Conditions: Healthy Volunteers
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: yes

Brief summary:
The objective of this study is to characterize the mass balance, absolute bioavailability, route and rates of elimination of RO7049839.

Detailed description:

Arms:
arm 1: Participants will receive oral \[14C\] RO7049389 under fasted conditions, followed by intravenous IV \[13C\] after a two-hour period. arm 2: In Periods 1 and 2, participants will receive oral \[12C\] RO7049389 under fasted conditions, followed by IV \[13C\] RO7049389. There is a minimum 7-day washout between periods.

Interventions: intervention 1: [12C] RO7049389 intervention 2: [13C] RO7049389 intervention 3: [14C] RO7049389
Intervention descriptions: intervention 1: Participants will receive oral \[12C\] RO7049389. intervention 2: Participants will receive IV \[13C\] RO7049389. intervention 3: Participants will receive an oral suspension of \[14C\] RO7049389.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: Open-Label Study to Investigate the Mass Balance and Absolute 
Bioavailability of a Single Oral Dose of [14C]-Labeled RO7049389 or 
RO7049389 and an Intravenous Micro-Dose of [13C]-Labeled 
RO7049389 in Healthy Volunteers 
NCT Number: NCT04729309 
Document Date: Protocol Version 3: 15-April-2021 
 
 




RO7049389 —F. Hoffmann-La Roche Ltd
2/Protocol BP41811, Version 3
PROTOCOL ACCEPTANCE FORM
TITLE:
OPEN-LABEL STUDY TO INVESTIGATE THE 
MASS BALANCE AND ABSOLUTE 
BIOAVAILABILITY OF A SINGLE ORAL DOSE 
OF [14C]-LABELED RO7049389 OR 
RO7049389 AND AN INTRAVENOUS 
MICRO-DOSE OF [13C]-LABELED RO7049389
IN HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
BP41811
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-005301-70
TEST PRODUCT:
RO7049389
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
BSc, MD, DPM, MFPM (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
Site Monitor.


RO7049389 —F. Hoffmann-La Roche Ltd
3/Protocol BP41811, Version 3
PROTOCOL AMENDMENT, VERSION 3
RATIONALE
During the Period 1 of the absolute bioavailability (BA) cohort, infusion pain events 
occurred in several participants after administration of [13C]-labeled RO7049389. These 
adverse events (AEs) were identified to be most likely related to high concentration of 
potassium in the infusion solution of [13C]-labeled RO7049389. Although these AEs were 
transient and the participants recovered soon after the infusion, Study BP41811 was 
temporarily halted after the completion of Period 1. The Sponsor amended this study 
protocol to ensure participant’s safety. Changes to the protocol, along with a rationale for 
each change, are summarized below:

In Table 3 (Section 1.3), the missing footnote (h) “Follicle stimulating hormone 
(females only to confirm post-menopausal status, performed at screening only)” has 
been added.

Following Medicines and Healthcare products Regulatory Agency (MHRA) guidance 
relating to the management of COVID-19 vaccine deployment for ongoing 
non-COVID-19 clinical trials, Section 2.3.1.3 (Assessment Regarding COVID-19 
Vaccination) has been added.

Section 4.1 and Section 4.1.2 have been updated to remove the upper limit of the 
washout period (21 days) and to allow participants to be discharged after completing 
Period 1 and re-admitted for Period 2. The longer washout period is not considered 
to affect either the safety of participants or the integrity of the study. As the study is 
temporarily halted, the 21-day washout period will not be sufficient for the 
administration process; this amendment is to provide flexibility to keep the 
participants who have completed Period 1 to continue with Period 2.

Since the upper limit of the washout period is removed and the participants are 
allowed to discharge from the site between the two periods of the absolute BA 
cohort, requirement for re-assessment of exclusion criteria 7, 8, 15 and 16 before
admission/pre-dose of each treatment period have been added (Section 5.2).

Section 5 and Section 9.1 have been update to remove the sentence “Up to 
4 participants of each ethnic group can be replaced.” As the participants have been 
discharged from the site and the washout period will be longer than 21 days, 
participants who prematurely discontinued from the study may be replaced due to 
non-safety related issues.

In Section 6.1.2, a dilution step is added to the [13C]-labeled RO7049389 infusion 
process, which will reduce the potassium concentration to below 30 mmol/L. The 
total dose and infusion time of [13C]-labeled RO7049389 remain unchanged, and 
thus no impact on pharmacokinetics of RO7049389 is expected.
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RO7049389 —F. Hoffmann-La Roche Ltd
4/Protocol BP41811, Version 3
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 12
1.1
Synopsis................................................................................ 12
1.2
Schematic of Study Design.................................................... 20
1.3
Schedule of Activities ............................................................ 20
2.
INTRODUCTION ........................................................................................ 28
2.1
Study Rationale ..................................................................... 28
2.2
Background ........................................................................... 28
2.3
Benefit/Risk Assessment....................................................... 30
2.3.1
COVID-19 Related Risks and Risk Mitigation 
Measures............................................................................... 31
2.3.1.1
IMP-related Risk.................................................................... 31
2.3.1.2
General COVID-19 Related Risk Mitigation 
Measures............................................................................... 31
2.3.1.3
Assessment Regarding COVID-19 Vaccination.................... 31
3.
OBJECTIVES AND ENDPOINTS ............................................................... 33
4.
STUDY DESIGN......................................................................................... 34
4.1
Overall Design ....................................................................... 34
4.1.1
Discharge Criteria for Mass Balance Cohort.......................... 35
4.1.2
Length of the Study ............................................................... 35
4.2
Scientific Rationale for Study Design..................................... 36
4.2.1
Rationale for Study Population .............................................. 37
4.3
Justification for Dose ............................................................. 38
4.3.1
Justification for Dose selection .............................................. 38
4.3.2
Justification for Radioactive Dose Selection.......................... 38
4.4
End of Study Definition .......................................................... 39
5.
STUDY POPULATION................................................................................ 39
5.1
Inclusion Criteria.................................................................... 39
5.2
Exclusion Criteria................................................................... 41
5.3
Lifestyle Considerations......................................................... 44


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5.3.1
Meals and Dietary Restrictions.............................................. 44
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 45
5.3.3
Activity ................................................................................... 45
5.4
Screen Failures ..................................................................... 45
5.5
Recruitment Procedures........................................................ 45
6.
TREATMENTS............................................................................................ 46
6.1
Treatments Administered....................................................... 46
6.1.1
[14C] RO7049389 Oral Suspension, 600 mg 
(NMT 2.2 MBq)...................................................................... 46
6.1.2
[13C] RO7049389 Solution for Infusion, 20 µg/mL ................. 46
6.1.3
RO7049389 Tablet, 200 mg .................................................. 47
6.2
Preparation/Handling/Storage/Accountability ........................ 47
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 49
6.3.1
Method of Treatment Assignment.......................................... 49
6.3.2
Blinding.................................................................................. 49
6.4
Treatment Compliance .......................................................... 49
6.5
Concomitant Therapy ............................................................ 50
6.5.1
Permitted Therapy................................................................. 50
6.5.2
Prohibited Therapy ................................................................ 50
6.6
Dose Modification.................................................................. 51
6.7
Treatment after the End of the Study..................................... 51
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 51
7.1
Discontinuation of Study Treatment....................................... 51
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 52
7.3
Lost to Follow-Up................................................................... 52
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 53
8.1
Efficacy Assessments............................................................ 53
8.2
Safety Assessments .............................................................. 53
8.2.1
Physical Examinations........................................................... 54
8.2.2
Vital Signs.............................................................................. 54


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8.2.3
Electrocardiograms................................................................ 55
8.2.4
Clinical Safety Laboratory Assessments................................ 55
8.2.5
Medical History and Demographic Data ................................ 57
8.2.6
SARS-CoV-2 Tests (If Required)........................................... 57
8.3
Adverse Events and Serious Adverse Events ....................... 57
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 58
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 58
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 59
8.3.3.1
Investigator Follow-Up........................................................... 59
8.3.3.2
Sponsor Follow-Up ................................................................ 59
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 59
8.3.4.1
Emergency Medical Contacts................................................ 60
8.3.5
Pregnancy ............................................................................. 60
8.3.6
Non-Serious Adverse Events of Special Interest................... 60
8.4
Treatment of Overdose.......................................................... 61
8.5
Pharmacokinetics .................................................................. 61
8.6
Pharmacodynamics and Biomarkers Analyses...................... 62
8.6.1
Clinical Genotyping................................................................ 63
8.7
Pharmacodynamics and Biomarker Samples........................ 63
8.8
Health Economics.................................................................. 63
8.9
Timing of Study Assessments ............................................... 63
8.9.1
Screening and Pre-treatment Assessments .......................... 63
8.9.2
Assessments during Treatment............................................. 64
8.9.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 64
8.9.4
Follow-Up Assessments ........................................................ 64
8.9.5
Assessments at Unscheduled Visits...................................... 64
9.
STATISTICAL CONSIDERATIONS ............................................................ 64
9.1
Sample Size Determination ................................................... 64


RO7049389 —F. Hoffmann-La Roche Ltd
7/Protocol BP41811, Version 3
9.2
Populations for Analyses ....................................................... 65
9.3
Statistical Analyses................................................................ 65
9.3.1
Demographics and Baseline Characteristics ......................... 65
9.3.2
Safety Analyses..................................................................... 65
9.3.3
Pharmacokinetic Analyses..................................................... 66
9.4
Summaries of Conduct of Study............................................ 68
10. REFERENCES ........................................................................................... 68
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.................................................................................... 69


RO7049389 —F. Hoffmann-La Roche Ltd
8/Protocol BP41811, Version 3
LIST OF TABLES
Table 1
Mass Balance Cohort – Main Table............................................ 21
Table 2
Mass Balance Cohort – Detailed Table....................................... 23
Table 3
Absolute BA Cohort – Main Table............................................... 25
Table 4
Absolute BA Cohort – Detailed Table ......................................... 27
Table 5
Summary of Treatments Administered........................................ 47
Table 6
Analysis Populations................................................................... 65
Table 7
Safety Statistical Analysis Methods ............................................ 66
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 20
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations........... 70
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting............................................................. 78
Appendix 3
Procedures for Recording Adverse Events ................................. 85
Appendix 4
Clinical Laboratory Tests ............................................................ 90
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information.................................................................................. 93
Appendix 6
Cockcroft Gault Equation for Calculation CrCl ............................ 97


RO7049389 —F. Hoffmann-La Roche Ltd
9/Protocol BP41811, Version 3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADME
Absorption, metabolism, distribution, and excretion
AE
Adverse event
aPTT
Activated partial thromboplastin time
ARSAC
Administration of Radioactive Substances Advisory 
Committee
AUC
Area under the curve
AUClast
Area under the concentration–time curve from Time 0 
to last measurable concentration
AUC0-inf
Area under the concentration–time curve from Time 0 
to infinity
BA
Bioavailability
BID
Twice daily
BP
Blood pressure
bpm
Beats per minute
CL
Clearance
CL/F
Apparent clearance
CLr
Renal clearance
Cmax
Maximum concentration
COVID-19
Coronavirus disease 2019
CrCl
Creatinine clearance
CRF
Case report form
CSR
Clinical study report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DIADS
Division of AIDS
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
F
Absolute bioavailability
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GI
Gastrointestinal
HAV
Hepatitis A virus
HBeAg
Hepatitis B surface antigen
HBsAg
Hepatitis B surface antigen


RO7049389 —F. Hoffmann-La Roche Ltd
10/Protocol BP41811, Version 3
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoproteins
HDV
Total hepatitis D virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormone replacement therapy
HV
Healthy volunteers
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICRP
International Commission on Radiological Protection
IEC
Independent ethics committee
IgM
Immunoglobulin M
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
IV
Intravenous
LC-MS
Liquid chromatography–mass spectrometry
LDL
Low-density lipoproteins
LPLO
Last participant, last observation
LSC
Liquid scintillation counting
MAD
Multiple-ascending doses
MB
Mass balance
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
NSAESI
Non-serious adverse event of special interest
NUC
Nucleos(t)ide analogue
OATP
Organic-anion-transporting polypeptides
OTC
Over-the-counter
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PK
Pharmacokinetic
PT
Prothrombin time


RO7049389 —F. Hoffmann-La Roche Ltd
11/Protocol BP41811, Version 3
QD
Once daily
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RNA
Ribonucleic acid
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
t1/2
Apparent terminal half life
tmax
Time of maximum concentration observed
ULN
Upper limit of normal
V/F
Apparent volume of distribution
Vss
Volume of distribution at steady-state
WBC
White blood cell
WHO
World Health Organization
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential




RO7049389 —F. Hoffmann-La Roche Ltd
13/Protocol BP41811, Version 3
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the mass balance (MB), 
routes, and rates of elimination of [14C] 
RO7049389.

Percentage of dose excreted in 
urine.

Percentage of dose excreted in 
feces.

To determine the absolute oral 
bioavailability (BA) of RO7049389.

Absolute oral BA for RO7049389.

Secondary

To determine the plasma concentration 
of RO7049389, its identified three 
metabolites (RO7121986, RO7255420, 
and RO7255422), total drug-related 
radioactivity and related 
pharmacokinetic (PK) parameters.

Cmax, AUClast, AUC0-inf, tmax, CL/F, 
CL, CLr, Ae, V/F and t½ of 
RO7049389 and its identified three 
metabolites, and total drug-related 
radioactivity, if appropriate.

To identify and quantify circulating and 
excreted metabolites of RO7049389 in 
plasma, urine, and fecal samples based 
on radioactive metabolic profiling.

A metabolic profile for RO7049389 
and metabolites, and their structural 
elucidation, if appropriate.

Cmax, AUClast, AUC0-inf, tmax, CL/F, 
CLr, Ae, V/F, and t½ of other major 
metabolites related radioactivity, if 
appropriate.

To evaluate the safety and tolerability of 
one or two single-doses of RO7049389 
in healthy participants.

Adverse events (AEs), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and 
physical examination.
OVERALL DESIGN
Study Design
This is an open-label, two-cohort (i.e., a MB cohort and an absolute BA cohort), single-dose 
study designed to evaluate the MB and absolute BA of RO7049389 in HVs. 
Male participants in the MB cohort will receive a 600 mg dose of [14C] RO7049389 as an oral 
suspension under fasted conditions. Participants will then receive a 100-μg dose of 
[13C] RO7049389 administered as a 10-minute intravenous (IV) infusion, 2 hours after the oral 
dose of [14C] RO7049389.
In the absolute BA cohort, each participant will take part in both Period 1 and Period 2. Male or 
female participants in Period 1 of the absolute BA cohort will receive a 600 mg dose of 
[12C] RO7049389 administered orally as a clinical formulation under fasted conditions. 
Participants will then receive a 100-μg dose of [13C] RO7049389 administered as a 10-minute IV 
infusion, 2 hours after the oral dose of RO7049389. 
After a washout period of at least 7 days, in Period 2, male or female participants will receive a 
1000 mg dose of [12C] RO7049389 administered orally as a clinical formulation under fasted 
conditions. Participants will then receive 100 μg of [13C] RO7049389 administered as a 
10-minute IV infusion, 2 hours after the oral dose of RO7049389.


RO7049389 —F. Hoffmann-La Roche Ltd
14/Protocol BP41811, Version 3
Treatment Groups and Duration
The investigational medicinal products (IMPs) required for completion of this study will be [12C]
RO7049389 tablet, 200 mg, [14C] RO7049389 oral suspension, 600 mg (NMT 2.2 MBq), and 
[13C] RO7049389 solution for infusion, 20 µg/mL.
[12C] RO7049389 tablet, 200 mg
An oral dose of RO7049389 600 mg (Period 1) or 1000 mg (Period 2) in the absolute BA cohort 
will be administered as a clinical formulation in the morning of Day 1 of Period 1 or Period 2, 
study drug administration will be after an overnight fast of at least 10 hours, followed by another 
4 hours of fasting until lunch. Water will be allowed ad libitum until 1 hour prior to dosing and 
from 1-hour post dosing, at a maximum of three liters a day.
Study drug will be swallowed whole with still water. 
[14C] RO7049389 oral suspension, 600 mg (NMT 2.2 MBq)
On the morning of Day 1 for MB cohort, a 20- mL drinking suspension containing 600 mg of 
RO7049389, providing a maximum of 2.2 MBq of [14C]-labeled RO7049389 (equivalent to 59.3
μCi) will be administered to all eligible participants after an overnight fast of at least 10 hours, 
followed by another four hours of fasting until lunch. Each participant will receive 190 mL of still 
water immediately after the dose has been swallowed, followed by a further 50 mL which will be 
used to rinse out the dosing vessels (50 mL will be used in five separate rinses). Water will be 
allowed ad libitum until 1 hour prior to dosing and from 1-hour post dosing, at a maximum of 
three liters a day.
[13C] RO7049389 solution for infusion, 20 µg/mL
On Day 1 of MB cohort, on Day 1 of both Period 1 and Period 2 of absolute BA cohort, a single 
microdose of [13C]-labeled RO7049389 100 μg will be administered by a 10-minute constant IV 
infusion. The IV infusion will start 2 hours after administration of the oral dose of RO7049389. 
Length of Study
In the MB cohort, the total duration of the study for each participant will be about 8 weeks, 
divided as follows:

Screening: Up to 28 days.

In-clinic period: Day -1 to the day when the discharge criteria are met. This is up to a 
maximum of 12 days. 

Safety follow-up: One call on Day 293. 
In the absolute BA cohort, the total duration of the study for each participant will be at least 
9 weeks, depending on the duration of the washout period, divided as follows:

Screening: Up to 28 days.

In-clinic period: Days -1 to 4 for both Periods 1 and 2.

Washout period: Defined as from Period 1 Day 1 to Period 2 Day 1 and lasts at least 7 days.

Safety follow-up: One call on Period 2 Day 29 3.
End of Study
A participant is considered to have completed the study if he/she has completed all parts of the 
study including the last scheduled procedure shown in the Schedule of Activities.
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur 283 days after the last dose of RO7049389 is administered.


RO7049389 —F. Hoffmann-La Roche Ltd
15/Protocol BP41811, Version 3
PARTICIPANT POPULATION
Inclusion Criteria
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to ICH and local regulations. 
Age
2.
35 to 65 years (MB cohort) or 18 to 60 years (absolute BA cohort), inclusive, at the time of 
signing the informed consent.
Type of Participants 
3.
Caucasian (both MB cohort and absolute BA cohort must have Caucasian parents and 
grandparents) or East Asian (for the absolute BA cohort only, participants must have 
Chinese, Korean or Japanese parents and grandparents).
4.
Healthy, as judged by the Investigator based on the following definition.
1.
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, and based on the laboratory safety test results.
Weight
5.
Body mass index between 18 to 30 kg/m2 (inclusive), and a weight range of 50 kg to 100 kg 
(inclusive) at screening.
Sex
6.
Male (both MB cohort and absolute BA cohort) and female (absolute BA cohort only) 
participants
The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle 
of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of preventing drug 
exposure.
Female Participants
For women of childbearing potential: agree to use two methods of contraception, with at least 
one method considered as highly effective during the study and for at least 90 days after the 
last dose of study drug.
a.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not 
reached a post-menopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).


RO7049389 —F. Hoffmann-La Roche Ltd
16/Protocol BP41811, Version 3
b.
Contraceptive methods considered as highly effective (failure rate < 1% per year when 
used consistently and correctly):

Combined (estrogen- and progestogen-containing) or progestogen-only hormonal 
contraception associated with inhibition of ovulation

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion/ligation

Vasectomized partner

Sexual abstinence: Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of study 
treatment and at least 90 days after the last dose of study drug. In such case, there 
is no need to use two contraceptive methods. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
c.
Contraceptive methods NOT considered as highly effective (failure rate > 1% per year):

Progestogen-only oral hormonal contraception (where inhibition of ovulation is not 
the primary mode of action)

Male or female condoms with or without spermicide

Cap, diaphragm, or sponge with spermicide
Male Participants

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
agree to use contraceptive measures, and agree to refrain from donating sperm, as defined 
below: 

Men must remain abstinent or use a condom during the treatment period and for at 
least 90 days after the last dose of study drug to avoid exposing the embryo. Men must 
refrain from donating semen during this same period.
Inclusions for Mass Balance Cohorts Only
7.
Must have regular bowel movements (i.e. average stool production of 1 and 3 stools per 
day).
For both study parts, inclusion criterion 4 from the list above will be re-assessed at 
admission/pre-dose of each treatment period.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Pregnant (positive pregnancy test) or lactating women, and male participants with partners 
who are pregnant or lactating.


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2.
Have a history or symptoms of any clinically significant cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematological, oncologic, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination of drugs; of 
constituting a risk when taking the study treatment; or of interfering with the interpretation of 
data.
3.
Confirmed (based on the average of three separate resting blood pressure (BP) 
measurements in a supine position, after at least 5 minutes of rest) systolic BP greater than 
140 mmHg or less than 90 mmHg, and diastolic BP greater than 90 mmHg or less than 
50 mmHg at screening and Day -1.
4.
Personal history or family history of congenital long QT interval (QT) syndrome and/or 
cardiac sudden death.
5.
History of Gilbert syndrome.
6.
Participants who have had significant acute infection, e.g., influenza, local infection, acute 
gastrointestinal (GI) 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 the 
conduct of the study, or in the opinion of the Investigator, would pose an unacceptable risk to 
the participant in this study.
Prior/Concomitant Therapy
9.
Taking any herbal medications or substances, supplements (including vitamins), traditional 
Chinese medicines, prescription medicine, or over-the-counter medications within 14 days of 
first dosing or within 5 times the elimination half-life of the medication prior to first dosing, 
whichever is longer. 
Exceptions are medications listed under Permitted Therapy.
10. History of having received 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.
Prior/Concurrent Clinical Study Experience
11. Are currently enrolled in or have participated in any other clinical study involving an 
investigational product or in any other type of medical research within the last 90 days (or 
within 5 half-lives of the investigational product, whichever is longer).
12. Donation or loss of blood or blood products in excess of 500 mL within three months of 
screening.


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18/Protocol BP41811, Version 3
Diagnostic Assessments
13. Clinically relevant ECG abnormalities on screening, Day 1, or Day 1 (pre-dose), e.g.:
a.
QT corrected for heart rate (HR) using the Fridericia’s correction factor 
(QTcF) 430 msec (males), >450 msec (females), or 300 msec (males and females).
b.
Notable resting bradycardia (HR 45 beats per minute [bpm]), or HR 90 bpm.
c.
Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-
Parkinson-White Syndrome, or cardiac pacemaker.
14. Clinically significant ECG with QRS complex (QRS) and/or T-wave judged by the 
Investigator to be unfavorable for a consistently accurate QT measurement (e.g., 
neuromuscular artifact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, 
low amplitude T-wave, merged T- and U-waves, prominent U-waves).
15. Creatinine clearance (CrCl) 70 mL/min (using the Cockcroft-Gault formula) at screening 
(may be repeated for confirmation) or on Day -1.
16. Evidence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., the 
virus that causes COVID-19) infection.
17. Positive test at screening of any of the following: hepatitis A virus (HAV immunoglobulin M 
[IgM] antibody), hepatitis B virus (HBV, HBsAg), hepatitis C virus (HCV ribonucleic acid 
[RNA]), hepatitis D virus (total HDV antibody), hepatitis E virus (HEV IgM antibody), and 
human immunodeficiency virus (HIV-1 antibody and HIV-2 antibody, or HIV-1/2 antibody).
18. Any other clinically significant abnormalities in laboratory test results at screening or on 
Day -1. In the case of uncertain or questionable results, tests performed during screening or 
Day -1 may be repeated once prior to enrollment to confirm eligibility unless deemed not 
clinically significant by the Investigator.
Other Exclusions
19. History of any drug or alcohol abuse in the past 2 years.
20. Regular alcohol consumption in males > 21 units per week and in females >14 units per 
week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of 
wine, depending on type). 
21. A confirmed positive alcohol breath test at screening and on Day 1.
22. Use of five cigarettes or equivalent nicotine-containing product per day prior to screening.
23. Participants under judicial supervision, guardianship, or curatorship.
24. Medical or social conditions that would potentially interfere with the participant’s ability to 
comply with the study visit schedule or the study assessments.
25. Sensitivity to any of the study treatments, or excipients thereof, or drug or other allergy that, 
in the opinion of the Investigator or Medical Monitor, contraindicates the participation in the 
study.
26. Participants who do not have suitable veins for multiple venipunctures/cannulation as 
assessed by the Investigator or delegate at screening.


RO7049389 —F. Hoffmann-La Roche Ltd
19/Protocol BP41811, Version 3
27. Participants who planned to attempt to have children within 90 days of dosing.
Exclusions for Mass Balance Cohorts Only
28. Regular work with ionizing radiation or radioactive material.
29. Radiation exposure, including that from the present study, excluding background radiation 
but including diagnostic X-rays and other medical exposures, exceeding 5 mSv in the last 12 
months or 10 mSv in the last five years. No occupationally exposed worker, as defined in the 
Ionising Radiation Regulations 2017, shall participate in the study. 
30. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of thorax 
and bony skeleton [excluding spinal column]), during work, or during participation in a 
medical trial in the previous year.
31. History of GI surgery (with the exception of appendectomy unless it was performed within 
the previous 12 months).
32. Acute diarrhea or constipation in the past seven days prior to admission. Diarrhea will be 
defined as the passage of liquid feces and/or a stool frequency of greater than three times 
per day. Constipation will be defined as a failure to open the bowels more frequently than 
every other day.
For both study parts, exclusion criteria 1, 3, 6, 7, 8, 9, 12, 13, 14, 15, 16, 18, 21, 22, 27, and 31 
from the list above will be re-assessed at admission/pre-dose of each treatment period.
NUMBER OF PARTICIPANTS
A sample size of 6 healthy male participants for MB cohort was selected for practical purposes. 
Six participants are customary for this type of study, and should suffice to meet the objectives of 
the study while limiting the exposure of healthy male participants to radiolabeled study drug. 
For the absolute BA cohort, the sample size of 16 participants (8 East Asian HVs and 
8 Caucasian HVs) was chosen to estimate the absolute BA of the 600 mg and 1000 mg 
single-dose with sufficient precision for each ethnic group. The number of either gender of the 
enrolled participants should not exceed 12 participants of the same gender, nor should they all 
be in the same ethnic group (Caucasian or East Asian).
Participants prematurely discontinued from the absolute BA cohort of this study may be replaced 
to ensure adequate numbers of evaluable participants. Participants withdrawn for safety reasons 
will not be replaced.
CONCOMITANT MEDICATIONS
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant from 
30 days prior to screening until after collection of the final sample must be recorded along with 
reason for use, dates of administration (including start and end dates) and dosage information 
(including dose and frequency).


RO7049389 —F. Hoffmann-La Roche Ltd
20/Protocol BP41811, Version 3
1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
1.3
SCHEDULE OF ACTIVITIES
The schedule of activities (SoA) for the mass balance (MB) cohort is provided in Table 1
and Table 2. The SoAs for the absolute bioavailability (BA) cohort is provided in Table 3
and Table 4. 


RO7049389 —F. Hoffmann-La Roche Ltd
21/Protocol BP41811, Version 3
Table 1
Mass Balance Cohort – Main Table
Screening
Follow Up Call
Day -28 to Day -2
Day -1
Day 1
Day 2
Day 3 to Day of 
Discharge
Day 29±3
Time Relative (h)
0
24
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Vein assessment for venipunctures/cannulation 
x
Medical History
x
x
Physical Examinationa
x
x
xj
x
Vital Signsb
x
x
x
xj
x
ECG-12 leadc
x
x
x
xj
x
Hematologyd
x
x
xj
x
Blood Chemistryd
x
x
xj
x
Coagulationd
x
x
xj
x
Urinalysisd
x
x
xj
x
Viral Serologye
x
SARS-CoV-2f
x
x
x
x
Lipidsd
x
x
xj
x
Drug/Alcohol Test
x
x
Oral Administration of [14C] RO7049389 suspension
x
IV Administration of [13C] RO7049389 solution
x
Blood sampling for PK, radioactivity counting
and metabolic profilingg
x
x
x
xl
Urine sampling for PK, radioactivity counting
and metabolic profilingg
x
x
x
Feces sampling for radioactivity counting and
metabolic profilingg
xk
x
x
x
Clinical Genotypingh
x
In-Clinic Stay
x
x
x
x
Dischargei
x
Adverse Events
Previous and Concomitant Treatments
Assessments
x
x
Treatment Period
Early termination or 
Unscheduled visit


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Table 1
Mass Balance Cohort – Main Table (cont.)
a)
A full physical examination is required at screening and day of discharge. At other visits (or as clinically indicated), limited, symptom-
directed physical examinations should be performed at the discretion of the Investigator. Body weight will be recorded each time. Height 
and BMI will only be done at screening. 
b)
Vital signs include triplicate measurements of blood pressure and heart rate (taken approximately 1 minute apart) and a single 
assessment of body temperature (oral). Blood pressure and heart rate measurements will be assessed in a supine position after 5 
minutes of rest.
c)
12-lead ECGs will be obtained after the participant has been in a supine position for at least 10 minutes. Automated ECG intervals (PR 
[PQ], QRS, QT, QTcF, RR) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will be 
documented.
d)
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis, and lipids) should be collected in the morning/at the 
most appropriate time. Creatinine clearance (CrCl) will be calculated using the Cockcroft-Gault formula at screening and on Day -1.
e)
Hepatitis A virus (HAV) IgM antibody, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, total hepatitis D virus (HDV) 
antibody, hepatitis E virus (HEV) IgM antibody, human immunodeficiency virus (HIV-1 antibody and HIV-2 antibody, or HIV-1/2 
antibody).
f)
Testing for SARS-CoV-2 may be performed based on current infection rates and availability of tests. If required, SARS-CoV-2 antibody 
will be done at screening. SARS-CoV-2 antigen will be done at screening, pre-admission, day before discharge or day of discharge.
g)
Radioactivity counting will be continued until discharge criteria are met. 
h)
If the blood sample is not collected on Day 1, it may be collected at any time during the conduct of the clinical study.
i)
The participant will not be discharged until criteria are met. This is up to a maximum of 264 hours post-dose (Day 12) in-clinic stay, and 
could include a further 5 days collection of urine and feces samples at home, if required.
j)
Assessments done on the day of discharge. Tests should be performed after an overnight fast (for at least 10 hours).
k)
Only one sample is collected. It will be kept and processed only if the pre-dose sample on Day 1 cannot be obtained.
l)
Only collecting the PK sample.


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23/Protocol BP41811, Version 3
Table 2
Mass Balance Cohort – Detailed Table
Period
Day
Scheduled 
Time (h)
Oral Administration of 
[
14C] RO7049389 
suspension
IV Administration of [
13C] 
RO7049389 solution
Blood sampling for PK of [
12C] 
RO7049389 and its [
12C] 
metabolites
Blood sampling for PK of [
13C] 
RO7049389 and [
13C] M5
Blood sampling for [
14C] 
drug related material 
radioactivity counting
Blood sampling for [
14C] drug 
related material metabolic 
profiling
Urine sampling for [
14C] drug related 
material radioactivity counting
and metabolic profiling
Feces sampling for [
14C] drug related 
materialradioactivity counting and 
metabolic profiling
Screening
Day -28 to Day -2
Day -1
x
f
Pre-dose
x
x
x
x
e
x
0
x
a
0.5
x
x
1
x
x
x
1.5
x
x
2
x
b
x
c
x
c
x
c
x
c
2.1333
x
d
3
x
x
x
4
x
x
x
x
6
x
x
x
8
x
x
x
x
10
x
x
x
12
x
x
x
x
24
x
x
x
x
12-24 hr
36
x
x
x
x
Day 3
48
x
x
x
x
Day 4
72
x
x
x
x
48-72 hr
48-72 hr
Day 5
96
x
x
72-96 hr
72-96 hr
Day 6
120
x
x
g
96-120 hr
96-120 hr
Day 7
144
x
x
g
120-144 hr
120-144 hr
Day 8
168
x
144-168 hr
144-168 hr
Day 9
192
x
h
168-192 hr
h
168-192 hr
h
Day 10
216
x
h
192-216 hr
h
192-216 hr
h
Day 11
240
x
h
216-240 hr
h
216-240 hr
h
Day 12
264
x
h
240-264 hr
h,i
240-264 hr
h,i
24-48 hr
0-24 hr
Period 1
0-4 hr
4-8 hr
8-12 hr
Day 1
Day 2
24-48 hr


RO7049389 —F. Hoffmann-La Roche Ltd
24/Protocol BP41811, Version 3
Table 2
Mass Balance Cohort – Detailed Table (cont.)
a)
Participants will fast overnight for at least 10 hours prior to oral administration and fasted 4 hours post administration.
b)
Intravenous infusion administration over 10 minutes.
c)
Collected prior to start of infusion.
d)
Collected at the end of infusion.
e)
Spot urine sample.
f)
Only one sample is collected. It will be kept and processed only if the pre-dose sample on Day 1 cannot be obtained.
g)
Metabolic profiling analyses may not be done depending on the radioactivity level.
h)
Continued until discharge criteria are met.
i)
If on Day 12 the discharge criteria are not met, the participant will be discharged and, urine and feces samples will be 
collected by the subject at home in 24 hours intervals for up to 5 days or until the discharge criteria are met.


RO7049389 —F. Hoffmann-La Roche Ltd
25/Protocol BP41811, Version 3
Table 3
Absolute BA Cohort – Main Table
Screening
Follow Up Call
Day -28 to Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Period 2, Day 29±3
Time Relative (h)
0
24
48
72
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
x
Vein assessment for venipunctures/cannulation 
x
Physical Examinationa
x
x
x
x
Vital Signsb
x
x
x
x
x
ECG-12 leadc
x
x
x
x
x
Hematologyd
x
x
x
x
Blood Chemistryd
x
x
x
x
Coagulationd
x
x
x
x
Urinalysisd
x
x
x
x
Viral Serologye
x
SARS-CoV-2f
x
x
x
x
Lipidsd
x
x
x
x
Drug/Alcohol Test
x
x
Pregnancy Testg
x
x
x
Follicle Stimulating Hormoneh
x
Oral Administration of [12C] RO7049389 tablet
x
IV Administration of [13C] RO7049389 solution
x
Blood sampling for PK
x
x
x
x
x
Urine sampling for PK
x
x
x
x
Clinical Genotypingi
x
In-Clinic Stay
x
x
x
x
Dischargej
x
Adverse Events
Previous and Concomitant Treatments
Assessments
Treatment Period
x
x
Early termination or 
Unscheduled visit


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26/Protocol BP41811, Version 3
Table 3
Absolute BA Cohort – Main Table (cont.)
a)
A full physical examination is required at screening and day of discharge. At other visits (or as clinically indicated), limited, 
symptom-directed physical examinations should be performed at the discretion of the Investigator. Body weight will be 
recorded each time. Height and BMI will only be done at screening.
b)
Vital signs include triplicate measurements of blood pressure and heart rate (taken approximately 1 minute apart) and a 
single assessment of body temperature (oral). Blood pressure and heart rate measurements will be assessed in a supine 
position after 5 minutes of rest.
c)
12-lead ECGs will be obtained after the participant has been in a supine position for at least 10 minutes. Automated ECG 
intervals (PR [PQ], QRS, QT, QTcF, RR) and HR will be captured or calculated, and the changes in T-wave and U-wave 
morphology will be documented.
d)
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis, and lipids) should be collected in the 
morning/at the most appropriate time. Creatinine clearance (CrCl) will be calculated using the Cockcroft-Gault formula at 
screening and on Day -1.
e)
Hepatitis A virus (HAV) IgM antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) RNA, total hepatitis D 
virus (HDV) antibody, hepatitis E virus (HEV) IgM antibody, human immunodeficiency virus (HIV-1 antibody and HIV-2 
antibody, or HIV-1/2 antibody).
f)
Testing for SARS-CoV-2 may be performed based on current infection rates and availability of tests. If required, SARS-CoV-
2 antibody will be done at screening. SARS-CoV-2 antigen will be done at screening, pre-admission, day before discharge 
or day of discharge.
g)
Serum beta-human chorionic gonadotropin (b-HCG) at screening, urine on all other occasions (females only). If urine test is 
positive, then a confirmatory serum test is needed.
h)
Follicle stimulating hormone (females only to confirm post-menopausal status, performed at screening only).
i)
If the blood sample is not collected on Day 1, it may be collected at any time during the conduct of the clinical study.
j)
Assessments will be performed after an overnight fast (for at least 10 hours).


RO7049389 —F. Hoffmann-La Roche Ltd
27/Protocol BP41811, Version 3
Table 4
Absolute BA Cohort – Detailed Table
a)
Participants will fast overnight for at least 10 hours prior to oral administration and fasted 4 hours post administration.
b)
Intravenous infusion administration over 10 minutes.
c)
Collected prior to start of infusion. 
d)
Collected at the end of infusion.
e)
Spot urine sample.
Period
Day
Scheduled 
Time (h)
Oral Administration of 
[
12C] RO7049389 tablet
IV Administration of [
13C] 
RO7049389 solution
Blood sampling for PK of [
12C] 
RO7049389 and its [
12C] 
metabolites
Blood sampling for PK of [
13C] 
RO7049389 and [
13C] M5
Urine sampling for PK of [
12C] 
RO7049389 and its [
12C] 
metabolites
Screening
Day -28 to Day -2
Day -1
Pre-dose
x
xe
0
xa
0.5
x
1
x
1.5
x
2
xb
xc
xc
2.1333
xd
3
x
x
4
x
x
6
x
x
8
x
x
10
x
x
12
x
x
24
x
x
12-24 hr
36
x
x
Day 3
48
x
x
Day 4
72
x
x
48-72 hr
Period 1 and Period 2
Day 1
0-4 hr
4-8 hr
8-12 hr
Day 2
24-48 hr


RO7049389 —F. Hoffmann-La Roche Ltd
28/Protocol BP41811, Version 3
2.
INTRODUCTION
RO7049389 is an orally administered small molecule that is being developed for the 
treatment of chronic hepatitis B virus (HBV) infection. 
2.1
STUDY RATIONALE
 
 
 
 
In order to better understand the disposition of 
RO7049389, it is important to characterize its metabolic profile and the rate and routes 
of elimination. To do this, it is necessary to administer a small amount of the drug, which 
has been radiolabeled in a stable position with carbon 14 [14C]. The intravenously 
(carbon 13 [13C]) will help differentiate non-absorbed drug and biliary secreted [13C]
parent/metabolites in feces. 
 
Therefore, in the absolute oral BA cohort of this study, RO7049389 will 
be administered orally (unlabeled) and intravenously [13C] to allow the quantification of 
absolute BA
 
The results from the study will provide a more 
comprehensive understanding of the PK of RO7049389 and metabolites and allow for a 
more complete comparison of the routes of elimination and metabolic pattern of 
RO7049389 between animals and humans. The risks to the individual participant due to 
exposure to RO7049389, radiation, or study-related procedures are considered 
acceptable in this study. 
 
 
the doses have been demonstrated to be 
safe and well tolerated in the Phase 1 study YP39364.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
HBV infection is a major cause of both acute hepatitis and chronic liver diseases, 
including cirrhosis and hepatocellular carcinoma. Approximately 257 million people 
worldwide are living with chronic HBV infection (defined as hepatitis B surface antigen 
[HBsAg] positive). In 2015, HBV resulted in an estimated 887,000 deaths, mostly from 
complications including cirrhosis and hepatocellular carcinoma (WHO 2020; EASL 
2017).
Currently, there are two classes of drugs available for the treatment of chronic HBV: 
subcutaneously administered interferon preparations and orally administered 
nucleos(t)ide analogues (NUCs). Although both types of treatment can induce the loss of 


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29/Protocol BP41811, Version 3
hepatitis B e antigen (HBeAg) with the development of anti-HBeAg antibody (serological 
response), the suppression of HBV deoxyribonucleic acid (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 in <15% after 1 to 5 years follow-up (EASL 
2017). In addition, interferon-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. Thus, there is an unmet medical need for 
a therapy that can achieve a higher rate of functional cure, has a finite treatment 
duration, and is well tolerated.
RO7049389 is an inhibitor of HBV capsid assembly and belongs to the well-studied 
class of heteroaryldihydropyrimidine compounds. This class of compounds induces 
formation of abnormal HBV core protein aggregates, which are subsequently recognized 
and depleted. Depleting functional core protein results in interruption of viral assembly 
and inhibition of HBV replication.
Three Phase I clinical studies of RO7049389 have been completed: YP39364 (Parts 1 
and 2), YP39406, and YP40218.
In Study YP39364, Parts 1 and 2 were randomized, Sponsor open, Investigator blinded, 
and participant-blinded. Part 1 was a single-ascending dose (SAD) and 
multiple-ascending doses (MAD) investigation of the safety, tolerability, and PK of 
RO7049389 following oral administration in HVs, including the effect of food on the PK of 
single-dose RO7049389 and the effect of multiple-dose RO7049389 on the PK of 
midazolam. Part 2 evaluated the safety, tolerability, PK, and pharmacodynamics (PD) of 
orally administered RO7049389 in patients chronically infected with HBV. 
Study YP39406 was a single center, randomized, Sponsor-open, Investigator-blinded, 
participant-blinded, placebo-controlled, SAD, and MAD study to investigate single and 
multiple doses of RO7049389 in HVs of Chinese descent for comparison with HVs in 
Part 1 of Study YP39364. 
Study YP40218 was a DDI study to assess the effects of RO7049389 as an OATP 
inhibitor on the PK of OATP substrate (pitavastatin as a probe drug). 
 
 
 
 
 
 
 




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31/Protocol BP41811, Version 3
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7049389 is provided in the 
RO7049389 IB.
2.3.1
COVID-19 Related Risks and Risk Mitigation Measures
The following risks and risk mitigating measures apply to parts of the study, which will be 
conducted during the coronavirus disease 2019 (COVID-19) pandemic.
2.3.1.1
IMP-related Risk
Against the background of the COVID-19 pandemic, the potential risk of a participant
developing COVID-19 has been considered in terms of the risk-benefit evaluation. The 
mode of action of the investigational medicinal product (IMP)–as an inhibitor of HBV 
capsid assembly – has been considered alongside available pre-clinical and clinical data 
(including class effects) and it is considered that a participant would not be at increased 
risk of either becoming infected with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2; the virus that causes COVID-19) or experiencing a more severe illness. 
That is, the IMP has no known immunomodulatory effect that would confer an increased 
risk to HVs enrolled in the study.
2.3.1.2
General COVID-19 Related Risk Mitigation Measures
General risk mitigation against COVID-19 will be implemented in accordance with 
Quotient Sciences clinical unit’s monitoring and prevention-control measures.
COVID-19 testing may be performed on the basis of current infection rates and 
availability of tests. If required, testing will comprise an antibody blood test performed at 
screening, and an antigen PCR test performed at screening, the day before admission to 
each treatment period, and discharge or the day before discharge from each treatment 
period. Testing time points may be changed and additional time points may be added 
throughout the study as required. The decision on COVID-19 testing and the definition of 
the testing time points will be agreed by the study team and documented in the 
Investigator site file (ISF) via the Clinical Kick-Off Meeting minutes.
The risk mitigation measures, where applicable, will be amended on the basis of 
emerging government guidance.  
2.3.1.3
Assessment Regarding COVID-19 Vaccination
Against the background of the COVID-19 pandemic, the risk assessment of the effect of 
the IMP RO7049389 and concomitant administration of a COVID-19 vaccination has 
been evaluated for this study. The mode of action of the IMP — as an inhibitor of HBV 
capsid assembly — has been considered alongside available pre-clinical and clinical data 
(including class effects) and it is considered that COVID-19 vaccinations are simple 
concomitant medicines with no interaction with the IMP. However, all concomitant 
medications are prohibited within 14 days prior to the first dosing or within 5 half-lives 


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32/Protocol BP41811, Version 3
of the medication prior to the first dosing until after collection of the final sample 
(Section 6.5.2). This is due to the nature and short duration of the study, but not for 
safety reason. As a mass balance and absolute bioavailability study conducting in 
healthy volunteers, prohibition of all concomitant medications is required to ensure the 
integrity of the study by minimizing any potential physiological changes.


RO7049389 —F. Hoffmann-La Roche Ltd
33/Protocol BP41811, Version 3
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the mass 
balance (MB), routes, and 
rates of elimination of [14C] 
RO7049389.

Percentage of dose 
excreted in urine.

Percentage of dose 
excreted in feces.

To determine the absolute oral 
bioavailability (BA) of 
RO7049389.

Absolute oral BA for 
RO7049389.
Secondary


To determine the plasma 
concentration of RO7049389,
its identified three metabolites 
(RO7121986, RO7255420,
and RO7255422), total 
drug-related radioactivity and 
related pharmacokinetic (PK) 
parameters.

Cmax, AUClast, AUC0-inf, tmax, 
CL/F, CL, CLr, Ae, V/F,
and t½ of RO7049389 and 
its identified three 
metabolites, and total 
drug-related radioactivity, if 
appropriate.

To identify and quantify 
circulating and excreted 
metabolites of RO7049389 in 
plasma, urine, and fecal 
samples based on radioactive 
metabolic profiling.

A metabolic profile for 
RO7049389 and 
metabolites, and their 
structural elucidation, if 
appropriate.

Cmax, AUClast, AUC0-inf, 
tmax, CL/F, CLr, Ae, V/F 
and t½ of other major 
metabolites related 
radioactivity, if 
appropriate.

To evaluate the safety and 
tolerability of one or two 
single-doses of RO7049389 in 
healthy participants.

Adverse events (AEs), 
clinical laboratory values, 
vital signs, 
electrocardiogram (ECG), 
and physical examination.


RO7049389 —F. Hoffmann-La Roche Ltd
34/Protocol BP41811, Version 3
OBJECTIVES AND ENDPOINT (CONT.)
Exploratory

To determine whether genes 
relating to drug-metabolizing 
enzymes and/or drug 
transporters affect the PK 
and/or the safety profile of 
RO7049389.

The pharmacogenetics of 
metabolizing enzymes 
(CYP3A4, UGT1A3) and 
transporters (OATP1B)
possibly involved in the 
absorption, distribution, 
metabolism, and excretion 
of RO7049389 and its 
major metabolites.

To determine the relative BA
of RO7121986.

Cmax, AUClast, AUC0-inf of 
RO7121986 after oral and 
intravenous (IV)
administration of 
RO7049389.
4.
STUDY DESIGN
4.1
OVERALL DESIGN
This is an open-label, two-cohort (i.e., a MB cohort and an absolute BA cohort), 
single-dose study designed to evaluate the MB and absolute BA of RO7049389 in HVs. 
An overview of the study design is provided in Section 1.2. The investigational
medicinal products (IMPs) required for completion of this study will be [12C] RO7049389 
tablet, 200 mg, [14C] RO7049389 oral suspension, 600 mg (NMT 2.2 MBq), and [13C] 
RO7049389 solution for infusion, 20 µg/mL.
Male participants in the MB cohort will receive a 600 mg dose of [14C] RO7049389 as 
an oral suspension under fasted conditions. Participants will then receive 100-μg dose 
of [13C] RO7049389 administered as a 10-minute intravenous (IV) infusion, 2 hours after 
the oral dose of [14C] RO7049389.
In the absolute BA cohort, each participant will take part in both Period 1 and Period 2. 
Male or female participants in Period 1 of the absolute BA cohort will receive a 600 mg 
dose of [12C] RO7049389 administered orally as a clinical formulation under fasted 
conditions. Participants will then receive a 100-μg dose of [13C] RO7049389
administered as a 10-minute IV infusion, 2 hours after the oral dose of RO7049389. 
After a washout period of at least 7 days, in Period 2, male or female participants will 
receive a 1000 mg dose of [12C] RO7049389 administered orally as a clinical 
formulation under fasted conditions. Participants will then receive 100 μg of [13C]


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RO7049389 administered as a 10-minute IV infusion, 2 hours after the oral dose of 
RO7049389.
4.1.1
Discharge Criteria for Mass Balance Cohort
In the MB cohort, total urine and feces will be collected at appropriate time intervals in 
the unit until the following discharge criteria are met:
At least 90% of the total radioactivity has been recovered in urine and feces, or 1% of 
the administered dose excreted in two consecutive 24-hour urine and fecal samples, 
whichever is shorter.
All participants are required to stay in the unit at least until the morning of Day 8. If the 
results from the samples collected for up to 144 hours show that all participants meet the 
discharge criteria, then all participants are discharged from the unit on Day 8. 
If the samples collected up to 144 hours show that not all participants meet the 
discharge criteria, then all participants will be kept in the unit to collect additional 
samples until the results from the samples collected for up to 192 hours show that all 
participants meet the discharge criteria. All participants are therefore discharged either 
on Day 9 or on Day 10, depending on when the discharge criteria are met by all 
participants.
If the samples collected up to 192 hours show that not all participants meet the 
discharge criteria, then all participants will be kept in the unit for a maximum of 
2 additional days (until the morning of Day 12) to collect additional samples. Based on 
the results from the samples collected up to 240 hours, participants are allowed to be 
discharged on an individual basis if the discharge criteria are met.
The remaining participants who do not meet the discharge criteria by the morning of 
Day 12 will be discharged from the unit and will be required to collect further samples 
(urine/feces) at home for up to a maximum of five additional days, until the discharge
criteria are met.
4.1.2
Length of the Study
The identity of the participants will be confirmed at admission and pre-dose. In addition, 
the ongoing eligibility of participants will be re-assessed at admission/pre dose, as 
described in Section 5.1 and Section 5.2. Admission/pre-dose safety procedures such 
as safety bloods tests, ECGs, vital signs, urinalysis, and drugs of abuse tests can be 
repeated as clinically indicated under the discretion of Investigator or sub-investigator if 
there is a concern regarding a participant’s safety or eligibility to participate in the 
clinical trial. Reserve participants for the first dose occasion, in any group, will not 
require admission procedures to be repeated if dosing is within 2 days. 


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The participants will be admitted to the clinical unit on the morning before dosing 
(Day -1).
In addition, participants may be required to visit the clinical unit on the day before 
admission for each treatment period for SARS-CoV-2 antigen tests (if required).
In the MB cohort, the total duration of the study for each participant will be about 
8 weeks, divided as follows:

Screening: Up to 28 days.

In-clinic period: Day 1 to the day when the discharge criteria (See Section 4.1.1) 
are met. This is up to a maximum of 12 days. 

Safety follow-up: One call on Day 29 3.
In the absolute BA cohort, the total duration of the study for each participant will be at 
least 9 weeks, depending on the duration of the washout period, divided as follows:

Screening: Up to 28 days.

In-clinic period: Days 1 to 4 for both Periods 1 and 2.

Washout period: Defined as from Period 1 Day 1 to Period 2 Day 1 and lasts at least 
7 days.

Safety follow-up: One call on Period 2 Day 29 3.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
The primary objectives of this study are to characterize the routes and rates of 
elimination of [14C]-labeled RO7049389 and to assess the absolute oral BA of a 
single-dose of 600 mg and 1000 mg of RO7049389. Drug concentrations or radioactivity
in plasma, urine, and feces is assumed to be objective measurements, which cannot be 
affected by volunteer or staff behavior. Therefore, it is generally accepted to conduct MB
study and absolute BA study with an open-label design, without placebo treatments, and 
since the evaluation of safety and tolerability is not a primary objective of this study, an 
open-label design was deemed appropriate.
For the absolute BA cohort, to minimize the number of participants needed and reduce 
inter-subject variability, this study will follow a two-period design instead of a parallel 
design. The duration of the washout period was established based on the known PK
profile of RO7049389.
The concept of simultaneous dosing with a labeled IV dose and an unlabeled oral dose 
to determine absolute oral BA is well-established using stable non-radioactive isotope 
such as 13C. This technique allows the fate of the IV dose to be distinguished from the 


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oral dose by means of the isotopic tracer. Plasma concentrations will be determined by 
LC-MS/MS and the [13C]-labeled drug administered intravenously will be distinguished 
from the [12C]-unlabeled drug (i.e., in this study RO7049389) administered orally by 
virtue of their different molecular masses, using mass spectrometry detection. Dose-
normalized AUCs of [12C]-unlabeled drug on the one hand and [13C]-labeled drug on the 
other hand will be compared to determine absolute oral BA. The principle advantage of 
the isotopic method is that the plasma drug concentration relating to the IV and oral 
doses will be measured in the same plasma sample, thereby eliminating inter-occasional 
variability and, in theory, eliminating any concentration-dependent clearance. 
In this study, 100 μg of [13C] RO7049389, the IV tracer, will be administered 2 hours (the 
estimated tmax of the oral dose) after the oral dose of RO7049389 as a 10-minute
infusion. Administering IV dose at the tmax of the oral dose is expected to reduce errors in 
BA estimation due to concentration dependent clearance considering the observed 
non-linear PK of RO7049389 in the Phase 1 studies.
4.2.1
Rationale for Study Population
In this study, HVs have been chosen to avoid any confounding disease processes, thus 
ensuring a clear and more consistent assessment of drug disposition. Additionally, HVs
are unlikely to require concomitant treatments, which could interfere with the absorption, 
distribution, metabolism, or excretion of RO7049389. 
We acknowledge that the Administration of Radioactive Substances Advisory Committee 
(ARSAC) Notes for Guidance recommend that wherever possible, HVs selected for 
research projects should be aged over 50 years. However, the current MB cohort of the
study is designed to generate data for supporting the investigation of the human 
absorption, metabolism, distribution, and excretion (ADME) of a drug, as well as 
generating samples for metabolite profiling and structural identification.
There are two main reasons for generating these data within a clinical development 
program. The first is to provide human metabolite data that can be used to interpret the 
metabolism profiles seen in the preclinical species employed in the longer-term toxicity 
studies, to ensure that there is adequate toxicology coverage for the safe development 
of the drug in patients. The second is to provide data to understand how the drug is 
processed in physiologically normal participants, because understanding the routes of 
metabolism and elimination in a healthy population generates the appropriate data to 
guide the clinical pharmacology package required to fulfil the regulatory requirements of 
a New Drug Application. 


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In order to address these two main aims of a MB study, investigation of the drug under 
development is required in a population with normal physiological function, as it is 
recognized that certain physiological processes e.g., renal function, deteriorate with age 
and therefore it is preferable to use as healthy a population to possibly mitigate against 
factors which may make interpretation of the data difficult. In addition, healthy subjects 
as a trial population are ideal, because they have a relatively stable physiological, 
biochemical and hormonal status, which removes any disease-related variations and 
variations due to concomitant medications. Therefore, given the aims of this MB cohort,
our target age range for the MB cohort of this study will be 35 to 65 years.
There are potential risks to female subjects with respect to pregnancy from exposure to 
ionizing radiation. Thus, evaluation in a group of healthy male volunteers, the population 
most widely used in this type of study, is appropriate for the MB cohort.
4.3
JUSTIFICATION FOR DOSE
4.3.1
Justification for Dose selection
 
 
 Therefore, a single oral dose of 600 mg of 
RO7049389 has been selected for this study. In addition, a dose of 1000 mg 
RO7049389 in the absolute BA cohort will be studied to investigate the dose-dependent 
changes in oral BA and/or clearance. 
In this study, an IV micro dose of [13C] RO7049389 is administered following 
administration of an oral dose of RO7049389 to determine the BA of the oral dose 
compared with that of the IV dose. According to the International Council for 
Harmonisation (ICH) M3 guidance, a micro dose is a dose that is 1/100th of the 
pharmacologically active dose up to a maximum of 100 µg. In addition, to ensure that the 
IV micro dose does not contribute significantly to the exposure following oral dosing, the 
IV dose has been reduced further and in this study will be 1/6000th (600 mg) or 
1/10000th (1000 mg) of the oral dose, and hence is an appropriate ‘IV microtracer dose’. 
4.3.2
Justification for Radioactive Dose Selection
The oral radioactive dose of not more than 2.2 MBq (59.3 μCi) was chosen based on 
calculations using the tissue distribution data from studies in rats to identify the critical 
organs and restrict the exposure of the participants to radioactivity within the limits set by 
the ICRP. A radioactive dose is necessary to investigate potential minor metabolites, as 
well as quantitatively measure the major metabolites of RO7049389 in urine and feces. 
The committed effective dose obtained for oral administration of [14C]-RO7049389 to 
male participants was calculated as 2.6 × 10-10 Sv Bq-1.
On this basis, the maximum administered activity that would comply with the World 
Health Organization (WHO) recommendation (WHO 1977) of a 500 μSv maximum for 


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Category 1 projects would be 1.92 MBq (52.4 μCi). The WHO categories have been 
modified by ICRP in the light of the 1990 recommendations, which call for the special 
consideration of dose constraints for scientific and clinical studies involving the exposure 
of participants. The dose to male participants proposed in the MB cohort of this study will 
be 0.57 mSv and so classed as ICRP Category IIa.
To ensure that the [14C] drug product to be used in this study does not exceed the limit 
for radioactive dose approved by the ARSAC, the target radioactive dose of the drug 
product will be set at 90% of the threshold radioactive dosing limit. This will allow for 
tolerance in the manufacturing processes for both drug substance and drug product,
thereby providing continued assurance for compliance with the ARSAC-approved limit 
for drug-product radioactivity dose.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he/she has completed all parts 
of the study, including the last scheduled procedure shown in the SoAs.
The end of the study is defined as the date when the last participant last observation 
(LPLO) occurs. LPLO is expected to occur 283 days after the last dose of RO7049389 
is administered.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.1.
Participants of this study are healthy male (both MB cohort and absolute BA cohort) and 
female (absolute BA cohort only) volunteers of 35 to 65 years (MB cohort) or 
18 to 60 years (absolute BA cohort) of age, inclusive.
For the absolute BA cohort, each participant will take part in both Period 1 and Period 2. 
The number of either gender of the enrolled participants should not exceed
12 participants of the same gender, nor should they all be in the same ethnic group 
(Caucasian or East Asian). 
Participants who drop out of the study for non-safety reasons in the absolute BA cohort
may be replaced. Participants who withdraw from the study due to poor tolerability or 
due to study drugs (RO7049389) related AEs will not be replaced.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:


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Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to ICH and local regulations. 
Age
2.
35 to 65 years (MB cohort) or 18 to 60 years (absolute BA cohort), inclusive, at the 
time of signing the informed consent.
Type of Participants 
3.
Caucasian (both MB cohort and absolute BA cohort must have Caucasian parents 
and grandparents) or East Asian (for the absolute BA cohort only, participants must 
have Chinese, Korean or Japanese parents and grandparents).
4.
Healthy, as judged by the Investigator based on the following definition.
5.
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, and based on the laboratory safety 
test results.
Weight
6.
Body mass index between 18 to 30 kg/m2 (inclusive), and a weight range of 50 kg to 
100 kg (inclusive) at screening.
Sex
7.
Male (both MB cohort and absolute BA cohort) and female (absolute BA cohort only) 
participants
The reliability of sexual abstinence for male and/or female enrollment eligibility 
needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of preventing drug exposure.
Female Participants
For women of childbearing potential: agree to use two methods of contraception, 
with at least one method considered as highly effective during the study and for at 
least 90 days after the last dose of study drug (Appendix 5).
a. A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
b. Contraceptive methods considered as highly effective (failure rate < 1% per year 
when used consistently and correctly):


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
Combined (estrogen- and progestogen-containing) or progestogen-
only hormonal contraception associated with inhibition of ovulation

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion/ligation

Vasectomized partner

Sexual abstinence: Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the 
entire period of study treatment and at least 90 days after the last dose of 
study drug. In such case, there is no need to use two contraceptive 
methods. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
c.
Contraceptive methods NOT considered as highly effective (failure rate > 1% 
per year):

Progestogen-only oral hormonal contraception (where inhibition of ovulation 
is not the primary mode of action)

Male or female condoms with or without spermicide

Cap, diaphragm, or sponge with spermicide
Male Participants

For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or agree to use contraceptive measures, and agree to refrain from donating sperm, 
as defined below: 

Men must remain abstinent or use a condom during the treatment period and 
for at least 90 days after the last dose of study drug to avoid exposing the embryo. 
Men must refrain from donating semen during this same period.
Inclusions for Mass Balance Cohorts Only
8.
Must have regular bowel movements (i.e., average stool production of 1 and 
3 stools per day).
For both cohorts, inclusion criterion 4 from the list above will be re-assessed at 
admission/pre-dose of each treatment period.
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Pregnant (positive pregnancy test) or lactating women, and male participants with 
partners who are pregnant or lactating.


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2.
Have a history or symptoms of any clinically significant cardiovascular, respiratory,
hepatic, renal, gastrointestinal (GI), endocrine, hematological, oncologic, or
neurological disorders capable of significantly altering the absorption, metabolism,
or elimination of drugs; of constituting a risk when taking the study treatment; or of
interfering with the interpretation of data.
3.
Confirmed (based on the average of three separate resting blood pressure [BP]
measurements in a supine position, after at least 5 minutes of rest) systolic BP
greater than 140 mmHg or less than 90 mmHg, and diastolic BP greater than
90 mmHg or less than 50 mmHg at screening and Day -1.
4.
Personal history or family history of congenital long QT interval (QT) syndrome
and/or cardiac sudden death.
5.
History of Gilbert syndrome.
6.
Participants who have had significant acute infection, e.g., influenza, local infection,
acute GI 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
the conduct of the study, or in the opinion of the Investigator, would pose an
unacceptable risk to the participant in this study.
Prior/Concomitant Therapy
9.
Taking any herbal medications or substances, supplements (including vitamins),
traditional Chinese medicines, prescription medicine, or over-the-counter (OTC)
medications within 14 days of first dosing or within 5 times the elimination half-life of
the medication prior to first dosing, whichever is longer.
Exceptions are medications listed under Permitted Therapy (Section 6.5.1).
10. History of having received 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.
Prior/Concurrent Clinical Study Experience
11. Are currently enrolled in or have participated in any other clinical study involving an
investigational product or in any other type of medical research within the last
90 days (or within 5 half-lives of the investigational product, whichever is longer).
12. Donation or loss of blood or blood products in excess of 500 mL within three months
of screening.
Diagnostic Assessments
13. Clinically relevant ECG abnormalities on screening, Day 1, or Day 1 (pre-dose), e.g.:


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a. QT corrected for heart rate (HR) using the Fridericia’s correction factor 
(QTcF) 430 msec (males), 450 msec (females), or 300 msec (males and 
females).
b. Notable resting bradycardia (HR 45 beats per minute [bpm]), or HR 90 bpm.
c.
Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-
Parkinson-White Syndrome, or cardiac pacemaker.
14. Clinically significant ECG with QRS complex (QRS) and/or T-wave judged by the 
Investigator to be unfavorable for a consistently accurate QT measurement (e.g., 
neuromuscular artifact that cannot be readily eliminated, arrhythmias, indistinct QRS 
onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves).
15. Creatinine clearance (CrCl) 70 mL/min (using the Cockcroft-Gault formula) at 
screening (may be repeated for confirmation) or on Day 1.
16. Evidence of current severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2; i.e., the virus that causes COVID-19) infection.
17. Positive test at screening of any of the following: hepatitis A virus (HAV 
immunoglobulin M [IgM] antibody), hepatitis B virus (HBV, HBsAg), hepatitis C virus 
(HCV ribonucleic acid [RNA]), hepatitis D virus (total HDV antibody), hepatitis E 
virus (HEV IgM antibody), and human immunodeficiency virus (HIV-1 antibody and 
HIV-2 antibody, or HIV-1/2 antibody).
18. Any other clinically significant abnormalities in laboratory test results at screening or 
on Day 1. In the case of uncertain or questionable results, tests performed during 
screening or Day -1 may be repeated once prior to enrollment to confirm eligibility 
unless deemed not clinically significant by the Investigator.
Other Exclusions
19. History of any drug or alcohol abuse in the past 2 years.
20. Regular alcohol consumption in males > 21 units per week and in females >14 units 
per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL 
glass of wine, depending on type). 
21. A confirmed positive alcohol breath test at screening and on Day 1.
22. Use of five cigarettes or equivalent nicotine-containing product per day prior to 
screening.
23. Participants under judicial supervision, guardianship, or curatorship.
24. Medical or social conditions that would potentially interfere with the participant’s 
ability to comply with the study visit schedule or the study assessments.
25. Sensitivity to any of the study treatments, or excipients thereof, or drug or other 
allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates the 
participation in the study.
26. Participants who do not have suitable veins for multiple venipunctures/cannulation 
as assessed by the Investigator or delegate at screening.


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27. Participants who planned to attempt to have children within 90 days of dosing.
Exclusions for Mass Balance Cohorts Only
28. Regular work with ionizing radiation or radioactive material.
29. Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic X-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last five years. No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017, shall 
participate in the study. 
30. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays 
of thorax and bony skeleton [excluding spinal column]), during work, or during 
participation in a medical trial in the previous year.
31. History of GI surgery (with the exception of appendectomy unless it was performed 
within the previous 12 months).
32. Acute diarrhea or constipation in the past seven days prior to admission. Diarrhea
will be defined as the passage of liquid feces and/or a stool frequency of greater 
than three times per day. Constipation will be defined as a failure to open the 
bowels more frequently than every other day.
For both study parts, exclusion criteria 1, 3, 6, 7, 8, 9, 12, 13, 14, 15, 16, 18, 21, 22, 27,
and 31 from the list above will be re-assessed at admission/pre-dose of each treatment 
period.
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
Food and water will be restricted as follows:

 
 
 

Participants should refrain from eating food containing poppy seeds for 48 hours
prior to screening and from 48 hours prior to admission until after collection of the 
final sample.

Still water at room temperature will be provided for each dose. No water is 
allowed from 1 hour prior to dosing until 1 hour after each oral dose, after which 
time, water is allowed ad libitum, up to a maximum of three liters a day.

Participants in the MB cohort must not eat anything likely to disturb GI transit 
(e.g., spicy or high-fat meals such as curry or fish and chips or foods of a 
high-fiber content such as All Bran) from 24 hours prior to admission until after 
collection of the final sample.


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5.3.2
Caffeine, Alcohol, and Tobacco
Caffeine, alcohol, and tobacco will be restricted as follows:

Participants must abstain from ingesting caffeine- or xanthine-containing
products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours before the 
start of dosing until after collection of the final sample.

Alcohol must not be consumed from 48 hours before screening, 48 hours before
admission until after collection of the final sample.

Participants who use tobacco products will be instructed that use of 
nicotine-containing products (including nicotine patches) will not be allowed from 
screening until after collection of the final sample. 
5.3.3
Activity
Participants must abstain from strenuous exercise for at least 72 hours before each 
blood collection for clinical laboratory tests. Participants may participate in light 
recreational activities during study (e.g., watching television, reading).
Participants must not donate blood or plasma (outside of this study) from clinical unit 
admission, throughout the study duration, and for at least 90 days following last dose of 
study medication.
Participants in the MB cohort will not be permitted to shower for 24 hours post-dose (to 
ensure the collection of all samples).
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study
but are not subsequently enrolled to study treatment. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
If a participant 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 participant fails a second time,
they will be classed as a screen failure and cannot be re-screened.
Re-screening is allowed for participants who were screened in the study and met study
inclusion/exclusion criteria but failed to be enrolled within 28 days after the start of
screening period because the enrollment was suspended. In order to re-screen such a
participant, all inclusion and exclusion criteria should be re-evaluated, and all applicable 
screening assessments repeated if done more than 28 days prior to the enrollment.
5.5
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using; clinical database and 
independent ethics committee (IEC)/Institutional Review Board (IRB) approved 


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newspaper/radio/television/social network service/campus poster advertisements, 
mailing lists, and other distributable documents prior to consenting to take place on this 
study.
6.
TREATMENTS
Study intervention is defined as any investigational product intended to be administered 
to a study participant according to the study protocol.
The IMPs for this study are [12C] RO7049389 tablet, 200 mg, [14C] RO7049389 oral 
suspension, 600 mg (NMT 2.2 MBq), and [13C] RO7049389 solution for infusion, 
20 µg/mL. All study drug administration will be at the study center under supervision of 
site staff.
Cases of accidental overdose or medication error, along with any associated AEs, 
should be reported as described in Appendix 2, Section 5.2.
6.1
TREATMENTS ADMINISTERED
Table 5 summarizes the treatments administered. Guidelines for dosage modification 
and treatment interruption or discontinuation are provided in Section 6.6 or Section 7, 
respectively.
6.1.1
[14C] RO7049389 Oral Suspension, 600 mg (NMT 2.2 MBq)
On the morning of Day 1 for MB cohort, a 20-mL drinking suspension containing 600 mg 
of RO7049389, providing a maximum of 2.2 MBq of [14C]-labeled RO7049389 
(equivalent to 59.3 μCi) will be administered to all eligible participants after an overnight 
fast of at least 10 hours, followed by another four hours of fasting until lunch. Each 
participant will receive 190 mL of still water immediately after the dose has been 
swallowed, followed by a further 50 mL which will be used to rinse out the dosing 
vessels (50 mL will be used in five separate rinses). Water will be allowed ad libitum until 
1 hour prior to dosing and from 1-hour post dosing, at a maximum of three liters a day.
6.1.2
[13C] RO7049389 Solution for Infusion, 20 µg/mL
On Day 1 of MB cohort, on Day 1 of both Period 1 and Period 2 of absolute BA cohort, a 
single microdose of [13C]-labeled RO7049389 100 μg will be administered by a 
10-minute constant IV infusion. Dilution of the [13C]-labeled RO7049389 solution 
for infusion using 0.9% saline will be performed at bedside. The IV infusion will 
start 2 hours after administration of the oral dose of RO7049389. 
Details on study drug preparation by the Quotient Sciences clinical unit will be described 
in the manufacturing batch record, which will be prepared by the Quotient Sciences
pharmacy. 


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6.1.3
RO7049389 Tablet, 200 mg
An oral dose of RO7049389 600 mg (Period 1) or 1000 mg (Period 2) in the absolute BA 
cohort will be administered as a clinical formulation in the morning of Day 1 of Period 1 
or Period 2, study drug administration will be after an overnight fast of at least 10 hours, 
followed by another 4 hours of fasting until lunch. Water will be allowed ad libitum until 
1 hour prior to dosing and from 1-hour post dosing, at a maximum of three liters a day.
Study drug will be swallowed whole with still water. Please see the dosing instructions 
and RO7049389 IB for more details. 
Table 5
Summary of Treatments Administered
Study Treatment 
Name:
RO7049389
[14C]-labeled 
RO7049389
[13C]-labeled 
RO7049389
IMP and NIMP
IMP
IMP
IMP
Dose Formulation:
Tablet
Suspension
Solution
Unit Dose 
Strength(s)/Dosage 
Level(s):
200 mg
20 mL
20 g/mL *
Dose:
600 mg or 1000 
mg
600 mg
100 μg
Route of 
Administration:
oral
oral
IV infusion
Sourcing:
Provided by the 
Sponsor.
API will be provided 
by the Sponsor and 
the formulation will 
be provided locally 
by the trial site.
API will be provided by 
the Sponsor and the 
formulation will be 
provided locally by the 
trial site. 
Packaging and 
Labeling:
Study treatment 
will be provided 
in labeled bottles.
Study treatment will 
be provided in 
labeled bottles.
Study treatment will be 
provided in labeled 
bottles.
*
Dilution will be performed at bedside.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
[13C]-labeled and [14C]-labeled RO7049389 API will be provided by the Sponsor. The 
investigational site will acknowledge receipt of [13C]-labeled and [14C]-labeled 
RO7049389, and confirm the shipment condition and contents. Any damaged shipments 
will be replaced. The investigational site will manufacture a drinking suspension using 
the API supplied for [14C]-labeled RO7049389 and a solution for infusion using the API 
supplied for [13C]-labeled RO7049389.
The RO7049389 tablets (clinical formulation) will be provided by the Sponsor.


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Study drug packaging will be overseen by the Sponsor’s clinical study supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification, and dosage.
The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations.
The study site should follow all instructions included with each shipment of IMP. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The Investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit for all IMPs received and that any discrepancies have been reported and resolved 
before use of the IMPs. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the Investigator and authorized staff.
The study site (i.e., Investigator or other authorized personnel [e.g., pharmacist) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol. Upon arrival of the IMPs at the site, site personnel will 
complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Study Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment assignment schedule.
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff.
The Investigator, Institution, or the Head of the Medical Institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records).


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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 with the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. Accurate records of all IMPs received at, dispensed from, returned to, 
and disposed of by the study site should be recorded on the drug accountability log.
Refer to the dosing instructions, the RO7049389 IB, and/or Investigational Medicinal 
Product Dossier for information on IMP formulation, IMP handling, including preparation 
and storage, and accountability.
According to Title 21, Part 320 of the U.S. Code of Federal Regulations, reserve 
samples of the clinical supplies used in a bioavailability or bioequivalence study must be 
retained by the organization that conducted the study and stored under conditions that 
will maintain the integrity, identity, strength, quality and purity of the samples. The 
samples for retention will be randomly selected by the Investigator or by a representative 
of the Investigator. All samples must be retained at the study site for a period of at least 
5 years following the date on which the application or supplemental application is 
approved by the U.S. Food and Drug Administration (FDA). If such application is not 
approved, all samples must be retained for at least 5 years following the date of 
completion of any bioavailability or bioequivalence study from which the reserve samples 
were obtained.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
This is a fixed sequence study. Randomization is not applicable.
6.3.2
Blinding
This is an open-label study; blinding procedures are not applicable.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment schedule. This individual will write the date 
dispensed and participant number on the study treatment bottle, label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study.
During all clinical phases of the study, participants will be observed by study staff to 
assure compliance to all study procedures, including dose administration. 


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Mouth and hand checks will be conducted after oral dosing to ensure the IMP has been 
swallowed.
The IV dose will be administered by trained staff to ensure dosing compliance.
The date and time that each participant is dosed will be recorded in the participant’s 
source data. Any violation of compliance will require evaluation by the Investigator and 
Sponsor to determine if the participant can continue in the study.
6.5
CONCOMITANT THERAPY
Any medication or vaccine (including OTC or prescription medicines, approved dietary 
and herbal supplements, and nutritional supplements) used by a participant from 
30 days prior to screening until after collection of the final sample must be recorded 
along with reason for use, dates of administration (including start and end dates) and 
dosage information (including dose and frequency).
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All medication administered to manage AEs should be recorded on the AE eCRF.
6.5.1
Permitted Therapy
The following medications will be permitted:

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 participant that should not be delayed. 
All therapy and/or medication administered to manage AEs should be recorded on 
the AE eCRF.

Hormone replacement therapy (HRT): permitted if initiated at least 2 months prior to 
study start.

Occasional use of acetaminophen (up to a maximum dose of 2 g/day up to 48 hours 
prior to dosing, not to exceed 4 g total during the week prior to dosing) will be 
permitted. 
6.5.2
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF.


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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), with the 
exception of medications listed in Section 6.5.1.
6.6
DOSE MODIFICATION
No dose modification of RO7049389 for safety reasons is expected in the study.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7049389 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal.
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study-specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed see the SoAs (Section 1.3).
Reasons for discontinuation of study treatment may include, but are not limited to, the 
following:

Participant withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may 
jeopardize the participant’s safety if he or she continues in the study.

Experiencing a serious or severe AE including but not limited to:
o
corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or 
increase in QTcF interval of >60 msec from baseline (confirmed following 
a repeat ECG) 
o
alanine aminotransferase (ALT) concentration >3 × the upper limit of the 
reference range (confirmed following a repeat ALT blood test)

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant.

Pregnancy.

Poor GI tolerability that is considered to affect the study participant’s well-being 
and/or the PK evaluation.


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
Evidence of current SARS-CoV-2 infection.
Every effort should be made to obtain information on participants who withdraw from the 
study but have not withdrawn consent. Participants who discontinue study treatment 
prematurely will be asked to return to the clinic for a study completion/early termination 
visit (see Section 8.9.3) and may undergo follow‑up assessments (see Section 8.9.4), 
unless the participant withdrew consent. The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. 
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determine, may jeopardize the 
participant’s safety if he/she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data.
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the absolute BA cohort of the study for other reasons 
may be replaced.
For data to be collected at the time of study discontinuation and at safety and follow-up 
calls, and for any further evaluations that need to be completed see SoAs (Section 1.3).
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant fails to return for the 
scheduled follow-up visit and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining the 


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assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant. These contact 
attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time points are summarized in the SoAs (Section 1.3). 
Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood counts) and obtained before signing of the Informed Consent Form (ICF) 
may be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time-frame defined in the SoA.
Emesis is not expected to occur; however, in the event that a participant spontaneously 
vomits within 6 hours after study drug administration in the MB cohort, the vomit will be 
collected and analyzed for radioactivity. 
At time points when several assessments coincide, the following sequence is suggested; 
at the discretion of the Investigator, the order can be adjusted to optimize site personnel 
and participant’s time management: 

Urine collection

Feces collection (MB cohort only)

ECG recordings

Vital signs

PK and safety blood sampling

Study treatment administration 
8.1
EFFICACY ASSESSMENTS
No efficacy assessments will be performed in this study.
8.2
SAFETY ASSESSMENTS
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Safety assessments will consist of monitoring and recording AEs, including serious 
adverse events (SAEs) and non-serious adverse events of special interest (NSAESI); 
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.
8.2.1
Physical Examinations
A complete physical examination should be performed at time points indicated in the 
SoAs (Section 1.3) and includes, at a minimum, assessments of the head, eyes, ears, 
nose, throat, neck and lymph nodes; and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, and neurological systems. 
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 participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the AE eCRF.
8.2.2
Vital Signs
Oral temperature, heart rate, and BP will be assessed.
BP and heart rate measurements will be assessed in a supine position for at least 
5 minutes with a completely automated device. Manual techniques will be used only if an 
automated device is not available. When possible, the same arm should be used for all 
BP measurements.
Vital signs (to be taken before blood collection for laboratory tests) will be measured in a 
supine position after at least 5 minutes rest and will include temperature, systolic and 
diastolic BP, and heart rate. Three readings of BP and heart rate will be taken
approximately 1 minute apart. The mean of three consecutive replicates will be used as 
the value for the defined time point to be recorded in the eCRF.
The acceptable deviations from the nominal vital signs measurement time points are:

The pre-dose vital signs measurements will be taken ≤2 hours before dosing.

Post-dose vital signs measurements will be taken ± 15 minutes from the nominal 
post-dose time points.

Discharge vital signs measurements will be taken ± 1 hour from the nominal time point.

For return visits, vital signs measurements will be taken ± 2 hours from the nominal 
return visit time point.


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8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoAs (see Section 1.3) using an 
ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QT 
corrected for HR (QTc) intervals. 
To minimize variability, it is important that participants be in a resting position for 
10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in HR. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement potentially
contributing to the ECG abnormality. 
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including HR, QRS duration, and PR, and QT intervals, will be 
recorded on the eCRF. QTcF (Fridericia’s correction) and RR interval (RR) will be 
calculated by the Sponsor. Changes in T-wave and U-wave morphology and overall 
ECG interpretation will be documented on the eCRF. T-wave information will be 
captured as normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
The acceptable deviations from the nominal ECG measurement time points are:

The pre-dose ECG measurements will be taken ≤2 hours before dosing

Post-dose ECG measurements will be taken ± 15 minutes from the nominal post-
dose time point.

Discharge ECG measurements will be taken ± 1 hour from the nominal time point. 

For return visits, ECG measurements will be taken ± 2 hours from the nominal return 
visit time point.
8.2.4
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the separate 
laboratory manual and the SoAs (Section 1.3).


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The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the case report 
form (CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those, which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant's condition.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified.
If laboratory values from non-protocol specified laboratory assessments performed at the 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (e.g., SAE or AE or dose-modification) then, the results 
must be recorded in the CRF.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety.
Where the clinical significance of abnormal laboratory results at screening is considered 
uncertain, screening laboratory tests may be repeated before admission to confirm 
eligibility.
If there is an alternative explanation for a positive urine or blood test for drugs of abuse 
(e.g., previous occasional intake of a medication or food containing for example, 
codeine, benzodiazepines or opiates), the test could be repeated to confirm washout.
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are:

The pre-dose blood sample will be taken ≤2 hours before dosing

Post-dose blood samples will be taken ± 1 hour from the nominal blood sampling 
time

The acceptable deviations from the nominal urine sampling time points for urinalysis 
are:


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
The pre-dose urine sample will be the first void of the day or a sample collected 
≤3 hours before dosing 

Post-dose urine samples will be taken ± 2 hours from the nominal urine sampling 
time.
8.2.5
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), 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 participant 
within 30 days prior to the screening visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.2.6
SARS-CoV-2 Tests (If Required)
Testing for the SARS-CoV-2 virus may be performed based on current infection rates 
and availability of tests. Tests will be performed according to the time schedule 
presented in Section 1.3. The samples will be collected and processed as detailed in the 
Screening Sample Processing Manual and Clinical Sample Processing Manual.
Testing time points may be changed and additional time points may be added 
throughout the study as required. The decision on COVID-19 testing and the definition of 
the testing time points will be agreed by the study team and documented in the ISF via 
the Clinical Kick-Off Meeting minutes.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The NSAESI are discussed 
in Sections 8.3.6.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity, and causality; see Appendix 2) are 
recorded on the AE eCRF and reported to the Sponsor in accordance with instructions 
provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3:
–
Diagnosis versus signs and symptoms:
-
Infusion reactions 
-
Other AEs

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values


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
Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Hospitalization or prolonged hospitalization
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the AE eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other AE should not be reported.
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until 28 days after the last dose of study treatment. 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period (28 days after the last dose 
of study treatment).
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all participant evaluation time points.


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8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow-up each AE until the event has resolved to baseline grade 
or better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the AE
eCRF and in the participant’s medical record to facilitate source data verification. If, after 
follow-up, return to baseline status or stabilization cannot be established, an explanation 
should be recorded on the AE eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow-up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event 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 
event.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded 
to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.


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For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, Investigators, IRB and EC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day, 7 days a week. Medical monitors contact details will be available on a 
separate list generated by the study management team.
8.3.5
Pregnancy
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 90 days after the final 
dose of study treatment.
Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 90 days after 
the final dose of study treatment.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest 
NSAESI are required to be reported by the Investigator to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Appendix 2 for reporting 
instructions).
NSAESI for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin 
or clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 


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infection in a participant exposed to a medicinal product. This term applies only
when a contamination of the study treatment is suspected.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental administration of a drug in a quantity that is 
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Sections 5 and 
5.2 of Appendix 2 for further details).
Decisions regarding dose-interruptions or modifications (if applicable) will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant.
In the event of an overdose, the Investigator should:
1. Contact the Sponsor’s Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3. Obtain a blood sample for PK analysis within 24 hours from the date of the final dose 
of study treatment, if requested by the Medical Monitor (determined on a case-by-
case basis).
4. Document the quantity of the excess dose, as well as the duration of the overdose, in 
the CRF.
For this study, any dose of RO7049389 greater than 1600 mg within a 24-hour time 
period (1.0 hour) will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose.
8.5
PHARMACOKINETICS
Mandatory blood and urine samples to evaluate concentrations of study treatment 
(RO7049389) and its metabolites (RO7121986, RO7255420, and/or RO7255422) will be 
collected. Mandatory blood, urine, and feces samples to measure the radioactivity and 
metabolic profiling will be also collected. The date and time of each sample collection will 
be recorded in the eCRF. The PK samples will be taken as outlined in the SoAs
(Section 1.3). 
A PK sample will also be collected following occurrence of a dose-limiting event or SAE.

Total radioactivity will be measured in plasma, whole blood, urine, and feces 
samples from MB cohort by liquid scintillation counting (LSC, Pharmaron, 
Hoddesdon EN11 9FH UK). Samples with low levels of radioactivity that cannot be 
quantified by LSC may be analyzed using AMS, if necessary.


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
Metabolic profiling will be conducted in plasma, urine, and feces and blood pellet (if 
appropriate). The metabolic profiling samples may not be assessed if there are 
insignificant levels of [14C]-radioactivity present. The best approach for the pooling 
strategy of metabolic profiling samples (e.g., urine, feces, plasma, and blood pellet) 
must be agreed upon between the clinical study site and the Sponsor prior to being 
performed. The results of the metabolic profiling analysis may be reported separately 
from the main clinical study report.

Concentrations of [12C] RO7049389, [12C] RO7121986, [12C] RO7255420 and 
[12C]-RO7255422 in plasma samples from both MB cohort and absolute BA cohort 
will be measured using a validated liquid chromatography–mass spectrometry (LC-
MS/MS) method by Q2 solution (Ithaca, NY 14850 USA).

Concentrations of [13C] RO7049389 and [13C] RO7121986 in plasma samples from 
both MB cohort and absolute BA cohort will be measured using a validated LC-
MS/MS method by Q2 solution (Ithaca, NY 14850 USA).

Concentrations of [12C] RO7049389, [12C] RO7121986, [12C] RO7255420 and [12C]
RO7255422 in urine samples from absolute BA cohort will be measured using a 
validated LC-MS/MS method by Q2 solution (Ithaca, NY 14850 USA).

Concentrations of RO7049389 other new identified metabolite(s) from absolute BA 
cohort as appropriate in plasma and urine samples may be measured using a 
validated LC-MS/MS method by Q2 solution (Ithaca, NY 14850 USA).
If required, remaining PK samples may also be used for assay development/validation 
experiments.
The PK blood samples will be destroyed 2 years after the date of final clinical study 
report (CSR), unless regulatory authorities require specimens to be maintained for a 
longer period. Details on sampling procedures, sample storage, and shipment are given 
in the Sample Handling Manual.
The acceptable deviations from the nominal blood sampling times are as follows:

The pre-dose samples will be taken ≤1 hour before dosing

0 to 1 hour post-dose samples will be taken within ± 2 minutes of the nominal post-
dose sampling time 

1.5 to 12 hours post-dose samples will be taken within ± 10 minutes of the nominal 
post-dose sampling time

24 hours to 264 hours post-dose samples will be taken within ± 30 minutes of the 
nominal post-dose sampling time.
8.6
PHARMACODYNAMICS AND BIOMARKERS ANALYSES
PD parameters are not evaluated in this study.


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8.6.1
Clinical Genotyping
The DNA will be used for, but analysis is not limited to:

 
Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to confidentiality standards described in Appendix 1.
8.7
PHARMACODYNAMICS AND BIOMARKER SAMPLES
No PD samples would be collected in this study.
A mandatory whole blood sample will be taken for DNA extraction from every participant. 
If the sample is missed on Day 1, it can be collected at any other scheduled visit.
The samples will be destroyed within 5 years after the date of final CSR, unless 
regulatory authorities require specimens to be maintained for a longer time period. 
Details on sampling procedures, sample storage, and shipment are given in the Sample 
Handling Manual.
8.8
HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
8.9
TIMING OF STUDY ASSESSMENTS
8.9.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. ICFs for enrolled 
participant and for participants who are not subsequently enrolled will be maintained at 
the study site.
All screening and pre-treatment assessments (related to entry criteria), must be 
completed and reviewed to confirm that participants meet all eligibility criteria. The 
Investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure.
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed within 28 days prior to 
Day 1, unless otherwise specified. 


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8.9.2
Assessments during Treatment
Under no circumstances, will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study.
All assessments must be performed as per the SoAs (Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the SoAs. 
8.9.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the last dose administration or discontinue from the study 
early will receive a follow-up call 293 days after the last dose of study treatment. The 
follow-up call will be reported as the study completion visit in eCRF.
In case of early termination of a participant, a blood sample for PK assessment of 
RO7049389 should be collected at the time of discontinuation. Please also see the SoAs
tables (Section 1.3) for activities that are required to be performed in case of an early 
termination.
8.9.4
Follow-Up Assessments
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3.
8.9.5
Assessments at Unscheduled Visits 
For activities that are required to be performed in case of an unscheduled visit, refer to 
the SoAs (Section 1.3).
9.
STATISTICAL CONSIDERATIONS
9.1
SAMPLE SIZE DETERMINATION
No formal sample size calculation has been performed. The sample size was 
determined by practical considerations and not based on statistical power calculations. 
A sample size of 6 healthy male participants for MB cohort was selected for practical 
purposes. Six participants are customary for this type of study, and should suffice to 
meet the objectives of the study while limiting the exposure of healthy male participants
to radiolabeled study drug. 
For the absolute BA cohort, the sample size of 16 participants (8 East Asian HVs and 
8 Caucasian HVs) was chosen to estimate the absolute BA of the 600 mg and 1000 mg 
single-dose with sufficient precision for each ethnic group. 
Participants prematurely discontinued from the absolute BA cohort of this study may be 
replaced to ensure adequate numbers of evaluable participants. Participants withdrawn 
for safety reasons will not be replaced.


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9.2
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 6.
Table 6
Analysis Populations
Population
Description
Safety
All participants who received at least one dose of the study 
treatment, whether prematurely withdrawn from the study or 
not, will be included in the safety analysis. 
Pharmacokinetic
All participants who have received at least one dose of study 
treatment and who have data from at least one post-dose 
sample will be included in the PK analysis population. 
Participants will be excluded from the PK analysis population if 
they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol, or if data are 
unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the 
reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure.
9.3
STATISTICAL ANALYSES
9.3.1
Demographics and Baseline Characteristics
Descriptive statistics will be used for demographic and baseline characteristics as 
applicable and will include sex, race (Asian and non-Asian), ethnicity, age, weight, height 
and BMI. For continuous variables, mean, standard deviation, median, and minimum
and maximum values will be presented. For categorical data, the proportion of 
participants in each category will be summarized。
9.3.2
Safety Analyses
All safety analyses will be based on the safety analysis population grouped according to 
cohort (see Table 7).


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Table 7
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results.
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events grading will be used to present shifts from 
baseline to the worst grade observed during treatment. For details on 
standard reference ranges, and data transformation and the definition of 
laboratory abnormalities, see Appendix 4.
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level.
Concomitant medications will be presented in summary tables and listings.
9.3.3
Pharmacokinetic Analyses 
Analyses will be carried out on the PK analysis population. 
Individual and mean plasma concentrations at each sampling time point for RO7049389 
and its metabolites (RO7121986, RO7255420, and RO7255422) as appropriate will be 
presented by listings and descriptive summary statistics, including means, geometric 
means, ranges, standard deviations, and coefficients of variation. Individual and mean 
concentration versus time will be plotted on semi-logarithmic scales. 
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 
period including means, geometric means, medians, ranges, standard deviations, and 
coefficients of variation. 
The main parameters of interest for the MB cohort are the recoveries of drug-related 
total radioactivity from urine and feces and its rate of elimination from plasma (and blood 
if appropriate). Data will be interpreted through inspection and descriptive analysis.
The following PK parameters were estimated if appropriate:


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Plasma PK parameters for non-radiolabeled drug and metabolites ([12C] and/or [13C] 
entities) and [14C] Total Radioactivity, if appropriate:

Cmax: the maximum observed plasma concentration

tmax: time to maximum observed plasma concentration time

t1/2: apparent terminal half life
AUC0-inf: the area under the plasma concentration versus time curve 
extrapolated to infinity
AUClast: the area under the plasma concentration-time curve from time 
zero to the last measurable plasma concentration time point (t)

CL/F: oral plasma clearance, 

CL: plasma clearance after IV dosing
V/F: apparent volume of distribution based on terminal phase 

Vss: volume of distribution at steady-state (calculated after IV dosing)

F: absolute BA
Absolute BA was calculated using dose-normalized geometric mean ratios and 90% 
confidence intervals (CIs) for AUC for oral versus IV dosing
In case AUC0-inf cannot be determined reliably, an appropriately truncated AUC may be 
used.
Urinary PK parameters for non-radiolabeled drug and metabolites [12C] entities and [14C] 
total radioactivity：

% of dose recovered as total [14C]-radioactivity

Ae: cumulative urinary amount of total [14C]-radioactivity
% of dose recovered for RO7049389 and its three metabolites from 
absolute BA cohort
Ae: cumulative urinary amount of RO7049389 and its metabolites from 
absolute BA cohort
CLr: renal clearance of RO7049389 and its metabolites from absolute BA 
study
Feces PK parameters for [14C] Total Radioactivity：

% of dose recovered as total [14C]-radioactivity
Additional PK parameters may be derived if deemed necessary.


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A population PK model analysis and a physiologically based PK model analysis may be 
performed. The results of those analyses will be reported in separated documents.
9.4
SUMMARIES OF CONDUCT OF STUDY
The number of participants who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study withdrawal will be listed and summarized by 
treatment period. Protocol deviations will be listed and evaluated for their potential 
impact on interpretation of study results. Study drug administration will be summarized 
by treatment period. Descriptive statistics will be used in evaluating the conduct of the 
study.
10.
REFERENCES
Administration of Radioactive Substances Advisory Committee. Notes for guidance on 
the clinical administration of radiopharmaceuticals and use of sealed radioactive 
sources. Administration of Radioactive Substances Advisory Committee. Nucl Med 
CommunSeptember 2020 (Suppl 21): S1–93.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines 
on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-98.
Investigator’s Brochure RO7049389.
ICRP, 1992. Radiological Protection in Biomedical Research. ICRP Publication 62. Ann. 
ICRP, Vol. 22 (3). 
World Health Organization. Use of ionising radiation and radionuclides on human beings 
for medical research, training and nonmedical purposes. Report of a WHO Expert 
Committee. World Health Organ Tech Rep Ser 1977;611:1–39.
World Health Organization. Hepatitis B [resource on the internet]. Fact Sheet N°204, 
[updated 20 July 2020; cited 02 December 2020]. Available from: 
http://www.who.int/mediacentre/factsheets/fs204/en/


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
The following section includes standard appendices such as:
Appendix 1 (For regulatory, ethical and study oversight considerations), 
Appendix 2 (For AE definitions, reporting), 
Appendix 3 (Procedures of recording), 
Appendix 4 (Clinical laboratory tests), 
Appendix 5 (Contraceptive guidance and collection of pregnancy information),
Appendix 6 (Cockcroft Gault Equation for Calculation CrCl).
Appendices are listed here below. Additional study-related appendices are in order of 
appearance in the protocol.


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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the United Kingdom (UK)
will comply with the Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031, the Medicines for Human Use (Clinical Trials) Amendment 
Regulations. Statutory Instruments 2006 No. 1928, the Medicines for Human Use 
(Clinical Trials) Amendment (No. 2) Regulations. Statutory Instruments 2006 No. 2984, 
the Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941.
1.2.
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the participant (e.g. 
advertisements, diaries, etc.), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix).
The Investigator should follow the requirements for reporting all adverse events (AEs) to 
the Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.
1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (ICF) (and ancillary sample ICFs such as 
a Child’s Assent or Caregiver's ICF, if applicable) will be provided to each site. If 


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applicable, it will be provided in a certified translation of the local language. Participants 
must be informed that their participation is voluntary. Participants will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
ICFs or any alternate consent forms proposed by the site (collectively, the “Consent 
Forms”) before IRB/EC submission. The final IRB/EC‑approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes according to local 
requirements. Participants must be re-consented to the most current version of the 
ICF(s) during their participation in the study. A copy of the ICF(s) signed by all parties 
must be provided to the participant 
The ICFs must be signed and dated by the participant before his or her participation in 
the study. The case history or clinical records for each participant shall document the 
informed consent process and that written informed consent was obtained prior to 
participation in the study.
The ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant to 
take part. The final revised IRB/EC-approved ICFs must be provided to the Sponsor for 
Health Authority submission purposes if required as per local regulations.
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant may be re-consented by signing the most 
current version of the ICFs or the addendum, in accordance with applicable laws and 
IRB/EC policy. For any updated or revised ICFs, the case history or clinical records for 
each participant shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the 
study. The study team will provide guidance for which participants need to re-consent in 
the event of an update to the ICF.
A copy of each signed ICF must be provided to the participant. All signed and dated 
ICFs must remain in each participant’s study file or in the site file and must be available 
for verification by study monitors at any time.
Participants who are re-screened are required to sign a new ICF.
1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 


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The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor and by inspectors from regulatory authorities.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
1.5.
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLO).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.


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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH Good Clinical Practice (GCP), and all applicable regulatory 
requirements.
2.1.2.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical study.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan or equivalent document.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 


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local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities.
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel.




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Study site will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met: 

A serious adverse reaction (ie a SAE considered at least possibly related to the IMP 
administration) in one subject.

Severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to the investigational medicinal product [IMP] administration) 
in two subjects in the same cohort, independent of within or not within the same 
system organ class.
Relatedness to IMP will be determined by the Investigator. 
If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment. The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC.
The Administration of Radioactive Substances Advisory Committee (ARSAC)
Practitioner will also be informed of the temporary halt.
Once exposure to dosing has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study. 

The occurrence of serious or severe AEs, as defined in Appendix 2 Section 2 and 
Section 3.1, if considered to be related to the IMP, as defined in Appendix 2 Section
3.2, on the dosing day.

New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for subjects participating in the study.

Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety.


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If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 2.3 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances,
termination can only take place with the agreement of the Investigator and Sponsor. The 
MHRA, EC, ARSAC practitioner and ARSAC will be informed of study termination.
If it becomes necessary to consider termination of the study on the dosing day, dosing 
may be suspended pending discussion between the Investigator, Sponsor and ARSAC 
practitioner (where discussion is related to administration of radiation). Dosing will be
stopped immediately on safety grounds.
The study may be terminated or suspended at the request of the MHRA or EC.


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Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse event (AE) is 
any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.
Events Meeting the AE Definition:

Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a 
change in study treatment or concomitant treatment or discontinuation from study 
treatment (see Appendix 3, Section 4).

Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

AEs 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).
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments, which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.


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2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A SAE is defined as any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.

The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event; it does not refer to 
an event, which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.

Results in persistent or significant disability/incapacity

Disability means substantial disruption of the participant’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.

Other significant events:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 


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dyscrasias, or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The Investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Medical Monitor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Medical Monitor.
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
ASSESSMENT OF SEVERITY
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing AE severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an AE (according to pre-defined Division of AIDS [DAIDS] criteria); the event itself may 
be of relatively minor medical significance (such as severe headache without any further 
findings).
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event.
The AE severity grading scale for the DAIDS (v2.1) will be used for assessing severity 
for AEs (see Table 1).


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Table 1
DAIDS Adverse Event Severity Grading Scale
Grade
Description
1
Mild; symptoms causing no or minimal interference with usual social and functional 
activities with intervention not indicated
2
Moderate; symptoms causing greater than minimal interference with usual social and
functional activities with intervention indicated
3
Severe; symptoms causing inability to perform usual social and functional activities with 
intervention or hospitalization indicated 
4
Potentially life-threatening; symptoms causing inability to perform basic self-care 
functions with intervention indicated to prevent permanent impairment, persistent 
disability, or death
5
Death
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to definition 
of a serious adverse event (see above). DAIDS v2.1 grading scale is available at: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
3.2.
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the study treatment, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
4.
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
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The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
5.
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

SAEs

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting SAEs to the local 
Health Authority and IRB/EC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL
INTEREST
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported. The SAE
Reporting Form provided to Investigators should be completed and submitted to the SAE
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Treatment Initiation
For reports of SAEs and NSAESI (Section 8.3.6) that occur after initiation of study 
treatment (Section 8.3.1), Investigators should record all case details that can be 


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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 SAE Responsible immediately (i.e., no more than 24 hours after 
learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other SAE occurring after the end of the AE 
reporting period, if the event is believed to be related to prior study treatment the event 
should be reported directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the SAE Reporting Form using the fax number or email address 
provided to Investigators.
5.2
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR
Accidental overdose and medication error are defined as follows:

Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of the 
drug.
Special situations are not in themselves AEs, but may result in AEs. Each AE associated 
with a special situation should be recorded separately on the AE eCRF. If the associated 
AE fulfills seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). For RO7049389, AEs 
associated with special situations should be recorded as described below for each 
situation:

Accidental overdose: Enter the AE term. Check the "Accidental overdose" and 
"Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the AE term. Check the 
"Medication error" box.

Medication error that qualifies as an overdose: Enter the AE term. Check the 
"Accidental overdose" and "Medication error" boxes. 


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In addition, all special situations associated with RO7049389, regardless of whether they 
result in an AE, should be recorded on the AE eCRF and should be recorded as 
described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication error" 
as the event term. Check the "Medication error" box. Enter a description of the error 
in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two AE eCRF pages, one to report the accidental overdose and one to 
report the headache. The "Accidental overdose" and "Medication error" boxes would 
need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and NSAESI against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators, IRBs, ECs, and applicable Health Authorities based on applicable 
legislation.
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events through use of the reference safety information in the 
document listed below:

RO7049389 IB
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
event (AEs) on the AE eCRF. Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the AE eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
1.1.
INFUSION REACTIONS
AEs considered to be infusion reactions that occur during or within 24 hours after study 
drug administration and are judged to be related to study treatment infusion should be 
captured as a diagnosis (e.g., infusion-related reaction, infusion site reaction or
"anaphylactic reaction") on the AE eCRF. If possible, avoid ambiguous terms such as 
“systemic reaction”. Associated signs and symptoms should be recorded on the 
dedicated Infusion Reaction eCRF. If a participant experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on 
the AE eCRF, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS 
For AEs other than infusion reactions (see Section 8.3), a diagnosis (if known) should be 
recorded on the AE 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 AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by one AE
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, AEs 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 AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the AE 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.


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
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 AEs should be recorded separately on the AE eCRF if it is unclear as to whether the 
events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time points. Such events should only be recorded once on the AE 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 AE eCRF should be updated to reflect this.
A recurrent AE is one that resolves between participant evaluation time points and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
AE eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be 
reported as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the AE eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the AE 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 


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characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE. 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 AE eCRF, unless the etiology changes. The 
initial severity of the event should be recorded, and the severity or seriousness should 
be updated any time the event worsens.
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported 
as an AE 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 AE.
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 AE eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF, unless the etiology changes. The 
initial severity of the event should be recorded, and the severity or seriousness should 
be updated any time the event worsens.
6.
ABNORMAL LIVER 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 AE the occurrence of either of the following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the AE eCRF (see Appendix 2) and reported to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event), either 
as an SAE or a non-serious adverse event of special interest (see Section 8.3.6).
7.
DEATHS
All deaths that occur during the protocol-specified AE reporting period (see Section 5 of 
Appendix 2), regardless of relationship to study treatment, must be recorded on the AE
eCRF and immediately reported to the Sponsor. 
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 AE eCRF. Generally, only one such event should be reported. If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the AE eCRF. If the cause of death later 
becomes available (e.g., after autopsy), “unexplained death” should be replaced by the 
established cause of death. The term "sudden death" should not be used unless 
combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the AE eCRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”).
9.
LACK OF EFFICACY OR WORSENING OF CONDITION BEING 
STUDIED 
Not applicable in this HV study.
10.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a SAE (per the definition of SAE in Appendix 2), except as outlined 
below.


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An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or a SAE:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration and intensive PK sampling).

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
o
The hospitalization was planned prior to the study or was scheduled during 
the study when elective surgery became necessary because of the expected 
normal progression of the disease.
o
The participant has not suffered an AE.
An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead:

Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting had an outpatient clinic been available.


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the local laboratory (The Doctors 
Laboratory, London, UK); the results must be captured in source documentation and 
entered into the eCRF.
The full contact details of the local laboratory:
The Doctors Laboratory
The Halo Building
1 Mabledon Place
London WC1H 9AX
Tel: + 44 (0)207 3077 404)
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.


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Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes), 
mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC),
mean corpuscular volume, and reticulocyte 
counts.
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose 
(fasting), urea, creatinine (creatinine clearance will 
be calculated at screening and Day 1 using the 
Cockcroft-Gault formula), protein, albumin, 
phosphate, calcium, total and direct bilirubin, 
alkaline phosphatase, ALT, AST, urate, creatine 
kinase, gamma glutamyl transferase, bile acid.
Coagulation

International normalized ratio (INR), activated 
partial thromboplastin time (aPTT), prothrombin 
time (PT).
Viral Serology

HIV (HIV-1 antibody and HIV-2 antibody, or HIV-
1/2 antibody), hepatitis A virus (HAV) IgM antibody, 
hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) ribonucleic acid (RNA), total hepatitis 
D virus (HDV) antibody, hepatitis E virus (HEV) 
IgM antibody.
Lipids

Cholesterol, low-density lipoproteins (LDL)
cholesterol, HDL cholesterol, triglycerides.
Hormone

Follicle-stimulating hormone (FSH) in females.
Pregnancy Test

All female participants will have a blood human 
chorionic gonadotropin (hCG) pregnancy test at 
screening. Urine pregnancy tests will be 
performed at specified subsequent visits. If a urine 
pregnancy test is positive, it must be confirmed by 
a blood pregnancy test.
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood, ketones, 
bilirubin, urobilinogen, nitrite, leukocytes

If there is a clinically significant positive result 
(e.g., 2+ or greater for blood, protein or 
leukocytes) confirmed by a positive repeated 
sample, urine will be sent to the laboratory for 
microscopy and/or microbiology, at the discretion 
of the Investigator. If there is an explanation for 
the positive dipstick results (e.g., menses), it 
should be recorded and there is no need to 
perform microscopy.

Microscopic examination: sediment, red blood cells 
(RBCs), white blood cells (WBCs), casts, crystals, 
epithelial cells, bacteria.
Other Screening Tests

Urine drug screen includes amphetamines, 
barbiturates, benzodiazepines, cocaine, 
marijuana/cannabis, methadone, 
methamphetamine/ecstasy, morphine/opiates, 
phencyclidine, tricyclic antidepressants.

Alcohol breath test.

SARS-CoV-2 Antibody and SARS-CoV-2 Antigen


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


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Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
f)
Pre-menarchal
g)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
h)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.
2.
CONTRACEPTION GUIDANCE

Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use two methods of contraception, with at least one method considered as highly 
effective during the study and for at least 90 days after the last dose of study drug.


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Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly as described in Table 1.
Table 1
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependenta
(Failure rate of 1% per year when used consistently and correctly)

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
Highly Effective Methods That Are User-Independent
(Failure rate of 1% per year)

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion/ligation
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective
(Failure rate of 1% per year when used consistently and correctly)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
primary mode of action

Male or female condom with or without spermicide b

Cap, diaphragm, or sponge with spermicide b


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a)
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.
b)
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely.
3.
PREGNANCY TESTING
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice.
4.
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.


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
Female participants who become pregnant
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Appendix 2. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.
5
ABORTIONS
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the AE eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as SAE, recorded on the AE eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5 of Appendix 2).
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant exposed to study treatment should be classified as a SAE, 
recorded on the AE eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Appendix 3, Section 5.1).


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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