Clinical trial NCT03570658
Conditions: Hepatitis B Virus
Sponsor: Hoffmann-La Roche
Start date: 2018-08-24; Completion date: 2019-01-28
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will assess the safety and tolerability of RO7049389 compared to placebo in single- and multiple-ascending doses in healthy Chinese participants.

Detailed description:

Arms: arm 1: Participants will receive a single dose of RO7049389. arm 2: Participants will receive multiple doses of RO7049389. arm 3: Participants will receive either a single dose (SAD cohorts) or multiple doses (MAD cohorts) of placebo matched to RO7049389.
Interventions: intervention 1: RO7049389 intervention 2: Placebo
Intervention descriptions: intervention 1: RO7049389 will be administered orally either as a single dose (SAD) or as multiple doses defined by the SAD portion of the study (MAD). intervention 2: Placebo will be administered orally at a dose and frequency matched to RO7049389.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR-BLINDED, 
SUBJECT-BLINDED, PLACEBO-CONTROLLED, SINGLE-
ASCENDING DOSE (SAD) AND MULTIPLE-ASCENDING DOSE 
(MAD) STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, 
AND PHARMACOKINETICS OF RO7049389 IN HEALTHY 
CHINESE SUBJECTS 
NCT Number: 
NCT03570658 
Document Date: 
Protocol Version 4: 20-Nov-2018 
 
 
 


Clinical Study Report: RO7049389 - F. Hoffmann-La Roche Ltd
Protocol YP39406     Report Number 1096087
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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The information contained in this document, especially any unpublished data, is the property of 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 YP39406, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
INVESTIGATOR-BLINDED, SUBJECT-BLINDED, 
PLACEBO-CONTROLLED, SINGLE-ASCENDING 
DOSE (SAD) AND MULTIPLE-ASCENDING DOSE 
(MAD) STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF 
RO7049389 IN HEALTHY CHINESE SUBJECTS
PROTOCOL NUMBER: YP39406
VERSION:
4
EUDRACT NUMBER:
N/A
IND NUMBER:
N/A
TEST PRODUCT:
RO7049389
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 27 January 2017
DATE AMENDED:
Version 2: 16 December 2017
Version 3: 23 February 2018
Version 4: See electronic date stamp below
 
20-Nov-2018 10:47:28
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
INVESTIGATOR-BLINDED, SUBJECT-BLINDED, 
PLACEBO-CONTROLLED, SINGLE-ASCENDING 
DOSE (SAD) AND MULTIPLE-ASCENDING DOSE 
(MAD) STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF 
RO7049389 IN HEALTHY CHINESE SUBJECTS
PROTOCOL NUMBER:
YP39406 
VERSION NUMBER:
4
EUDRACT NUMBER:
N/A
IND NUMBER:
N/A
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.


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PROTOCOL AMENDMENT, VERSION 4
RATIONALE
Protocol YP39406 has been amended to incorporate the following changes based on the 
emerging data from this study (YP39406) and the first-in-human (FIH) study (YP39364):

 
 
 
 
 
 
The modification to the 
study design will support characterization of safety, tolerability and PK profiles of 
RO7049389 in healthy Chinese subjects.

 
 
 The highest dose level 
to be included in this study will now be based on the observed exposure in the 
FIH study (YP39364) which has been demonstrated to be safe and well tolerated. 
Additional minor changes have been made to correct typographical errors and to 
improve clarity and consistency. Substantial new information appears in italics. This 
amendment represents cumulative changes to the original protocol.


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PROTOCOL AMENDMENT, VERSION 4:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
3.1.1 Overview of Study Design
This study will leverage the data which will have been generated in the FIH study, 
allowing targeted evaluation of fewer doses. In addition, this study proposes to evaluate 
SAD and MAD of the same total daily dose level in a single subject cohort after 
approximately 1 week washout. The total daily dose in the MAD part will be equal or 
lower than the dose used in the SAD part for the same cohort.
[…]


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Figure 1Overall Study Design and Dose-escalation – new Figure
Dotted lines indicate optional cohorts. See Table 1 for additional information.
Escalation to the next single dose cohort will be based primarily on the safety and 
available PK data through 24 hours post-single dose in the previous cohorts. The MAD 
phase may start after a wash-out period of approximately 1-week, providing that the 
safety information through 24 hours post-dose in the SAD phase at the same cohortdose 
level, and available safety information from MAD cohorts in the entry-into-human study 
(YP39364), have been reviewed.
[….]


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[….]
 
The 
highest dose level and exposure to be included in this study will be within the dose and 
exposure range that which has been demonstrated to be safe and well tolerated in FIH 
Study YP39364.
3.1.1.3 Dietary Requirements
[….]
In the MAD phase (except cohort 4, which will be in the fasted state), a standard breakfast 
or dinner will be served to healthy volunteers 30 minutes prior to dosing, which 
should be consumed within 30 minutes.
[….]
3.1.2.1 Dose Escalation Stopping Rules
[….]

It is predicted that further dose-escalation will not result in a further increase in 
plasma exposure.

The proposed dose or exposure exceeds those previously evaluated in the study 
YP39364.
[….]


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3.2.1 Rationale for Dosage Selection
[….]
Subsequent dose-levels may be adjusted based on the PK, tolerability and safety results 
from FIH Study YP39364 and available data from current Study YP39406. The highest 
dose-level and exposure to be included in this study will be within the dose range and 
exposure which has been demonstrated to be safe and well tolerated in FIH Study 
YP39364.
4.3.2.1 RO7049389 and Placebo
MAD Phase
[….]
Except for cohort 4, which will be in the fasted state, aA standard breakfast or dinner 
will be served to healthy volunteers 30 minutes prior to dosing, which should be 
consumed within 30 minutes. RO7049389 or placebo will then be administered.
[….]


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 21
1.
BACKGROUND AND RATIONALE ............................................................ 23
1.1
Background on Disease......................................................... 23
1.2
Background on RO7049389 .................................................. 24
1.2.1
Previous Non-Clinical Studies ............................................... 24
1.2.2
Previous Clinical Studies ....................................................... 26
1.3
Study Rationale and Benefit–Risk Assessment..................... 27
1.3.1
Study Rationale ..................................................................... 27
1.3.2
Benefit/ Risk Assessment...................................................... 28
2.
OBJECTIVES.............................................................................................. 28
2.1
Primary Objective .................................................................. 28
2.2
Secondary Objective ............................................................. 28
3.
STUDY DESIGN......................................................................................... 29
3.1
Description of Study .............................................................. 29
3.1.1
Overview of Study Design ..................................................... 29
3.1.1.1
SAD Phase............................................................................ 30
3.1.1.2
MAD Phase ........................................................................... 30
3.1.1.3
Dietary Requirements............................................................ 30
3.1.2
Dose-Escalation Decision Criteria ......................................... 31
3.1.2.1
Dose-Escalation Stopping Rules ........................................... 31
3.1.3
End of Study.......................................................................... 32
3.2
Rationale for Study Design.................................................... 32
3.2.1
Rationale for Dosage Selection ............................................. 32
3.2.2
Rationale for Study Population .............................................. 33
3.3
Outcome Measures ............................................................... 33
3.3.1
Safety Outcome Measures .................................................... 33
3.3.2
Pharmacokinetic Outcome Measures.................................... 34


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4.
MATERIALS AND METHODS .................................................................... 34
4.1
Study Population ................................................................... 34
4.1.1
Recruitment Procedures........................................................ 35
4.1.2
Inclusion Criteria.................................................................... 35
4.1.3
Exclusion Criteria................................................................... 36
4.2
Method of Treatment Assignment and Blinding..................... 37
4.2.1
Method of Blinding................................................................. 37
4.3
Study Treatment.................................................................... 38
4.3.1
Formulation, Packaging, and Handling.................................. 38
4.3.1.1
RO7049389 and Placebo ...................................................... 38
4.3.2
Dosage, Administration and Compliance............................... 39
4.3.2.1
RO7049389 and Placebo ...................................................... 39
4.3.3
Investigational Medicinal Product Accountability ................... 40
4.4
Concomitant Therapy and Food ............................................ 41
4.4.1
Permitted Therapy................................................................. 41
4.4.2
Prohibited Therapy ................................................................ 42
4.4.3
Prohibited Food ..................................................................... 42
4.4.4
Dietary and Special Requirements ........................................ 43
4.5
Study Assessments ............................................................... 43
4.5.1
Description of Study Assessments ........................................ 43
4.5.1.1
Medical History and Demographic Data ................................ 43
4.5.1.2
Physical Examinations........................................................... 43
4.5.1.3
Vital Signs.............................................................................. 44
4.5.1.4
Electrocardiograms................................................................ 44
4.5.1.5
Laboratory Assessments ....................................................... 45
4.5.1.6
Pharmacokinetic Assessments.............................................. 47
4.5.2
Timing of Study Assessments ............................................... 47
4.5.2.1
Screening and Pretreatment Assessments............................ 47
4.5.2.2
Assessments during Treatment............................................. 48
4.5.2.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 48
4.5.2.4
Follow-Up Assessments ........................................................ 48
4.5.2.5
Assessments at Unscheduled Visits...................................... 48


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4.6
Study Subject, Study, and Site Discontinuation..................... 49
4.6.1
Study Subject Discontinuation............................................... 49
4.6.1.1
Discontinuation from Study Drug........................................... 49
4.6.1.2
Withdrawal from Study........................................................... 49
4.6.2
Study and Site Discontinuation.............................................. 50
5.
ASSESSMENT OF SAFETY....................................................................... 50
5.1
Safety Parameters and Definitions ........................................ 50
5.1.1
Adverse Events ..................................................................... 51
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 51
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 52
5.2
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 52
5.2.1
Adverse Event Reporting Period ........................................... 53
5.2.2
Eliciting Adverse Event Information....................................... 53
5.2.3
Assessment of Severity of Adverse Events ........................... 53
5.2.4
Assessment of Causality of Adverse Events ......................... 54
5.2.5
Procedures for Recording Adverse Events............................ 54
5.2.5.1
Diagnosis versus Signs and Symptoms................................. 54
5.2.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 55
5.2.5.3
Persistent or Recurrent Adverse Events................................ 55
5.2.5.4
Abnormal Laboratory Values ................................................. 55
5.2.5.5
Abnormal Vital Sign Values ................................................... 56
5.2.5.6
Abnormal Liver Function Tests.............................................. 57
5.2.5.7
Deaths ................................................................................... 57
5.2.5.8
Preexisting Medical Conditions.............................................. 57
5.2.5.9
Hospitalization or Prolonged Hospitalization.......................... 58
5.2.5.10
Overdoses ............................................................................. 58
5.3
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 58
5.3.1
Emergency Medical Contacts................................................ 59


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5.3.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 59
5.3.3
Reporting Requirements for Pregnancies.............................. 60
5.3.3.1
Pregnancies in Female Subjects ........................................... 60
5.3.3.2
Pregnancies in Female Partners of Male Study 
Subjects................................................................................. 60
5.3.3.3
Abortions ............................................................................... 61
5.3.3.4
Congenital Anomalies/Birth Defects ...................................... 61
5.4
Follow-Up of Subjects after Adverse Events.......................... 61
5.4.1
Investigator Follow-Up........................................................... 61
5.4.2
Sponsor Follow-Up ................................................................ 62
5.5
Post-Study Adverse Events................................................... 62
5.6
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 62
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 62
6.1
Determination of Sample Size ............................................... 63
6.2
Summaries of Conduct of Study............................................ 63
6.3
Analysis Populations ............................................................. 63
6.3.1
Safety Analysis Population .................................................... 63
6.3.2
Pharmacokinetic Analysis Population.................................... 63
6.4
Summaries of Treatment Group Comparability ..................... 63
6.5
Safety Analyses..................................................................... 64
6.5.1
Adverse Events ..................................................................... 64
6.5.2
Clinical Laboratory Test Results............................................ 64
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 64
6.5.2.2
Definition of Laboratory Abnormalities................................... 65
6.5.3
Vital Signs.............................................................................. 65
6.5.4
ECG Data Analysis................................................................ 65
6.5.5
Concomitant Medications ...................................................... 65
6.6
Pharmacokinetic Analyses..................................................... 66
6.7
Interim Analysis ..................................................................... 66


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7.
DATA COLLECTION AND MANAGEMENT ............................................... 66
7.1
Data Quality Assurance......................................................... 66
7.2
Electronic Case Report Forms............................................... 67
7.3
Source Data Documentation.................................................. 67
7.4
Use of Computerized Systems .............................................. 68
7.5
Retention of Records............................................................. 68
8.
ETHICAL CONSIDERATIONS.................................................................... 68
8.1
Compliance with Laws and Regulations ................................ 68
8.2
Informed Consent.................................................................. 69
8.3
Institutional Review Board or Ethics Committee.................... 69
8.4
Confidentiality........................................................................ 70
8.5
Financial Disclosure .............................................................. 70
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 70
9.1
Study Documentation ............................................................ 70
9.2
Site Inspections ..................................................................... 70
9.3
Administrative Structure......................................................... 71
9.4
Publication of Data and Protection of Trade 
Secrets .................................................................................. 71
9.5
Protocol Amendments ........................................................... 71
10. REFERENCES ........................................................................................... 72
LIST OF TABLES
Table 1
Initial Dose of RO7049389 or Placebo........................................ 30
Table 2
Adverse Event Severity Grading Scale ....................................... 53
LIST OF FIGURES
Figure 1
Overall Study Design and Dose-Escalation................................. 29




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PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR-
BLINDED, SUBJECT-BLINDED, PLACEBO-
CONTROLLED, SINGLE-ASCENDING DOSE (SAD) 
AND MULTIPLE-ASCENDING DOSE (MAD) STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF RO7049389 IN HEALTHY
CHINESE SUBJECTS
PROTOCOL NUMBER:
YP39406
VERSION:
4
EUDRACT NUMBER:
N/A
IND NUMBER:
N/A
TEST PRODUCT:
RO7049389
PHASE:
I
INDICATION:
N/A
SPONSOR:
F. Hoffmann-La Roche Ltd


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OBJECTIVES
The primary objective of this study is as follows:

To assess the safety and tolerability of RO7049389 compared to placebo after single- and 
multiple-ascending oral doses in healthy Chinese subjects.
The secondary objective of this study is as follows:

To assess the pharmacokinetics (PK) of RO7049389 after single-ascending and multiple-
ascending oral doses in healthy Chinese subjects.

To investigate metabolites (M5, M6, and M11) of RO7049389 in selected plasma samples. 
STUDY DESIGN
Description of Study
Healthy subjects will be enrolled into one of 3 planned cohorts and one optional cohort. 
Cohort 1 will include 4 healthy subjects, with 2 randomly assigned to RO7049389 (200mg) and 
2 assigned to placebo. From Cohort 2 to Cohort 4, each of the cohorts will include 12 healthy 
subjects with 10 subjects randomly assigned to RO7049389 and 2 subjects randomly assigned 
to placebo.
In Cohort 1, subjects will receive one single dose of the assigned study medication. In 
subsequent cohorts, subjects will receive one single dose of the assigned study medication, 
followed by a wash out period of approximately 1-week before entering into a MAD phase of the 
study. Subjects in the MAD cohorts will be from the SAD cohorts after the wash out period, or 
from new enrollments if there are discontinuations between the SAD phase and MAD phase for 
reasons other than safety.
Escalation to the next single dose cohort will be based primarily on the safety and available PK 
data through 24 hours post single dose in the previous cohorts. The MAD phase may start after 
a wash out period of approximately 1-week, providing that the safety information through 
24 hours post dose in the SAD phase at the same dose level, and available safety information 
from MAD cohorts in the entry-into-human study (YP39364), have been reviewed.
NUMBER OF STUDY SUBJECTS
Due to the nature of this study, the actual number of subjects will be determined during the 
study. This study may require up to 76 subjects, including:

About 40 healthy subjects to be enrolled in Cohort 1 of 4 subjects and Cohort 2 to Cohort 4 
of about 12 subjects each.

Up to 36 healthy subjects to be enrolled if new subjects are needed for the MAD phase, in 
case of non-safety related discontinuations between two periods (i.e., replacement 
subjects), 

For each part, 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.
Subjects 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. Subjects 
who withdraw from the study due to poor tolerability, or, due to study drug-related adverse 
events, will not be replaced.
TARGET POPULATION
The study will be conducted in Chinese healthy, male and female subjects of non-childbearing 
potential, 18 to 60 years of age.


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INCLUSION/EXCLUSION CRITERIA
Inclusion Criteria
Study subjects must meet the following criteria for study entry:
1.
Chinese 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) of between 19 to 27 kg/m2 inclusive, and a body weight of at least 
45 kg.
3.
Women should be of non-childbearing potential. 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, men must remain abstinent or use two 
methods of contraception with their partner, one of which must be a barrier method 
(i.e., condom), for the duration of the study 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.
b.
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.
c.
Other acceptable forms of contraception for this study include vasectomy, bilateral 
tubal occlusion, intrauterine device (IUD) or proper use of hormonal contraceptives.
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.
Exclusion Criteria
Study subjects who meet any of the following criteria will be excluded from study entry:
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 of congenital long QT syndrome or family history of 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 


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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 three separate resting blood pressure measurements, 
properly measured with well-maintained equipment, after at least 10 minutes rest) systolic 
BP 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 QTS 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 1 and 2 (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. Any suspicion or history of drug and/or alcohol abuse within the last year.
19. History (within 3 months of screening) of alcohol consumption exceeding two 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 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


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LENGTH OF STUDY
The total duration of the SAD part of the study will be approximately 8 weeks (from 
screening through study completion) for each randomized subject as follows:

Screening: Up to 4 weeks

In clinic period: Days to 3

Ambulatory visits: Days 4, 5, 8

Safety Follow-up Call: Day 29
The total duration of the MAD part of the study will be approximately 10 weeks* (from 
screening through study completion) for each randomized subject as follows:

Screening: Up to 4 weeks

In Clinic period: Day -1 to Day 16

Safety Follow-up Visit: Day 21

Safety Follow-up Call: Day 42
*For subjects who previously participated in the SAD part of the study, their total duration 
in the study will be approximately 12 weeks: up to 4 weeks screening for SAD, 
approximately 1 week treatment on SAD, approximately 1 week washout, and 6 weeks for 
MAD (no additional screening visit).
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 28 days after the last dose is administered.
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.

ECGs.

Vital signs including blood pressure (BP), pulse rate and body temperature.
PHARMACOKINETIC OUTCOME MEASURES
The pharmacokinetic outcome measures for this study are as follows:
PK parameters (SAD)

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-inf: 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
PK parameters (MAD)

Cmax: Maximum observed plasma concentration after single dose and at steady-state

Tmax: Time to maximum observed plasma concentration after single-dose and at 
steady-state


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
Ctrough: Trough plasma concentration

AUC0-: Area under the plasma concentration-time curve for a dosing interval after single 
dose and at steady-state

T1/2: Apparent terminal phase half-life after single-dose and at steady-state

Accumulation index of RO7049389
PK parameters (SAD and MAD):
Plasma samples collected in the study will be qualitatively and/or quantitatively analyzed for the 
metabolites (M5, M6, and M11) of RO7049389 in selected samples. 
INVESTIGATIONAL MEDICINAL PRODUCT(S)
The investigational medicinal product in this study are:
RO7049389 and placebo, which will be supplied and packaged by the Sponsor. 
 
 A matching-placebo, in terms of size, shape 
and color, has also been developed for clinical usage.
PROCEDURES
Schedules of Assessments (SoA) are provided in Appendices 1-4.
STATISTICAL METHODS
SAFETY ANALYSES
All study subjects who have received at least one dose of the study medication (RO7049389 or 
matching placebo), whether prematurely withdrawn from the study or not, and with at least one 
safety assessment, will be included in the safety analysis. The safety data, including AEs, 
reasons for withdrawal from study, laboratory data, ECG, concomitant medications, vital signs, 
and physical examination results will be listed and summarized descriptively. Laboratory test 
values will be presented by individual listings with flagging of values outside the normal ranges.
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. Non-compartmental analysis will be 
employed for estimation of PK parameters. 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. Plasma samples collected in the study 
will be qualitatively and/or quantitatively analyzed for the presence of metabolites of 
RO7049389. A population PK model development and analysis may be performed. The 
Population PK results will be reported in a separated document.
SAMPLE SIZE JUSTIFICATION
The sample size was determined by practical considerations and not based on statistical power 
calculations. Approximately four subjects will be enrolled in SAD cohort 1 (2 active treatment 
and 2 placebo). Approximately twelve subjects will be enrolled in each of the other SAD and 
MAD cohorts. They will be randomized to either active treatment (10 subjects per dose level) or 
placebo (2 subjects per dose level). 
With ten subjects on active drug per dose group or cohort, there is a 94% chance to observe at 
least one AE that has an incidence rate of 25% in the population.
INTERIM ANALYSIS
No interim analysis is planned for this study. 


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LIST OF PROHIBITED MEDICATIONS
All medications (prescription and OTC) taken within 4 weeks 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, with the exception of the cases listed in the protocol. Exceptions may be 
made on a case-by-case basis following discussion and agreement between the Investigator 
and the Sponsor after the rationale for exception is discussed and clearly documented.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse Events
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BID
Twice daily
BP
Blood pressure
cccDNA
Covalently closed circular DNA
CHB
Chronic Hepatitis B
CL
Clearance
CL/F
Apparent clearance
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiograms
eCRF
Electronic case report form
EDC
Electronic data capture
ESF
Eligibility screening form
FDA
Food and Drug Administration
FIH
First in human
FSH
Follicle-stimulating hormone
HBeAG
Hepatitis B envelope antigen
HBsAG
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High density lipoproteins
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IMP
Investigational medicinal product


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IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IV
Intravenous
LDL
Low density lipoproteins
LSLO
Last subject, last observation
LSLV
Last subject, last visit
MAD
Multiple ascending doses
NOAEL
No-observed-adverse-effect level
NUC
Nucleos(t)ide analogue
PD
Pharmacodynamic
PK
Pharmacokinetic
PT
Prothrombin time
Q12h
Twice daily, every 12 hours
Q24h
Once daily, every 24 hours
QD
Once daily
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia 
correction factor
RBC
Red blood cell
RNA
Ribonucleic acid
RR
RR interval
SAD
Single ascending dose
SAE
Serious adverse event
SD
Single dose
SoA
Schedule of assessments
ULN
Upper limit of normal
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 DISEASE
Hepatitis B virus (HBV) infection is a major cause of both acute hepatitis and chronic 
liver diseases, including cirrhosis and hepatocellular carcinoma. Approximately two 
billion people worldwide have serological evidence of past or present HBV infection. An 
estimated 686,000 people are estimated to die each year due to the acute or chronic 
consequences of hepatitis B (WHO 2016). In China, about 7% of the population 
(approximately 90 million) is chronically infected with HBV (Yu et al 2014; Liang et al 
2009).
Chronic HBV infection can be characterized by the persistence of high levels of HBV 
antigens (including capsid protein, core protein, hepatitis B envelope 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 (HCC). Accordingly, sustained HBsAg loss with or without 
seroconversion has been defined as ‘functional cure’, and is specified by current 
treatment guidelines as the ideal treatment endpoint. Achieving functional cure allows 
treatment cessation (EASL 2012) 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 chronic hepatitis B 
(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 drugs available for the treatment of CHB: 
subcutaneously-administered interferon (IFN) preparations, and orally-administered
nucleos(t)ide analogues (NUCs). Although both types of treatment can induce the loss of 
HBV envelope antigen with development of anti-HBeAg antibody (serological response), 


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the suppression of HBV DNA to an undetectable level by sensitive polymerase chain 
reaction (PCR) methods (virological response), and are able 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15% after one to five years’ follow-up (EASL 2012). 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 
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), and subsequent initiation of 
reverse transcription. It is also an important component of the cccDNA mini chromosome. 
Furthermore, it has been suggested that the HBV core protein may play a role in 
suppressing host innate immune responses (Twu et al 1998; 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.
See the RO7049389 Investigator’s Brochure for more details on non-clinical and clinical 
studies.
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.
 
 
 
 








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that will provide guidance on future clinical studies and optimize the benefit-risk in 
Chinese HBV patients.
1.3.2
Benefit/ Risk Assessment
As this is a Phase I study in healthy subjects, no therapeutic benefit is anticipated for 
these subjects. However, this study will be essential in the development of new 
treatments for chronic HBV infection in populations of Asian descent, and for selecting 
the most appropriate dose for a proof-of--concept study in such patients.
The evaluation of the potential risks of treatment and the specific tests, observations, 
and precautions required for clinical studies with RO7049389 are based on information 
from non-clinical toxicology and safety pharmacology studies. Furthermore, this study 
leverages data generated in the ongoing FIH study YP39364. Safety and tolerability will 
be carefully assessed, and study subjects 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 200 mg is considered to 
be safe (please refer to Section 3.1.2 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. All 
dose-levels to be included in this study will be within the dose-range which will have 
been considered to be safe and well-tolerated in the FIH study YP39364. The risks for 
an individual study subject due to ascending doses of RO7049389 or study-related
procedures are considered to be minimal. The starting-dose level of 200 mg may be 
adjusted based on the available data from FIH study YP39364.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary objective of this study is as follows:

To assess the safety and tolerability of RO7049389 compared to placebo after 
single- and multiple-ascending oral doses in healthy Chinese subjects.
2.2
SECONDARY OBJECTIVE
The secondary objective of this study is:

To assess the pharmacokinetics (PK) of RO7049389 after single-ascending and 
multiple-ascending oral doses in healthy Chinese subjects.

To investigate metabolites (M5, M6, and M11) of RO7049389 in selected plasma 
samples. 


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This study will leverage the data which will have been generated in the FIH study, 
allowing targeted evaluation of fewer doses.
Healthy subjects will be enrolled into one of 3 planned cohorts and one optional 
cohort. Cohort 1 will include 4 healthy subjects, with 2 randomly assigned to RO7049389 
and 2 assigned to placebo. From Cohort 2 to Cohort 4, each of the cohorts will include 
12 healthy subjects with 10 subjects randomly assigned to RO7049389 and 2 subjects 
randomly assigned to placebo.
In Cohort 1, subjects will receive one single dose of the assigned study medication. In 
subsequent cohorts, subjects will receive one single dose of the assigned study 
medication, followed by a wash-out period of approximately 1-week before entering into 
a MAD phase of the study. Subjects in the MAD cohorts will be from the SAD cohorts 
after the wash-out period (see Figure 1), or from new enrollments if there are 
discontinuations between the SAD phase and MAD phase for reasons other than safety.
Figure 1
Overall Study Design and Dose-escalation
Dotted lines indicate optional cohorts. See Table 1 for additional information.
Escalation to the next single dose cohort will be based primarily on the safety and 
available PK data through 24 hours post-single dose in the previous cohorts. The MAD 
phase may start after a wash-out period of approximately 1-week, providing that the 
safety information through 24 hours post-dose in the SAD phase at the same cohort, and 
available safety information in the entry-into-human study (YP39364), have been 
reviewed.


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The projected dose levels, which may be adjusted based on the emerging safety, 
tolerability, and PK data from this study and study YP39364 (entry into human), are 
shown in Table 1.
Table 1
Initial Dose of RO7049389 or Placebo
Cohort 1
Cohort 2
Cohort 3
Cohort 4a
SAD
200 mg
400 mg
600 mg
800 mg
MAD
N/A
200 mg q12hb,c
400 mg q12h
600 or 800 mg 
q24h
a. Cohort 4 is optional and will be conducted in case that the total daily dose of the estimated 
efficacious dose from YP39364 is between 400 mg to 600 mg q12h or higher. 
b. The dose of 200 mg q12h in MAD cohort 2 will be optional and will be conducted in case the
total daily dose of the estimated efficacious dose from YP39364 is lower than 400 mg q12h. 
The rationale for dose selection is described in Section 3.2.1.
The highest dose level and exposure to be included in this study will be within the dose 
and exposure that has been demonstrated to be safe and well tolerated in FIH Study 
YP39364.
3.1.1.1
SAD Phase
All subjects will be admitted to a clinical research unit for 3 nights from Day -1 through 
Day 2, and discharged on Day 3. On Day 1, subjects will be administered a single dose 
of either RO7049389 or placebo. Subjects who will not enter the MAD phase (Cohort 1) 
will return for a follow-up visit on Day 8 (1), and will receive a follow-up call on Day 29.
3.1.1.2
MAD Phase
In Cohorts 2, 3 and 4, after a post-SAD phase wash-out period of at least one week, all 
subjects will be admitted to a clinical research unit for 16 nights from Day -1 to Day 16 
(discharged on Day 16). Subjects will be administered multiple oral doses of either 
RO7049389 or placebo twice daily (q12h) or once daily (q24h) from Day 1 to Day 14 
(the currently planned regimen is q12h, but will be evaluated based on emerging data 
from Study YP39364). The allocation of RO7049389 or placebo will be the same as that 
which was administered in the SAD phase. All subjects will return for a follow-up visit on 
Day 21 (1), and will receive a follow-up call on Day 42.
3.1.1.3
Dietary Requirements
In the SAD phase, all healthy volunteers will receive either RO7049389 or placebo in 
the fasted state (overnight at least 8 hours). Subjects will not eat for at least 4 hours 
after the dose is administered. Lunch will be served approximately 4-5 hours post-
morning-dose. In the MAD phase (except cohort 4, which will be in the fasted state), a 
standard breakfast or dinner will be served to healthy volunteers 30 minutes 
prior to dosing, which should be consumed within 30 minutes. RO7049389 or 
placebo will then be administered. Lunch will be served approximately 4-5 hours 


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post-morning-dose. An optional evening snack may be allowed provided that the fasting 
period is fulfilled before the next morning assessments.
Water will be allowed ad libitum until one hour prior to dosing and after one hour post 
dosing.
3.1.2
Dose-Escalation Decision Criteria
A Safety Review of the data will be conducted by the Principal Investigator, the Medical 
Monitor, and the Sponsor Clinical Team prior to each RO7049389 dose-escalation.
Escalation to the next dose cohort will be based primarily on the safety and tolerability 
information (including adverse events [AEs], electrocardiograms [ECGs], vital signs, 
clinical laboratory test results) up to 48 hours post-dose (SAD), and secondarily on all 
available PK data up to 24 hours post-dose (SAD) in a minimum of 8 subjects (receiving 
active study drug or placebo) within the previous cohort. Doses will be escalated by
three-fold increments but for higher doses the increments will be smaller than 
three-fold. The decision to escalate the dose will be made by mutual agreement 
between the Sponsor and the Investigator.
The MAD phase (Cohorts 2, 3, and 4) can begin after a washout period of at least one
week, and once safety and tolerability information through 24 hours post-dose in the 
SAD phase (see Figure 1), and available safety and tolerability information from MAD 
cohorts in the entry-into-human study (YP39364) have been reviewed. Additionally, both 
the Sponsor and the Investigator must agree that the safety data can support continuing 
with the multiple-dose phase.
3.1.2.1
Dose-Escalation Stopping Rules
Any serious adverse event considered related to study drug will lead to an immediate 
halt of study drug dosing, dose escalation and enrollment of new subjects until a 
thorough investigation has been conducted by the Sponsor’s Clinical Team and the 
Principal Investigator. The sponsor or designee will notify all investigators and IRBs/EC, 
if required (see Section 5.3), regarding the outcome of such investigation. The study will 
only continue if agreed by the IRBs/EC.
An internal safety review of the unblinded data by Sponsor representatives from 
Translational Medicine, Drug Safety, Clinical Pharmacology and Biostatistics will be 
performed prior to each RO7049389 dose-escalation. 
Planned dose-escalation will not be implemented if one of the following circumstances 
occurs in subjects treated with RO7049389, unless it is obvious that the occurrence is 
not related to the administration of study medication:

If at any dose level, more than two subjects on active drug experience:
–
Severe and clinically significant (as defined by the Investigator) 
RO7049389-related AEs of the same character.


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–
Clinically significant RO7049389-related laboratory abnormalities of the same 
character (e.g., ALT or AST3ULN, and total bilirubin2ULN).
–
Clinically significant RO7049389-related changes in vital signs or ECGs of the 
same character (e.g., QTcF500 msec, or > 60 msec longer than the pre-dose 
baseline, within the first 48 hours post-dose).

It is predicted that further dose-escalation will not result in a further increase in 
plasma exposure.

The proposed dose or exposure exceeds those previously evaluated in the study 
YP39364.

Other findings (regardless of the incidence rates) that at the joint discretion of the 
Sponsor and the Investigator indicate dose-escalation should be halted.
If dose-escalation is stopped, lower doses within the tolerated dose range could be 
investigated, or a dose repeated in the subsequent cohorts by mutual agreement 
between the Sponsor and Investigator, in order to increase the amount of data within this 
tolerated dose range.
For an individual subject, dosing should not continue if there are:

Clinically significant RO7049389-related changes in safety parameters that are 
considered not acceptable by the Investigator and/or the Sponsor; or

Poor gastrointestinal (GI) tolerability that is considered to affect the subject’s 
wellbeing and/or the PK evaluation.
Due to the exploratory nature of this clinical study, its conduct can be discontinued at 
any time at the discretion of the Sponsor. This will not constitute a premature termination 
of the study.
3.1.3
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 28 days after the last dose is administered.
3.2
RATIONALE FOR STUDY DESIGN
The rationale for the design of study YP39406 is given in Section 1.3.1.
3.2.1
Rationale for Dosage Selection
The first SAD cohort will receive 200 mg (~1/4 of the total projected clinically efficacious 
dose). This starting-dose is considered to have been safe and well tolerated in the FIH 
Study YP39364. 
 
 


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Furthermore, the starting-dose level of 200 mg is considered to be safe based on FDA 
guidance. 
 
 
 Using the lowest HED of 40 mg/kg 
 
 and a safety factor of 10, the maximum recommended 
starting-dose (MRSD) for a 60 kg individual is 240 mg. The starting-dose of 200 mg
proposed in this study is approximately 1.2-fold lower than the MRSD. 
Subsequent dose-levels may be adjusted based on the PK, tolerability and safety results 
from FIH Study YP39364 and available data from current Study YP39406. The highest 
dose-level and exposure to be included in this study will be within the dose range and 
exposure which has been demonstrated to be safe and well tolerated in FIH Study 
YP39364. 
3.2.2
Rationale for Study Population
The study will be conducted in Chinese healthy, male and female subjects of non-
childbearing potential, 18 to 60 years of age. The absence of confounding diseases and 
co-medications in healthy subjects allows for a clearer and more consistent assessment 
of drug disposition and safety profile.
The data generated from this study will help to evaluate potential ethnic differences 
between Chinese and non-Chinese subjects with regards to safety, tolerability and 
pharmacokinetic characteristics that will provide guidance on future clinical studies and 
optimize the benefit-risk in Chinese HBV patients.
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.

ECGs.

Vital signs including blood pressure (BP), pulse rate and body temperature.


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3.3.2
Pharmacokinetic Outcome Measures
Plasma concentrations will be measured by specific validated methods. Pharmacokinetic 
(PK) parameters will be estimated using standard non-compartmental methods for 
RO7049389.
The pharmacokinetic outcome measures for this study are as follows:
PK parameters (SAD):

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-inf: 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
PK parameters (MAD):

Cmax: Maximum observed plasma concentration after single-dose and at 
steady-state

Tmax: Time to maximum observed plasma concentration after single-dose and at 
steady-state

Ctrough: Trough plasma concentration

AUC0-: Area under the plasma concentration-time curve for a dosing interval after 
single-dose and at steady-state

T1/2: Apparent terminal phase half-life after single-dose and at steady-state

Accumulation index of RO7049389
PK parameters (SAD and MAD):

Plasma samples collected in the study will be qualitatively and/or quantitatively 
analyzed for the metabolites (M5, M6, and M11) of RO7049389 in selected samples. 
4.
MATERIALS AND METHODS
4.1
STUDY POPULATION
Due to the nature of this study, the actual number of subjects will be determined during 
the study. This study may require up to 76 subjects, including:

About 40 healthy subjects to be enrolled in Cohort 1 of 4 subjects and Cohort 2 to 
Cohort 4 of about 12 subjects each.


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
Up to 36 healthy subjects to be enrolled if new subjects are needed for the MAD 
phase, in case of non-safety related discontinuations between two periods (i.e., 
replacement subjects), 

For each part, 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.
Subjects 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. Subjects who withdraw from the study due to poor tolerability, or, due to study 
drug-related adverse events, will not be replaced.
4.1.1
Recruitment Procedures 
Study subjects will be identified for potential recruitment using pre-screening enrollment 
logs, IEC/IRB approved newspaper/radio advertisements and mailing lists prior to 
consenting to take place on this study.
4.1.2
Inclusion Criteria
Study subjects must meet the following criteria for study entry:
1.
Chinese 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) of between 19 to 27 kg/m2 inclusive, and a body weight of 
at least 45 kg.
3.
Women should be of non-childbearing potential. 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, men must remain abstinent or use 
two methods of contraception with their partner, one of which must be a barrier 
method (i.e., condom), for the duration of the study 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.
b)
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.
c)
Other acceptable forms of contraception for this study include vasectomy, bilateral 
tubal occlusion, intrauterine device (IUD) or proper use of hormonal contraceptives.


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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.
4.1.3
Exclusion Criteria
Study subjects who meet any of the following criteria will be excluded from study entry:
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 of congenital long QT syndrome or family history of 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 three separate resting blood pressure 
measurements, properly measured with well-maintained equipment, after at least 
10 minutes rest) systolic BP 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 QTS 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).


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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 1 
and 2 (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. Any suspicion or history of drug and/or alcohol abuse within the last year.
19. History (within 3 months of screening) of alcohol consumption exceeding two 
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 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.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
4.2.1
Method of Blinding
Randomization numbers will be generated by the Sponsor or its designee.
The study is Investigator-blinded and Subject-blinded. In order to minimize bias in 
reporting, collecting, and interpreting safety data. Study subjects, 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.
The study is 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, and 
the individual responsible for PK sample bioanalysis – members of the Sponsor’s project 
and study teams who do not have direct contact with the subjects – will be unblinded to 


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treatment assignment. 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, and 
available PK data will be reviewed in a blinded fashion by the Investigator and the 
Sponsor’s clinical team during the Safety Review Meeting. 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 5.2.1) that are 
considered by the Investigator to be related to study drug. 
All such occurrences should be documented in the study file. Treatment codes should 
not be broken except in emergency situations and, if possible, the responsible scientific 
leader should be contacted before the code is opened. At the final monitoring visit, the 
unused treatment codes 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 treatment codes will be returned to 
Roche.
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.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
RO7049389 and Placebo
RO7049389 and matching placebo (IMP) to be used in the study will be provided by 
Roche.
 
 
 
 
 


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 A matching-placebo, in terms of size, shape and color, has also been 
developed for clinical usage. 
 
 
Film-coated tablets of RO7049389 should be stored under the recommended storage 
conditions “Store at 2-8C, protect from light and moisture”. For information on the 
shelf-life of RO7049389 film-coated tablets and the respective placebos, 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.
4.3.2
Dosage, Administration and Compliance
4.3.2.1
RO7049389 and Placebo
The health care professionals at the study site administering the study drug to the 
subject must check to be sure that the study drug is swallowed.
The qualified pharmacist at the pharmacy will keep drug accountability and record the 
study drug batch or lot number received by each subject during the study.
Accountability and subject compliance will be assessed by maintaining adequate study 
drug dispensing records. The Investigator is responsible for ensuring that dosing is 
administered in compliance with the protocol. Delegation of this task must be clearly 
documented and approved by the Investigator.
Active or placebo 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 can be given to assist dose administration only if needed. 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 consumed during dose administration will be 
recorded during the in-clinic period). 
 
 


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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 
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 Section 3.1.2.
SAD Phase
RO7049389 or matching-placebo will be administered orally with 240 mL of water to the 
healthy subjects by investigational staff in 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.
MAD Phase
RO7049389 or matching-placebo will be administered orally with 240 mL of water to the 
healthy subjects by investigational staff from Day 1 through to Day 13 q12h, and on Day 
14 once in the morning. 
Except for cohort 4, which will be in the fasted state, a standard breakfast or dinner will 
be served to healthy volunteers 30 minutes prior to dosing, which should be consumed 
within 30 minutes. RO7049389 or placebo will then be administered. 
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. 
Timing of meals relative to dosing may be changed according to emerging data. 
Guidelines for dietary stipulations are provided in Section 4.4.3 and Section 4.4.4.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(RO7049389 and matching-placebo) will be provided by the Sponsor. The investigational 
site will acknowledge receipt of IMPs, to confirm the shipment condition and content. 
Any damaged shipments will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 


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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]
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.
4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted Therapy 
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 subject from 
4 weeks prior to the first dosing through the study completion. All concomitant 


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medications should be reported to the Investigator and recorded on the Concomitant 
Medications eCRF.
As a general rule, no other 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, unless the rationale for use is discussed 
between the Investigator and Sponsor and is clearly documented. 
The following medications are exceptions:

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): continue using if initiated at least 2 months 
prior to study start.

Occasional use of acetaminophen (up to 2g per day, not to exceed 3g/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.
4.4.2
Prohibited Therapy
All medications (prescription and OTC) taken within 4 weeks 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, 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 the rationale for exception is discussed 
and clearly documented. 
4.4.3
Prohibited Food
Use of the following is prohibited:

Alcohol must not be consumed from 48 hours before screening, 48 hours before 
admission until completion of follow-up visit.
 
 


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4.4.4
Dietary and Special Requirements
The following requirements will also be applied:

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.

On the days of a study visit caffeine (i.e., beverage including green tea, chocolate or 
supplements) should not be consumed from 48 hours prior to study drug 
administration until discharge from the clinic. 

No strenuous exercise is permitted during the study from 96 hours before admission 
until completion of the follow-up visit.

The use of tobacco is not permitted during the study.
Meals will be similar in composition and time of administration across all cohorts during 
the in-house period. 
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, Appendix 2, Appendix 3, and Appendix 4.
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, safety blood sampling

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 
subject within 30 days prior to the screening visit.
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, genitourinary, and neurological systems. A 


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genitourinary examination may be performed in case of evocative symptoms at the 
Investigator discretion.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in 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.
4.5.1.3
Vital Signs
Blood pressure (BP), pulse rate, and body temperature (tympanic or oral) will be 
recorded at the time-points‑specified in Overall Schedule of Assessments (Appendix 1
and Appendix 3), and Specific Schedule of Assessments (Appendix 2 and Appendix 4).
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. After 
the study subject has been in a supine position for at least 5 minutes, blood pressure 
and pulse rate will be obtained.
Blood pressure and pulse rate will be performed in triplicate (can be as short as 20 sec 
to 1-min interval between measurements) after the subject has rested in 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 2-5-minute interval, and recorded 
in CRF. Triplicate recordings should be taken for any unscheduled ECG.
All ECG recordings must be performed using a standard digital high-quality, high-fidelity 
ECG machine equipped with computer-based interval measurements. Automated ECG 
intervals (PR [PQ], QRS, QT, QTcF [to be derived in eCRF]) and 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 
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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.
2.
Three useful recordings must be collected without artefacts, per time-point.
3.
Body position should also be consistently maintained for each ECG performed. In 
particular, changes in HR should be avoided. The absence of any environmental 
distractions (TV, radio, conversation) during the pre-ECG rest and the ECG 
recording in the clinic must be emphasized.
4.
Avoid ECG recordings within 2 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 sec.
8.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper 
lead placement as contributing to the ECG abnormality.
9.
ECG machines should have periodic calibration and service records (minimum once 
a year).
10. If any QT/QTc values500 msec or increases from pre-dose on Day 1 
QTc60 msec (as provided by the machine), the site should repeat the ECG within 
the next 5 minutes and notify the Sponsor. If confirmed, ECG recordings should be 
repeated at least hourly until two successive ECGs show QTc values below the 
threshold value that triggered the repeated measurement.
4.5.1.5
Laboratory Assessments
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 (Appendix 1 and Appendix 3).
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor study subject safety. Where the clinical significance of 
abnormal lab results is considered uncertain, screening lab tests may be repeated 
before randomization to confirm eligibility. If there is an alternative explanation for a 


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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 or central laboratory.
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, international normalized ratio (INR), activated 
thromboplastin time (aPTT).

Blood Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total and indirect bilirubin, alkaline phosphatase (ALP), gamma-glutamyl 
transferase (at screening only), creatinine phosphokinase (at screening only), total 
protein, albumin, urea, creatinine, CrCl (at screening only, using the Cockcroft-Gault 
formula (Appendix 6), uric acid, total cholesterol, LDL, HDL, triglycerides, fasting 
glucose, sodium, chloride, potassium, calcium, phosphorus.

Urinalysis: a midstream, clean-catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leucocytes 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 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: 
–
Hepatitis A (HAV IgM Ab), hepatitis B (HBsAg), hepatitis C (HCV RNA or HCV 
Ab), human immunodeficiency virus 1 and 2 (HIV Ab). 

Pregnancy Test: plasma or serum beta-human chorionic gonadotropin (-HCG) at 
screening, urine on all other occasions (females only).

Hormones: follicle-stimulating hormone (females only to confirm post-menopausal 
status).


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4.5.1.6
Pharmacokinetic Assessments
Blood samples will be collected to evaluate the PK as specified in the SoA (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4). 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. The actual date and time of each blood 
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.
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.
Plasma samples will be analyzed for metabolite characterization of RO7049389 (M5, M6, 
and M11) with the use of quantitative and/or qualitative methods.
For sampling procedures, storage conditions, and shipment instructions, see the 
separate laboratory manual.
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 subject and for study subjects who are not subsequently enrolled will 
be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that Study Subjects meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all study subjects screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened study subject with regard to the protocol’s inclusion and exclusion criteria is to 
be completed by the Investigator and kept at the investigational site. 


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Screening assessments will be performed within 28 days prior to randomization, 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.
For subjects who participate in both SAD and MAD parts of the study, a brief and limited 
re-screening will be conducted prior to initiation of the MAD part (see Appendix 3).
Re-screening is allowed for subjects who were screened in the study and met study 
inclusion/exclusion criteria but failed to be randomized within 28 days after the start of 
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 randomization. 
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 study.
All assessments must be performed as per SoA (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4).
4.5.2.3
Assessments at Study Completion/Early Termination Visit
Study subjects who complete the study or discontinue from the study early will be asked 
to return to the clinic 7 days (1 day) after the last dose of study drug for a follow‑up
visit and to complete assessments as specified in the SOA.
In case of early termination of a subject in SAD or MAD, a blood sample for PK 
assessment should be collected at the time of discontinuation.
4.5.2.4
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.5.
4.5.2.5
Assessments at Unscheduled Visits
Please see Appendix 1 and Appendix 3 for assessments that are required to be 
performed in case of an unscheduled visit. 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 study subject. 


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4.6
STUDY SUBJECT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Subject 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.

Study subject non-compliance.
An early termination blood sample for RO7049389 PK assessment will be collected at 
the time of discontinuation.
4.6.1.1
Discontinuation from Study Drug
Individual study subjects should 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.
All study subjects 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.
Study Subjects who withdraw from the study prematurely will be asked to return to the 
clinic for a follow-up visit in 7 days after the last dose of study drug. The primary reason 
for premature study drug discontinuation should be documented on the appropriate 
eCRF.
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.
Study subjects will not be followed for any reason after consent has been withdrawn.


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When a subject voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless subject 
specifically requests for these to be discarded or local laws require their immediate 
destruction.
Study subjects who withdraw from the study for safety reasons will not be replaced. 
Study subjects who withdraw from the study for other reasons will be replaced.
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.

Previously unknown data become available which raise significant concerns about 
the potential risk to participants from continuation of the study
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 Harmonization (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 
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 5.3.


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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.

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 
subject 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 5.2.5.9).

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the study subject’s ability to conduct normal life 
functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
study subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (e.g., National Cancer Institute Common Terminology Criteria for 


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Adverse Events [NCI CTCAE] criteria; see Section 5.2.3); 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 5.3.2, 
for reporting instructions) and to the local health authority and IRB/EC, if required 
by local requirements.
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 5.3.2 for reporting instructions). Adverse events of special interest for 
this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.2.5.6.

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 Subject exposed to a medicinal product. This term applies only
when a contamination of the study drug is suspected.
5.2
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 5.3, 5.4, and 5.5.
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 5.2.3), and causality (see Section 5.2.4).


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5.2.1
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 28 days after the last dose of study drug.
After a period of 28 days from the last dose of study drug, 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 5.5).
5.2.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all study subject evaluation time‑points. Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.2.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing adverse event severity.
Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2).


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5.2.4
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
5.2.5
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.
5.2.5.1
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.


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5.2.5.2
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.
5.2.5.3
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 
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 Subject evaluation time-points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.2.5.4
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.


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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.
5.2.5.5
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.


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5.2.5.6
Abnormal Liver Function Tests
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. 
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.
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 5.2.5.1) 
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 5.3.2) and to the local health authority and IRB/EC, if 
required by local requirements.
5.2.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.2.1), 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 subject with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the subject 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.
5.2.5.8
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.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”).


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5.2.5.9
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 5.2.5.9), 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:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The study subject has not suffered an adverse event.
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
5.2.5.10
Overdoses
Study drug 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 5.3.2) and to the local health 
authority and IRB/EC, if required by local requirements.
5.3
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 


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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 (see Section 5.3.3)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.3.1
Emergency Medical Contacts
To ensure the safety of Study Subjects, access to the Medical monitors is available 
24 hours a day 7 days a week. Medical monitors contact details are listed in the 
“Protocol Administrative and Contact Information & List of Investigators”. 
5.3.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).


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Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(see Section 5.1.2 and 5.1.3) that occur after initiation of study treatment until the end of 
the adverse event reporting period (defined in Section 5.5), investigators should record 
all case details that can be gathered immediately (i.e., within 24 hours after learning of 
the event) on the appropriate Adverse Event of Special Interest/ Serious Adverse Event 
eCRF form and submit the report via the electronic data capture (EDC) system. A report 
will be generated and sent to the Sponsor’s Safety Risk Management department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event) and to the local health authority and 
IRB/EC, if required by local requirements.
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
5.3.3
Reporting Requirements for Pregnancies
5.3.3.1
Pregnancies in Female Subjects
Female subjects of childbearing potential will not be allowed to participate in this study. 
However, if a female subject becomes pregnant during the study or within 28 days after
the last dose of study drug, a Clinical Trial Pregnancy Reporting Form should be 
completed by the investigator and submitted to the sponsor within 24 hours after 
learning of the pregnancy. 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 subject should continue until conclusion of the pregnancy.
5.3.3.2
Pregnancies in Female Partners of Male Study Subjects
Male Subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
28 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed by the Investigator and submitted to the Sponsor within 24 hours 
after learning of the pregnancy. Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male study subject 
exposed to study drug. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of the 
pregnancy. An Investigator who is contacted by the male study subject or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 


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on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
5.3.3.3
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 5.3.2) and to the local health 
authority and IRB/EC, if required by local requirements.
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 5.3.2) and to the local health authority and IRB/EC, if required by local 
requirements.
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.
5.3.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female subject or female partner 
of a male subject exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.3.2) and to the local 
health authority and IRB/EC, if required by local requirements.
5.4
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS
5.4.1
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 subject 
is lost to follow-up, or the subject 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 subject’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 5.3.3.


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5.4.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.5
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as 28 days after the last dose of 
study drug). 
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. 
5.6
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

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 this study is to characterize the safety profile associated with a 
single dose and with multiple doses of RO7049389 in healthy volunteers. Statistical 
analyses will be descriptive in nature. Subjects will be grouped according to the actual 
treatment they received. All subjects who receive any amount of study medication 
(RO7049389 or matching placebo) and with at least one safety assessment will be 


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included in the safety analysis. All subjects who receive placebo will be combined into a 
single pooled placebo control group.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size was determined by practical considerations and not based on statistical 
power calculations. Approximately four subjects will be enrolled in SAD cohort 1 (2 
active treatment and 2 placebo). Approximately twelve subjects will be enrolled in each 
of the other SAD and MAD cohorts. They will be randomized to either active treatment 
(10 subjects per dose level) or placebo (2 subjects per dose level). 
With ten subjects on active drug per dose group or cohort, there is a 94% chance to 
observe at least one AE that has an incidence rate of 25% in the population.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of study subjects who enroll, discontinue, or complete the study will be
summarized by treatment (RO7049389 vs. matching placebo) for each dose cohort in 
the study. Reasons for premature study withdrawal will be listed and summarized by 
treatment and dose cohort. Enrollment and protocol deviations will be listed and 
evaluated for their potential impact on interpretation of study results. Study drug 
administration (RO7049389 or matching placebo) will be summarized with number of 
doses and percentage of assigned dose subjects received by treatment and dose cohort.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All study subjects who have received at least one dose of the study medication 
(RO7049389 or matching placebo), whether prematurely withdrawn from the study or not, 
and with at least one safety assessment, 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.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Study subjects randomized to receive placebo will be pooled together to form a pooled 
placebo group. Demographic and baseline characteristics (age, sex, etc.) will be 
summarized by treatment (each dose level of RO7049389 vs. pooled placebo group) for 
the safety population using descriptive statistics. For continuous variables, mean, 
standard deviation, median, and ranges will be presented. For categorical data, the 


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proportion of subjects in each category will be summarized. Summaries will be 
presented in overall and by cohorts.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population. Subjects will be
grouped based on the treatment they actually receive. Safety will be assessed through
physical exams, adverse events, changes in laboratory results, changes in ECG
measurements, and changes in vital sign measurements.
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 coded term. In addition, adverse 
events will be summarized by their toxicity level (according to the maximum reported 
severity level) and severity (severe vs. non-severe). All serious adverse events, 
including deaths, severe adverse events (Grade3), and adverse events of special 
interest will be listed and summarized separately. Adverse events leading to study drug 
discontinuation or interruption will be summarized as well. Subjects will be tabulated by 
treatment (RO7049389 vs. pooled placebo group) and dose level.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Study subject listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
The proportion of study subjects with laboratory abnormalities will be summarized by 
treatment (RO7049389 vs. pooled placebo group) and dose level. Additionally, the 
absolute value and change from baseline in all laboratory tests 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 


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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.
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. In addition, tabular summaries will 
be used, as appropriate.
Summary descriptive statistics for the actual values and changes from baseline will be 
tabulated by nominal time for HR, QRS duration, PR and QTcF (see Appendix 5). 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.
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.


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Concomitant medications will be presented in summary tables and listings.
6.6
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, 
AUC0-last and AUC0-inf versus the logarithmically transformed dose. A 95% confidence 
interval for the slope which includes the value 1 would be consistent with 
dose-proportionality.
Plasma samples collected in the study will be qualitatively and/or quantitatively analyzed 
for the presence of metabolites of RO7049389.
A population PK model development and analysis may be performed. The Population 
PK results will be reported in a separated document.
6.7
INTERIM ANALYSIS
No interim analysis is planned for this study.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system.
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Laboratory electronic data 


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will be sent directly to the Sponsor, using the Sponsor’s standard procedures to handle 
and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line EDC system. The data collected in the 
source documents is entered onto the study eCRF. An audit trail will maintain a record of 
initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change. For each study subject enrolled, an eCRF 
must be completed and electronically signed by the Principal Investigator or authorized 
delegate from the study staff. If a study subject withdraws from the study, the reason 
must be noted on the eCRF. If a study subject is withdrawn from the study because of a 
treatment‑limiting adverse event, thorough efforts should be made to clearly document 
the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the Investigator will receive subject 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 subject 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, subject -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, 
subject files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local Health Authorities, whichever is longer. After that period of time, 
the documents may be destroyed, subject to local regulations. No records may be 
disposed of without the written approval of the Sponsor. Written notification should be 
provided to the Sponsor prior to transferring any records to another party or moving
them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to the site. If applicable, 
it will be provided in a certified translation of the local language. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission. The final IRB/EC‑
approved Consent Forms must be provided to the Sponsor for Health Authority 
submission purposes according to local requirements.
The Consent Forms must be signed and dated by the subject before his or her 
participation in the study. The case history or clinical records for each subject 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 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes.
Subjects 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 subject 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 subject. All signed and 
dated Consent Forms must remain in each subject’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 subject, 
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 subject 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 


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or other safety‑related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with Health 
Authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject 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 subject, 
unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’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., LSLV).
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 Subject data, which includes an audit trail containing a complete record of all 
changes to data.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs. The Investigator will 


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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.
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 subjects or any non-substantial changes, as defined 
by regulatory requirements.


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10.
REFERENCES
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4-hydroxycholesterol with midazolam as markers for CYP3A4 induction by 
rifampicin. Drug Metab Dispos. 2013;41(8):1488-1493.
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–185.
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
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) 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
2/07/WC500129606.pdf
Guideline on the Investigation of Drug Interactions (EMA) Retrieved 
from:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline
/2012/07/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) 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidiscip
linary/M3_R2/Step4/M3_R2__Guideline.pdf
Investigator’s Brochure, RO7049389. Second Version, October 2017.  
Liang X, Bi S, Yang W et al. Epidemiological serosurvey of hepatitis B in China--
declining HBV prevalence due to hepatitis B vaccination. 
Vaccine. 2009;27(47):6550-6557.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.
Truven Health Analytics; c1974-2013.Retrieved from: 
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.


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WHO Fact Sheet N°204, updated July 2016 
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 
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Appendix 5
Correction Formulas for QTc Intervals
Fridericia’s correction for QTc Measurement – QTcF
Example: QTcF of a subject with a QT of 386 msec and a RR of 848 msec
QT (msec) = 386
RR (msec) = 848


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Appendix 6
Cockcroft Gault Equation for Calculation CrCl
The Cockcroft-Gault equation will be 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 x 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