
m. A follow up visit to be completed in 56 days (±2 weeks) after the last dose of study medication.
n.
A follow up visit to be completed in 84 days (±2 weeks) after the last dose of study medication.


RO7049389 —F. Hoffmann-La Roche Ltd
140/Protocol YP39364, Version 6
Appendix 6 Schedule of Assessments: Part 2 (POM) – Detailed Table
a.
Vital signs include triplicate measurements of blood pressure and heart rate and single assessment of body temperature.
b.
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 3 – 5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
c.
Plasma samples will be collected at pre-dose, 1, 2, 3, 4, 6, and 8 hours after the first dose (Day 1); and pre-dose, 1, 2, 3, 4, 6, 8, 24 hours 
after the last morning dose (Day 28). The time points of these samples may be adjusted based on PK data in SAD and MAD cohorts. Trough 
samples will be collected on Days 2, 3, 4, 8, 15, and 22 before the morning dose (i.e., pre-dose).
Day
Day2
Day3
Day4
Day8
Day15
Day22
Day 29
Scheduled Time (h)
Predose 0
1
2
3
4
6
8
12 Predose Predose Predose Predose Predose Predose Predose
0
1
2
3
4
6
8
24
Vital Signsa
x
x x
x x
x
x
x
x
x
x
x
x
x
x
x
x
ECG-12 leadb
x
x
x
x
x
x
x
x
x
Randomisation
x
Administration of 
Study Medication
x
x
x
Plasma PK Samplec
x
x x x x x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Day 1
Day 28


RO7049389 —F. Hoffmann-La Roche Ltd
141/Protocol YP39364, Version 6
Appendix 7 Schedule of Assessments: Part 3 (POM) – Main Table
Screening
Treatment period
Follow-up period
Early 
Termination/
Study Drug 
Discontinuati
on u
Protocol Activity
Day
-28 to
-2
Day
-1
Day 
1
2w
±3d
4w
±3d
8w
±6d
12w
±6d
16w
±6d
20w
±6d
24w
±6d
28w
±6d
32w
±6d
36w
±6d
40w
±6d
44w
±6d
48w
±6d
50w
±3d
s
52w
±3d
s
54w
±3d
s
56w
±3d/
6d t
58w
±3d
s
60w
±3d
s
64w
±6d
68w
±6d
s
72w
±6d
Assessment
Informed consent
x
Eligibility
x
x
Demography
x
Medical history
x
Physical 
examination a
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG 12-lead c
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood chemistry d
x
2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
GLDH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
α-fetoprotein
x
x
x
x
x
x
x
x
x
FT3,FT4, TSH
x
x
x
x
x
x
x
x
x
Liver biopsy/ 
Fibroscan e
x
x
x
x
x
x
x
x
x
B ultrasound
x
x
x
x
x
x
x
x
Viral markers 
(HAV, HCV, HIV, 
HDV, HEV) f
x
HBV Viral 
genotyping based 
on HBV RNA g
x
HBV Viral 
genotyping based 
on HBV DNA h
x
Viral dynamic 
response 
measures (HBV 
DNA, HBsAg and 
HBeAg, anti-HBs, 
anti-HBe)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Total HBsAg i, q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


RO7049389 —F. Hoffmann-La Roche Ltd
142/Protocol YP39364, Version 6
Appendix 7 Schedule of Assessments: Part 3 (POM) – Main Table (cont.)
Screening
Treatment period
Follow-up period
Early 
Termination/
Study Drug 
Discontinuati
on u
Protocol 
Activity
Day
-28 to
-2
Day
-1
Day 
1
2w
±3d
4w
±3d
8w
±6d
12w
±6d
16w
±6d
20w
±6d
24w
±6d
28w
±6d
32w
±6d
36w
±6d
40w
±6d
44w
±6d
48w
±6d  
50w
±3d
s
52w
±3d
s
54w
±3d
s
56w
±3d/
6d t
58w
±3d
s
60w
±3d
s
64w
±6d
68w
±6d
s
72w
±6d
Viral resistance 
monitoring, HBV 
RNA, HBcrAg, 
anti-HBc j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Substance use
x
x
Pregnancy test k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FSH l
x
RBR DNA q
x
RBR RNA q
x
RBR serum q
x
RBR plasma q
x
Clinical 
Genotyping q
x
Plasma PK for 
RO7049389 m
7
2
7
2
2
2
2
7
2
2
2
2
2
8
x
Plasma PK for 
NUC m
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK for 
Peg-IFN m, q
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense 
RO7049389 
(IMP)
x
x
x
x
x
x
x
x
x
x
x
x r
Dispense NUC 
and Peg-IFN 
(non-IMP)
x
x
x
x
x
x
x
x
x
x
x
x
Patient diary 
review and drug 
accountability 
(IMP and non-
IMP) n
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events 
& concomitant 
treatments o
x
Optional 
hospitalization p
x
x
x 


RO7049389 —F. Hoffmann-La Roche Ltd
143/Protocol YP39364, Version 6
Appendix 7 Schedule of Assessments: Part 3 (POM) – Main Table (cont.)
a.
A full physical exam is required at screening and follow-up. At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations 
should be performed at the discretion of the Investigator. Height will only be recorded at screening. BMI will be calculated at screening.
b.
Vital signs include blood pressure, pulse rate, and body temperature. To be obtained at least 5 minutes after patient has been in a supine position.
c.
A single interpretable 12-lead ECG will be obtained after the subject has been in a supine position for at least 10 minutes. Automated ECG intervals (PR 
(PQ), QRS, QT, QTcF) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be documented.
d.
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) should be collected in the morning of the same time pre-dose (i.e., before 
the morning dose) under fasting status. At all other time points, samples should be taken at the most appropriate time. On Day -1 a duplicate sample will be 
taken for liver tests (including at least ALT, AST, total bilirubin) and sent to the local laboratory. The local laboratory result will be used to confirm eligibility for 
liver parameters before dosing on Day 1. 
e.
At screening biopsy, Fibroscan or equivalent test documented within 6 months of randomization will be used to assess the eligibility. During the study, only 
Fibroscan is used to monitor the change of liver stiffness. If Fibroscan is obtained during Day 28 to 2 with the same device to be used throughout the 
study, then Fibroscan on Day 1 can be optional.
f.
Hepatitis A (HAV IgM Ab), Hepatitis C (HCV RNA and HCV Ab), Hepatitis D (HDV Ab), Hepatitis E (HEV IgM Ab and IgG Ab), human immunodeficiency virus 
(HIV-1 and HIV-2 Ab).
g.
HBV viral genotyping based on HBV RNA will be conducted only for NUC-suppressed patients (e.g., Cohort A).
h.
HBV viral genotyping based on HBV DNA will be conducted only for treatment naïve patients (e.g., Cohort B and Cohort C).
i.
Total HBsAg = post-dissociation of HBsAg/anti-HBs complexes.
j.
Serum will be collected as scheduled for potential resistance surveillance.
k.
Plasma or serum beta-human chronic gonadotropic (β-HCG) at screening, urine on all other occasions (females only). If urine pregnancy test is positive, it 
must be confirmed by a serum/plasma pregnancy test.
l.
Follicle stimulating hormone (females only to confirm post-menopausal status, performed at screening only).
m.
For RO7049389 and its three metabolites (RO7121986, RO7255420 and RO7255422), plasma PK samples will be collected at pre-dose, 1, 2, 3, 4, 6, and 8 
hours post-dose (Day 1 and week 24); and pre-dose, 1, 2, 3, 4, 6, 8, 24 hours after the last dose (week 48). Additional plasma PK samples will be collected at 
weeks 2, 4, 8, 12, 16, 20, 28, 32, 36, 40 and 44 pre-dose and between 1-4 hours post-dose. But for POM Cohort B, at week 4, plasma PK samples will be 
collected at pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose. For SoC, pre-dose PK samples will be collected at weeks 2 (Cohort A and C only), 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44 and 48. For Peg-IFN, when the pre-dose PK samples cannot be collected, the post dose PK samples will be collected. Peg-IFN PK 
samples are only for POM Cohort C.
n.
The patient’s diary will be dispensed at each visit (except for the week 2 visit) and reviewed at the following visit.
o.
Pre-treatment, only serious adverse events should be reported.
p.
Optional hospitalization from Study Day-1/Day 1, from Day 168 to Day 169, or from Day 336 to Day 337, to facilitate collection of the post dose PK sample.
q.
Since these measures are set to be exploratory, in some circumstances, these measures will only be tested in a subset of the patients or part of the visits.


RO7049389 —F. Hoffmann-La Roche Ltd
144/Protocol YP39364, Version 6
r.
The patients should be continually dosed with RO7049389 until the actual end-of-treatment (EOT) visit at week 48, during which the pre- and post-dose 
PK samples will be collected for the last dose of RO7049389.
s.
Only applicable to participants who meet NUC Stopping Criteria (HBsAg 100 IU/mL and HBV DNA 20 IU/mL) at EOT visit.
t.
For week 56 follow-up visit, 3 days window is allowed for participants who meet NUC Stopping Criteria at EOT visit, while 6 day window is allowed 
for participants who do not meet NUC Stopping Criteria at EOT visit.
u.
In case of early termination or study drug discontinuation, a subject should complete an “early termination” visit with the assessments listed in this 
column within 7 days after the last dose of study drug or at the earliest possible time after “early termination” occurs, and then enter into the follow-up
period in 2 weeks (3 days) (meeting NUC Stopping Criteria) or 8 weeks (6 days) (not meeting NUC Stopping Criteria) after the last dose of study drug 
with the assessments listed in respective columns.


RO7049389 —F. Hoffmann-La Roche Ltd
145/Protocol YP39364, Version 6
Appendix 8 Schedule of Assessments: Part 3 (POM) – Detailed Table
Week
0
2
4
8
12
16
20
Day
Day 1
14
28
56
84
112
140
Scheduled Time (h)
Predos
e
0 1 2 3 4 6 8 Predos
e
1-4 
h
Predos
e
1 2 3 4 6 8
1-4 
h
Predos
e
1-4 
h
Predos
e
1-4 
h
Predos
e
1-4 
h
Predos
e
1-4 
h
Vital Signsa
x
x
x
x
x
ECG-12 leadb
x
x
x
x
x
Administration of Study 
Medication at Clinical 
Site
x
x
x
x
x
x
x
Plasma PK Sample 
(RO7049389/metabolites)
c
x
x x x x x x
x
x
x
x x x x x x
x
x
x
x
x
x
x
x
Plasma PK for NUCc
x
x
x
x
x
x
Serum PK for Peg-IFNc
x
x
x
x
x
x
Week
24
28
32
36
40
44
48
Day
168
196
224
252
280
308
336
337
Scheduled Time (h)
Predose
1 2 3 4 6 8
Pre
dose
1-4 h
Pre
dose
1-4 h
Pre
dose
1-4 h
Pre
dose
1-4 h
Pre
dose
1-4 h
Pre
dose
1
2
3
4
6
8
24
Vital Signsa
x
x
x
ECG-12 leadb
x
x
x
Administration of Study 
Medication at Clinical 
Site
x
x
x
x
x
x
x
Plasma PK Sample 
(RO7049389/metabolites)c
x
x x x x x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma PK for NUCc
x
x
x
x
x
x
x
Serum PK for Peg-IFN)c
x
x
x
x
x
x
x
a.
Vital signs include blood pressure, pulse rate, and body temperature. To be obtained at least 5 minutes after patient has been in supine position.
b.
A single interpretable 12-lead ECG will be obtained after the subject has been in a supine position for at least 10 minutes. Automated ECG intervals (PR 
(PQ), QRS, QT, QTcF) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be documented.


RO7049389 —F. Hoffmann-La Roche Ltd
146/Protocol YP39364, Version 6
Appendix 8 Schedule of Assessments: Part 3 (POM) – Detailed Table (cont.)
c.
For RO7049389 and its three metabolites (RO7121986, RO7255420 and RO7255422), plasma PK samples will be collected at pre-dose, 1, 2, 3, 4, 6, and 
8 hours post-dose (Day 1 and week 24); and pre-dose, 1, 2, 3, 4, 6, 8, 24 hours after the last dose (week 48). Additional plasma PK samples will be 
collected at weeks 2, 4, 8, 12, 16, 20, 28, 32, 36, 40 and 44 pre-dose and between 1-4 hours post-dose. But for POM Cohort B, at week 4, plasma PK 
samples will be collected at pre-dose, 1, 2, 3, 4, 6, and 8 hours post-dose. For SoC, pre-dose PK samples will be collected at weeks 2 (cohort A and C 
only), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48. For Peg-IFN, when the pre-dose PK samples cannot be collected, the post dose PK samples will be 
collected (i.e., if the day of weekly Peg-IFN administration does not coincide with the visit day). Peg-IFN PK samples are only for POM Cohort C.


RO7049389 —F. Hoffmann-La Roche Ltd
147/Protocol YP39364, Version 6
Appendix 9 High-Fat Breakfast for the Food Effect Cohort
Subjects participating in the food effect cohort will fast overnight for at least 8 hours prior 
to Day 16. Subjects will then be fed a high fat breakfast 30 minutes before dosing. The 
meal should be completed within 30 minutes. All subjects will be administered lunch 
approximately 5 hours post-dose.
The high-fat meal will be as recommended by the FDA for food effect bioavailability and 
bioequivalence studies. The fat content of the breakfast will be approximately 50 percent 
of the total caloric content of the meal. The meal will be high-calorie (approximately 800 
to 1000 calories). This test meal will derive approximately 150, 250, and 
500-600 calories from protein, carbohydrate, and fat, respectively.
The meal will consist of:

Two eggs in butter

Two strips of bacon

Two slices of toast with butter

Four ounces of hash brown potatoes

Eight ounces of whole milk
Substitutions in this meal can be made (for example for vegetarians) as long as the meal 
provides a similar amount of calories from protein, carbohydrate, and fat and has 
comparable meal volume and viscosity.


RO7049389 —F. Hoffmann-La Roche Ltd
148/Protocol YP39364, Version 6
Appendix 10
Cockcroft Gault Equation for Calculation CrCl 
and eGFR Equation for eGFR
The Cockcroft-Gault equation: 
Used to calculate creatinine clearance (CrCl) (Conventional units = mL/min or SI units = 
mL/sec). Baseline body weight (ABW) will be used for calculation of CrCl.
Conventional Units:
(140 – Age) * ABW (kg)
Males (mL/min) =
72 * Serum Creatinine (mg/dL)
Females (mL/min) = Male value × 0.85
Conversion Factor for Creatinine Clearance:

SI Units (mL/sec) = Conventional units (mL/min)0.0167

Conventional Units (mL/min) = SI Units (mL/sec) / 0.0167
Conversion Factor for Serum Creatinine:

Conventional units (mg/dL) = SI units (μmol/L) / 88.4

SI Units (μmol/L) = Conventional Units88.4
The Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) is 
used to estimate eGFR: 
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr/κ or 1, and
max indicates the maximum of Scr/κ or 1.
 = 141 × min
 , 1

× max
 , 1
−1.209
× 0.993 ! × [1.018 $% %& '] × [1.159 $% *' +]


RO7049389 —F. Hoffmann-La Roche Ltd
149/Protocol YP39364, Version 6
Appendix 11
Child-Pugh Classification of Severity of Liver 
Disease
Clinical and Biochemical Measurements
Points Scored for Increasing 
Abnormality
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
µmol/L
< 34
34 – 51
51
Albumin 
g per 100 mL
3.5
2.8 – 3.5
2.8
g/L
35
28 – 35
28
Prothrombin time 
Second 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


RO7049389 —F. Hoffmann-La Roche Ltd
150/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a)
This section documents the simulation of the Part1a (SAD) and the operating 
characteristics for the model-based predictions of MTD with control for overdosing for a 
variety of dose-response profiles.
The following possible dose-levels were used in the simulation for RO7049389:
0.1 (as placebo), 150, 450, 750, 1000, 1400, 1800, 2400, 3000, 3750, 4500, 5000 and 
6000 mg. 
Four different scenarios for the true dose-toxicity profile were considered for the 
simulation:

Scenario A: the doses of RO7049389 with true DLE rate in the target interval 
(between 20% and 35% DLE rate) are 150, 450, 750 and 1000 mg, i.e., similar to 
the prior 

Scenario B: the doses of RO7049389 with true DLE rate in the target interval 
(between 20% and 35% DLE rate) are 750, 1000 and 1400 mg.

Scenario C: the doses of RO7049389 with true DLE rate in the target interval 
(between 20% and 35% DLE rate) are 150 and 450 mg.

Scenario D: the doses of RO7049389 with true DLE rate in the target interval 
(between 20% and 35% DLE rate) are 3750, 4500, 5000 and 6000 mg.
For each scenario, 1000 simulations were run. The true relationship between the 
probability of DLE and dose of RO7049389 is shown in Figure A1 for each scenario.


RO7049389 —F. Hoffmann-La Roche Ltd
151/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a) (cont.)
Figure A1
Considered Scenarios for the True Dose-Toxicity Relationship
Each simulation mimicked a complete dose-escalation study outcome, starting with the 
first cohort receiving a dose of RO7049389 of 150 mg. After a new cohort was 
completed, the dose for the next cohort (current estimate of MTD) was predicted based 
on the observed pattern of DLEs, as the dose for which:

The probability of being within the target safety interval (of 20% to 35% DLE rate) 
was maximized

The probability of being within the excessive toxicity interval (above 35% DLE rate) 
was below 30%
In all trials, the dose for the next cohort did not exceed the fold increase of the dose from 
the previous cohort shown in the Table A1 below for the doses considered:
Table A1
Maximum Fold Increases in Dose from Previous Cohort
Dose of Previous 
Cohort (mg)
150 - 450
450 - 1000
1000 - 1800
1800 - 3000
3000 - 6000
Maximum Fold 
Increase
2
1.22
0.8
0.67
0.25


RO7049389 —F. Hoffmann-La Roche Ltd
152/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a) (cont.)
If no DLEs were observed, the dose-escalation would proceed as follows: 150 to 450 to 
1000 to 1800 to 3000 to 6000 mg.
The initial cohort size was set to 3 (active) + 1 (placebo). Once a DLE occurred, the size 
of the next cohort was set to 6 (active) + 2 (placebo).
The following stopping rules were used in the simulation to stop the study:

If 51 active subjects (maximum sample size in Part 1) were already dosed, 
then the study was stopped.

If the predicted MTD had a probability of being within the target interval 
greater than or equal to 60%, and there were 6 subjects already dosed at that 
predicted MTD, then the study was stopped.

If the probability of under-dosing (DLE rate below 20%) for the maximum 
dose was above 60% and there were 6 subjects already dosed at the 
maximum dose, then the study was stopped.
Note that if all doses were already too toxic, i.e., the probability of being within the 
excessive toxicity interval (above 35% DLE rate) was greater than 30%, the study was 
stopped.
The operating characteristics of the proposed design under the four alternative true 
scenarios, based on 1000 simulations, are presented in Table A2.
For each scenario, the following results are presented:

True MTD: the RO7049389 doses with a true DLE rate in the target interval of 
20%-35%.

Predicted MTD: the predicted MTD (median, 10% and 90% quantiles) across 
all simulations (this includes no dose found).

% Trials selecting MTD: the percentage of total times the MTD was correctly 
predicted across all simulations.

True toxicity at doses selected: the true percentage of toxicity at the selected 
MTD across all simulations.

n treated above true MTD: the number of subjects (median, 10% and 90% 
quantiles) receiving a RO7049389 dose above the true MTD across all 
simulations.

n: number of subjects enrolled (median, 10% and 90% quantiles) across all 
simulations.

n of cohorts: number of cohorts of size 3 or 6 (median, 10% and 90% 
quantiles) across all simulations.


RO7049389 —F. Hoffmann-La Roche Ltd
153/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a) (cont.)
Table A2
Operating Characteristics
Scenario
True MTD 
(mg)
Predicted 
MTD (mg)
% Trials’ 
Selecting 
MTD
True 
Toxicity at 
Doses 
Selected 
(%)
n Treated 
above 
True 
MTD
n
A (red)
433.8 -1066.4
688
(150, 1000)
82
24
(9, 34)
2 (0, 6)
45
(33, 56)
B (green)
861- 1729.5
1148
(450, 1800)
55
25
(11, 36)
5 (0, 18)
47
(35, 56)
C (blue)
371-544.4
369.5
(150, 450)
67
21
(4, 27)
4 (0, 12)
46
(28, 56)
D (black)
3004.1- NA
4017.7
(2400, 6000)
64
24
(17, 31)
0 (0, 0)
53
(49, 56)
NA=Not applicable, Tox.= toxicity, MTD = Maximum Tolerated Dose.
Note: Median (10% and 90% quantiles) of 1000 simulations per scenario are shown. Simulations 
are based upon the low clearance dose levels and do not allow for an increase to 6 subjects 
for food effect dose level unless recommended by the algorithm.
As shown in Table A2, for all scenarios, in median, the MTD was correctly estimated 
with true toxicity percentage in the target toxicity interval, and a low number of 6 subjects 
who received doses with toxicity greater than 35%.
In addition, Figure A2 shows for each scenario the true dose-toxicity profile and the 
model-based estimate of the probability of DLE (mean and 95% credible intervals) 
across different doses of RO7049389.


RO7049389 —F. Hoffmann-La Roche Ltd
154/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a) (cont.)
Figure A2
True Dose-Toxicity Profile and Model Based Estimate of DLE Rate 
across Different Doses of RO7049389
Scenario A
Scenario B


RO7049389 —F. Hoffmann-La Roche Ltd
155/Protocol YP39364, Version 6
Appendix 12 Simulation of the Operating Characteristics of the 
Planned SAD Design (Part 1a) (cont.)
Figure A2 
True Dose-Toxicity Profile and Model Based Estimate of DLE Rate 
across Different Doses of RO7049389 (cont.)
Scenario C
Scenario D


RO7049389 —F. Hoffmann-La Roche Ltd
156/Protocol YP39364, Version 6
Appendix 13 Correction Formulas for QTc Intervals
Fridericia’s correction for QTc Measurement - QTcF
QTcF (msec) 
=
QT (ms)
Example:
QTcF of a subject with a QT of 386 msec and a RR of 848 msec
QT (msec) = 386
RR(msec) = 848
QT (msec)
=
408 msec
Bazett’s correction for QTc Measurement - QTcB
QTcB 
(msec) =
QT (msec)
Example:
QTcB of a subject with a QT of 386 msec and a RR of 848 msec
QT (msec) = 386
RR (msec) = 848
QT (msec)
=
419 msec


RO7049389 —F. Hoffmann-La Roche Ltd
157/Protocol YP39364, Version 6
Appendix 14 Alcohol Volume Calculation
A standard drink is any drink containing 10 grams of alcohol. One standard drink 
contains the same amount of alcohol regardless of container size or alcohol type (i.e., 
beer, wine, or spirit).
Calculation for the standard number of drinks per day:
Drink volume (mL) x Percent alcohol by volume x Density of ethyl alcohol (g/mL)
Example:
375mL0.050.789g/mL15g1.5 standard drinks
Examples from Australian Department of Health (Population Health Division) 
http://www.alcohol.gov.au/internet/alcohol/publishing.nsf/Content/standard


RO7049389 —F. Hoffmann-La Roche Ltd
158/Protocol YP39364, Version 6
Appendix 14 Alcohol Volume Calculation (cont.)






RO7049389 —F. Hoffmann-La Roche Ltd
161/Protocol YP39364, Version 6
Appendix 17 Alternative Study Visits and Study Drug (IMP and 
non-IMP) Dispensing during COVID-19 or Similar Epidemic
This appendix describes the guidance on how the study visits may be conducted to 
ensure subjects’ safety while continuing to participate in Study YP39364 during 
COVID-19 or similar epidemic. Everything in the protocol still applies unless 
otherwise noted in this appendix.
1.
Telemedicine Visit
In case a study participant is not able to attend visits at the study site, it is 
recommended that a Telemedicine visit be scheduled by the Investigator/Delegate to 
conduct for some study assessments by telephone or video call. 
The assessments shall include the review of intercurrent illness, adverse events, 
concomitant medications, drug compliance, etc., and the results shall be documented on 
eCRF with specific annotation that the assessments are done remotely due to COVID-
19 or similar epidemic. Once the telemedicine visit confirms that there is no apparent 
safety concern leading to a change in study treatment, the investigator may continue 
study treatment to the subject.
This recommendation is based on the nature of the Chronic Hepatitis B disease and 
experience with standard of care i.e. nucleos(t)ide analogs in which premature 
discontinuation of anti-HBV treatment often leads to viral relapse and, in rare cases, 
fatal liver failure.
To further ensure patient's safety during administration of study medication, it is 
highly recommended for the patient to take safety laboratory tests (liver function test 
and hematology as a minimum) at other hospital, clinics or community lab services per 
standard of care for which the cost will be covered by Sponsor.
2.
Study Drug (IMP and non-IMP) Dispensing
In addition, to ensure that all the subjects participating in the study can continue 
receiving their protocol defined treatment, in compliance with applicable global and 
local regulations and ICH GCP. Based on the self administrable nature of the study 
drug, a courier service may be used to deliver study drugs from the site directly to a 
subject’s home. This activity must ensure that the storage requirements according to 
the product label are maintained. Transporting without temperature monitoring is 
possible only in very specific circumstances and should only happen in very exceptional 
cases, and need to be assessed on a site by site basis. In all cases, decisions need to be 
made by the Investigator in consultation with the Sponsor and IRB/EC/HA as required. 
Alternatively, study drugs can be dispensed to a relative or a person attending on 
behalf of the study subject. This scenario is possible only if the relative or person 
receiving the study drug demonstrates that it has been legally delegated by the subject 
according to local applicable regulatory requirements.
In both circumstances, the study participant will be asked to acknowledge the receipt of 
the study drug, and the Investigator/Delegate is requested to document this study drug 
transfer process appropriately.


RO7049389 —F. Hoffmann-La Roche Ltd
162/Protocol YP39364, Version 6
3.
Discontinuation of Study Treatment
Study participants will not be discontinued from the study purely due to missed visits 
or deviations due to COVID-19 or similar epidemic. However, if study drug cannot be 
dispensed to the subjects or subjects’ safety cannot be assured by Telemedicine visit and 
minimum safety assessments, or lack of either of them, investigators can consider 
discontinuing the subject after assessing the risk/benefit. The Medical Monitors should 
be informed when such decision is made. An “early termination” visit should be 
arranged as soon as on-site visit becomes possible.