Clinical trial NCT03530917
Conditions: Healthy Participants
Sponsor: Hoffmann-La Roche
Start date: 2018-05-15; Completion date: 2019-05-15
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To evaluate the safety and tolerability of single and multiple ascending doses of oral RO7020531 in Chinese healthy participants.

Detailed description:

Arms: arm 1: In SAD Cohorts 1-4, there will be eight participants in total receiving placebo, two in each cohort. arm 2: Eight participants will be administered 40mg RO7020531 orally on Day 1. arm 3: Eight participants will be administered 100mg RO7020531 orally on Day 1. arm 4: Eight participants will be administered 140mg RO7020531 orally on Day 1. arm 5: Eight participants will be administered 170mg RO7020531 orally on Day 1. arm 6: In MAD Cohorts 1-3, there will be six participants in total receiving placebo, two in each cohort. arm 7: Eight participants will be administered 100mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days. arm 8: Sixteen participants will be administered 150mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days.
Interventions: intervention 1: RO7020531 intervention 2: Placebo
Intervention descriptions: intervention 1: 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above. intervention 2: Placebo hard capsules will be administered orally as per the dosing schedules described above.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR-BLINDED, 
SUBJECT-BLINDED, PLACEBO-CONTROLLED, SINGLE AND 
MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF RO7020531 AND METABOLITES 
FOLLOWING ORAL ADMINISTRATION TO CHINESE HEALTHY 
VOLUNTEERS 
NCT Number: 
NCT03530917 
Document Date: 
Protocol Version 2: 18 November 2017 
 
 
 


CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F.Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an Investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7020531 —F. Hoffmann-La Roche Ltd
Protocol YP39553, Version 2
PROTOCOL
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
INVESTIGATOR-BLINDED, SUBJECT-BLINDED, 
PLACEBO-CONTROLLED, SINGLE AND MULTIPLE 
ASCENDING DOSE STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF RO7020531 AND 
METABOLITES FOLLOWING ORAL 
ADMINISTRATION TO CHINESE HEALTHY 
VOLUNTEERS
PROTOCOL NUMBER:
YP39553
VERSION:
2
TEST PRODUCT:
RO7020531
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 07 April 2017
DATE AMENDED:
Version 2: See electronic date stamp below
FINAL PROTOCOL APPROVAL
 
18-Nov-2017 06:26:39
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7020531 —F. Hoffmann-La Roche Ltd
2/Protocol YP39553, Version 2
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, SPONSOR-OPEN, 
INVESTIGATOR-BLINDED, SUBJECT-BLINDED, 
PLACEBO-CONTROLLED, SINGLE AND MULTIPLE 
ASCENDING DOSE STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS  
AND PHARMACODYNAMICS OF RO7020531 AND 
METABOLITES FOLLOWING ORAL 
ADMINISTRATION TO CHINESE HEALTHY 
VOLUNTEERS
PROTOCOL NUMBER:
YP39553
VERSION NUMBER:
2
TEST PRODUCT:
RO7020531
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local Study Monitor.


RO7020531 —F. Hoffmann-La Roche Ltd
3/Protocol YP39553, Version 2
PROTOCOL AMENDMENT, VERSION 2
RATIONALE
Protocol YP39553 has been amended to incorporate the following changes: 

The dose sequence in the single ascending dose (SAD) portion of the study 
has been modified based on availability of new safety, pharmacokinetic, and 
pharmacodynamic (PD) data in the ongoing entry-in-human (EIH) study
NP39305 (Sections 3.1.1, 3.1.1.1, 3.1.2, 3.2.1, 4.4.1.1, and 4.4.2.1). 
The newly available data in NP39305 indicated very good safety and tolerability with 
single RO7020531 doses up to 170 mg and PD effects documented only from
doses100 mg. The starting dose in this study was modified from 10 mg to 40 mg.
This is expected to avoid very low doses/exposures that may not produce PD 
effects, while ensuring appropriate safety margins expected with the first dose. A 
planned dose escalation sequence of the SAD cohorts is anticipated to be 40 mg, 
100 mg, and 140 mg and 170 mg. This sequence is based on the global EIH study 
results and ranges from one inactive dose through safe doses found to have PD 
activity.

The protocol text and reference to the Investigator’s Brochure have been 
updated to incorporate new clinical safety, pharmacokinetic, and 
pharmacodynamic information from the ongoing study NP39305 (Sections 
1.2.1, 1.2.2, and 10).

Pharmacodynamic outcome measures (e.g., ISG15, OAS-1, MX1 and TLR7) 
have been added to evaluate markers of transcriptional responses to improve 
dose selection for the MAD part of the study (Section 1.3.1, 3.1.1.2, 3.2.4, 3.3.3, 
and 4.6.1.7, and 6.7 and Appendices 1-4).
The determination of TLR7 response by measuring various markers including ISG15, 
OAS-1, MX1 and TLR7 at the transcriptional level (mRNA determinations) has been 
shown to be a sensitive method to demonstrate TLR7- dependent response in the 
NP39305 study.  In that study, higher level of response was noted for changes in 
the transcriptional markers than for the cytokines or neopterin at the 100 mg dose.  
This enabled clear determination of suitable doses for evaluation in the MAD portion 
of that study and it is anticipated will better enable dose selection in YP39553. 
The PD activity in the SAD part, including changes in the expression of the 
interferon response genes, will be used to help choose the starting dose in the MAD 
part of the study.
Additional minor changes have been made to correct typographical errors and to 
improve clarity and consistency. Substantial new information appears in italics. This 
amendment represents cumulative changes to the original protocol.


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4/Protocol YP39553, Version 2
PROTOCOL AMENDMENT, VERSION 2:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
1.2.1
Previous Non-Clinical Studies
[…] 
No genotoxic potential was observed for RO7020531 in the Ames test, nor in the in vitro 
and in vivo micronucleus test. No evidence of teratogenicity or embryo-fetal toxicity was 
observed in definitive (GLP) embryo-fetal toxicity studies in rats (up to 150 mg/kg/day) or 
rabbits (up to 100 mg/kg/day), other than increased incidences of non-adverse fetal 
skeletal variations. In a definitive (GLP) fertility study in rats, no adverse effects of 
RO7011785 on mating performance, fertility, or early embryonic development were 
noted (up to 300 mg/kg, every other day [QOD]), despite slightly reduced body weight 
gain. See the RO7020531 Investigator’s Brochure IB and RO7020531 IB Addendum for 
details on the properties of RO7020531 and RO7011785.
1.2.2
Previous Clinical Studies
A global entry-into-human (EIH) study (NP39305) is ongoing, where RO7020531 is 
being evaluated in healthy volunteers in single ascending doses (SAD) and multiple 
ascending doses (MAD) and subsequently will be evaluated in virologically suppressed 
CHB patients. The first two cohorts (3 and 10 mg) have been completed and these 
doses were considered safe and well tolerated. The dose escalation is ongoing.
As of 1 October, 2017, 80 healthy volunteers (HVs; 64 males and 16 females) have been 
dosed with RO7020531/placebo in eight SAD cohorts. All dose levels (3 mg, 10 mg, 20 
mg, 40 mg, 60 mg, 100 mg, 140 mg and 170 mg) were considered safe and well 
tolerated. There had been few adverse events (AEs) per cohort, all were reported as of 
mild intensity, and only three subjects (two in the second cohort [10mg] and one in the 
170 mg cohort) had AEs that were considered “related” to study drug. No serious 
adverse events (SAEs) or discontinuations due to AEs had been reported; and there 
were no dose related trends in nature, incidence or severity of AEs. In addition, there 
have been no clinically significant changes (or trends) in ECG parameters, vital signs, 
or laboratory safety test results in any subjects.
The main active metabolite, RO7011785, exposure (AUC0-inf ) values increased 
proportionally with dose and was consistent with values predicted for humans from 
preclinical pharmacokinetics (PK) models. PD biomarkers did not have significant 
changes after single doses up to 60 mg in SAD Cohorts 1-5. Three out of eight subjects 


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5/Protocol YP39553, Version 2
in SAD Cohort 6 who received a single RO7020531 dose of 100 mg exhibited changes in 
interferon alpha indicative of TLR7 activation. Two of these subjects exhibited 
increased activity for IP10 and neopterin.  The fraction of subjects responding as well 
as the amplitude of the response increased at the 140 mg dose.  Changes in mRNA 
levels for ISG15, OAS-1, MX1 and TLR7 initially found at the 100 mg dose were 
amplified at the 140 mg dose.
1.3.1
Study Rationale
[…]
Evidence for TLR activation in the SAD and MAD studies will be provided by measuring 
post-dose changes in selectselected biomarkers including the protein and metabolite 
markers IFN-, IP-10, TNF-, IL-6, IL-10, IL-12p40 and neopterin, and markers of 
transcriptional responses (ISG15, OAS-1, MX1 and TLR7), known to be stimulated by 
activation of TLR7 and/or TLR8.
3.1.1
Overview of Study Design
For both SAD and MAD parts of the study, each cohort will enroll ten subjects, with eight 
subjects randomly assigned to RO7020531 and two subjects randomly assigned to 
placebo (Table 1). Each cohort will include a minimum of two females, with at least one 
female receiving active drug. All single and multiple doses will be administered in the 
fasted state.
Table 1 Study Cohorts
Cohort
Stage
Dose (mg)a
Total Doses 
Administered
Route
Planned Number of 
Healthy Volunteers
Active Drug
Placebo
1
SAD
1040
1
PO
8
2
2
SAD
30100
1
PO
8
2
3
SAD
90140
1
PO
8
2
4
SAD
TBDb170b
1
PO
8
2
1
MAD
TBD
7 QOD
PO
8
2
2
MAD
TBD
7 QOD
PO
8
2
SAD =single ascending doses; MAD=multiple ascending doses; TBD = to be determined; 
QOD= every other day.
a.
Proposed doses, which will be refined based on PK, safety and tolerability found in the 
global EIH study NP39305 and/or in the previous cohorts in the current study YP39553;
b.
Optional cohort.
Additional cohorts may be explored in the SAD and MAD part as required.


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3.1.1.1
Single Ascending Dose Study
For dose escalation, subjects will be sequentially enrolled into approximately four to six 
dose cohorts that may range between 1040 mg and 180170 mg, the maximum dose 
proposed in the global EIH study, NP39305. Based on the newly available data in 
NP39305 indicating very good safety and tolerability with single RO7020531 doses up 
to 170 mg and PD effects documented only with doses ≥100 mg, the starting dose in 
this study was selected to be 40 mg, which is expected to avoid very low 
doses/exposures that may not produce pharmacodynamic effects, while ensuring 
appropriate safety margins expected with the first dose (See Section 3.2.1).
The anticipated ascending dose scheme in the first three SAD cohorts is 1040 mg, 
30100 mg 140 mg and 90170 mg. Additional cohorts may be added within a dose range 
between 10 mg and 180170 mg (Figure 1). As an additional safety precaution in this 
study, the subjects participating in each single dose cohort will be dosed according to a 
sentinel dosing design. Initially, two subjects will be dosed: one subject with RO7020531 
and one subject with placebo. If the safety and tolerability results from the first 24 hours 
following dosing for the initial subjects are acceptable to the Investigator, the remaining 
subjects of each cohort may be dosed soon after.
[…]
3.1.1.2
Multiple Ascending Dose Study
The trigger to start the first cohort in the MAD includes documentation of adequate 
safety and tolerability in the SAD cohorts and evidence of PD effects. For a given dose 
evaluated in the SAD, evidence in at least two subjects exhibiting responses above 
placebo-defined baseline for select PD biomarkers, including the protein and metabolite 
markers IFN-, IP-10, TNF-, IL-6, IL-10, IL-12p40 orand neopterin, and markers of 
transcriptional responses (ISG15, OAS-1, MX1 and TLR7), should be demonstrated. If 
the next dose in the SAD has been considered safe, then the previous dose 
demonstrating TLR-associated PD activity will be considered as the starting dose for the 
MAD. In addition, the starting dose/exposure in the MAD part of this study should have 
been considered safe in the global EIH study (NP39305). Only doses covered by the 
dose range evaluated in the SAD part will be used in the MAD, and two to three dose 
levels will be evaluated (Figure 1).
[…]




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8/Protocol YP39553, Version 2 
[…] 
3.2.1 
Rationale for Dosage Selection and Dosage Regimen 
The dose selection for this study is supported by the non-clinical safety data and may be 
modified based on the clinical data collected from the global EIH study, NP39305. The 
current study in Chinese healthy volunteers (YP39553) is planned to consist of four to 
six dose levels in SAD and two to three dose levels in MAD, which will be within the 
dose-range considered to be safe and with acceptable tolerability in the global EIH study, 
NP39305.  
Based on the non-clinical data with RO7020531 (see Section 1.2.1), the half-life of the 
active TLR7 agonist RO7011785 is relatively short. However, previous experience in 
monkeys and humans with another TLR7 agonist (RO6864018) indicate that a short 
exposure of the TLR7 agonist initiates a series of pharmacodynamic events with 
biomarker activity that peaks as late as 48 hours post dose. Similar results are 
anticipated following dosing with RO7020531 and are supported by activity measured in 
non-clinical models. 
In the ongoing global EIH study (NP39305), all dose levels tested in SAD (3 mg – 170 
mg) have been observed to be safe and well tolerated. In SAD Cohort 6 (100 mg),  3/8 
healthy volunteers demonstrated increases in interferon alpha and which met the 
predefined criteria for TLR7 marker activity.  
The starting dose of 10 40 mg was selected for the SAD portion of this study in Chinese 
patients based on the safety and tolerability documented in the study NP39305, avoiding 
very low doses/exposures that may not produce pharmacodynamic effects, while 
ensuring appropriate safety margins expected with the first dose.  
[…] 
3.2.4 
Rationale for Pharmacodynamic Assessments 
TLR7 is expressed on human pDC and B-cells, and its activation induces both humoral 
and cellular changes (Iwasaki and Medzhitov 2004, Lester and Li 2014). These changes 
include the production of cytokines and chemokines such as IFN-, IP-10, TNF-, IL-6, 
IL-10, IL-12p40 and changes in the expression of ISGs, e.g., ISG15, OAS-1 and 
myxovirus resistance 1 gene (MX1) and of the TLR7 gene itself (Fidock et al 2011), as 
well as changes in markers of immune stimulation such as neopterin.   
To capture the immunomodulatory effects of TLR7 agonism, cytokines,  and chemokines 
and peripheral blood gene expression will be measured at time-points outlined in the SoA 
(Appendix 1, Appendix 2, Appendix 3 and Appendix 4). These markers showed a 
dose-dependent PD profile with other TLR7 agonists when assessed in patients and 


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9/Protocol YP39553, Version 2
healthy volunteers. The PD activity signature in the SAD part of the study will be used 
to help choose the starting dose in the MAD part of the study. 
In previous healthy volunteer clinical studies, IFN-, neopterin, IL10 and IP-10 were 
activated with another TLR7-selective agonist, RO6864018 and no activation of the 
TLR8 markers, IL-6 and TNF-was seen. Thus, in the current study, any activation of 
IL-6 and TNF-may be indicative of activation of TLR8.
3.3.3
Pharmacodynamic Outcome Measures
The PD outcome measures for this study are as follows:

Blood samples will be collected to evaluate a number of PD outcome measures 
including the protein and metabolite markers of humoral response:(: IFN-, IP-10, 
TNF-, IL-6, IL-10, IL-12p40 and neopterin) and markers of transcriptional 
responses (ISG15, OAS-1, MX1 and TLR7).
4.4.1
Formulation, Packaging, and Handling
4.4.1.1
RO7020531 and Placebo
RO7020531 and placebo will be supplied by Roche.
Investigational Medicinal Product (IMP): Hard gelatin capsule for oral administration 
containing 1 mg, 10 mg, or 100 mg of RO7020531 drug substance.
[…]
4.4.2
Dosage, Administration and Compliance
4.4.2.1
RO7020531 and Placebo
Both RO7020531 and placebo will be administered orally in capsules.
In the SAD cohorts, RO7020531 or matching-placebo will be administered orally to the 
subjects by investigational staff on the morning of Day 1 after an overnight fast of at 
least 10 hours. Subjects in the SAD cohorts will not eat for 4 hours after the dose is 
administered. Water will be allowed ad libitum until one hour prior to dosing and after 
one hour post-dosing. Approximately 4 hours after dosing, subjects will be given lunch. 
The SAD part of the study will include an adaptive number of cohorts (approximately 
four). Each dose cohort will include 10 subjects (eight active and two placebo). AThe 
planned dose-escalation sequence for SAD is 10 mg, 30 mg and 90 mg. The actual 
doseshown in Cohort 4 will be determined based on data collected in the global EIH 
study and/or from the previous cohorts in the current study, but will be maximally 
180 mg.Table 1. 


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10/Protocol YP39553, Version 2
The starting doseDoses of 10 mg RO7020531 will be administered as one 10 mg capsule. 
All other doses in SAD and MAD cohorts will be administered as a combination of 1 mg,
10 mg or 100 mg capsules with the requisite number of capsules being administered per 
specific dose cohort. Should an intermediate dose be required due to a change in the 
anticipated dose-escalation, the dose will be composed of the appropriate combination 
of 1 mg, 10 mg and 100 mg capsules.
In the MAD cohorts, RO7020531 or matching-placebo will be administered orally to the 
subjects by investigational staff QOD from Day 1 through to Day 13. In total, seven 
doses will be given (for time-points see Appendix 3 and Appendix 4). Each dose will be 
given in a fasted state (after an overnight fast of at least 10 hours). Subjects will not eat 
for 4 hours after each dose is administered. Water will be allowed ad libitum until one 
hour prior to dosing and after one hour post-dosing. The MAD part of the study will
include an adaptive number of cohorts (two to three). Each dose cohort will include ten 
subjects (eight active and two placebo). Dose levels for MAD will be defined during the 
study conduct based on emerging data. (See Table 1).
Doses will be given orally with 240 mL of water. Additional amounts of water up to 
100 mL could be given to assist dose administration only if needed. 
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose according to the randomization schedule. This individual will write the date 
dispensed and subject number and initials on the study drug vial label and on the Drug 
Accountability Record. This individual will also record the study drug batch or lot number 
received by each subject during the study. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 4.7.
4.5.3
Dietary and Special Requirements
There are data suggesting that concentrated green tea (including bottled green tea 
beverages) may inhibit aldehyde oxidase (Tayama et al 2011). Therefore, subjects 
should minimize the amount of bottled green tea beverages and other green tea 
preparations they drink from Day 7 until the follow-up visit at Day 8.
Subjects must fast overnight (at least 10 hours) before the dosing and must not eat for 
4 hours after the dose is administered. Approximately 4 hours after dosing, subjects will 
be administered lunch. Meals will be similar in composition and time of administration 
across all SAD/MAD cohorts.
[…]


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4.6.1.7
Pharmacodynamic Assessments
Blood samples will be collected to evaluate a number of PD parameters including the 
protein and metabolite markers of humoral response:(: IFN-, IP-10, TNF-, IL-6, IL-10, 
IL-12p40, and neopterin.). and markers of transcriptional responses (ISG15, OAS-1, 
MX1 and TLR7).
6.1 Determination of Sample Size
Approximately fourFour to six cohorts may be evaluated in the SAD part of the study 
(approximately 40-60 subjects in total), and approximatelytwo to three cohorts are 
anticipated for the MAD part of the study with approximately 20-30 subjects in total.
Ten healthy volunteers are planned to be enrolled at each dose level. They will be 
randomized to either active treatment (eight healthy volunteers per dose level) or 
placebo (two healthy volunteers per dose level). With eight healthy volunteers per dose 
group or cohorts, there is a 90% chance to observe at least one AE that has an 
incidence rate of 25% in the population.
6.7 Pharmacodynamic Analyses
Summary descriptive statistics will be presented for the induction of cytokines, 
chemokines, and neopterin and of interferon-response genes separately by treatment 
arm. Exploratory analysis will be performed to assess the TLR7 agonist induced 
response under different dosing conditions. Graphical and statistical techniques 
including linear, non-linear, and logistic regression will be used to explore potential 
relationships between dosing regimen, PK and PD.
10. References
[…]
Fattovich G, Giustina G, Sanchez-Tapias J. Delayed clearance of serum HBsAg in 
compensated cirrhosis B: relation to interferon alpha therapy and disease 
prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J 
Gastroenterol. 1998;93:896-900.
Fidock MD, Souberbielle BE, Laxton C. The innate immune response, clinical outcomes, 
and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin 
Pharmacol Ther. 2011;89:821-829.
Funk E, Kottilil S, Gilliam B. Tickling the TLR7 to cure viral hepatitis. J Transl Med. 
2014;12:129.
Gane EJ, Lim YS, Gordon SC, et al. The oral toll-like receptor-7 agonist GS-9620 in 
patients with chronic hepatitis B virus infection. J of Hepatology. 2015; 63: 320–
328.


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Grippo J, Folitar I, van de Wetering de Rooij J, et al. Optimization of a Phase 2 Study 
Design in Chronic Hepatitis B (CHB) Patients Based on Safety, Pharmacokinetics 
(PK) and Pharmacodynamics (PD) from Phase 1 Studies Using Two Prodrugs of a 
Toll-like Receptor 7 (TLR7) Agonist. 2016; AASLD Abstract nr. 1869.
Horscroft NJ, Pryde DC, Bright H. Antiviral applications of toll-like receptor agonists. J 
Antimicrob Chemother. 2012;67:789-801.
Investigator’s Brochure, RO7020531. First version, September 2016.
Investigator’s Brochure, RO7020531. Addendum 1, March 2017 (First version, 
September 2016).
[…]
Appendices 1 – 4
Appendices and footnotes have been updated to reflect changes to the protocol.


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 19
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 27
1.
BACKGROUND AND RATIONALE ............................................................ 30
1.1
Background on Disease......................................................... 30
1.2
Background on RO7020531 .................................................. 31
1.2.1
Previous Non-Clinical Studies ............................................... 32
1.2.2
Previous Clinical Studies ....................................................... 34
1.3
Study Rationale and Benefit–Risk Assessment..................... 34
1.3.1
Study Rationale ..................................................................... 34
1.3.2
Benefit-Risk Assessment....................................................... 35
2.
OBJECTIVES.............................................................................................. 35
2.1
Primary Objectives ................................................................ 35
2.2
Secondary Objectives............................................................ 36
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of Study .............................................................. 36
3.1.1
Overview of Study Design ..................................................... 36
3.1.1.1
Single Ascending Dose Study ............................................... 37
3.1.1.2
Multiple Ascending Dose Study............................................. 38
3.1.2
Dose Escalation Decision Criteria ......................................... 39
3.1.3
Treatment Stopping Rules..................................................... 40
3.1.4
Length of Study ..................................................................... 41
3.1.5
End of Study.......................................................................... 41
3.2
Rationale for Study Design.................................................... 41
3.2.1
Rationale for Dosage Selection and Dosage 
Regimen ................................................................................ 41
3.2.2
Rationale for Study Population .............................................. 42
3.2.3
Rationale for Pharmacokinetic Assessments......................... 43
3.2.4
Rationale for Pharmacodynamic Assessments ..................... 44
3.2.5
Rationale for Clinical Genotyping .......................................... 44


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3.3
Outcome Measures ............................................................... 44
3.3.1
Safety Outcome Measures .................................................... 44
3.3.2
Pharmacokinetic Outcome Measures.................................... 45
3.3.3
Pharmacodynamic Outcome Measures................................. 45
3.3.4
Clinical Genotyping Outcome Measures................................ 45
4.
MATERIALS AND METHODS .................................................................... 45
4.1
Center.................................................................................... 45
4.2
Study Population ................................................................... 45
4.2.1
Recruitment Procedures........................................................ 46
4.2.2
Inclusion Criteria.................................................................... 46
4.2.3
Exclusion Criteria................................................................... 47
4.3
Method of Treatment Assignment and Blinding..................... 49
4.4
Study Treatment.................................................................... 51
4.4.1
Formulation, Packaging, and Handling.................................. 51
4.4.1.1
RO7020531 and Placebo ...................................................... 51
4.4.2
Dosage, Administration and Compliance............................... 51
4.4.2.1
RO7020531 and Placebo ...................................................... 51
4.4.3
Investigational Medicinal Product Accountability ................... 52
4.5
Concomitant Therapy, Dietary and Special 
 Requirements....................................................................... 53
4.5.1
Permitted Therapy................................................................. 53
4.5.2
Prohibited Therapy ................................................................ 54
4.5.3
Dietary and Special Requirements ........................................ 54
4.6
Study Assessments ............................................................... 55
4.6.1
Description of Study Assessments ........................................ 55
4.6.1.1
Medical History and Demographic Data ................................ 55
4.6.1.2
Physical Examinations........................................................... 55
4.6.1.3
Vital Signs.............................................................................. 56
4.6.1.4
Electrocardiograms................................................................ 56
4.6.1.5
Laboratory Assessments ....................................................... 57
4.6.1.6
Pharmacokinetic Assessments.............................................. 58
4.6.1.7
Pharmacodynamic Assessments........................................... 59
4.6.1.8
Clinical Genotyping................................................................ 59


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4.6.2
Timing of Study Assessments ............................................... 60
4.6.2.1
Screening and Pretreatment Assessments............................ 60
4.6.2.2
Assessments during Treatment............................................. 60
4.6.2.3
Follow Up Assessments ........................................................ 60
4.6.2.4
Assessments at Unscheduled Visits...................................... 60
4.7
Healthy Volunteer, Study, and Site 
Discontinuation...................................................................... 61
4.7.1
Healthy Volunteer Discontinuation......................................... 61
4.7.1.1
Discontinuation from Study Drug during MAD ....................... 61
4.7.1.2
Withdrawal from Study........................................................... 61
4.7.2
Study and Site Discontinuation.............................................. 62
5.
ASSESSMENT OF SAFETY....................................................................... 62
5.1
Safety Parameters and Definitions ........................................ 62
5.1.1
Adverse Events ..................................................................... 63
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 63
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 64
5.2
Safety Plan ............................................................................ 64
5.2.1
Management of Specific Adverse Events .............................. 64
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 65
5.3.1
Adverse Event Reporting Period ........................................... 65
5.3.2
Eliciting Adverse Event Information....................................... 65
5.3.3
Assessment of Severity of Adverse Events ........................... 65
5.3.4
Assessment of Causality of Adverse Events ......................... 66
5.3.5
Procedures for Recording Adverse Events............................ 66
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 66
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 67
5.3.5.3
Persistent or Recurrent Adverse Events................................ 67
5.3.5.4
Abnormal Laboratory Values ................................................. 67
5.3.5.5
Abnormal Vital Sign Values ................................................... 68
5.3.5.6
Abnormal Liver Function Tests.............................................. 69


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5.3.5.7
Deaths ................................................................................... 69
5.3.5.8
Preexisting Medical Conditions.............................................. 69
5.3.5.9
Hospitalization or Prolonged Hospitalization.......................... 70
5.3.5.10
Overdoses ............................................................................. 70
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 70
5.4.1
Emergency Medical Contacts................................................ 71
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 71
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 71
5.4.2.2
Events That Occur after Study Drug Initiation........................ 71
5.4.3
Reporting Requirements for Pregnancies.............................. 72
5.4.3.1
Pregnancies in Female Healthy Volunteers........................... 72
5.4.3.2
Pregnancies in Female Partners of Male Healthy 
Volunteer ............................................................................... 72
5.4.3.3
Abortions ............................................................................... 72
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 73
5.5
Follow-Up of Subjects after Adverse Events.......................... 73
5.5.1
Investigator Follow-Up........................................................... 73
5.5.2
Sponsor Follow-Up ................................................................ 73
5.6
Post-Study Adverse Events................................................... 73
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 74
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 74
6.1
Determination of Sample Size ............................................... 74
6.2
Summaries of Conduct of Study............................................ 74
6.3
Analysis Populations ............................................................. 75
6.3.1
Safety Analysis Population .................................................... 75
6.3.2
Pharmacokinetic Analysis Population.................................... 75
6.3.3
Pharmacodynamic Analysis Population................................. 75
6.3.4
Clinical Genotyping Analysis Population................................ 75
6.4
Summaries of Treatment Group Comparability ..................... 75


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6.5
Safety Analyses..................................................................... 75
6.5.1
Adverse Events ..................................................................... 75
6.5.2
Clinical Laboratory Test Results............................................ 75
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 76
6.5.2.2
Definition of Laboratory Abnormalities................................... 76
6.5.3
Vital Signs.............................................................................. 76
6.5.4
ECG Data Analysis................................................................ 76
6.5.5
Concomitant Medications ...................................................... 77
6.6
Pharmacokinetic Analyses..................................................... 77
6.7
Pharmacodynamic Analyses ................................................. 77
6.8
Clinical Genotyping Analyses ................................................ 78
6.9
Interim Analyses .................................................................... 78
7.
DATA COLLECTION AND MANAGEMENT ............................................... 78
7.1
Data Quality Assurance......................................................... 78
7.2
Electronic Case Report Forms............................................... 78
7.3
Source Data Documentation.................................................. 79
7.4
Use of Computerized Systems .............................................. 79
7.5
Retention of Records............................................................. 79
8.
ETHICAL CONSIDERATIONS.................................................................... 80
8.1
Compliance with Laws and Regulations ................................ 80
8.2
Informed Consent.................................................................. 80
8.3
Institutional Review Board or Ethics Committee.................... 81
8.4
Confidentiality........................................................................ 81
8.5
Financial Disclosure .............................................................. 82
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 82
9.1
Study Documentation ............................................................ 82
9.2
Site Inspections ..................................................................... 82
9.3
Administrative Structure......................................................... 82
9.4
Publication of Data and Protection of Trade 
Secrets .................................................................................. 82
9.5
Protocol Amendments ........................................................... 83


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10. REFERENCES ........................................................................................... 84
LIST OF TABLES
Table 1
Study Cohorts ............................................................................. 37
Table 2
Adverse Event Severity Grading Scale ....................................... 66
LIST OF FIGURES
Figure 1
Study Design............................................................................... 39
LIST OF APPENDICES
Appendix 1
Schedule of Assessments: SAD ................................................. 87
Appendix 2
Schedule of Assessments: SAD Detailed ................................... 89
Appendix 3
Schedule of Assessments: MAD................................................. 91
Appendix 4
Schedule of Assessments: MAD Detailed................................... 93
Appendix 5
Formula for Calculation of BMI.................................................... 95
Appendix 6
Correction Formulas for QTc Intervals ........................................ 96
Appendix 7
Cockcroft-Gault Equation for Calculation CrCl............................ 97
Appendix 8
Alcohol Volume Calculation ........................................................ 98


RO7020531—F. Hoffmann-La Roche Ltd
19/Protocol YP39553, Version 2
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR-BLINDED, 
SUBJECT-BLINDED, PLACEBO-CONTROLLED, SINGLE AND 
MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS  AND 
PHARMACODYNAMICS OF RO7020531 AND METABOLITES 
FOLLOWING ORAL ADMINISTRATION TO CHINESE HEALTHY 
VOLUNTEERS
PROTOCOL NUMBER:
YP39553
VERSION:
2
TEST PRODUCT:
RO7020531
PHASE:
I
SPONSOR:
F. Hoffmann-La Roche Ltd


RO7020531 —F. Hoffmann-La Roche Ltd
20/Protocol YP39553, Version 2
OBJECTIVES 
Primary Objectives
The primary objective of this study is:

To assess the safety and tolerability of single and multiple ascending doses of oral 
RO7020531 in Chinese healthy subjects.
Secondary Objectives
The secondary objectives for this study are as follows:

To investigate the plasma pharmacokinetics (PK) of RO7020531 and the main active 
metabolite, RO7011785, following single and multiple ascending doses of RO7020531 in 
Chinese healthy subjects. Additional metabolites may be measured, including RO7018822 
and RO7033805.

To investigate the urine PK of RO7020531 (if detectable) and the main active metabolite, 
RO7011785, in urine samples of Chinese healthy subjects after single ascending oral doses 
of RO7020531. Additional metabolites may be measured in urine, including RO7018822 
and RO7033805.

To investigate the effect of RO7020531 on pharmacodynamic (PD) parameters following 
single or multiple oral doses administered every other day (QOD) in Chinese healthy 
subjects.
STUDY DESIGN
Description of Study
This study will be a randomized, Sponsor-open, Investigator/subject-blinded, placebo controlled, 
single ascending dose (SAD) and multiple ascending dose (MAD) study to evaluate the safety, 
tolerability, PK and PD of RO7020531 and metabolites following oral administration to Chinese 
healthy subjects. PK, PD, safety and tolerability data collected in the SAD part of this study will 
be used to determine doses at which to initiate the MAD part of the study. The subjects 
participating in each single dose cohort will be dosed according to a sentinel dosing design. 
Initially, two subjects will be dosed: one subject with RO7020531 and one subject with placebo. 
If the safety and tolerability results from the first 24 hours following dosing for the initial subjects 
are acceptable to the Investigator, the remaining subjects of each cohort will be dosed. 
NUMBER OF HEALTHY VOLUNTEERS
SAD
Approximately 40-60 subjects with an adaptive number of cohorts. There will be eight active and 
two placebo subjects planned for each cohort.
MAD
Approximately 20-30 subjects with an adaptive number of cohorts. There will be eight active 
and two placebo subjects planned for each cohort.
TARGET POPULATION
Healthy male and female subjects between 18 to 60 years of age, inclusive.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria:
Healthy subjects must meet the following criteria for study entry:
1.
Chinese healthy male and female subjects. Healthy status is defined by absence of 
evidence of any active or chronic disease following a detailed medical and surgical 
history, a complete physical examination including vital signs, 12-lead ECG, 
hematology, blood chemistry, and urinalysis.
2.
18 to 60 years of age, inclusive.
3.
A Body Mass Index (BMI) of 19 to less than 28 kg/m2 and a body weight of at least 
45 kg.
4.
Informed of, and willing and able to comply with, all of the protocol requirements and 


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the investigational nature of the study, and have signed an informed consent form (ICF) 
in accordance with institutional and regulatory requirements.
5.
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two approved contraceptive methods, of which one 
must be a barrier method and the other should be an established non-barrier form of 
contraception with a failure rate of < 1% per year, during the treatment period and for 
at least one month after the last dose of study drug. 

A woman is considered to be of childbearing potential if she has not reached a 
post-menopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal occlusion, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine device
(IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
6.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 

With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or be willing to use two methods of contraception 
with their partners, one of which must be a condom and the other should be an 
established form of contraception, during the treatment period and for at least 
one month after the last dose of study drug to avoid exposing the embryo. 
Other acceptable forms of contraception include vasectomy, bilateral tubal 
occlusion, IUD or proper use of hormonal contraceptives (e.g. contraceptive 
pills). Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and 
withdrawal are not acceptable methods of contraception. 
7.
Negative pregnancy test on Day1 for female subjects.
8.
Non-smokers, or use of10 cigarettes (or equivalent nicotine-containing product) per 
day.
9.
Negative anti-nuclear antibody (ANA) test; or positive with dilutions not greater than 
1:40 and with no associated history or symptoms of potential connective tissue disease 
or other immune mediated diseases.
Exclusion criteria:
Healthy subjects who meet any of the following criteria will be excluded from study entry:
1.
Pregnant (positive pregnancy test) or lactating women, and male partners of women 
who are pregnant or lactating.
2.
History of immunologically mediated disease (e.g., inflammatory bowel disease, 
idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic 
anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any 
other autoimmune disease).
3.
History or symptoms of any clinically significant disease including (but not limited to), 
neurological, cardiovascular, endocrine, respiratory, hepatic, ocular, or renal disorder 
(as per Investigator’s judgment).
4.
Personal or family history of congenital long QT syndrome or sudden cardiac death.
5.
Evidence of an active or suspected cancer or a history of malignancy, where in the 


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Investigator’s opinion, there is a risk of recurrence.
6.
History of having received or currently receiving any systemic anti-neoplastic (including 
radiation) or immune-modulatory treatment (including systemic oral or 
inhaled corticosteroids, IFN or PEG-IFN) within 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. Eye drop-containing and infrequent inhaled corticosteroids are permissible up to 
4 weeks prior to the first dose of study drug.
7.
History of clinically significant thyroid disease; also, subjects with clinically significant 
elevated thyroid stimulating hormone (TSH) concentrations at Screening.
8.
Any confirmed clinically significant allergic reactions (anaphylaxis) against any drug, or 
multiple drug allergies (non-active hay fever is acceptable).
9.
History of clinically significant psychiatric disease, especially major depression 
(significant psychiatric disease is defined as treatment with an antidepressant 
medication or a major tranquilizer at therapeutic doses for major depression or 
psychosis, respectively, or any history of the following: a suicide attempt, hospitalization 
for psychiatric disease, or a period of disability due to a psychiatric disease).
10. Clinically significant acute infection, e.g., influenza, local infection or any other clinically 
significant illness within two weeks of randomization.
11. History of clinically significant gastrointestinal (GI) disease including inflammatory bowel 
disease, peptic ulcer disease, GI hemorrhage. 
12. Confirmed systolic blood pressure (BP) greater than 140 or less than 90 mmHg, and 
diastolic BP greater than 90 or less than 50 mmHg at Screening (based on the average 
of three separate resting BP measurements, properly measured with well-maintained 
equipment, after at least 5 minutes rest).
13. Clinically relevant electrocardiogram (ECG) abnormalities on Screening ECG: e.g.,

QTc interval (QTcF450 msec or300 msec)

Notable resting bradycardia (heart rate [HR]45 bpm), or HR90 bpm

Difference between highest and lowest of any Screening QTc 30 msec

ECGs with documented machine errors in the interval duration assessments 

ECG with QRS and / or T-wave judged to be unfavorable for a consistently accurate
QT measurement (e.g., neuromuscular artifact that cannot be readily eliminated, 
arrhythmias, indistinct QRS onset, low amplitude T-wave, merged T- and U-waves, 
prominent U-waves).

Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolff-
Parkinson-White Syndrome, or cardiac pacemaker.
14. Any of the following laboratory parameters prior to dosing: 

White blood cells (WBC)3000 cells/mm3

Neutrophil count1500 cells/mm3

Platelet count140,000 cells/mm3

Activated partial thromboplastin time (aPTT)40 seconds, international normalized 
ratio (INR) 1.2

Hemoglobin (Hb) 12 g/dL in females or 13 g/dL in males
15. Abnormal renal function including serum creatinineupper limit of normal (ULN) or 
calculated CrCl70 mL/min (using the Cockcroft Gault formula).
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at 
screening above ULN and judged clinically significant by the Investigator.
17. Positive results for anti-mitochondrial antibody (AMA), anti-smooth muscle antibody 
(ASMA) or thyroid peroxidase antibody.
18. Positive hepatitis A IgM antibody (HAV Ab IgM), hepatitis B surface antigen (HBsAg), 


 
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hepatitis C antibody (HCV Ab), or positive for human immunodeficiency virus (HIV) at 
screening. 
19. Any other clinically significant abnormalities in laboratory test results at Screening. In 
the case of uncertain or questionable results, tests performed during screening may be 
repeated before randomization to confirm eligibility or judged to be clinically irrelevant 
for healthy subjects 
20. History of alcohol abuse (consumption of more than two standard drinks per day on 
average; one standard drink = 10 grams of alcohol) and/or drug abuse within one year of 
randomization. Alcohol consumption will be prohibited at least 48 hours before 
screening, 48 hours before admission until discharge from the clinic, and 48 hours 
before each scheduled visit. 
21. Positive test for drugs of abuse or positive alcohol test at screening or Day − 1. 
22. Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment of, might interfere with, the conduct of the study, or that would, in 
the opinion of the Investigator, pose an unacceptable risk to the subject in this study. 
23. Use of any medication (prescription or over the counter [OTC], including health 
supplements, vitamins or herbal remedies) within two weeks prior to the first dosing or 
within five half-lives of the medication prior to first dosing (whichever is longer). 
Exceptions may be made on a case-by-case basis following discussion and agreement 
between the Investigator and the Sponsor. 
24. Participation in an investigational drug or device study within 90 days prior to 
randomization. 
25. Donation or loss of blood over 500 mL, or administration of any blood product, within 
90 days prior to starting study medication. 
26. Subjects under judicial supervision, guardianship or curatorship. 
27. Any medical or social condition which may interfere with the subject’s ability to comply 
with the study visit schedule or the study assessments. 
LENGTH OF STUDY 
SAD: Up to 9 weeks (from screening through study completion) for each randomized subject as 
follows:  
• Screening: Up to 28 days; 
• Dosing period: 1 day; 
• Follow up: 28 days after dosing. 
MAD: Up to 10 weeks (from Screening through study completion) for each randomized subject 
as follows: 
• Screening: Up to 28 days; 
• Dosing period: 14 days; 
• Follow-up: 28 days after dosing. 
END OF STUDY 
The end of the study is defined as the date when the last subject last observation (LSLO) 
occurs. LSLO is expected to occur 6 weeks after the last subject is randomized.  
OUTCOME MEASURES 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events (AE). 
• 
Incidence of laboratory abnormalities based on hematology, clinical chemistry, coagulation 
and urinalysis test results. 
• 
Incidence of vital signs or ECG abnormalities. 


 
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PHARMACOKINETIC OUTCOME MEASURES 
The PK evaluations for this study are as follows: 
• 
Summary descriptive statistics of plasma PK parameters for RO7020531 and the main 
active metabolite, RO7011785, and additional metabolites, including RO7018822 and 
RO7033805 will be computed. These parameters include Cmax, Tmax, AUCinf, AUClast, and t1/2 
and will be presented by dose cohorts including mean, standard deviation (SD), co-efficient 
of variation (CV), medians and ranges. 
• 
Where available, descriptive statistics of urine PK parameters (total amount excreted, 
fraction excreted of total administered dose, renal clearance), if available, for RO7020531, 
RO7011785 and other metabolites will be presented. 
 
PHARMACODYNAMIC OUTCOME MEASURES 
The PD outcome measures for this study are as follows: 
Blood samples will be collected to evaluate a number of PD outcome measures including the 
protein and metabolite markers of humoral response (IFN-α, IP-10, TNF-α, IL-6, IL-10, IL-12p40 
and neopterin) and markers of transcriptional responses (ISG15, OAS-1, MX1 and TLR7). 
 
CLINICAL GENOTYPING OUTCOME MEASURES 
The clinical genotyping outcome measures for this study are as follows: 
• 
Correlation of single nucleotide polymorphisms (SNP) status with the observed exposure. 
• 
Correlation of SNP status with the observed cytokine/chemokine levels. 
BIOMARKER/GENOTYPING SAMPLE COLLECTION 
Clinical Genotyping (CG) Samples 
On Day 1 (or any time during the conduct of the clinical study), a mandatory whole blood 
sample will be taken for DNA extraction from every subject. The DNA will be used to determine 
if alleles of drug metabolizing enzymes (such as aldehyde oxidases) and TLR7 affect the PK/PD 
of RO7020531. Data arising from this study will be subject to the same confidentiality as the rest 
of the study. 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Test Product: RO7020531 will be supplied by Roche as hard gelatin capsules containing 10 
mg, or 100 mg of RO7020531 drug substance. 
Placebo: Placebo will be supplied by Roche as hard gelatin capsules identical in size and 
appearance to the corresponding active capsules, containing microcrystalline cellulose of 
compendial grade but no active substance. 
 
Both RO7020531 and placebo will be administered orally in capsules. Doses will be given with 
240 mL of water. Additional amounts of water up to 100 mL could be given to assist dose 
administration, if needed. 
Doses of RO7020531 in SAD and MAD cohorts will be administered as a combination of 10 
mg or 100 mg capsules with the requisite number of capsules being administered per specific 
dose cohort. 
 
SAD 
In the SAD cohorts, RO7020531 or matching placebo will be administered orally to the subjects 
by investigational staff on the morning of Day 1 after an overnight fast of at least 10 hours. 
Subjects in the SAD cohorts will not eat for 4 hours after the dose is administered. Water will be 
allowed ad libitum until one hour prior to dosing and after one hour post dosing. Approximately 
4 hours after dosing, subjects will be given lunch. A planned dose escalation sequence of the 
SAD cohorts is anticipated to be 40 mg, 100 mg, 140 mg and 170mg. Additional cohorts may  
 


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be added within a dose range between 10 mg and 170 mg.
MAD
In the MAD cohorts, RO7020531 or matching placebo will be administered orally to the subjects 
by investigational staff QOD from Day 1 through to Day 13. In total, seven doses will be given. 
Each dose will be given in a fasted state (after an overnight fast of at least 10 hours). Subjects 
will not eat for 4 hours after each dose is administered. Water will be allowed ad libitum until 
one hour prior to dosing and after one hour post-dosing. Dose levels for MAD will be defined 
during the study conduct based on the emerging study data.
PROCEDURES
Detailed Schedule of Assessments and procedures are tabulated in the appendices of the 
protocol.
BLINDING OR UNBLINDING:
This study is observer-blinded and Sponsor open.
In exceptional cases, (e.g., if deemed important for dose decisions or for the more thorough 
evaluation of safety-related concerns that may impact dosing of future subjects on this or other 
currently conducted or shortly to start studies involving administration of RO7020531) and in the 
interest of the subjects’ safety, the Investigator may be unblinded after approval by the Clinical 
Pharmacologist.
STATISTICAL METHODS
SAFETY ANALYSES
All healthy volunteers who have received at least one dose of the study medication, whether 
prematurely withdrawn from the study or not, will be included in the safety analysis. The safety 
data, including AEs, reasons for withdrawal from study, laboratory data, ECG, concomitant 
medications, vital signs, and physical examination results will be listed and summarized 
descriptively.
As appropriate, listings, summary tables and graphs (subject plot and/or mean plots) will be 
provided for safety and tolerability assessments.
Adverse events will be listed and summarized by body system and preferred term.
For laboratory data, subject listings will be presented with abnormalities flagged.
PHARMACOKINETIC ANALYSES
Non-compartmental analysis using WinNonlin software will be used to calculate PK parameters 
where appropriate. Summary descriptive statistics of plasma PK parameters including Cmax, 
Tmax, AUCinf, AUClast and t1/2 for RO7020531 and RO7011785 and additional metabolites, 
including RO7018822 and RO7033805, will be presented by treatment arm including means, 
SD, CV, geometric means, medians and ranges. Where appropriate, data may be pooled and 
analyzed. Listings, summary tables and graphs (individual plots and/or mean plots) by treatment 
group will be provided. Descriptive statistics of urine PK parameters including total amount 
excreted, fraction excreted of total administered dose; renal clearance for RO7020531 and 
RO7011875 and additional metabolites including RO7018822 and RO7033805 will be 
presented, where available.
Additional PK analyses, including population PK and/or PD analyses, will be conducted as 
appropriate.
PHARMACODYNAMIC ANALYSES 
Summary descriptive statistics will be presented for the induction of cytokines, chemokines, and 
neopterin and of interferon-response genes separately by treatment arm. Exploratory analysis 
will be performed to assess the TLR7 agonist induced response under different dosing 
conditions. Graphical and statistical techniques including linear, non-linear, and logistic 
regression will be used to explore potential relationships between dosing regimen, PK and PD.
CLINICAL GENOTYPING ANALYSES:
Potential PD and/or PK differences will be studied by clinical genotyping, exploring whether 
genetic polymorphisms of drug metabolizing enzymes (such as aldehyde oxidases) and TLR7
can be correlated to PK/PD profile of RO7020531.


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SAMPLE SIZE JUSTIFICATION
Ten healthy volunteers are planned to be enrolled at each dose level. They will be randomized 
to either active treatment (eight healthy volunteers per dose level) or placebo (two healthy 
volunteers per dose level). The current planned study design and sample size complies with 
standard safety review rules applied in single and multiple ascending dose studies.
With eight healthy volunteers per dose group or cohorts, there is a 90% chance to observe at 
least one AE that has an incidence rate of 25% in the population.
LIST OF PROHIBITED MEDICATIONS
As a general rule, no concomitant medication (including health supplements, vitamins or herbal 
remedies) will be permitted, unless the rationale for use is discussed between the Investigator 
and Sponsor and is clearly documented (with the exception of medications to treat AEs [after 
discussion with Sponsor, unless the subject is at risk] and use of hormone replacement therapy 
can continue if initiated 2 months prior to study start. Use of acetaminophen/paracetamol is 
allowed up to a maximum dose of 2 g per day (with restricted use in relation to study drug 
administration).
Use of the following therapies is prohibited: 

Any prescribed or OTC medications (except for the cases given in Section 4.5.1), including 
health supplements, vitamins or herbal remedies within 5 half-lives or 2 weeks, whichever is 
longer, prior to the first dosing until the follow up visit.

Any systemic anti-neoplastic (including radiation) or immune-modulatory treatment 
(including systemic oral or inhaled corticosteroids, IFN or PEG-IFN; see exclusion criteria). 
Eye drop-containing and infrequent inhaled corticosteroids are prohibited from 4 weeks 
prior to the first dose of study drug until the follow up visit.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
Ab
Antibody
AE
Adverse events
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AMA
Anti-mitochondrial antibody
ANA
Anti-nuclear antibody
aPTT
Activated partial thromboplastin time
ASMA
Anti-smooth muscle antibody
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUCinf
Area under the plasma concentration versus time curve 
extrapolated to infinity
AUClast
Area under the plasma concentration versus time curve 
up to the last measurable concentration
BMI
Body mass index
BP
Blood pressure
cccDNA
Covalently closed circular DNA
CHB
Chronic hepatitis B
CL
Clearance
Cmax
Maximum observed plasma concentration
CRO
Contract research organization
CV
Coefficient of variation
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European economic area
EIH
Entry into human
ESF
Eligibility Screening Form
EU
European Union
FSH
Follicle-stimulating hormone
GGT
Gamma glutamyl transpeptidase 
GI
Gastrointestinal
GLP
Good Laboratory Practice
HAV
Hepatitis A virus
Hb
Hemoglobin


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HbA1c
Glycated hemoglobin
HBeAg
Hepatitis B envelope antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IgM
Immunoglobulin M
IL
Interleukin
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
MAD
Multiple ascending dose
NOAEL
No-observed-adverse-effect level
NUC
Nucleoside/nucleotide analogue
OATP
Organic anion transporting polypeptide
PD
Pharmacodynamic
pDC
Plasmacytoid dendritic cell
PEG-IFN
Pegylated interferon
pH
Measure of acidity or alkalinity
PK
Pharmacokinetic
PQ
PQ interval
PR
PR interval
QOD
Every other day
QRS
QRS complex
QT
QT interval
QTc
Corrected QT interval
QTcF
Fridericia's correction of QT interval
QW
Once a week
SAD
Single ascending dose
SAE
Serious adverse event


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SD
Standard deviation
SI
Système International d’Unités
SNP
Single nucleotide polymorphism
SoA
Schedule of assessments
t1/2
Half-life
TLR
Toll-like receptor
Tmax
Time to maximum observed plasma concentration
TNF
Tumor necrosis factor
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
Vss
Volume of distribution at steady-state
WBC
White blood cell
WHO
World Health Organization


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1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
Chronic hepatitis B (CHB) and its sequelae are major global healthcare problems. 
Despite the implementation of effective vaccination in many countries, hepatitis B is one 
of the most common infectious diseases in the world. It is estimated that more than 
2 billion people or one third of the world’s population have been infected with the 
hepatitis B virus (HBV) at some time in their lives, and an estimated 240 million are now 
chronically infected, with approximately one-third of those subjects in China (WHO 2002, 
WHO 2016). Nearly 25% of all chronic HBV carriers develop serious liver diseases such 
as chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. More than 
686 000 people die every year due to the consequences of hepatitis B (WHO 2016).
The endemicity of HBV varies substantially by region, with East Asia and sub-Saharan 
Africa having prevalence rates of CHB above 8% (Ott et al 2012). In these highly 
endemic areas, the most common means of transmission is by perinatal infection, and 
up to 90% of the population has serological evidence of prior infection (Alter et al 2003). 
Although prevalence levels in developed countries are relatively low, immigration from 
highly endemic regions has had a significant influence on the local need for therapy, and 
even countries with low endemicity are currently experiencing the burden of CHB 
(Wasley et al 2010).
HBV belongs to the Hepadnaviridae family. It is a partly double-stranded DNA virus with 
approximately 3200 base pairs. The transcriptional template of HBV is the covalently 
closed circular DNA (cccDNA), which resides inside the hepatocyte nucleus as a 
minichromosome (Locarnini et al 2010). Several HBV subtypes have been identified. 
Most CHB patients are infected with the wild-type strain of HBV, which produces large 
amounts of the hepatitis B envelope antigen (HBeAg) resulting in the HBeAg-positive 
form of CHB. However, in a significant proportion of patients, variant forms of the virus 
predominate later in the course of the disease, which have diminished ability to produce 
HBeAg. Another serological marker, hepatitis B surface antigen (HBsAg), is a hallmark 
of the infection and remains persistently positive in CHB patients. There is a correlation 
between the presence of HBsAg and patients’ outcome with HBsAg level being 
predictive of fibrosis severity, development of hepatocellular carcinoma and survival 
rates (Fattovich et al 1998, Tseng et al 2012, Martinot-Peignoux et al 2013).
HBV is not cytopathic: both liver damage and viral control are immunomediated (Trepo 
et al 2014). The clinical outcome of infection is dependent on the complex interplay 
between HBV replication and both the innate and adaptive immune responses. Patients 
with CHB have defects in innate and adaptive immune responses, characterized by 
exhaustion of antigen specific T cells, suboptimal antigen presentation, and insufficient 
antibody production (Bertoletti et al 2012). The dominant cause of the long-term viral 
persistence and pathogenesis of HBV liver disease is the development of an inefficient 
antiviral response to the viral antigens (Bertoletti et al 2012).


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Currently available treatments for CHB include interferon (IFN), pegylated interferon 
(PEG-IFN), and nucleos(t)ide analogues (NUC): lamivudine, adefovir, entecavir, 
tenofovir and telbivudine (Papatheodoridis et al 2012; Sarin et al 2016; Terrault et al 
2016). Although these therapies achieve long-term effects in lowering HBV DNA levels, 
chronic HBV infection cannot be completely eradicated with currently approved 
therapeutics due to the persistence of cccDNA in the nucleus of infected hepatocytes 
(Lucifora et al 2014). With these treatments, rates of HBsAg clearance and 
seroconversion, which are associated with reduced or reversed cirrhosis and prevention 
of HCC development, are low (15% HBsAg seroconversion after 1 to 5 years follow-up)
(Chang et al 2010, Marcellin et al 2013). In addition, the notable deficiencies of current 
HBV treatments include indefinite duration of NUCs and risk of viral resistance with 
some NUC treatments, while PEG-IFN therapy is poorly tolerated and a significant 
portion of patients do not have a virological response (Papatheodoridis et al 2008).
Due to the therapeutic limitations of the currently available agents for the management 
of HBV infection, there is a need for new treatments of CHB that can provide clinical 
cure (HBsAg loss) and sustained suppression of HBV replication (Wang and Chen 2014).
One promising strategy to stimulate the immune system in CHB is by the use of toll-like 
receptors (TLRs). TLRs are a family of pathogen-recognition receptors that activate the 
innate immune response. Stimulation of TLRs leads to the release of multiple cytokines, 
including type I and type II IFNs, to the induction of pathways and enzymes that destroy 
intracellular pathogens, and to the maturation of professional antigen-presenting cells, 
resulting in the activation of the adaptive immune response (Iwasaki and Medzhitov 
2004). To date, 11 functional TLRs have been identified in humans. Most TLRs are 
located in the plasma membrane, except TLR3, TLR7, TLR8 and TLR9, which are 
intracellularly expressed, particularly in endosomes. TLR7 receptors are able to 
recognize viral components and induce IFN production and downstream responses 
(Lester and Li 2014). 
A number of small molecule agonists for TLR7 have been identified (Horscroft et al 
2012). The stimulation of TLR7 mediates an endogenous type I IFN response, which is 
critical in development of a broad, effective and protective immunity against hepatitis 
viruses (Horscroft et al 2012, Funk et al 2014). Compared to PEG-IFN therapy, 
treatment with a TLR7 agonist induces broader immuno-modulatory effects that are 
likely to lead to more effective control and functional cure of chronic HBV infection 
(Strader et al 2004, Isogawa et al 2005). TLR7 agonists induce the production of multiple 
isotypes of IFN from plasmacytoid dendritic cells (pDCs) which have been shown in vitro 
to possess additive or synergistic antiviral effects compared to exogenous PEG-IFN.
1.2
BACKGROUND ON RO7020531 
RO7020531, an oral double prodrug of the TLR7-specific agonist, RO7011785, is being 
developed for the treatment of CHB patients. A prodrug approach was chosen for oral 
delivery of the TLR7 agonist RO7011785 in order to improve bioavailability and 


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potentially limit TLR7 activation in the gastrointestinal (GI) tract, which may be 
associated with GI intolerability. Non-clinical studies with RO7020531 suggest that it is 
rapidly converted to the active metabolite RO7011785. Data from in vivo studies with 
RO7020531 and in vitro studies with RO7011785 support immune activation as the 
mechanism of action. A clinical study (NP39305) of RO7020531 exploring safety, PK 
and PD effects is ongoing (see Section 1.2.2).
See the RO7020531 Investigator’s Brochure (RO7020531 IB) for details on non-clinical 
studies.
1.2.1
Previous Non-Clinical Studies
RO7011785 showed in vitro potency to activate TLR7 and triggered downstream 
TLR7-mediated nuclear factor-kappa B (NF-B) signaling in an engineered HEK293 
reporter cell line expressing human TLR7. RO7011785 was shown to be a selective 
hTLR7 agonist with less potency to activate hTLR8 in vitro. Ex vivo stimulation of human 
peripheral blood mononuclear cells (PBMCs) from healthy donors by RO7011785 
resulted in dose-dependent induction of various cytokines and chemokines, including 
IFN-, tumor necrosis factor-(TNF-, interleukin-6 (IL-6), and IFN gamma-inducible 
protein 10 (IP-10). 
In an HBV mouse model, C57BL/6 mice were injected with recombinant 
adeno-associated virus harboring 1.3 copies of the HBV genome, and demonstrated 
high levels of HBV viral makers including HBV DNA, HBsAg, and HBeAg. Oral 
administration of RO7020531, once a week (QW) or every other day (QOD) for 6 weeks, 
proved to have in vivo anti-HBV activity in this mouse model, i.e., clear reduction in HBV 
DNA and HBsAg (by more than 1 log after the 42-day treatment period). With the same 
administration frequency, higher doses resulted in faster and greater reduction in HBV 
DNA and HBsAg. With the same dose of 100 mg/kg, QOD administration resulted in 
greater viral reduction on Day 42 than QW administration. In addition, RO7020531 
induced interferon-stimulated gene expression in peripheral whole blood in this mouse 
model.
RO7020531 showed high oral bioavailability and rapid conversion to the active moiety, 
RO7011785. RO7011785 exhibited a relatively short half-life (t1/2) of 1.51 hours in rats 
and 2.12 hours in monkeys, moderate systemic clearance (CL) of ~50% liver blood flow 
in rats, and CL of approximately 30% liver blood flow in monkeys. RO7011785 had a 
moderate volume of distribution (Vss) in the range of body water or slightly higher for both 
rats and monkeys. Differences in metabolite exposure were noted between species, 
although RO7011785 was the predominant metabolite in both rats and monkeys, 
confirming good conversion to active drug.
Conversion of RO7020531 to the active form RO7011785 was observed in animal and 
human hepatocytes, with both the ester hydrolysis and aldehyde oxidase-mediated 
pathways active. The relative strength of the oxidase versus esterase pathways varied 


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between species and influenced the concentrations of the different intermediate 
prodrugs: RO7033805 was the predominant intermediate for cynomolgus monkey, 
whereas RO7018822 was the predominant intermediate for mouse, rat, and human. 
RO7020531 was found to be a good substrate of multidrug resistance protein 1 (MDR1; 
P-glycoprotein), with a high apparent membrane permeability. Therefore, in vivo 
drug-drug interactions due to co-administration with MDR1 inhibitors cannot be excluded. 
However, interactions of strong MDR1 inhibitors with the absorption of RO7020531 are 
considered unlikely due to the high permeability, high solubility, and high oral 
bioavailability of RO7020531, which makes it unlikely that MDR1 plays a major role in 
RO7020531 trans-intestinal absorption in vivo.
RO7011785 can be directly glucuronidated by UDP-glucuronosyltransferase 1A1 
(UGT1A1); thus, drug-drug interactions with UGT1A1 inhibitors cannot be excluded. 
Drug-drug interaction potential was low, as determined in vitro with cytochrome P450 
(CYP) enzymes and with transporters (organic anion transporting polypeptide 1B1 
[OATP1B1], OATP1B3, organic anion transporter 1 [OAT1], OAT3, and breast cancer 
resistance protein [BCRP]). Therefore, the interactions with CYPs and substrates for 
hepatic uptake transporters and kidney transporters (for example NUCs) in vivo are 
unlikely.
Repeat-dose toxicity studies with treatment duration of up to 13 weeks have been 
performed with RO7020531 in rats and monkeys. The effects observed were considered 
to be consistent with exaggerated pharmacology, i.e., TLR7 agonism leading to the 
intended immune/cytokine stimulation and subsequent tolerability or pro-inflammatory
findings. QOD and QW dosing regimens were investigated in Good Laboratory Practice 
(GLP) toxicology studies. The no-observed-adverse-effect level (NOAEL) for the 
13-week rat toxicology study was 3 mg/kg QOD (area under the concentrationtime 
curve for males and females [AUC M/F]186/503 h ng/mL) and 30 mg/kg QW (AUC 
M/F2950/4660 h ng/mL). The NOAEL for the 13-week monkey toxicology study was 3 
mg/kg QOD (AUC M/F858/706 h ng/mL) and 10 mg/kg QW (AUC M/F3340/2960 
h ng/mL).
Neither the double prodrug RO7020531, nor its metabolites RO7011785 and 
RO7018822, significantly affected potassium channels in the in vitro human 
ether-à-go-go-related gene (hERG) assay. Dosing at 3 mg/kg in monkeys caused 
reversible heart rate (HR) increase (with decreased RR interval and shortened QT 
and/or heart-rate corrected QT [QTc] interval), non-adverse increase in PR interval and 
increase in body temperature. There were no RO7020531-related effects on respiratory 
or central nervous system function in rats up to the highest dose tested (300 mg/kg).
No genotoxic potential was observed for RO7020531 in the Ames test, nor in the in vitro 
and in vivo micronucleus test. No evidence of teratogenicity or embryo-fetal toxicity was 
observed in definitive (GLP) embryo-fetal toxicity studies in rats (up to 150 mg/kg/day) or 


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rabbits (up to 100 mg/kg/day), other than increased incidences of non-adverse fetal 
skeletal variations. In a definitive (GLP) fertility study in rats, no adverse effects of 
RO7011785 on mating performance, fertility, or early embryonic development were 
noted (up to 300 mg/kg, every other day [QOD]), despite slightly reduced body weight 
gain. See the RO7020531 Investigator’s Brochure for details on the properties of 
RO7020531 and RO7011785.
1.2.2
Previous Clinical Studies
A global entry-into-human (EIH) study (NP39305) is ongoing, where RO7020531 is 
being evaluated in healthy volunteers in single ascending doses (SAD) and multiple 
ascending doses (MAD) and subsequently will be evaluated in virologically suppressed 
CHB patients. 
As of 1 October, 2017, 80 healthy volunteers (HVs; 64 males and 16 females) have been 
dosed with RO7020531/placebo in eight SAD cohorts. All dose levels (3 mg, 10 mg, 20 
mg, 40 mg, 60 mg, 100 mg, 140 mg and 170 mg) were considered safe and well 
tolerated. There had been few adverse events (AEs) per cohort, all were reported as of 
mild intensity, and only three subjects (two in the second cohort [10mg] and one in the 
170 mg cohort) had AEs that were considered “related” to study drug. No serious 
adverse events (SAEs) or discontinuations due to AEs had been reported; and there 
were no dose related trends in nature, incidence or severity of AEs. In addition, there 
have been no clinically significant changes (or trends) in ECG parameters, vital signs, 
or laboratory safety test results in any subjects.
Exposure (AUC0-inf) of the main active metabolite, RO7011785, increased 
proportionally with dose and was consistent with values predicted for humans from 
preclinical pharmacokinetics (PK) models. PD biomarkers did not have significant 
changes after single doses up to 60 mg in SAD Cohorts 1-5. Three out of eight subjects 
in SAD Cohort 6 who received a single RO7020531 dose of 100 mg exhibited changes in 
interferon alpha indicative of TLR7 activation. Two of these subjects exhibited
increased activity for IP10 and neopterin.  The fraction of subjects responding as well 
as the amplitude of the response increased at the 140 mg dose.  Changes in mRNA 
levels for ISG15, OAS-1, MX1 and TLR7 initially found at the 100 mg dose were 
amplified at the 140 mg dose.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.3.1
Study Rationale
Study YP39553, is a Phase I study to assess the safety, tolerability, pharmacokinetics 
(PK) and pharmacodynamics (PD) of RO7020531 following oral administration of SAD 
and MAD in Chinese healthy subjects.
Safety and tolerability of ascending doses of RO7020531 will be the primary endpoint in 
this study. In addition, PK and PD measured via the appearance of select biomarkers 


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indicating activation of TLR7 and/or TLR8, will be evaluated. These biomarkers will be 
evaluated for each cohort in the SAD and will be used in a decision to initiate the MAD.  
The MAD part is designed to dose subjects with RO7020531 using a QOD regimen that 
will proceed for two weeks. Previous clinical and non-clinical data with another TLR7 
agonist, RO6864018, have shown that the QOD dose schedule provides additional 
priming of the TLR7 response and is thought to be a dose regimen that may optimize the 
benefit-risk ratio for HBV treatment.
Evidence for TLR activation in the SAD and MAD studies will be provided by measuring 
post-dose changes in selected biomarkers including the protein and metabolite markers 
IFN-, IP-10, TNF-, IL-6, IL-10, IL-12p40 and neopterin and markers of transcriptional 
responses (ISG15, OAS-1, MX1 and TLR7), known to be stimulated by activation of 
TLR7 and/or TLR8.
1.3.2
Benefit-Risk Assessment
The evaluation of potential risks of treatment and specific tests, observations, and 
precautions required for clinical studies with RO7020531 are based on information from 
non-clinical toxicology and safety pharmacology studies, and on information/in house 
experience from clinical studies with other TLR7 agonists (Gane 2015, Grippo, 2016). 
Furthermore, information from clinical data collected from the global EIH Study NP39305 
will be available prior to starting to dose subjects in this study. The doses/exposures to 
be explored in this study should be considered safe and with acceptable tolerability 
based on study NP39305. 
Safety and tolerability will be carefully assessed, and healthy volunteers will be closely 
monitored. The RO7020531 IB summarizes potential risks and key risk management 
activities to consider when dosing this compound.
As for all early clinical studies in healthy volunteers, there is no direct benefit to the 
subjects participating in this study. However, this study will be essential in the 
development of a new treatment for chronic HBV infection, and for selecting the most 
appropriate dose for a study in HBV-infected patients. 
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objective of this study is:

To assess the safety and tolerability of single and multiple ascending doses of oral 
RO7020531 in Chinese healthy subjects.


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2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:

To investigate the plasma PK of RO7020531 and the main active metabolite, 
RO7011785, following single and multiple ascending doses of RO7020531 in 
Chinese healthy subjects. Additional metabolites may be measured, including 
RO7018822 and RO7033805.

To investigate the urine PK of RO7020531 (if detectable) and the main active 
metabolite, RO7011785, in urine samples of Chinese healthy subjects after single 
ascending oral doses of RO7020531. Additional metabolites may be measured in 
urine, including RO7018822 and RO7033805.

To investigate the effect of RO7020531 on PD parameters following single or 
multiple oral doses administered QOD in Chinese healthy subjects.
3.
STUDY DESIGN
This study will be a randomized, Sponsor-open, Investigator/subject-blinded, 
placebo-controlled, SAD and MAD study to evaluate the safety, tolerability, PK and PD 
of RO7020531 and metabolites following oral administration to Chinese healthy subjects. 
PK, PD, safety and tolerability data collected in the SAD part of this study will be used to 
determine doses at which to initiate the MAD part of the study. A QOD dosing regimen 
will be evaluated in the MAD portion of this study.
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
For both SAD and MAD parts of the study, each cohort will enroll ten subjects, with eight 
subjects randomly assigned to RO7020531 and two subjects randomly assigned to 
placebo (Table 1). Each cohort will include a minimum of two females, with at least one 
female receiving active drug. All single and multiple doses will be administered in the 
fasted state.


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Table 1
Study Cohorts
Cohort
Stage
Dose (mg)a
Total Doses 
Administered
Route
Planned Number of 
Healthy Volunteers
Active Drug
Placebo
1
SAD
40
1
PO
8
2
2
SAD
100
1
PO
8
2
3
SAD
140
1
PO
8
2
4
SAD
170b
1
PO
8
2
1
MAD
TBD
7 QOD
PO
8
2
2
MAD
TBD
7 QOD
PO
8
2
SADsingle ascending doses; MADmultiple ascending doses; TBDto be determined; 
QOD every other day.
a.
Proposed doses, which will be refined based on PK, safety and tolerability found in the 
global EIH study NP39305 and/or in the previous cohorts in the current study YP39553; 
b.
Optional cohort.
Additional cohorts may be explored in the SAD and MAD part as required.
3.1.1.1
Single Ascending Dose Study
For dose escalation, subjects will be sequentially enrolled into approximately four to six 
dose cohorts that may range between 40 mg and 170 mg, the maximum dose proposed 
in the global EIH study, NP39305. Based on the newly available data in NP39305 
indicating very good safety and tolerability with single RO7020531 doses up to 170 mg 
and PD effects documented only with doses ≥100 mg, the starting dose in this study 
was selected to be 40 mg, which is expected to avoid very low doses/exposures that may 
not produce pharmacodynamic effects, while ensuring appropriate safety margins 
expected with the first dose (See Section 3.2.1).
The anticipated ascending dose scheme in the SAD cohorts is 40 mg, 100 mg 140 mg
and 170 mg. Additional cohorts may be added within a dose range between 10 mg and 
170 mg (Figure 1). As an additional safety precaution in this study, the subjects 
participating in each single dose cohort will be dosed according to a sentinel dosing 
design. Initially, two subjects will be dosed: one subject with RO7020531 and one 
subject with placebo. If the safety and tolerability results from the first 24 hours following 
dosing for the initial subjects are acceptable to the Investigator, the remaining subjects 
of each cohort may be dosed soon after.
As described below, PK/PD and safety data from the SAD cohorts will be utilized to 
select the starting dose for the MAD. If only three cohorts are required to choose a 
starting dose for the MAD, then further cohorts may not be evaluated. The final doses 
chosen for evaluation may be modified based on data collected in Study NP39305 
and/or from the previous cohorts in the current study. If adequate safety and tolerability 
are documented in a dosing cohort, further dose progression may be explored but not 


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until a consensus agreement is reached between the Sponsor and the Investigator; the 
Ethics Committee will be informed. RO7020531 doses planned for this study in Chinese 
healthy volunteers will not be evaluated if they are expected to result in RO7011785 
exposures which are not found to be safe and tolerable in the global EIH study. In 
addition, doses will not be escalated in both the SAD and MAD if stopping rules have 
been met (see Section 3.1.3). Safety and tolerability at each dose level will determine 
eligibility for dose escalation. Measurement of PK and select PD markers will be made 
with each cohort and, upon availability, will be utilized along with safety data to 
determine the first dose with which to initiate the MAD. The MAD part of this study may 
be initiated before the SAD part is completed. Therefore, both SAD and MAD parts of 
this study may run in parallel.
In the SAD cohorts, subjects will be screened up to 28 days before randomization and 
asked to remain in the unit from Day2 until Day 3 with dosing occurring on Day 1. After 
being discharged on Day 3, subjects will return for an outpatient visit on Day 5 and a 
follow-up visit on Day 8. All subjects will have a follow-up phone call 28 days after the 
study drug administration. Subjects will be asked to report any AEs that occur during this 
period.
3.1.1.2
Multiple Ascending Dose Study
The trigger to start the first cohort in the MAD includes documentation of adequate 
safety and tolerability in the SAD cohorts and evidence of PD effects. For a given dose 
evaluated in the SAD, evidence in at least two subjects exhibiting responses above 
placebo-defined baseline for select PD biomarkers, including the protein and metabolite 
markers IFN-, IP-10, TNF-, IL-6, IL-10, IL-12p40 and neopterin and markers of 
transcriptional responses (ISG15, OAS-1, MX1 and TLR7), should be demonstrated. If 
the next dose in the SAD has been considered safe, then the previous dose 
demonstrating TLR-associated PD activity will be considered as the starting dose for the 
MAD. In addition, the starting dose/exposure in the MAD part of this study should have 
been considered safe in the global EIH study (NP39305). Only doses covered by the 
dose range evaluated in the SAD part will be used in the MAD, and two to three dose 
levels will be evaluated (Figure 1).
Once criteria have been reached to determine an initial dose for MAD, subjects will be 
screened up to 28 days before enrollment into the MAD part of this study. They will be 
asked to remain in the unit from Day -2 until Day 14 with QOD dosing initiated on Day 1. 
In total, 7 QOD doses will be administered with the last dose given on Day 13. Subjects 
will be discharged on Day 14. After completing 7 QOD doses, each subject in the MAD 
cohorts will return for an outpatient follow-up visit 7 days after the last dose. All subjects 
will have a follow-up phone call 28 days after their last dose. Subjects will be asked to 
report any AEs that occur during this period. 
Upon safety review of the MAD cohort(s) data, dose escalation will proceed in the MAD 
part of this study. The maximum dose investigated in MAD will not exceed doses 


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evaluated in the SAD part of this study nor will it exceed doses and exposures 
considered to be safe and with acceptable tolerability in the global EIH study. 
Based on the PK, PD and safety evaluation of the previous dose cohorts, additional 
cohorts of subjects may be enrolled at higher or lower dose levels, or at a dose level 
already tested.
Figure 1
Study Design
a.
Doses shown in this figure may be modified based on emerging data. Four to six cohorts will 
be evaluated in the SAD part of the study with a dose range between 40 mg and 170 mg. 
b.
Two to three cohorts will be evaluated in the MAD part of the study. Doses in the MAD part 
will not exceed the dose considered to be safe and well-tolerated in the SAD part. 
3.1.2
Dose Escalation Decision Criteria
A Safety Review Meeting will be conducted by the Principal Investigator and the 
Sponsor Clinical Team prior to each dose escalation.
The decision to escalate to the next dose level in the SAD cohorts will be based primarily 
on the available safety and tolerability information through Day 4 (including adverse 
events [AEs], electrocardiograms [ECGs], vital signs, clinical laboratory test results) and, 
secondarily, on available PK and PD data through 24 hours post-dose at the previous 
dosage level. In addition, all available safety and PK data from the previous dose level(s) 
will be reviewed. The anticipated dose escalation sequence for the SAD is 40 mg, 
100 mg, 140 mg and 170 mg (See Table 1).
The decision to escalate to the next dose level in the MAD cohorts will be based 
primarily on the safety and tolerability information (including AEs, ECGs, vital signs, 
clinical laboratory test results) through Day 14 and secondarily on available PK data. In 
addition, all available safety and PK data from the previous dose level(s), including SAD 
cohorts, will be reviewed.


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Depending on the evaluation of the safety and/or PK data: the same dose may be 
repeated; a lower dose may be administered; or intermediate dose escalation steps 
other than those anticipated above may be used at the discretion of the Study 
Investigator and the Sponsor.
The recommendation for the subsequent cohort dose level will be shared with the Ethics 
Committee.
3.1.3
Treatment Stopping Rules
Any serious adverse event (SAE) considered related to study drug will lead to an 
immediate halt of study drug dosing and enrollment of new subjects until a thorough 
investigation has been conducted by the Sponsor’s Clinical Team and the Principal 
Investigator. The sponsor or designee will notify all investigators and IRBs/EC regarding 
the outcome of such investigation, and the study will only continue if agreed by the 
IRBs/EC.
Planned dose escalation will be stopped if one of the following circumstances occurs in 
subjects dosed with RO7020531, unless it is apparent that the occurrence is not related 
to the administration of study medication:

Within a cohort, three or more subjects on active drug experience:
–
Severe and clinically significant (as defined by the Investigator) RO7020531-related 
AEs of the same character, or
–
Clinically significant RO7020531-related laboratory abnormalities of the same 
character, or
–
Clinically significant RO7020531-related changes in vital signs or ECGs of the same 
character (e.g., confirmation of mean corrected QT interval [QTc] 500 msec or 60 
msec longer than the pre-dose baseline).

Within two consecutive dose cohorts, four occurrences of any of the above 
conditions in subjects receiving active drug.

Any other findings (regardless of the incidence rates) that, at the joint discretion of 
the Sponsor and the Investigator, indicate dose escalation should be halted.

Dose escalation will not proceed if it is predicted that higher doses of RO7020531 
will not result in a further increase in RO7011785 plasma exposure; or if the mean 
systemic exposure (AUC) reaches the RO7011785 plasma levels found to be 
associated with dose-limiting toxicities in the global EIH study.
If dose escalation is stopped, lower doses could be investigated by mutual agreement 
between the Sponsor and the Investigator.


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For an individual subject in the MAD cohorts, dose continuation will not occur if the 
subject experiences any of the following:

Clinically significant RO7020531-related changes in safety parameters that are 
considered not acceptable by the Investigator and/or the Sponsor; or

Poor tolerability, which is considered to affect the subject’s well-being and/or the PK 
evaluation.
Due to the exploratory nature of this clinical study, its conduct can be discontinued at 
any time at the discretion of the Sponsor.
3.1.4
Length of Study
SAD: The total duration of the study will be up to 9 weeks (from Screening through study 
completion) for each randomized subject as follows: 

Screening: Up to 28 days;

Dosing period: 1 day;

Follow up: 28 days after dosing.
The in-clinic period will be from Day 2 until Day 3.
MAD: The total duration of the study will be up to 10 weeks (from Screening through 
study completion) for each randomized subject as follows:

Screening: Up to 28 days;

Dosing period: 14 days;

Follow-up: 28 days after last dosing.
3.1.5
End of Study
The end of the study is defined as the date when the last subject last observation (LSLO) 
occurs. LSLO is expected to occur 6 weeks after the last subject is randomized.
3.2
RATIONALE FOR STUDY DESIGN
3.2.1
Rationale for Dosage Selection and Dosage Regimen
The dose selection for this study is supported by the non-clinical safety data and may be 
modified based on the clinical data collected from the global EIH study, NP39305. The 
current study in Chinese healthy volunteers (YP39553) is planned to consist of four to 
six dose levels in SAD and two to three dose levels in MAD, which will be within the 
dose-range considered to be safe and with acceptable tolerability in the global EIH study, 
NP39305. 
Based on the non-clinical data with RO7020531 (see Section 1.2.1), the half-life of the 
active TLR7 agonist RO7011785 is relatively short. However, previous experience in 
monkeys and humans with another TLR7 agonist (RO6864018) indicate that a short 
exposure of the TLR7 agonist initiates a series of pharmacodynamic events with 
biomarker activity that peaks as late as 48 hours post dose. Similar results are 


 
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anticipated following dosing with RO7020531 and are supported by activity measured in 
non-clinical models. 
In the ongoing global EIH study (NP39305), all dose levels tested in SAD (3 mg – 170 
mg) have been observed to be safe and well tolerated. In SAD Cohort 6 (100 mg), 3/8 
healthy volunteers demonstrated increases in interferon alpha and which met the 
predefined criteria for TLR7 marker activity.  
The starting dose of 40 mg was selected for the SAD portion of this study in Chinese 
patients based on the safety and tolerability documented in the study NP39305, avoiding 
very low doses/exposures that may not produce pharmacodynamic effects, while 
ensuring appropriate safety margins expected with the first dose.   
The phenomena of response priming (increase in PD effects with the second dose) and 
tachyphylaxis (reduced response with chronic and frequent doses) are expected with 
RO7020531 based on clinical and non-clinical data observed with another TLR7 agonist, 
RO6864018. The phenomenon of TLR7 priming was frequently observed with 
RO6864018 in cynomolgus monkeys after the second dose administration and was 
followed by a subsequent response tachyphylaxis. Similarly, in healthy volunteers and 
HCV patients (Study ANA773-601), there is evidence of response priming with QOD 
schedule of RO6864018 showing an increase in PD response with the second dose, and 
evidence of tachyphylaxis to systemic IFN with repeated dosing on QOD schedule. 
The QOD schedule has been selected for the multiple dosing part of this study based on 
information acquired from non-clinical studies with RO7020531 and clinical studies with 
RO6864018, and is aimed to optimize PD responses while minimizing safety risks, such 
as poor tolerability with every day dosing.  
Based on clinical data with another TLR7 agonist (Study ANA773-601), it is expected 
that priming of PD effects and tachyphylaxis to systemic IFN release provided by the 
QOD schedule might be a desirable effect that can potentially limit AEs, and improve 
tolerability and efficacy. 
3.2.2 
Rationale for Study Population  
Healthy subjects were chosen for this SAD and MAD study to allow (in a safe and 
well-controlled setting) better understanding of the tolerability, safety and PK of oral 
dosing with RO7020531 while avoiding the confounding variables of co-medications and 
co-morbidities found in HBV patients. Another prodrug, RO6864018, which is rapidly 
converted to the TLR7 agonist, RO6871765, has been tested in both healthy volunteers, 
hepatitis C virus (HCV) and is being tested in an ongoing study in HBV patients. Data 
from single and multiple dose administrations indicate that PK/PD relationships 
determined in healthy volunteers and HCV patients were comparable. These in house 
data and other literature data with TLR7 agonists comparing healthy volunteers and 
CHB patients indicate that PD/dose relationships determined in healthy volunteers, CHB 


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and HCV patients were comparable, suggesting that healthy volunteers represent a 
suitable population for the evaluation of safety, tolerability, PK and PD of TLR agonists 
that will be predictive of the dose-effect relationships anticipated in CHB patients.
Healthy status in study subjects will be confirmed during the screening period. Due to 
immunomodulatory mechanism of action of RO7020531, all subjects with a history of 
immunologically mediated disease will be excluded. All healthy volunteers will be tested 
for autoimmune markers to exclude participants with potential connective tissue disease 
or other immune-mediated diseases.
In this SAD and MAD study, each cohort will include ten subjects (eight active, two 
placebo). Sex differences in TLR7-mediated response have been reported, including 
higher immune activation and IFN-production by pDCs in females (Berghofer et al 
2006). Females appear to be more sensitive to TLR7 activation than males and exhibit 
greater PD responses in peripheral blood such as fold change from baseline for several 
genes and cyto/chemokines investigated in previous clinical studies of another TLR7 
agonist, RO6864018. It was also shown that female healthy volunteers appeared to 
have higher exposure of the active TLR7 agonist, RO6871765. These facts warrant 
further investigation in this study, and so, to allow evaluation of potential sex differences 
in PK and PD response, a minimum number of two female subjects per cohort (with at 
least one female receiving active drug) is implemented in each one of the study cohorts.
3.2.3
Rationale for Pharmacokinetic Assessments
In general, PK data will be used to describe the concentration-time profile for 
RO7020531 and its metabolites, as well as key PK characteristics including elimination 
half-life, dose/exposure and PK/PD relationships for safety and specific TLR7-dependent 
biomarkers.
For the SAD part of the study, subjects will be asked to remain in the unit for up to 
3 days post-dose for safety monitoring and to collect plasma samples for PK. With the 
proposed collection of up to 48 hours post-dose, it is assumed that the full 
concentration-time profile for RO7020531 and its metabolites will be determined. Urine 
samples will be collected in intervals to determine the fraction of RO7020531 and its 
metabolites that are eliminated in the urine. Previous work with the TLR7 agonist 
RO6864018 has shown extensive elimination of the active TLR7 agonist RO6871765 in 
the urine. As both RO7020531 and RO6864018 are from the same chemical class, it is 
expected that extensive renal elimination of the active TLR7 agonist RO7011785 will 
occur. It is anticipated that the 24-hour urine collection will allow characterization of this 
elimination pathway. 
For the MAD part of the study, a QOD dosing schedule will be used, and extensive PK 
sampling will be made over a 24-hour period on Day 1 following the first dose and on 
Day 13 following multiple doses to determine if PK parameters change with multiple 
doses. With subsequent doses throughout the dosing period, sparse PK sampling will 


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also be used to characterize trough values and Cmax values to determine that exposure 
of RO7011785 is maintained during this dose regimen. No urine samples will be 
collected in the MAD part of the study.
3.2.4
Rationale for Pharmacodynamic Assessments
TLR7 is expressed on human pDC and B-cells, and its activation induces both humoral 
and cellular changes (Iwasaki and Medzhitov 2004, Lester and Li 2014). These changes 
include the production of cytokines and chemokines such as IFN-, IP-10, TNF-, IL-6, 
IL-10, IL-12p40 and changes in the expression of ISGs, e.g., ISG15, OAS-1 and 
myxovirus resistance 1 gene (MX1) and of the TLR7 gene itself (Fidock et al 2011), as 
well as changes in markers of immune stimulation such as neopterin.
To capture the immunomodulatory effects of TLR7 agonism, cytokines, chemokines and 
peripheral blood gene expression will be measured at time-points outlined in the SoA 
(Appendix 1, Appendix 2, Appendix 3 and Appendix 4). These markers showed a 
dose-dependent PD profile with other TLR7 agonists when assessed in patients and 
healthy volunteers. The PD activity in the SAD part of the study will be used to help 
choose the starting dose in the MAD part of the study. 
In previous healthy volunteer clinical studies, IFN-, neopterin, IL10 and IP-10 were 
activated with another TLR7-selective agonist, RO6864018 and no activation of the 
TLR8 markers, IL-6 and TNF-was seen. Thus, in the current study, any activation of 
IL-6 and TNF-may be indicative of activation of TLR8.
3.2.5
Rationale for Clinical Genotyping
Various single nucleotide polymorphisms (SNPs) have been described for the TLR7
gene. These SNPs may be associated with differential expression of IFN, TLR7 and 
certain cytokines, or carry an increased risk of developing autoimmune diseases such as 
lupus erythematosus (Askar et al 2010, Kawasaki et al 2011). Furthermore, there seems 
to be a pronounced difference in the frequency of these SNPs in Asians and Caucasians 
(IGSR: 1000 Genomes Project).
Potential PD and/or PK differences will be studied by clinical genotyping, exploring 
whether genetic polymorphisms of drug metabolizing enzymes (such as aldehyde 
oxidase) and TLR7 can be related to the PK/PD profile of RO7020531.
3.3
OUTCOME MEASURES 
3.3.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events. 

Incidence of laboratory abnormalities based on hematology, clinical chemistry, 
coagulation and urinalysis test results.


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
Incidence of vital signs (blood pressure [BP], pulse rate, respiratory rate and body 
temperature) or ECG (PR [PQ], QRS, QT, QTcF) abnormalities.
3.3.2
Pharmacokinetic Outcome Measures
The PK evaluations for this study are as follows:

Summary descriptive statistics of plasma PK parameters for RO7020531 and the 
main active metabolite, RO7011785, and additional metabolites, including 
RO7018822 and RO7033805, will be computed. These parameters include Cmax, 
Tmax, AUCinf, AUClast, and t1/2 and will be presented by dose cohorts including means, 
standard deviation (SD), coefficient of variation (CV), geometric means, medians 
and ranges. 

Where available, descriptive statistics of urine PK parameters (total amount 
excreted, fraction excreted of total administered dose, renal clearance), if available, 
for RO7020531, RO7011785 and other metabolites will be presented.
3.3.3
Pharmacodynamic Outcome Measures
The PD outcome measures for this study are as follows:

Blood samples will be collected to evaluate a number of PD outcome measures 
including the protein and metabolite markers of humoral response(IFN-, IP-10, 
TNF-, IL-6, IL-10, IL-12p40 and neopterin) and markers of transcriptional 
responses (ISG15, OAS-1, MX1 and TLR7). .
3.3.4
Clinical Genotyping Outcome Measures
The outcome measures for this study are as follows:

Correlation of SNP status with the observed exposure.

Correlation of SNP status with the observed cytokine/chemokine levels.
See rationale Section 3.2.5 for information on SNP analysis.
4.
MATERIALS AND METHODS
4.1
CENTER
One site is currently planned; however, additional site(s) may be included for back-up 
purposes and may be activated if needed. Administrative and Contact Information, and 
List of Investigators are provided separately.
4.2
STUDY POPULATION
The target population consists of Chinese male and female healthy subjects between the 
ages of 18 and 60, inclusive. Healthy subjects must satisfy all inclusion and exclusion 
criteria to be enrolled into the study. Under no circumstances are subjects who are 
randomized in this study permitted to be re-randomized to another cohort of this study.
Study subjects who drop out of the study for non-safety reasons may be replaced to 
ensure sufficient data to characterize the safety, tolerability, and PK and/or to make 


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dose-escalation decisions. Study subjects who withdraw from the study due to poor 
tolerability or for study drug-related adverse events will not be replaced.
4.2.1
Recruitment Procedures 
Healthy volunteers will be identified for potential recruitment using pre-screening 
enrollment logs, IEC/IRB approved newspaper, radio or other advertisements and 
mailing lists prior to consenting to take place on this study.
4.2.2
Inclusion Criteria
Healthy subjects must meet the following criteria for study entry:
1.
Chinese healthy male and female subjects. Healthy status is defined by absence of 
evidence of any active or chronic disease following a detailed medical and surgical 
history, a complete physical examination including vital signs, 12-lead ECG, 
hematology, blood chemistry, and urinalysis.
2.
18 to 60 years of age, inclusive.
3.
A Body Mass Index (BMI) of 19 to less than 28 kg/m2 and a body weight of at least 
45 kg.
4.
Informed of, and willing and able to comply with, all of the protocol requirements and 
the investigational nature of the study, and have signed an informed consent form 
(ICF) in accordance with institutional and regulatory requirements.
5.
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two approved contraceptive methods, of which one 
must be a barrier method and the other should be an established non-barrier form of 
contraception with a failure rate of1% per year, during the treatment period and for 
at least one month after the last dose of study drug.

A woman is considered to be of childbearing potential if she has not reached 
a post-menopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 

Examples of contraceptive methods with a failure rate of1% per year 
include bilateral tubal occlusion, male sterilization, established proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing IUDs, and 
copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
6.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 


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
With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or be willing to use two methods of contraception 
with their partners, one of which must be a condom and the other should be 
an established form of contraception, during the treatment period and for at 
least one month after the last dose of study drug to avoid exposing the 
embryo. Other acceptable forms of contraception include vasectomy, 
bilateral tubal occlusion, IUD or proper use of hormonal contraceptives (e.g. 
contraceptive pills). Men must refrain from donating sperm during this same 
period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence and withdrawal are not acceptable methods of contraception. 
7.
Negative pregnancy test on Day1 for female subjects.
8.
Non-smokers, or use of10 cigarettes (or equivalent nicotine-containing product) 
per day.
9.
Negative anti-nuclear antibody (ANA) test; or positive with dilutions not greater than 
1:40 and with no associated history or symptoms of potential connective tissue 
disease or other immune-mediated diseases.
4.2.3
Exclusion Criteria
Healthy subjects who meet any of the following criteria will be excluded from study entry:
1.
Pregnant (positive pregnancy test) or lactating women, and male partners of women 
who are pregnant or lactating.
2.
History of immunologically mediated disease (e.g., inflammatory bowel disease, 
idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic 
anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or 
any other autoimmune disease).
3.
History or symptoms of any clinically significant disease including (but not limited to), 
neurological, cardiovascular, endocrine, respiratory, hepatic, ocular, or renal 
disorder (as per Investigator’s judgment).
4.
Personal or family history of congenital long QT syndrome or sudden cardiac death.
5.
Evidence of an active or suspected cancer or a history of malignancy, where in the 
Investigator’s opinion, there is a risk of recurrence.
6.
History of having received or currently receiving any systemic anti-neoplastic 
(including radiation) or immune-modulatory treatment (including systemic oral or 
inhaled corticosteroids, IFN or PEG-IFN) within 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. Eye drop-containing and infrequent inhaled corticosteroids are 
permissible up to 4 weeks prior to the first dose of study drug.
7.
History of clinically significant thyroid disease; also, subjects with clinically 
significant elevated thyroid-stimulating hormone (TSH) concentrations at Screening.


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8.
Any confirmed clinically significant allergic reactions (anaphylaxis) against any drug, 
or multiple drug allergies (non-active hay fever is acceptable).
9.
History of clinically significant psychiatric disease, especially major depression 
(significant psychiatric disease is defined as treatment with an antidepressant 
medication or a major tranquilizer at therapeutic doses for major depression or 
psychosis, respectively, or any history of the following: a suicide attempt, 
hospitalization for psychiatric disease, or a period of disability due to a psychiatric 
disease).
10. Clinically significant acute infection, e.g., influenza, local infection or any other 
clinically significant illness within two weeks of randomization.
11. History of clinically significant GI disease including inflammatory bowel disease, 
peptic ulcer disease, GI hemorrhage. 
12. Confirmed systolic BP greater than 140 or less than 90 mmHg, and diastolic BP 
greater than 90 or less than 50 mmHg at Screening (based on the average of three 
separate resting BP measurements, properly measured with well-maintained 
equipment, after at least 5 minutes rest).
13. Clinically relevant ECG abnormalities on screening ECG, e.g.:

QTc interval (QTcF450 msec or300 msec)

Notable resting bradycardia (HR45 bpm), or HR90 bpm

Difference between highest and lowest of any screening QTc30 msec

ECGs with documented machine errors in the interval duration 
assessments 

ECG with QRS and / or T-wave judged to be unfavorable for a consistently 
accurate QT measurement (e.g., neuromuscular artifact that cannot be 
readily eliminated, arrhythmias, indistinct QRS onset, low amplitude 
T-wave, merged T- and U-waves, prominent U-waves).

Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, 
Wolff-Parkinson-White Syndrome, or cardiac pacemaker.
14. Any of the following laboratory parameters prior to dosing: 

White blood cells (WBC)3000 cells/mm3

Neutrophil count1500 cells/mm3

Platelet count140,000 cells/mm3

Activated partial thromboplastin time (aPTT)40 seconds, international 
normalized ratio (INR)1.2

Hemoglobin (Hb)12 g/dL in females or 13 g/dL in males
15. Abnormal renal function including serum creatinineupper limit of normal (ULN) or 
calculated CrCl70 mL/min (using the Cockcroft Gault formula; see Appendix 7).
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at 
Screening above ULN and judged clinically significant by the Investigator.


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17. Positive results for anti-mitochondrial antibody (AMA), anti-smooth muscle antibody 
(ASMA) or thyroid peroxidase antibody.
18. Positive hepatitis A IgM antibody (HAV Ab IgM), hepatitis B surface antigen (HBsAg), 
hepatitis C antibody (HCV Ab), or positive for human immunodeficiency virus (HIV) 
at Screening.
19. Any other clinically significant abnormalities in laboratory test results at Screening. 
In the case of uncertain or questionable results, tests performed during screening 
may be repeated before randomization to confirm eligibility or judged to be clinically 
irrelevant for healthy subjects.
20. History of alcohol abuse (consumption of more than two standard drinks per day on 
average; one standard drink10 grams of alcohol) and/or drug abuse within one 
year of randomization. Alcohol consumption will be prohibited at least 48 hours 
before screening, 48 hours before admission until discharge from the clinic, and 
48 hours before each scheduled visit. 
21. Positive test for drugs of abuse or positive alcohol test at Screening or Day -1.
22. Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment of, might interfere with, the conduct of the study, or that 
would, in the opinion of the Investigator, pose an unacceptable risk to the subject in 
this study.
23. Use of any medication (prescription or over-the-counter [OTC], including health 
supplements, vitamins or herbal remedies) within two weeks prior to the first dosing 
or within five half-lives of the medication prior to first dosing (whichever is longer). 
Exceptions may be made on a case-by-case basis following discussion and 
agreement between the Investigator and the Sponsor.
24. Participation in an investigational drug or device study within 90 days prior to 
randomization.
25. Donation or loss of blood over 500 mL, or administration of any blood product, within 
90 days prior to starting study medication.
26. Subjects under judicial supervision, guardianship or curatorship.
27. Any medical or social condition which may interfere with the subject’s ability to 
comply with the study visit schedule or the study assessments.
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This study is observer-blinded. This means that the subjects, the Investigator, and all 
individuals in direct contact with the subjects at the investigative site will be blinded, 
except for the pharmacy staff handling the study drug distribution.
This study is Sponsor-open; members of the Sponsor’s project and study teams who do 
not have direct contact with the subjects will be unblinded. This may exclude contract 
research organization (CRO) staff in direct contact with the site.


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Healthy volunteers will be randomized 4:1 to RO7020531 or to placebo in each dose 
cohort. The randomization numbers will be generated by the Sponsor or its designee. 
The randomized treatment assignment will be allocated from the list sequentially to 
subjects in the order in which they are randomized. A minimum of two females per 
cohort will be randomized, with at least one female receiving active drug. The treatment 
allocation will be managed by the unblinded site pharmacist(s) and will be based on the 
randomization code list.
To allow informed recommendations or decisions regarding the dose decisions in this 
study, an integrated assessment of the available data on PK, select PD, safety and 
tolerability will be made prior to each dose decision.
In exceptional cases, (e.g., if deemed important for dose decisions or for the more 
thorough evaluation of safety-related concerns that may impact dosing of future subjects 
on this or other currently conducted or shortly to start studies involving administration of 
RO7020531) and in the interest of the subjects’ safety, the Investigator may be 
unblinded after approval by the Clinical Pharmacologist.
The Principal Investigator(s) will receive a set of sealed treatment codes. These may 
have the form of sealed envelopes or scratch codes. If the identity of the test medication 
needs to be known in order to manage the healthy volunteer’s condition, the treatment 
code for that healthy volunteer may be broken.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (see Section 5.1) that are considered by 
the Investigator to be related to study drug.
All treatment code breakages should be documented in the study file. Treatment codes 
should not be broken except in emergency situations and, if possible, the responsible 
clinical pharmacologist should be contacted before the code is opened. At the final 
monitoring visit, the unused treatment codes will be counted and checked and a 
statement to the effect that all are intact (or not as the case may be) will be made by the 
Monitor; this statement will be included or referred to in the final study report. All code 
labels will be destroyed by the investigator site after verification by the Study Monitor, 
and once permission is granted by Roche.
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data. Any unblinding, at the 
investigating site end, will be documented in the study report with date, reason for 
identifying the drug and the name of all the person(s) who had to be unblinded.


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4.4
STUDY TREATMENT
4.4.1
Formulation, Packaging, and Handling
4.4.1.1
RO7020531 and Placebo
RO7020531 and placebo will be supplied by Roche.
Investigational Medicinal Product (IMP): Hard gelatin capsule for oral administration 
containing 10 mg, or 100 mg of RO7020531 drug substance.
Placebo: Hard gelatin capsule identical in size and appearance to the corresponding 
active capsules, containing microcrystalline cellulose of compendial grade but no active 
substance.
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.
The study drug must be stored according to the details on the product label: “Store at 
2°C-8°C, protect from light and moisture”.
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery.
For further details, refer to the most updated RO7020531 IB.
4.4.2
Dosage, Administration and Compliance
4.4.2.1
RO7020531 and Placebo
Both RO7020531 and placebo will be administered orally in capsules.
In the SAD cohorts, RO7020531 or matching-placebo will be administered orally to the 
subjects by investigational staff on the morning of Day 1 after an overnight fast of at 
least 10 hours. Subjects in the SAD cohorts will not eat for 4 hours after the dose is 
administered. Water will be allowed ad libitum until one hour prior to dosing and after 
one hour post-dosing. Approximately 4 hours after dosing, subjects will be given lunch. 
The SAD part of the study will include an adaptive number of cohorts (approximately 
four). Each dose cohort will include 10 subjects (eight active and two placebo). The 
planned dose-escalation sequence for SAD is shown in Table 1.
Doses of RO7020531 in SAD and MAD cohorts will be administered as a combination of 
10 mg or 100 mg capsules with the requisite number of capsules being administered per 
specific dose cohort. Should an intermediate dose be required due to a change in the 


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anticipated dose-escalation, the dose will be composed of the appropriate combination 
of 10 mg and 100 mg capsules.
In the MAD cohorts, RO7020531 or matching-placebo will be administered orally to the 
subjects by investigational staff QOD from Day 1 through to Day 13. In total, seven 
doses will be given (for time-points see Appendix 3 and Appendix 4). Each dose will be 
given in a fasted state (after an overnight fast of at least 10 hours). Subjects will not eat 
for 4 hours after each dose is administered. Water will be allowed ad libitum until one 
hour prior to dosing and after one hour post-dosing. The MAD part of the study will 
include an adaptive number of cohorts (two to three). Each dose cohort will include ten 
subjects (eight active and two placebo). Dose levels for MAD will be defined during the 
study conduct based on emerging data (See Table 1).
Doses will be given orally with 240 mL of water. Additional amounts of water up to 
100 mL could be given to assist dose administration only if needed. 
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose according to the randomization schedule. This individual will write the date 
dispensed and subject number and initials on the study drug vial label and on the Drug 
Accountability Record. This individual will also record the study drug batch or lot number 
received by each subject during the study. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 4.7.
4.4.3
Investigational Medicinal Product Accountability
IMP (RO7020531) and placebo required for completion of this study will be provided by 
the Sponsor. The investigational site will acknowledge receipt of IMPs, to confirm the 
shipment condition and content. Any damaged shipments will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the healthy volunteer to whom the study drug was dispensed 
(for example healthy volunteer initials and date of birth).

All records and drug supplies must be available for inspection by the Roche Monitor 
[at every monitoring visit].
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons. In these cases, it may be 


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acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Written documentation of destruction must contain the following:

Identity of investigational product destroyed.

Quantity of investigational product destroyed.

Date of destruction.

Method of destruction.

Name and signature of responsible person (or company) who destroyed 
investigational products.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.5
CONCOMITANT THERAPY, DIETARY AND SPECIAL 
REQUIREMENTS
4.5.1
Permitted Therapy 
As a general rule, no concomitant medication (including health supplements, vitamins or 
herbal remedies) will be permitted, unless the rationale for use is discussed between the 
Investigator and Sponsor and is clearly documented. The following medications are 
exceptions:

Medications used to treat an AE may only be prescribed after consultation with the 
Sponsor (with the exception of acetaminophen/paracetamol), unless there is a 
medical need to ensure the well-being of the subject that should not be delayed. All 
therapy and/or medication administered to manage AEs should be recorded on the 
AE electronic case report form (eCRF).

Hormone replacement therapy (HRT), continue using if initiated two months prior to 
study start.

Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g per day. 
During the period of confinement to the clinical research unit, subjects will be 
restricted from the use of acetaminophen/paracetamol and other non-prescription 
medications beginning 4 hours prior to dosing through 4 hours after dosing unless 
deemed necessary to treat an AE by the Investigator. 


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All medications (prescription drugs, over-the-counter [OTC] drugs, approved dietary and 
herbal supplements, nutritional supplements) taken within 4 weeks of study screening 
will be recorded on the appropriate eCRF.
4.5.2
Prohibited Therapy
Use of the following therapies is prohibited: 

Any prescribed or OTC medications (except for the cases given in Section 4.5.1), 
including health supplements, vitamins or herbal remedies within 5 half-lives or 
2 weeks, whichever is longer, prior to the first dosing until the follow-up visit.

Any systemic anti-neoplastic (including radiation) or immune-modulatory treatment 
(including systemic oral or inhaled corticosteroids, IFN or PEG-IFN) within 6 months  
prior to the first dose of study drug until the follow-up visit (Day 8 for SAD and 
Day 20 for MAD). Eye drop-containing and infrequent inhaled corticosteroids are 
prohibited from 4 weeks prior to the first dose of study drug until the follow up visit.
4.5.3
Dietary and Special Requirements
There are data suggesting that concentrated green tea (including bottled green tea 
beverages) may inhibit aldehyde oxidase (Tayama et al 2011). Therefore, subjects 
should minimize the amount of bottled green tea beverages and other green tea 
preparations they drink from Day 7 until the follow-up visit at Day 8.
Subjects must fast overnight (at least 10 hours) before the dosing and must not eat for 
4 hours after the dose is administered. Approximately 4 hours after dosing, subjects will 
be administered lunch. 
Water will be allowed ad libitum until one hour prior to dosing and from one hour 
post-dosing. However, the excessive consumption of fluids (greater than 3 liters per day) 
should be avoided until completion of the follow-up visit.
Laboratory safety assessments should be conducted after subjects have been fasted for 
a minimum of 8 hours. 
Alcohol must not be consumed from 48 hours before screening, 48 hours before 
admission until discharge from the clinic, and 48 hours before each scheduled visit. 
Please refer to Appendix 8 for the calculation of alcohol standard drinks as relates to 
eligibility criteria.
Caffeine (i.e., beverage, chocolate or supplements) must not be consumed from 
48 hours prior to study drug administration until discharge from the clinic. 
Strenuous exercise is not permitted during the study from 96 hours before admission
until completion of the follow-up visit.


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The use of tobacco is not permitted from Day -2 till Day 3 for the SAD part and from Day 
-2 till Day 14 for the MAD part of the study.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the Schedule of 
Assessments (SoA) outlined in Appendix 1, Appendix 2, Appendix 3 and Appendix 4.
At time-points when several pre-dose assessments coincide, the following sequence 
should be followed: 

Urine collection (urinalysis, urine PK pre-dose sample).

ECG recordings.

Vital signs.

Pre-dose blood sampling (pre-dose PK, pre-dose PD, exploratory samples, safety 
blood tests).

RO7020531/placebo intake.
For the post-dose assessments, the following sequence should be followed with the PK 
blood sample (or PD blood sample if there is no PK sampling) to be taken at the nominal 
time-point:

ECG recordings.

Vital signs.

Post-dose blood sampling (post-dose PK, post-dose PD).
4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse and all medications (e.g., 
prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional supplements) 
used by the healthy volunteer within 4 weeks prior to the screening visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
4.6.1.2
Physical Examinations
A complete physical examination should be performed at time-points indicated in the 
SoA (Appendix 1, Appendix 2, Appendix 3 and Appendix 4) and includes an evaluation 
of the head, eyes, ears, nose, throat, neck and lymph nodes, and the cardiovascular, 
dermatological, musculo-skeletal, respiratory, GI and neurological systems. A 
genitourinary examination may be performed in case of evocative symptoms at the 
Investigator’s discretion. Any abnormality identified at Screening or at baseline should be 
recorded on the Medical History eCRF. 


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At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in the healthy volunteer’s notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
Height will only be recorded at Screening. Weight will be recorded at time-points for 
complete Physical Examination as specified in the SoA (Appendix 1, Appendix 2, 
Appendix 3 and Appendix 4). BMI will be calculated at Screening in accordance with the 
formula provided in Appendix 5.
4.6.1.3
Vital Signs
BP, pulse rate, respiratory rate and body temperature will be recorded at the time-points 
specified in the SoA (Appendix 1, Appendix 2, Appendix 3 and Appendix 4).
BP, pulse rate and respiratory rate should be obtained in a quiet room at a comfortable 
temperature, with the healthy volunteer's arm unconstrained by clothing or other material. 
BP, respiratory rate and pulse rate will be obtained after the subject has been in a 
supine or sitting position for at least 5 minutes. All BP and pulse rate measurements will 
be obtained from the same arm (where possible), in the same position and with the 
same cuff size, using a well-calibrated automatic instrument with a digital readout, 
throughout the study. BP measurement will be performed in triplicate (can be as short as 
20 second to 1 minute interval between measurements). The mean of three consecutive 
replicates will be used as the value for the defined time-point.
Body temperature measurement can be either oral or tympanic; the method should be 
maintained throughout the study.
4.6.1.4
Electrocardiograms
Triplicate 12-lead ECG recordings (i.e., three useful ECGs without artifacts) will be 
obtained within approximately 2-5 minutes at each specified time‑point. The average of 
the three readings will be used to determine ECG intervals (PR [PQ], QRS, QT, QTcF). 
The intervals will be captured or calculated, and the changes in T-wave and U-wave 
morphology will be documented. T-wave information will be captured as normal or 
abnormal, U-wave information will be captured in two categories: absent/normal or 
abnormal.
Whenever possible, the same brand/model of a standard digital high‑quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements 
should be used for each subject. The conditions should be as close as possible to 
pre-dose time-points; this includes but is not limited to food intake, activity level, 
stressors and room temperature.
To minimize variability, it is important that subjects be in a resting position 
for10 minutes prior to each ECG evaluation. Body position should be consistently 


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maintained for each ECG evaluation to prevent changes in heart rate. 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 as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator must review, sign and date all ECG 
tracings. Paper copies will be kept at the study centers with the subject’s clinical file as 
part of the permanent record. The ECG intervals and interpretation will be recorded on 
the eCRF or may be sent electronically. If considered appropriate by Roche, ECGs may 
be analyzed retrospectively at a central laboratory.
If any ECG recording documents QT/QTc values500 msec or increases from Day -1 
QTc60 msec (as provided by the machine), the site should repeat the ECG triplicate 
within the next 5 minutes and notify the Sponsor. If confirmed, ECG recordings should 
be repeated at least hourly until two successive ECGs show QTc values below the 
threshold value that triggered the repeated measurement.
4.6.1.5
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points specified 
in the Schedule of Assessments (Appendix 1).
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 healthy volunteer’s safety. Where the clinical significance of 
abnormal lab results is considered uncertain, screening lab tests may be repeated 
before randomization to confirm eligibility. If there is an alternative explanation for a 
positive urine test for drugs of abuse, e.g., previous occasional intake of a medication or 
food containing for example codeine, benzodiazepines or opiates, the test could be 
repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory.


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Samples for the following laboratory tests will be sent to one or several laboratories or to 
the Sponsor for analysis. Instruction manuals and supply kits will be provided for all 
laboratory assessments.

Hematology: Hb, hematocrit, total WBC count, differential WBC count (including 
basophils, eosinophils, lymphocytes, monocytes and neutrophils), platelet count, red 
blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration and reticulocyte (%) counts.

Coagulation: INR and aPTT.

Blood chemistry: ALT, AST, total and indirect bilirubin, alkaline phosphatase (ALP), 
gamma glutamyl transpeptidase (GGT; only at Screening), total protein, albumin, 
urea, creatinine, uric acid, total cholesterol, triglycerides, glucose, sodium, chloride, 
potassium, calcium, phosphorus, bicarbonate, cystatin C, HbA1c (only at Screening).

Urinalysis: A midstream, clean-catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leucocytes and pH. If the dipstick result is 2or 
greater for blood, protein or leukocytes, urine will be sent to the laboratory for 
microscopy. If there is an explanation for the positive dipstick result, e.g., menses, it 
should be recorded, and there is no need to perform microscopy.

Substance use: Drugs of abuse urine test and alcohol test (only at Screening and 
Day 1). A breath test may be used to test for alcohol.

Viral serology (only at Screening):
HIV
HAV Ab IgM
HBsAg
HCV Ab

Pregnancy test:
Serum or plasma beta-human chorionic gonadotropin (β-HCG) at Screening, urine 
on all other occasions (females only).

Hormones (only at screening): follicle-stimulating hormone (females only to confirm 
post-menopausal status). 

Thyroid function tests (only at screening): TSH, free T3 and free T4.

Autoimmune panel (only at screening): ANA, AMA, ASMA and thyroid peroxidase 
antibody.
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
4.6.1.6
Pharmacokinetic Assessments
Blood and urine (SAD only) samples for determination of plasma and urine 
concentrations of RO7020531, the main active metabolite RO7011785, and additional 


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metabolites (as applicable) including RO7018822 and RO7033805, will be collected at 
time-points specified in the SoA (Appendix 1, Appendix 2, Appendix 3 and Appendix 4).
RO7020531, RO7011785, RO7018822 and RO7033805 plasma and urine 
concentrations will be measured by a specific and validated method. The plasma PK 
parameter will be read directly from the plasma concentration versus time profiles, or 
calculated using standard non-compartmental methods. Total drug concentrations of 
RO7020531, the main active metabolite RO7011785, and additional metabolites (as 
applicable) including RO7018822 and RO7033805, will be calculated over a 24-hour 
interval.
The volume and pH of urine voided at each interval will be recorded and aliquots will be 
collected from the pooled samples at each time interval for analysis.
Details on sampling procedures, sample storage, and shipment are given in the 
Laboratory Manual.
4.6.1.7
Pharmacodynamic Assessments
Blood samples will be collected to evaluate a number of PD parameters including the 
protein and metabolite markers of humoral response (IFN-, IP-10, TNF-, IL-6, IL-10, 
IL-12p40, and neopterin) and markers of transcriptional responses (ISG15, OAS-1, 
MX1 and TLR7).
Instruction manuals and supply kits will be provided for the collection of all PD samples.
Time-points of PD blood sample collection are provided in the SoA (Appendix 1, 
Appendix 2, Appendix 3 and Appendix 4).
These samples will be stored for up to 5 years for the protocol assessments defined 
above, unless otherwise indicated. Samples will be destroyed no later than 5 years after 
the date of final closure of the clinical database, unless Regulatory Authorities require 
specimens to be maintained for a longer time period.
4.6.1.8
Clinical Genotyping
Instruction manuals and supply kits will be provided for the collection of all biomarker 
samples. One blood sample will be collected before first intake of drug. If sample 
collection was missed, it can be collected at any time thereafter. Collection time is 
provided in the SoA (Appendix 1, Appendix 2, Appendix 3 and Appendix 4). Data arising 
from all biosamples will be subject to the confidentiality standards described in 
Section 8.4.
These samples will be stored for up to 5 years for the protocol assessments defined 
above, unless otherwise indicated. Samples will be destroyed no later than 5 years after 
the date of final closure of the clinical database, unless Regulatory Authorities require 
specimens to be maintained for a longer time period.


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4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study specific screening tests or evaluations. Informed Consent Forms 
for enrolled healthy volunteer and for healthy volunteers who are not subsequently 
enrolled will be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that healthy volunteers meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all healthy volunteers screened and to confirm eligibility 
or record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened healthy volunteer with regard to the protocol’s inclusion and exclusion criteria 
is to be completed by the Investigator and kept at the investigational site.
A screening examination should be performed from Day -28 to Day -2 for SAD and MAD 
parts of the study. Subjects must fulfill all entry criteria to be accepted into the study. 
Assessments as detailed in the SoA (Appendix 1, Appendix 2, Appendix 3 and 
Appendix 4) will be conducted.
4.6.2.2
Assessments during Treatment
Under no circumstances will healthy volunteers who enroll in this study and have 
completed treatment as specified, be permitted to be allocated a new randomization 
number and re-enroll in the study.
All assessments must be performed as per SoA (Appendix 1, Appendix 2, Appendix 3
and Appendix 4).
4.6.2.3
Follow Up Assessments
Healthy volunteers who complete the study (SAD and MAD parts) or discontinue from 
the dosing early (MAD part only) will be asked to return to the clinic approximately 
7 days (1 day) after the last dose of study drug for a follow-up visit and will be 
contacted for a follow-up call approximately 21 days (3 days) after the follow-up visit to 
complete assessments as specified in the SoA (Appendix 1, Appendix 2, Appendix 3
and Appendix 4). After the follow-up call, adverse events should be followed as outlined 
in Section 5.5, Section 5.6.
4.6.2.4
Assessments at Unscheduled Visits
If an unscheduled visit is required for safety reasons, necessary assessments will be 
undertaken at the discretion of the Investigator. All unscheduled assessments should be 
reported in eCRF.
In case of early termination of a subject in MAD part, a blood sample for PK assessment 
may be collected at the time of discontinuation.


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4.7
HEALTHY VOLUNTEER, STUDY, AND SITE DISCONTINUATION
4.7.1
Healthy Volunteer Discontinuation
The Investigator has the right to discontinue a healthy volunteer from RO7020531 or 
withdraw a healthy volunteer from the study at any time. In addition, healthy volunteers 
have the right to voluntarily discontinue study drug (MAD part only) or withdraw from the 
study at any time for any reason. Reasons for discontinuation of study drug or 
withdrawal from the study may include, but are not limited to, the following:

Healthy volunteer withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the healthy volunteer’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the healthy volunteer.

Healthy volunteer non-compliance.
Healthy volunteers in the MAD part of the study who discontinue study treatment due to 
poor tolerability to study drug, or other safety-related reasons will not be replaced. 
Healthy volunteers who discontinue study treatment early for non-safety reasons may be 
replaced to ensure sufficient data to make dose-escalation and drug development 
decisions. 
The decision to replace a subject will be made by a mutual agreement between the 
Sponsor and Investigator.
4.7.1.1
Discontinuation from Study Drug during MAD
For an individual subject in the MAD part of the study, dose continuation will not occur if 
the subject experiences any of the following:

Clinically significant RO7020531-related changes in safety parameters that are 
considered not acceptable by the Investigator and/or the Sponsor; or

Poor tolerability, which is considered to affect the healthy volunteer’s well-being 
and/or the PK evaluation.

Pregnancy.
Healthy volunteers who discontinue study drug prematurely will be asked to return to the 
clinic within 7 days for a follow-up visit to complete follow‑up assessments 
(Section 4.6.2.3). The primary reason for premature study drug discontinuation should 
be documented on the appropriate eCRF. Healthy volunteers who discontinue study 
drug prematurely for safety reasons will not be replaced.
4.7.1.2
Withdrawal from Study
Every effort should be made to obtain information on healthy volunteers who withdraw 
from the study. The primary reason for withdrawal from the study should be documented 
on the appropriate eCRF.


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Healthy volunteers will not be followed for any reason after consent has been withdrawn.
When a subject voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless the subject 
specifically requests for these to be discarded or local laws require their immediate 
destruction.
Healthy volunteers who withdraw from the study for safety reasons will not be replaced. 
Healthy volunteers who withdraw from the study for other reasons may be replaced.
4.7.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to healthy volunteers.

Healthy volunteer enrollment is unsatisfactory.

Previously unknown data become available which raise significant concerns about 
the potential risk to participants from continuation of the study.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following:

Excessively slow recruitment.

Poor protocol adherence.

Inaccurate or incomplete data recording.

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.1.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition).

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline.

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X‑ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies).
5.1.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death).

Life-threatening (i.e., the adverse event, in the view of the Investigator, places the 
subject at immediate risk of death).
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.9).

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the healthy volunteer’s ability to conduct normal 
life functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.

Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
healthy volunteer or may require medical/surgical intervention to prevent one of the 
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The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for 
reporting instructions).
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4 for reporting instructions). Adverse events of special interest for 
this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6.

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product. This term applies only
when a contamination of the study drug is suspected.
5.2
SAFETY PLAN
5.2.1
Management of Specific Adverse Events
Flu-like symptoms: TLR7 agonists can be associated with dose-dependent flu-like 
symptoms. A percentage of healthy volunteers may develop fever, chills, fatigue, 
myalgia, malaise, and headache within several hours after the dosing with RO7020531. 
Symptomatic treatment is recommended in case these events occur.
No dose modification of RO7020531/placebo for safety reasons will be implemented in 
the MAD part of this study. At the discretion of the Investigator, study treatment can be 
discontinued. For the treatment stopping rules in individual healthy volunteers and dose 
escalation stopping rules, please see Section 3.1.3 and Section 4.7.1.1.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1.1) 
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.5 to Section 5.7.
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each healthy volunteer contact. 
All adverse events, whether reported by the healthy volunteer or noted by study 
personnel, will be recorded in the healthy volunteer’s medical record. Adverse events will 
then be reported on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies). Any 
other adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 28 days after the last dose of study drug.
After a period of 28 days from the last dose of study drug, Investigators should report 
any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all healthy volunteer evaluation time‑points. Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing adverse event severity.


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Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the healthy volunteer, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study drug, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study drug.

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug.

Known association of the event with the study drug or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the healthy volunteer or use of concomitant medications 
known to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
healthy volunteer evaluation time‑points. Such events should only be recorded once on 
the Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between subject evaluation time‑points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.


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It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times ULN associated with cholecystitis), only
the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high BP), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 


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changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4).
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a subject with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the subject was last seen alive and stable. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be
replaced by the established cause of death.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the Screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).


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5.3.5.9
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), except as outlined below.
The following hospitalization scenarios are not considered to be serious adverse events:

Planned in-clinic stay required by the protocol for the SAD and MAD parts of the 
study.
5.3.5.10
Overdoses
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events.

Non-serious adverse events of special interest.

Pregnancies.
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.


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
Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.4.1
Emergency Medical Contacts
To ensure the safety of study subjects, access to the Medical monitors is available 
24 hours a day 7 days a week. Medical monitors’ contact details are listed in the 
“Protocol Administrative and Contact Information & List of Investigators”.  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the SAE Responsible immediately 
(i.e., no more than 24 hours after learning of the event).
5.4.2.2
Events That Occur after Study Drug Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(see Section 5.1.2 and Section 5.1.3) that occur after initiation of study drug, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the appropriate Adverse Event of Special 
Interest/ Serious Adverse Event eCRF form and submit the report via the electronic data 
capture (EDC) system. A report will be generated and sent to the Sponsor’s Safety Risk 
Management department.
In the case of electronic reporting, investigators should record all case details that can 
be gathered immediately (i.e., within 24 hours after learning of the event) on the 
appropriate Serious Adverse Event / Adverse Event of Special Interest eCRF form and 
submit the report via the electronic data capture (EDC) system. A report will be 
generated and sent to the Sponsor’s Safety Risk Management department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the SAE Responsible immediately (i.e., no more than 24 hours after 
learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Healthy Volunteers
A female healthy volunteer of childbearing potential will be instructed to immediately 
inform the Investigator if she becomes pregnant during the study, and until the end of the 
follow-up period of 28 days.
A Clinical Trial Pregnancy Reporting Form should be completed by the Investigator and 
submitted to the Sponsor within 24 hours after learning of the pregnancy. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel the subject, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the subject should continue until conclusion 
of the pregnancy.
5.4.3.2
Pregnancies in Female Partners of Male Healthy Volunteer
Male healthy volunteers will be instructed through the Informed Consent Form to 
immediately inform the Investigator if their partner becomes pregnant during the study or 
within 28 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting 
Form should be completed by the Investigator and submitted to the Sponsor within 
24 hours after learning of the pregnancy. Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male healthy 
volunteer exposed to study drug. The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. Once the authorization has been signed, the Investigator will update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy. An Investigator who is contacted by the male healthy 
volunteer or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4)
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.


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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female subject or female partner 
of a male subject exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4).
5.5
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the subject 
is lost to follow-up, or the subject withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the subject’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as 28 days after the last dose of 
study drug). 
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the adverse event reporting period, if the event is believed to be related to prior 
study drug treatment the event should be reported directly to the Sponsor or its designee, 
either by faxing or by scanning and emailing the Serious Adverse Event Reporting Form 
using the fax number or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable Health Authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO7020531 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis of complete data for the study will be performed when all healthy 
volunteers have either completed the follow-up period or have discontinued early from 
the study, all data from the study are in the database and have been cleaned and 
verified, and the database is locked.
6.1
DETERMINATION OF SAMPLE SIZE
Four to six cohorts may be evaluated in the SAD part of the study (approximately 40-60 
subjects in total), and two to three cohorts are anticipated for the MAD part of the study 
with approximately 20-30 subjects in total.
Ten healthy volunteers are planned to be enrolled at each dose level. They will be 
randomized to either active treatment (eight healthy volunteers per dose level) or 
placebo (two healthy volunteers per dose level). With eight healthy volunteers per dose 
group or cohorts, there is a 90% chance to observe at least one AE that has an 
incidence rate of 25% in the population.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of healthy volunteers who are randomized, discontinue, or complete the 
study treatment and/or the entire study (including follow-up period) will be summarized 
by treatment. Reasons for premature study withdrawal during MAD treatment and 
follow-up phase will be listed and summarized by treatment. Enrollment and protocol 
deviations will be listed and evaluated for their potential impact on interpretation of study 
results. Descriptive statistics will be used to evaluate the conduct of the study.


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6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All healthy volunteers who have received at least one dose of the study medication, 
whether prematurely withdrawn from the study or not, will be included in the safety 
analysis.
6.3.2
Pharmacokinetic Analysis Population
A per protocol analysis including all healthy volunteers randomized and adherent to the 
protocol will be performed. Healthy volunteers will be excluded from the pharmacokinetic 
analysis population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol or if data are unavailable or incomplete which may 
influence the pharmacokinetic analysis. Excluded cases will be documented together 
with the reason for exclusion. All decisions on exclusions from the analysis will be made 
prior to database closure.
6.3.3
Pharmacodynamic Analysis Population
PD analysis population will include all subjects who were randomized, received at least 
one dose of study medication (RO7020531 or placebo), and have PD data available. 
Subjects will be analyzed according to the treatment group to which they are randomized. 
6.3.4
Clinical Genotyping Analysis Population
All healthy volunteers who have provided a sample will be included in the analysis. 
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Descriptive statistics will be generated for demographic and baseline disease 
characteristics including sex, age, weight, height, body mass index. 
For continuous variables, mean, standard deviation, median, and minimum and 
maximum values will be presented. For categorical data, the proportion of study subjects 
in each category will be summarized.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor.
Adverse events will be summarized by mapped term and appropriate thesaurus level.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Healthy volunteers listings and summary statistics at each assessment time 


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will be presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
6.5.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
6.5.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in healthy volunteer listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a healthy volunteer, the midpoint of the standard reference range will be 
used as the healthy volunteer’s baseline value for the purposes of determining marked 
laboratory abnormalities. Marked laboratory abnormalities will be labeled in the healthy 
volunteer listings as “HH” for very high or “LL” for very low.
6.5.3
Vital Signs
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.


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Summary descriptive statistics for the actual values and changes from baseline will be 
tabulated by nominal time for HR, QRS duration, PR and QTcF (see Appendix 6). For 
multiple measurements taken at a nominal time-point, the average of these 
measurements will be used as the value at that nominal time-point in all summaries. In 
addition, QTcF will be categorized at each time-point as 450 msec, 450-480 msec, 
480-500 msec and500 msec and summarized. Similarly, a summary will be provided 
of the QTcF changes from baseline at each time-point categorized as30 msec, 
30-60 msec, and60 msec. Changes of the overall ECG interpretation, T-wave and 
U-wave morphology will be summarized.
6.5.5
Concomitant Medications
The original terms recorded on the healthy volunteers’ eCRF by the Investigator for 
concomitant medications will be standardized by the Sponsor by assigning preferred 
terms.
Concomitant medications will be presented in summary tables and listings.
6.6
PHARMACOKINETIC ANALYSES
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Summary descriptive statistics of plasma PK parameters 
including Cmax, Tmax, AUCinf, AUClast and t1/2 for RO7020531 and RO7011785 and 
additional metabolites including RO7018822 and RO7033805, will be presented by 
treatment arm including means, SD, CV, geometric means, medians and ranges. Where 
appropriate, data may be pooled and analyzed. Listings, summary tables and graphs 
(individual plots and/or mean plots) by treatment group will be provided. Descriptive 
statistics of urine PK parameters including total amount excreted; fraction excreted of 
total administered dose; renal clearance for RO7020531 and RO7011875 and additional 
metabolites including RO7018822 and RO7033805 will be presented, where available.
Additional PK analyses, including population PK and/or PD analyses will be conducted 
as appropriate.
6.7
PHARMACODYNAMIC ANALYSES
Summary descriptive statistics will be presented for the induction of cytokines, 
chemokines, and neopterin and of interferon-response genes separately by treatment 
arm. Exploratory analysis will be performed to assess the TLR7 agonist induced 
response under different dosing conditions. Graphical and statistical techniques 
including linear, non-linear, and logistic regression will be used to explore potential 
relationships between dosing regimen, PK and PD.


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6.8
CLINICAL GENOTYPING ANALYSES
Potential PD and/or PK differences will be studied by clinical genotyping, exploring 
whether genetic polymorphisms of drug metabolizing enzymes (such as aldehyde 
oxidases) and TLR7 can be correlated to PK/PD profile of RO7020531.
6.9
INTERIM ANALYSES
There will be no Interim Analysis for this study.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the Electronic Data 
Capture system (EDC) system.
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and/or a Data Management Plan that 
describes the quality checking to be performed on the data. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line Electronic Data Capture (EDC) system. 
The data collected in the source documents is entered onto the study eCRF. An audit 
trail will maintain a record of initial entries and changes made; reasons for change; time 
and date of entry; and user name of person authorizing entry or change. For each 
healthy volunteer enrolled, an eCRF must be completed and electronically signed by the 
Principal Investigator or authorized delegate from the study staff. If a healthy volunteer 
withdraws from the study, the reason must be noted on the eCRF. If a healthy volunteer 
is withdrawn from the study because of a treatment‑limiting adverse event, thorough 
efforts should be made to clearly document the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.


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At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which subject data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subject-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X‑rays, 
subject files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 


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test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local Health Authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. No records may be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for Health Authority submission purposes according to local requirements.
The Consent Forms must be signed and dated by the healthy volunteer or the subject’s 
legally authorized representative before his or her participation in the study. The case 
history or clinical records for each subject shall document the informed consent process 
and that written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes.
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each subject shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.


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A copy of each signed Consent Form must be provided to the subject or the subject’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. In 
addition, any subject recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local Health Authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety‑related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with Health 
Authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the subject, 
unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., after last subject 
last observation).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the Investigator will receive 
the subject data, which includes an audit trail containing a complete record of all 
changes to data.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.3
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for the 
study management, data management, statistical analysis and medical writing for the 
clinical study report.
The Sponsor is also responsible for managing CROs and central laboratories used in the 
study.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission. This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the Investigator.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 


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support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.5
PROTOCOL AMENDMENTS
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or any non-substantial changes, as defined 
by regulatory requirements.


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10.
REFERENCES
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2003;39:S54-S69.
Askar E, Ramadori G, Mihm S. Toll-like receptor 7 rs179008/Gln11Leu gene variants in 
chronic hepatitis C virus infection. J Med Virol. 2010;82:1859-1868.
Berghofer B, Frommer T, Haley G, et al. TLR7 ligands induce higher IFN-production in 
females. J Immunol. 2006;177:2088–2096.
Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B 
virus infections: towards restoration of immune control of viral infection. Gut. 
2012;61:1754–1764.
Boonstra A, Liu BS, Groothuismink ZM. Potent immune activation in chronic hepatitis C 
patients upon administration of an oral inducer of endogenous interferons that acts 
via Toll-like receptor 7. Antivir Ther. 2012;17:657-667.
Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients 
with hepatitis B e antigen-positive chronic hepatitis B. Hepatol. 2010;51:422–430.
Fattovich G, Giustina G, Sanchez-Tapias J. Delayed clearance of serum HBsAg in 
compensated cirrhosis B: relation to interferon alpha therapy and disease 
prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J 
Gastroenterol. 1998;93:896-900.
Fidock MD, Souberbielle BE, Laxton C. The innate immune response, clinical outcomes, 
and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin 
Pharmacol Ther. 2011;89:821-829.
Funk E, Kottilil S, Gilliam B. Tickling the TLR7 to cure viral hepatitis. J Transl Med. 
2014;12:129.
Gane EJ, Lim YS, Gordon SC, et al. The oral toll-like receptor-7 agonist GS-9620 in 
patients with chronic hepatitis B virus infection. J of Hepatology. 2015; 63: 320–
328.
Grippo J, Folitar I, van de Wetering de Rooij J, et al. Optimization of a Phase 2 Study 
Design in Chronic Hepatitis B (CHB) Patients Based on Safety, Pharmacokinetics 
(PK) and Pharmacodynamics (PD) from Phase 1 Studies Using Two Prodrugs of a 
Toll-like Receptor 7 (TLR7) Agonist. 2016; AASLD Abstract nr. 1869.
Horscroft NJ, Pryde DC, Bright H. Antiviral applications of toll-like receptor agonists. J 
Antimicrob Chemother. 2012;67:789-801.
Investigator’s Brochure, RO7020531. 
Isogawa M, Robek MD, Furuichi Y, et al. Toll-like receptor signaling inhibits hepatitis B 
virus replication in vivo. J Virol. 2005;79:7269–7272.


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Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. 
Nat Immunol. 2004;5:987-995.
Kawasaki A, Furukawa H, Kondoet Y, et al. TLR7 single-nucleotide polymorphisms in 
the 3’untranslated region and intron 2 independently contribute to systemic lupus 
erythematosus in Japanese women: a case-control association study. Arthritis 
Research & Therapy. 2011;13:R41.
Lester SN, Li K. Toll-like receptors in antiviral innate immunity. J Mol Biol. 
2014;426:1246-1264.
Locarnini S, Zoulim F. Molecular genetics of HBV infection. Antivir Ther. 2010;15:3–14.
Lucifora J, Xia Y, Reisinger F. Specific and nonhepatotoxic degradation of nuclear 
hepatitis B virus cccDNA. Science. 2014;343:1221-1228.
Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir 
disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. 
Lancet. 2013;381:468–475.
Martinot-Peignoux M, Carvalho-Filho R, Lapalus M. Hepatitis B surface antigen serum 
level is associated with fibrosis severity in treatment-naïve, e antigen-positive 
patients. J Hepatol. 2013;58:1089-1095.
Ott JJ, Stevens GA, Groeger J. Global epidemiology of hepatitis B virus infection: New 
estimates of age-specific HBsAg seroprevalence and endemicity. J Vaccine. 
2012;30:2212–2219.
Papatheodoridis G, Buti M, Cornberg M, et al. EASL clinical practice guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-185.
Papatheodoridis GV, Manolakopoulos S, Dusheiko G. Therapeutic strategies in the 
management of patients with chronic hepatitis B virus infection. Lancet Infect Dis. 
2008;8:167-178.
Sarin SK, Kumar M, Lau GK, at al. Asian-Pacific clinical practice guidelines on the 
management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98.
Strader DB, Wright T, Thomas L, et al. Diagnosis, management and treatment of 
hepatitis C. Hepatol. 2004;39:1147-1171.
Tayama Y, Sugihara K, Sanoh S. Effect of tea beverages on aldehyde oxidase activity. 
Drug Metab Pharmacokinet. 2011;26:94-101.
Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic 
hepatitis B. Hepatol. 2016;63:261-283.
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Tseng TC, Liu CJ, Yang HC. High levels of hepatitis B surface antigen increase risk of 
hepatocellular carcinoma in patients with low HBV load. Gastroenterol. 
2012;142:1140-1149.
Wang XY, Chen HS. Emerging antivirals for the treatment of hepatitis B. World J 
Gastroenterol. 2014;20:7707-7717.
Wasley A., Kruszon-Moran D, Kuhnert W. The Prevalence of Hepatitis B Virus Infection 
in the United States in the Era of Vaccination. J Infect Dis. 2010;202:192-201.
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World Health Organization. Hepatitis B. World Health Organization Fact Sheet. Updated 
July 2016.


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Appendix 1 Schedule of Assessments: SAD
Visit
Screening
Follow Up 
Visit
Follow Up 
Call
Day
D-28 to D-2
Day -1
Day 1
Day 2
Day 3
Day 5
Day 8a
Day 29b
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationc
x
x
x
Vital Signsd
x
x
7
2
x
x
ECG-12 leade
x
x
7
x
x
x
Plasma PK Sample
12
2
x
Urine PK Sample
5
x
PD for Protein Biomarkers
x
4
x
xf
xf
x
Whole Blood for RNA
x
4
x
x
Hematology, Blood Chemistry, Coagulation, Urinalysis
x
x
x
x
Pregnancy Testg
x
x
x
Administration of Study Medicationh
x
Randomisation
x
Autoimmune panel, Thyroid Function
x
Viral Serology (HAV, HBV, HCV, HIV)
x
Follicle Stimulating Hormonei
x
Substance Usej
x
x
In-Clinic Stayk
x
x
x
x
Ambulatory Visit
x
x
x
Clinical Genotypingl
x
Adverse Eventsm
xm
xm
x
x
x
x
x
x
Previous and Concomitant Treatments
x
x
x
x
x
x
x
x
Treatment Period


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Appendix 1 Schedule of Assessments: SAD (cont.)
a)
A follow-up visit to be completed 7 days (1) after the last dose of study medication.
b)
A follow-up call to be completed 28 days (3) after the last dose of study medication.
c)
Full physical examination, including recording of weight, is required at Screening, Day1 and Follow-Up visit. At all other visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed at the discretion of the Investigator. Height will only be 
recorded at Screening. BMI will be calculated at Screening.
d)
Vital signs include blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure, respiratory rate and pulse rate will be 
obtained after the subject has been in a supine or sitting position for at least 5 minutes. Blood pressure measurement will be performed in 
triplicate (can be as short as 20-second to 1-minute interval between measurements). Pulse rate and body temperature measurement will be 
performed as single assessments.
e)
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 2-5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
f)
PD samples at 48 and 96 hours for neopterin only (no other PD markers).
g)
Serum or plasma beta-human chorionic gonadotropin (‑HCG) at Screening, urine on all other occasions (females only).
h)
Study drug will be administered in fasted state (after an overnight fast of at least 10 hours).
i)
Follicle-stimulating hormone (females only to confirm post‑menopausal status, performed at screening only).
j)
At Screening and Day1 only (drugs of abuse and alcohol test).
k)
Subjects will be admitted to the unit on Day1 to start time-matching ECG assessments. The discharge from the unit will be on Day 3 after 
48-hour assessments.
l)
If the clinical genotyping blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
m) At Screening, Day2 and Day1, only serious adverse events caused by a protocol-mandated intervention should be reported.


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Appendix 2 Schedule of Assessments: SAD Detailed
Visit
Day
Scheduled 
Time (h)
Vital Signsa
ECG-12 leadb
Hematology, Blood 
Chemistry, 
Coagulation, 
Urinalysis
Plasma PK 
Samplec
Urine PK 
Sampled
PD for 
Protein 
Biomarkerse
Whole Blood 
for RNAe
Clinical 
Genotypingf
Administration 
of Study 
Medicationg
Day -1
x
x
x
x
x
Predose
x
x
x
x
x
x
x
0
x
0.25
x
0.5
x
x
x
1
x
x
x
1.5
x
2
x
x
x
x
x
3
x
4
x
x
x
6
x
x
x
x
x
8
x
12
x
x
x
8-12
x
x
18
x
24
x
x
x
x
x
x
36
x
x
Day 3
48
x
x
x
x
Day 5
96
x
Follow Up 
Visit
Day 8h
x
x
x
x
x
Day 1
Day 2
0-4
4-8
12-24


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Appendix 2 Schedule of Assessments: SAD Detailed (cont.)
a)
Vital signs include blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure, respiratory rate and pulse rate will be 
obtained after the subject has been in a supine or sitting position for at least 5 minutes. Blood pressure measurement will be performed in 
triplicate (can be as short as 20-second to 1-minute interval between measurements). Pulse rate and body temperature measurement will be 
performed as single assessments.
b)
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs within a 2-5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
c)
Plasma PK samples will be collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 hours post-dose.
d)
A single void urine sample will be collected pre-dose on Day 1. Pooled urine PK samples will be collected 0 to 4 hours, 4 to 8 hours, 8 to 
12 hours and 12 to 24 hours post-dose.
e)
PD samples will be collected at pre-dose, 2, 6, 12, 24, 48 and 96 hours post-dose and follow up visit. Samples at 48 and 96 hours post-dose 
will be collected for neopterin only (no other PD markers).
f)
If the clinical genotyping blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
g)
Study drug will be administered in fasted state (after an overnight fast of at least 10 hours).
h)
A follow up visit to be completed 7 days (1) after the last dose of study medication.


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Appendix 3
Schedule of Assessments: MAD
Visit  
Screening
Follow Up 
Visit
Follow Up 
Call
Day
D-28 to D-2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 20a
Day 41b
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationc
x
x
x
x
x
Vital Signsd
x
x
6
x
4
x
2
x
2
x
2
x
2
x
6
x
x
ECG-12 leade
x
x
6
3
x
6
x
Plasma PK Sample
12
x
3
x
3
x
3
x
3
x
3
x
12
x
PD for Protein 
Biomarkers
x
4
x
3
x
3
x
3
x
3
x
x
Whole Blood for RNA
x
4
x
3
x
3
x
3
x
3
x
x
Hematology, Blood 
Chemistry, Coagulation, 
Urinalysis
x
x
x
x
x
x
x
x
Pregnancy Testf
x
x
x
Administration of Study 
Medicationg
x
x
x
x
x
x
x
In-Clinic Stayh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ambulatory Vist
x
x
Randomisation
x
Autoimmune panel, 
Thyroid function
x
Viral Serology ( HAV, 
HBV, HCV, HIV)
x
x
Follocle Stimulating 
Hormonei
x
Substance Usej
x
x
Clinical Genotypingk
x
Adverse Events
xl
xl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Previous and 
Concomitant 
Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Treatment Period


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Appendix 3 Schedule of Assessments: MAD (cont.)
a)
A follow-up visit to be completed 7 days (1) after the last dose of study medication.
b)
A follow-up call to be completed 28 days (3) after the last dose of study medication.
c)
Full physical examination, including recording of weight, is required at Screening, Day 1 and Follow-Up visit. At all other visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed at the discretion of the Investigator. Height will only be 
recorded at Screening. BMI will be calculated at Screening.
d)
Vital signs include blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure, respiratory rate and pulse rate will be 
obtained after the subject has been in a supine or sitting position for at least 5 minutes. Blood pressure measurement will be performed in 
triplicate (can be as short as 20-second to 1-minute interval between measurements). Pulse rate and body temperature measurement will be 
performed as single assessments.
e)
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12‑lead ECGs within a 2-5 minute interval) after the subject has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented.
f)
Serum or plasma beta‑human chorionic gonadotropin (-HCG) at Screening, urine on all other occasions (females only).
g)
Study drug will be administered in fasted state (after an overnight fast of at least 10 hours).
h)
Subjects will be admitted to the unit on Day2 to start time-matching ECG assessments in the morning of Day1. Subjects will stay in the unit 
till Day 14, with the first dose given on Day 1 and last dose given on Day 13.
i)
Follicle-stimulating hormone (females only to confirm post-menopausal status, performed at screening only).
j)
At Screening and Day1 only (drugs of abuse urine test and alcohol test).
k)
If the clinical genotyping blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
l)
At Screening, Day2 and Day1, only serious adverse events caused by a protocol-mandated intervention should be reported.


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93/Protocol YP39553, Version 2
Appendix 4 Schedule of Assessments: MAD Detailed
Period
Day
Scheduled 
Time (h)
Vital 
Signsa
ECG-12 
leadb
Hematology, 
Blood 
Chemistry, 
Coagulation, 
Urinalysis
Plasma PK 
Samplec
PD for 
Protein 
Biomarkersd
Whole Blood 
for RNAd
Clinical 
Genotypinge
Administration 
of Study 
Medicationf
Day -1
x
x
x
x
x
Predose
x
x
x
x
x
x
0
x
0.25
x
0.5
x
x
x
1
x
x
x
1.5
x
2
x
x
x
x
x
3
x
4
x
x
x
6
x
x
x
8
x
12
x
x
x
x
x
18
x
Day 2
24
x
x
x
x
Predose
x
x
x
x
x
0
x
2
x
x
x
x
x
4
x
x
6
x
x
x
x
Day 4
24
x
x
x
x
x
Predose
x
x
x
x
0
x
2
x
x
x
6
x
x
x
x
Day 6
24
x
x
x
x
Predose
x
x
x
x
x
0
x
2
x
x
x
6
x
x
x
x
Day 8
24
x
x
x
x
x
Predose
x
x
0
x
2
x
6
x
x
Day 10
24
x
x
Predose
x
x
x
0
x
2
x
6
x
x
Day 12
24
x
x
Predose
x
x
x
x
x
x
0
x
0.25
x
0.5
x
x
x
1
x
x
x
1.5
x
2
x
x
x
x
x
3
x
4
x
x
x
6
x
x
x
8
x
12
x
x
x
18
x
Day 14
24
x
x
x
x
x
Follow Up 
Visit
Day 20g
x
x
x
x
x
Treatment 
Period
Day 1
Day 3
Day 5
Day 7
Day 9
Day 11
Day 13


RO7020531—F. Hoffmann-La Roche Ltd
94/Protocol YP39553, Version 2
Appendix 4 Schedule of Assessments: MAD Detailed (cont.)
a)
Vital signs include blood pressure, pulse rate, respiratory rate and body temperature. Blood 
pressure, respiratory rate and pulse rate will be obtained after the subject has been in a 
supine or sitting position for at least 5 minutes. Blood pressure measurement will be 
performed in triplicate (can be as short as 20-second to 1-minute interval between 
measurements). Pulse rate and body temperature measurement will be performed as single 
assessments.
b)
12-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs 
within a 2-5 minute interval) after the subject has been in a supine position for at least 
10 minutes. Automated ECG intervals (PR (PQ), QRS, QT, QTcF) and HR will be captured or 
calculated, and the changes in T-wave and U-wave morphology will be documented.
c)
Plasma PK samples will be collected: pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 and 
24 post-dose from Day 1 to Day 2 and from Day 13 to Day 14. On Days 3, 5, 7, 9, and 11, 
samples for PK will be taken at pre‑dose and 2, 6 and 24 hours post-dose.
d)
PD samples will be collected: pre-dose and 2, 6, 12 and 24 post-dose from Day 1 to Day 2. 
On Days 3, 5, 7 and 13 samples for PD will be taken at pre‑dose and 2, 6 and 24 hours 
post-dose. PD samples will be collected on follow-up visit.
e)
If the clinical genotyping blood sample is not collected at Day 1, it may be collected at any 
time during the conduct of the clinical study.
f)
Study drug will be administered in fasted state (after an overnight fast of at least 10 hours). 
g)
A follow-up visit to be completed 7 days (1) after the last dose of study medication.


RO7020531—F. Hoffmann-La Roche Ltd
95/Protocol YP39553, Version 2
Appendix 5 Formula for Calculation of BMI
BMI =
Weight (kg)
Height (m)2
Unit Conversion: 1 kg 
= 2.2 lbs
1 inch = 2.54 cm
Example:
BMI of a subject being 1.70 m tall and weighing 80 kg:
80kg
= 27.7 kg/m2
(1.70m)2
The subject’s standing height will be measured in bare feet standing with his/her heels 
and back in contact with the vertical bar of a wall mounted measuring device. The head 
is held so the subject looks straight forward. A level will be placed on the subject’s head 
to ensure that the subject is looking straight forward. The point at which the lower 
surface of the level intersects with the vertical measuring device will be the standing 
height.


RO7020531—F. Hoffmann-La Roche Ltd
96/Protocol YP39553, Version 2
Appendix 6 Correction Formulas for QTc Intervals
Fridericia’s correction for QTc Measurement - QTcF
QTcF (msec) =
QT (msec)
3
1000
/)
msec
(
RR
Example:
QTcF of a subject with a QT of 386 msec and a RR of 848 msec
QT (msec) = 386
RR (msec) = 848
QT (msec)
=
408 msec
3
1000
/)
msec
(
RR


RO7020531—F. Hoffmann-La Roche Ltd
97/Protocol YP39553, Version 2
Appendix 7 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:
Males (ml/min) =
(140 – Age) * ABW (kg)
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 (mol/L) / 88.4
SI Units (mol/L) = Conventional Units × 88.4


RO7020531—F. Hoffmann-La Roche Ltd
98/Protocol YP39553, Version 2
Appendix 8 Alcohol Volume Calculation
This appendix is to facilitate the assessment of exclusion criterion in Section 4.2.3. It 
shows a calculation for the study entry assessment on whether a subject drinks more 
than two standard drinks per day.
A standard drink is any drink containing 10 grams of alcohol. One standard drink always 
contains the same amount of alcohol regardless of container size or alcohol type, that is 
beer, wine, or spirit.
The formula for calculating standard drinks:
Number of standard drinks = Volume (liter) x Vol% of alcoholic beverage x 0.789 
For example, one bottle of 375 mL of full strength beer 5% alcohol by volume equals to 
1.5 standard drinks:
0.37550.7891.5 standard drinks