Clinical trial NCT03505190
Conditions: Healthy Participants
Sponsor: Hoffmann-La Roche
Start date: 2018-05-03; Completion date: 2019-07-05
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This randomized study will evaluate the safety, tolerability and pharmacokinetics of single ascending subcutaneously administered doses of RO7062931 in healthy volunteers.

Detailed description:

Arms: arm 1: Participants will receive subcutaneously (SC) 0.3 milligram per kilogram (mg/kg) of RO7062931. arm 2: Participants will receive subcutaneously (SC) 1.0 milligram per kilogram (mg/kg) of RO7062931. arm 3: Participants will receive subcutaneously (SC) 2.0 milligram per kilogram (mg/kg) of RO7062931. arm 4: Participants will receive subcutaneously (SC) 4.0 milligram per kilogram (mg/kg) of RO7062931. arm 5: Participants will receive matching placebo.
Interventions: intervention 1: RO7062931 intervention 2: Placebo
Intervention descriptions: intervention 1: RO7062931 will be administered SC in single ascending doses with starting of 0.3 mg/kg and subsequent doses of 1.0 mg/kg, 2.0 mg/kg and 3.0 mg/kg, respectively. Additional (optional) dose of 4.0 mg/kg may be administered based on safety, tolerability and PK data. intervention 2: Matching placebo will be administered subcutaneously (SC).

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Randomized, Sponsor-Open, Investigator-Blind, Subject-Blind, 
Placebo-Controlled, Single Ascending Dose, to Investigate the Safety, 
Tolerability and Pharmacokinetics of RO7062931 Following 
Subcutaneously Administration in Healthy Chinese Volunteers 
NCT Number: 
NCT03505190 
Document Date: 
Protocol Version 2: 29-November-2017 
 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7062931 —F. Hoffmann-La Roche Ltd
Protocol YP39432, Version 2
PROTOCOL
TITLE:
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR–
BLIND, SUBJECT-BLIND, PLACEBO-CONTROLLED, 
SINGLE ASCENDING DOSE, TO INVESTIGATE THE 
SAFETY, TOLERABILITY AND PHARMACOKINETICS
OF RO7062931 FOLLOWING SUBCUTANEOUSLY 
ADMINISTRATION IN HEALTHY CHINESE 
VOLUNTEERS
PROTOCOL NUMBER:
YP39432
VERSION:
2
TEST PRODUCT:
RO7062931
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 9 January 2017
Version 2: See electronic date stamp below
 
29-Nov-2017 12:43:38
(
)
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7062931—F. Hoffmann-La Roche Ltd
2/Protocol YP39432, Version 2
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR–
BLIND, SUBJECT-BLIND, PLACEBO-CONTROLLED, 
SINGLE ASCENDING DOSE, TO INVESTIGATE THE 
SAFETY, TOLERABILITY AND PHARMACOKINETICS
OF RO7062931 FOLLOWING SUBCUTANEOUSLY 
ADMINISTRATION IN HEALTHY CHINESE 
VOLUNTEERS
PROTOCOL NUMBER:
YP39432
VERSION NUMBER:
2
TEST PRODUCT:
RO7062931
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
study monitor.


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PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE
Protocol YP39432 has been amended to incorporate the following changes:
Substantial changes

One cohort with a projected dose of 3.0 mg/kg and an optional cohort with a 
projected dose of 4.0 mg/kg have been added, in response to newly available 
pharmacokinetic data in the ongoing global study BP39405 (Sections 3.1.1, 3.2.1, 
6.1 and Figure 1).
 
 Both doses were 
considered to be safe and well tolerated in participants enrolled in study BP39405. 
This change will align this protocol with the ongoing global study.

A dose escalation stopping rule has been added to Section 3.1.2.2 ‘Dose Escalation 
Stopping Criteria’ in response to feedback from the pre-IND meeting with the 
Chinese Center for Drug Evaluation (CDE). 

The follow up period has been extended in all clinical studies with RO7062931 to 
proactively collect long term safety data. The follow up period for this protocol has 
been extended to include a follow up visit on Study Day 85, which is consistent with 
four times the estimated liver tissue half-life of RO7062931 (Section 4.6.2.3 and 
Appendix 1 and 2). This change is not triggered by any new safety data.

Additional specification of normal ranges for liver and renal function tests, which are 
two of the organs where toxicities were observed in the pre-clinical toxicology 
studies, as follows:
–
The entry safety criteria have been set within the normal ranges for liver and 
renal function tests (Section 4.2.3).
–
Addition of renal safety variable ‘calculated creatinine clearance’ (Section 
4.6.1.5).

Information from the addendum to the Investigator’s Brochure has been 
incorporated, including new toxicology data (Section 1.2.1) and new information on 
drug color (Section 4.4.1.1). 

Additional details for the grading of pre-defined injection site reaction symptoms 
have been added (Section 5.3.5.1 and Appendix 4).
Clarification of study procedures

The dose escalation/review meetings will take place after receipt of Day 29 safety 
data to simplify study conduct and data evaluation (Section 3.1.2).

A cut-off value has been assigned for follicle-stimulating hormone in Inclusion 
Criterion 4 (Section 4.2.2).

Exclusion Criteria 3, 4, 5, 6, 7 and 8 have been updated since tests/assessments 
are done both at Screening and at Day 1 (Section 4.2.3).


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
Concomitant therapy and food has been modified to remove duplications and 
provide clarity (Section 4.5).

Correction of inconsistencies in the method for measurement of blood pressure and 
pulse rate (Section 4.6.1.3).

Urine microscopy is performed on all urine samples for this study, irrespective of the 
dipstick result (Section 4.6.1.5).

Those healthy volunteers who have completed the study dose, or who discontinue 
from the study early, will be encouraged to attend the clinic for long term follow up 
(Section 4.6.2.3). 

To accommodate sites in the preparation of the study drug, if the sites prefer, they 
could randomize and prepare the study drug the day before dosing. Stability of the 
prepared study drug allows for this. Therefore randomization will also be allowed on 
Day 1 (Appendix 1). 

Due to the long follow up period the following visit windows will be applicable to the 
follow up visits, to allow flexibility to the study participants and sites with scheduling: 
Day 15 1 Day, Day 29 2 Days, Day 85 1 week (Appendix 1). 

Blood PK sampling on Day 15 and Day 29 have been deleted (Appendix 1).

Modification of text to update the SAE reporting tool (Section 5.4.2.2).
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 






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1.3.2
Benefit–Risk Assessment
No prior Limited clinical experience with RO7062931 currently exists. The evaluation of
the potential risks of drug administration and the specific tests, observations, and 
precautions required for this clinical study with RO7062931 will be based on information 
from non-clinical toxicology and safety pharmacology studies as well as available data 
from the FIH study BP39405. 
3.1.1
Overview of Study Design
This study is randomized, Sponsor-open, Investigator-blind and subject-blind. Up to four 
five ascending dose-levels (cohorts) will be explored within the dose-range shown to be 
safe and well-tolerated in Study BP39405. The planned doses for the first three four 
cohorts will be 0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg and 3.0 mg/kg, respectively (see Figure 
1). The planned dose-levels may be modified and an additional (optional, 4.0 mg/kg) 
cohort enrolled based on emerging results from ongoing preclinical and clinical studies
(including this study). The dose level for the optional Cohort 4 will be determined based 
on all available safety and PK data from Cohorts 1 3, as well as data collected from
Study BP39405, however without exceeding a 3 fold increase of the dose administered 
in Cohort 3.
It is planned to enroll 10 HVs in each cohort; eight HVs will receive RO7062931 and two 
will receive placebo. Sentinel dosing will be employed in each cohort, where two 
subjects will be dosed on Day 1, of which at least one HV will receive RO7062931 in 
order to monitor for potential acute injection reactions. The remaining 8 subjects will be
dosed on the following day (24 hours after the initial administrations) following 
satisfactory safety assessment of the first two HVs by the Investigator. The sentinel 
dosing requirements may be modified based on the data from Study BP39405.
Figure 1.
Study Design
Figure 1 now reflects the addition of one cohort and specification of the dose for the 
optional cohort.
The total duration of the study for each HV will be up to 8 16 weeks divided as follows:

Screening: Up to 4 weeks;

In-Clinic period: Days -1 to 3;

Safety Follow-up: up to at least Day 29 85
3.1.2
Dose Escalation Decisions
Dose-escalation/review meetings will be conducted by the Investigator, the Medical 
Monitor, and the Sponsor Clinical Team prior to each RO7062931 dose-escalation (see 
Section 3.1.2.1). The actual doses may be modified based on emerging data from this 
study, and emerging results from ongoing preclinical studies and Study BP39405.
Escalation to the next dose cohort will be based primarily on the review of safety and 
tolerability information (including adverse events, electrocardiograms [ECGs], vital signs, 
clinical laboratory test results) collected at least up to 28 days post-dose 
(Day 29 2 Days) and, all available PK data collected at least 7 days post-dose in a




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starting-dose not expected to exhibit liver saturation up through higher doses shown or 
anticipated to be safe in humans (i.e., 0.3-24.0 mg/kg or higher), is believed to increase 
the chances of identifying the 
, which would greatly inform 
the dosing regimen for subsequent studies in Chinese CHB patients. 
 
 
 
 
 
 
 
 
 It has been shown in preclinical rat and monkey studies 
that once the specific receptor-mediated uptake in the liver is saturated, RO7062931 is 
taken up more readily into other organs. Minimizing this non-specific organ uptake by 
dosing 
 is thought to result in a better risk/benefit profile in 
CHB patients.
4.2.2
Inclusion Criteria
4.
Women should be of non-childbearing potential. A woman is considered to be of 
childbearing potential if she is post menarcheal but has not reached aThese include 
those who have undergone surgical sterilization (removal of ovaries and/or uterus)
or are post-menopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause, confirmed by follicle-stimulating hormone 
[FSH] ≥LLN (Local Lab), or amenorrhea for at least 24 months if on hormone 
replacement therapy [HRT])., and has not undergone surgical sterilization (removal 
of ovaries and/or uterus).
4.2.3
Exclusion Criteria
3.
Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone, 
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or 
positive cotinine test at Screening or Day -1.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency 
virus (HIV)-1 and -2 at Screening.
5.
Confirmed (e.g., two consecutive triplicate measurements) average systolic blood 
pressure (SBP)140 or90 mmHg, and diastolic blood pressure (DBP)90 
or45 mmHg at Screening or Day -1.
6.
Confirmed (e.g., two consecutive triplicate measurements) average resting pulse 
rate > 90 or < 45 beats per minute (bpm) at Screening or Day -1.
7.
A personal history of unexplained blackouts or faints, or known risk factors for 
Torsade de Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal 
ECG, including arrhythmias or marked QT abnormalities (QTcF < 300 msec 
or450 msec at Screening or Day -1).


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8.
ECG morphology at screening or Day -1 that renders measurement of QT interval 
imprecise (e.g., neuromuscular artifact that cannot be readily eliminated, indistinct 
QRS onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves, 
arrhythmias, etc.).
9.
Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right 
or left bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Any out of range findings in liver function tests, INR and renal function tests or 
any clinically significant abnormalities (as judged by the Investigator) in the physical 
examination and in the remaining laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel and urinalysis) at Screening and or 
on Day-1. Abnormal renal function including serum creatinine ULN (Local Lab) 
or calculated creatinine clearance 70 mL/min (using the Cockcroft Gault formula).
4.4.1.1 RO7062931 and Placebo
RO7062931 and placebo investigational medicinal products (IMPs) to be used in the 
study will be provided by Roche. 
 
 
 As the formulation contains no preservatives, it 
should be diluted under appropriate aseptic conditions. An in-line filter must be used 
prior to administration (see Pharmacy Manual for further details).
4.5 CONCOMITANT THERAPY AND FOOD
The following restrictions for HVs should be maintained:

Any prescribed or over the counter (OTC) medication, vitamins, fish oils, protein 
powders, including herbal remedies, taken within 2 weeks prior to study drug 
administration (with the exception of HRT, which is allowed throughout the study). 
Paracetamol (up to 1 g per day) will be allowed. 

However, in the event that a HV requires additional medication during the course of 
the trial, this may be allowed after consultation with the Investigator and Sponsor.
There are no other concomitant treatment restrictions at this time as no drug drug
interactions are foreseen for RO7062931.
It is unlikely that food will have an impact on the PK of RO7062931, however, 
RO7062931 should be administered in a fasted state. (It is unlikely that food will have an 
impact on the PK of RO7062931, however, RO7062931 should be administered in a 
fasted state [i.e., 2 hours before, or, 2 hours after a meal]).
4.5.1
Permitted Therapy
Concomitant therapy includes any mediation, e.g., prescription drugs, OTC drugs, 
approved dietary and herbal supplements, nutritional supplements used by a HV from 30 
days prior to screening until the follow up visit (with some restrictions as given above, 
see Section 4.5).


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Patients will be permitted to use the following therapies during the study:

Hormone-replacement therapy

Paracetamol (up to 1 g per day)

Medications used to treat an AE may only be prescribed after consultation with the 
Sponsor (with the exception of 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).
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF.
4.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be prohibited due to no foreseen 
RO7062931 drug drug interactions, however the restrictions described in Section 4.5 
apply.
Use of any prescribed or over-the-counter (OTC) medication, vitamins, fish oils, 
protein powders, including herbal remedies; taken within 2 weeks prior to first study 
drug administration, with the exceptions of therapies listed in Section 4.5.1. However, 
in the event that a HV requires additional medication during the course of the trial, 
this may be allowed after consultation with the Investigator and Sponsor. 
There are no other concomitant treatment restrictions at this time as no drug-drug
interactions are foreseen for RO7062931.
4.5.3
Prohibited Food
There are no prohibited foods.
It is unlikely that food will have an impact on the PK of RO7062931, however, 
RO7062931 should be administered in a fasted state (i.e., 2 hours before, or, 2 hours 
after a meal).
4.6.1.3 Vital Signs
Vital signs will be obtained after the subject has been resting in a supine position for at 
least 10 minutes. 
Blood pressure (BP; systolic and diastolic), pulse rate and body temperature (tympanic) 
will be recorded at the time-points specified in the Schedule of Assessments tables (see 
Appendix 1 and Appendix 2). Blood pressure and pulse rate will be performed in 
triplicate (can be as short as 20 seconds to 1-minute interval between measurements)


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and recorded in eCRF. The mean of three consecutive replicates will be used as the
value for the defined time point. Vital signs should be measured prior to blood draw. 
When possible, the same arm should be used for all blood pressure measurements.
Blood pressure and pulse rate should be obtained in a quiet room at a comfortable 
temperature, with the subject's arm unconstrained by clothing or other material. Where 
possible all measurements will be obtained from the same arm and, with the same cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (the “ideal” cuff should have a bladder length that is 80% and a width that is at 
least 40% of arm circumference [a length-to-width ratio of 2:1]). The study subject should 
be asked to remove all clothing that covers the location of cuff placement. The individual 
should be comfortably seated, with the legs uncrossed, and the back and arm supported, 
such that the middle of the cuff on the upper arm is at the level of the right atrium (the 
mid point of the sternum).
4.6.1.5 Laboratory Assessments
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. The following blood and urine 
samples will be collected:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), mean 
corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration 
(MCHC).

Blood chemistry: ALT, AST, total and indirect bilirubin, alkaline phosphatase (ALP), 
blood urea nitrogen (BUN), gamma-glutamyl transferase (GGT) (at Screening only), 
creatine phosphokinase (at Screening only), total protein, albumin, creatinine and
calculated creatinine clearance using Cockcroft Gault formula, glomerular filtration
rate (GFR) calculated, uric acid, cystatin c, fasting glucose, total cholesterol, low
density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, 
triglycerides, sodium, chloride, potassium, calcium, magnesium, phosphate and 
bicarbonate. 

Coagulation: prothrombin time (PT), International Normalized Ratio (INR), activated 
partial thromboplastin time (aPTT).

Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocytes, specific gravity and pH. All urine 
samples will also be sent to the laboratory to perform microscopy to examine urine 
sediment for casts and cells. If there is a clinically significant positive dipstick result, 
(i.e., confirmed by a positive repeated sample), urine will be sent to the laboratory 
for microscopy and culture. 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.


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Urine color may be evaluated from urinalysis or urine PK samples if considered 
necessary. Urinary sediment (casts, cells).
4.6.1.8 Other Assessments
The following urinary kidney biomarkers will be analyzed from urine samples:  
α1-microglobulin, β2-microglobulin, and KIM-1. Each biomarker will be normalized to 
urine creatinine.
4.6.2.3 Follow-Up Assessments and Study Completion
HVs who complete the study, or who discontinue from the study early, will be 
encouraged to attend the clinic for long term follow up as per the SOA in Appendix 1. 
will be asked to return to the clinic after the dose of study drug for a follow up visit.
5.3.5.1 Diagnosis versus Signs and Symptoms
Injection Site Reactions
Adverse events that occur during or after study drug administration and are judged to be 
related to the SC study drug injection should be captured as a diagnosis (e.g., “injection 
reaction") on the Adverse Event eCRF. If possible, avoid ambiguous terms (such as 
"systemic reaction"). Associated signs and symptoms should be recorded on the 
dedicated Injection Reaction eCRF. Grading of pre-defined injection site reaction 
symptoms is described in Appendix 4. If a subject experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on 
the Adverse Event eCRF, with signs and symptoms also recorded separately on the 
dedicated Injection Reaction eCRF.
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”. Medical 
monitors’ contact details will be available on a separate list generated by the study 
management team.
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 Sections 5.1.2 and 5.1.3) that occur after initiation of study drug, investigators 
should record all case details that can be gathered on the Serious Adverse Reporting 
Form and forward this form to the Serious Adverse Event Responsible within 24 hours.


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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.
6.1 DETERMINATION OF SAMPLE SIZE
The planned sample size of 8 active per cohort was chosen not only to allow adequate 
assessment of safety and tolerability but also to increase the precision of the estimates 
of mean PK and urinary parameters, as comparisons of these parameters across doses 
will be used in part 
. 
Up to 40 50 HVs will be included in this study. Up to 4 5 cohorts of 10 HVs (8 on active 
and 2 on placebo per dose level) are planned with the fourth fifth and last cohort being 
optional and based on the analysis of emerging PK and safety data from this study and
available data from study BP39405.
Appendix 1
Schedule of Assessments – Main table
The table has been updated to include follow up visit Day 85, visit window and deletion 
of the blood PK sampling on Day 15 and Day 29. The possibility for randomization has 
also been added on Day -1.
Appendix 2
Schedule of Assessments –Detailed table
The table has been updated to include: follow up visit Day 85; the time windows Day 
15 1day, Day 29 2days, Day 85 1week. Columns for drug-induced antibodies, ADA, 
urine kidney biomarkers and blood liver biomarkers and rows for 'Screening' and 
'Day 1' are added for clarification. 
Appendix 4
Toxicity Table for Grading Injection Reactions
A new appendix has been added with a table for grading injection reactions.


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 21
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 27
1.
BACKGROUND AND RATIONALE............................................... 30
1.1
Background on Disease........................................................... 30
1.2
Background on RO7062931 .................................................... 31
1.2.1
Previous Non-Clinical Studies.................................................. 31
1.2.2
Previous Clinical Studies ......................................................... 33
1.3
Study Rationale and Benefit–Risk Assessment....................... 33
1.3.1
Study Rationale ....................................................................... 33
1.3.2
Benefit–Risk Assessment ........................................................ 34
2.
OBJECTIVES................................................................................ 35
2.1
Primary Objectives................................................................... 35
2.2
Secondary Objectives.............................................................. 35
3.
STUDY DESIGN ........................................................................... 35
3.1
Description of Study................................................................. 35
3.1.1
Overview of Study Design........................................................ 35
3.1.2
Dose- Escalation Decisions ..................................................... 36
3.1.2.1
Dose-Escalation Decision Criteria ........................................... 36
3.1.2.2
Dose-Escalation Stopping Criteria ........................................... 37
3.1.3
Communication Strategy.......................................................... 38
3.1.4
End of Study ............................................................................ 38
3.2
Rationale for Study Design ...................................................... 38
3.2.1
Rationale for Dosage Selection ............................................... 38
3.2.2
Rationale for Study Population ................................................ 39
3.2.3
Rationale for Control Group..................................................... 40
3.2.4
Rationale for Biomarker Assessments..................................... 40
3.3
Outcome Measures ................................................................. 40
3.3.1
Safety Outcome Measures ...................................................... 40
3.3.2
Pharmacokinetic Outcome Measures ...................................... 41


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3.3.3
Other Outcome Measures........................................................ 41
4.
MATERIALS AND METHODS ...................................................... 41
4.1
Center...................................................................................... 41
4.2
Study Population...................................................................... 42
4.2.1
Recruitment Procedures .......................................................... 42
4.2.2
Inclusion Criteria...................................................................... 42
4.2.3
Exclusion Criteria..................................................................... 43
4.3
Method of Treatment Assignment and Blinding ....................... 44
4.4
Study Treatment ...................................................................... 45
4.4.1
Formulation, Packaging, and Handling.................................... 45
4.4.1.1
RO7062931 and Placebo......................................................... 45
4.4.2
Dosage, Administration and Compliance................................. 45
4.4.2.1
RO7062931 and Placebo......................................................... 45
4.4.3
Investigational Medicinal Product Accountability ..................... 46
4.5
Concomitant Therapy and Food .............................................. 47
4.5.1
Permitted Therapy ................................................................... 47
4.5.2
Prohibited Therapy .................................................................. 47
4.5.3
Prohibited Food ....................................................................... 47
4.6
Study Assessments ................................................................. 47
4.6.1
Description of Study Assessments .......................................... 47
4.6.1.1
Medical History and Demographic Data .................................. 48
4.6.1.2
Physical Examinations............................................................. 48
4.6.1.3
Vital Signs................................................................................ 48
4.6.1.4
Electrocardiograms.................................................................. 49
4.6.1.5
Laboratory Assessments ......................................................... 50
4.6.1.6
Pharmacokinetic Assessments................................................ 51
4.6.1.7
Assessments for Inflammatory Markers, 
Drug-Induced Autoantibodies and Anti-Drug 
Antibodies (ADA) ..................................................................... 52
4.6.1.8
Other Assessments ................................................................. 53
4.6.2
Timing of Study Assessments.................................................. 54
4.6.2.1
Screening and Predosing Assessments .................................. 54
4.6.2.2
Assessments during Drug Administration ................................ 54


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4.6.2.3
Follow-Up Assessments and Study Completion ...................... 54
4.7
Healthy Volunteer, Study, and Site Discontinuation................. 55
4.7.1
Healthy Volunteer Discontinuation........................................... 55
4.7.1.1
Withdrawal from Study............................................................. 55
4.7.2
Study and Site Discontinuation................................................ 55
5.
ASSESSMENT OF SAFETY......................................................... 56
5.1
Safety Parameters and Definitions .......................................... 56
5.1.1
Adverse Events........................................................................ 56
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................ 57
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................ 57
5.2
Safety Plan .............................................................................. 58
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters................................................................... 58
5.3.1
Adverse Event Reporting Period.............................................. 58
5.3.2
Eliciting Adverse Event Information ......................................... 59
5.3.3
Assessment of Severity of Adverse Events ............................. 59
5.3.4
Assessment of Causality of Adverse Events............................ 59
5.3.5
Procedures for Recording Adverse Events.............................. 60
5.3.5.1
Diagnosis versus Signs and Symptoms................................... 60
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events...................................................................................... 60
5.3.5.3
Persistent or Recurrent Adverse Events.................................. 61
5.3.5.4
Abnormal Laboratory Values ................................................... 61
5.3.5.5
Abnormal Vital Sign Values ..................................................... 62
5.3.5.6
Abnormal Liver Function Tests ................................................ 62
5.3.5.7
Deaths ..................................................................................... 63
5.3.5.8
Preexisting Medical Conditions................................................ 63
5.3.5.9
Hospitalization or Prolonged Hospitalization............................ 63
5.3.5.10
Overdoses ............................................................................... 64
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor............................................................ 64
5.4.1
Emergency Medical Contacts .................................................. 64


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5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ........................................................................ 65 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 65 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 65 
5.4.3 
Reporting Requirements for Pregnancies ................................ 65 
5.4.3.1 
Pregnancies in Female Healthy Volunteers ............................. 65 
5.4.3.2 
Pregnancies in Female Partners of Male Healthy 
Volunteer ................................................................................. 65 
5.4.3.3 
Abortions .................................................................................. 66 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 66 
5.5 
Follow-Up of Subjects after Adverse Events ............................ 66 
5.5.1 
Investigator Follow-Up ............................................................. 66 
5.5.2 
Sponsor Follow-Up .................................................................. 67 
5.6 
Post-Study Adverse Events ..................................................... 67 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................... 67 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN ............................................................................................. 67 
6.1 
Determination of Sample Size ................................................. 67 
6.2 
Summaries of Conduct of Study .............................................. 68 
6.3 
Analysis Populations ................................................................ 68 
6.3.1 
Safety Analysis Population ...................................................... 68 
6.3.2 
Pharmacokinetic Analysis Population ...................................... 68 
6.3.3 
Immunogenicity Analysis Population ....................................... 68 
6.4 
Summaries of Treatment Group Comparability ........................ 68 
6.5 
Safety Analyses ....................................................................... 69 
6.5.1 
Adverse Events ........................................................................ 69 
6.5.2 
Clinical Laboratory Test Results .............................................. 69 
6.5.2.1 
Standard Reference Ranges and Transformation 
of Data ..................................................................................... 69 
6.5.2.2 
Definition of Laboratory Abnormalities ..................................... 69 
6.5.3 
Vital Signs ................................................................................ 70 
6.5.4 
ECG Data Analysis .................................................................. 70 


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6.5.5 
Concomitant Medications......................................................... 70 
6.6 
Pharmacokinetic Analyses ....................................................... 70 
 
 71 
6.7 
Other Analyses ........................................................................ 71 
6.7.1 
Liver and Kidney Biomarker Data ............................................ 71 
6.8 
Inflammatory Markers, Drug-Induced 
Autoantibodies and ADA Data ................................................. 71 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 71 
7.1 
Data Quality Assurance ........................................................... 71 
7.2 
Electronic Case Report Forms ................................................. 72 
7.3 
Source Data Documentation .................................................... 72 
7.4 
Use of Computerized Systems ................................................ 73 
7.5 
Retention of Records ............................................................... 73 
8. 
ETHICAL CONSIDERATIONS ...................................................... 73 
8.1 
Compliance with Laws and Regulations .................................. 73 
8.2 
Informed Consent .................................................................... 74 
8.3 
Institutional Review Board or Ethics Committee ...................... 74 
8.4 
Confidentiality .......................................................................... 75 
8.5 
Financial Disclosure ................................................................. 75 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 75 
9.1 
Study Documentation .............................................................. 75 
9.2 
Site Inspections ....................................................................... 76 
9.3 
Administrative Structure ........................................................... 76 
9.4 
Publication of Data and Protection of Trade 
Secrets..................................................................................... 76 
9.5 
Protocol Amendments ............................................................. 77 
10. 
REFERENCES.............................................................................. 78 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale ....................................... 59 


RO7062931—F. Hoffmann-La Roche Ltd
20/Protocol YP39432, Version 2
LIST OF FIGURES
Figure 1
Study Design............................................................................... 36
LIST OF APPENDICES
Appendix 1
Schedule of Assessments – Main Table .................................... 79
Appendix 2
Schedule of Assessments – Detailed Table................................ 81
Appendix 3
Alcohol Unit Calculation - Examples ........................................... 82
Appendix 4
Toxicity Table for Grading Injection Reactions .......................... 84


RO7062931—F. Hoffmann-La Roche Ltd
21/Protocol YP39432, Version 2
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, SPONSOR-OPEN, INVESTIGATOR–BLIND, 
SUBJECT-BLIND, PLACEBO-CONTROLLED, SINGLE 
ASCENDING DOSE, TO INVESTIGATE THE SAFETY, 
TOLERABILITY AND PHARMACOKINETICS OF RO7062931 
FOLLOWING SUBCUTANEOUSLY ADMINISTRATION IN 
HEALTHY CHINESE VOLUNTEERS
PROTOCOL NUMBER:
YP39432
VERSION:
2
TEST PRODUCT:
RO7062931
PHASE:
I
INDICATION:
NA
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES
Primary Objective:
The primary objective of this study is:

To assess the safety and tolerability of RO7062931 compared to placebo after single-
ascending doses in healthy Chinese volunteers.
Secondary Objectives:
The secondary objective for this study is:

To assess plasma and urine PK of RO7062931 and, if applicable metabolite(s), after single-
ascending doses in healthy Chinese volunteers.
STUDY DESIGN
Description of Study
This study is randomized, Sponsor-open, Investigator-blind and subject-blind. Up to five 
ascending dose-levels (cohorts) will be explored within the dose-range shown to be safe and 
well-tolerated in Study BP39405. The planned doses for the first four cohorts will be 0.3 mg/kg, 
1.0 mg/kg, 2.0 mg/kg and 3.0 mg/kg, respectively (see Figure 1). The planned dose-levels may 
be modified and an additional (optional, 4.0 mg/kg) cohort enrolled based on emerging results 
from ongoing preclinical and clinical studies (including this study).
It is planned to enroll 10 healthy volunteers (HVs) in each cohort; eight HVs will receive 
RO7062931 and two will receive placebo. Sentinel dosing will be employed in each cohort, 
where two subjects will be dosed on Day 1, of which at least one HV will receive RO7062931 
in order to monitor for potential acute reactions. The remaining 8 subjects will be dosed on the 
following day (24 hours after the initial administrations) following satisfactory safety 
assessment of the first two HVs by the Investigator. The sentinel dosing requirements may be 
modified based on the data from Study BP39405.
NUMBER OF PATIENTS
Up to 50 HVs will be included in this study. Up to 5 cohorts of 10 HVs (8 on active and 2 on 
placebo per dose level) are planned with the fifth and last cohort being optional and based on 
the analysis of emerging PK and safety data from this study and available data from Study 
BP39405.


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TARGET POPULATION
Chinese healthy male and post-menopausal or surgically sterile female HVs of 18 to 60 years 
of age.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria:
Healthy volunteers must meet the below criteria for study entry.
1.
Chinese healthy male and female (of non-childbearing potential) volunteers. Healthy status 
is defined by absence of evidence of any active or chronic disease following a detailed 
medical and surgical history, concomitant drug use (including hormonal supplements), a 
complete physical examination including vital signs, 12-lead ECG, hematology, blood 
chemistry, serology and urinalysis.
2.
18 to 60 years of age, inclusive.
3.
A Body Mass Index (BMI) between 19 to 27 kg/m2 inclusive and a body weight of at least 45
kg.
4.
Women should be of non-childbearing potential. These include those who have undergone 
surgical sterilization (removal of ovaries and/or uterus) or are post-menopausal ( 12 
continuous months of amenorrhea with no identified cause other than menopause, 
confirmed by follicle-stimulating hormone [FSH] ≥LLN (Local Lab), or amenorrhea for at 
least 24 months if on hormone replacement therapy [HRT]).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agree to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom up to 105 days after the last RO7062931 dose to 
avoid exposing the embryo to the study drug. 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 HV. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
5.
Able to participate and willing to give written informed consent and to comply with the study 
restrictions.
6.
Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1 
and agree to remain as non-smoker during the study.
Exclusion criteria:
Healthy volunteers who meet any of the below criteria will be excluded from study entry.
1.
Women who are lactating.
2.
Any suspicion or history of alcohol and/or other substance abuse or dependence in the past 
6 months.
3.
Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone, 
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or 


RO7062931—F. Hoffmann-La Roche Ltd
23/Protocol YP39432, Version 2
positive cotinine test at Screening or Day -1.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus 
(HIV)-1 and -2 at Screening.
5.
Confirmed (e.g., two consecutive triplicate measurements) average systolic blood pressure 
(SBP) 140 or 90 mmHg, and diastolic blood pressure (DBP) 90 or 45 mmHg at 
Screening or Day -1.
6.
Confirmed (e.g., two consecutive triplicate measurements) average resting pulse rate > 90 
or < 45 beats per minute (bpm) at Screening or Day -1.
7.
A personal history of unexplained blackouts or faints, or known risk factors for Torsade de 
Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal ECG, including 
arrhythmias or marked QT abnormalities (QTcF < 300 msec or 450 msec at Screening or 
Day -1).
8.
ECG morphology at Screening or Day -1 that renders measurement of QT interval 
imprecise (e.g., neuromuscular artifact that cannot be readily eliminated, indistinct QRS 
onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves, arrhythmias, 
etc.).
9.
Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right or left 
bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Any out of range findings in liver function tests, INR and renal function tests or any 
clinically significant abnormalities (as judged by the Investigator) in the physical examination 
and in the remaining laboratory test results (including hepatic and renal panels, complete 
blood count, chemistry panel and urinalysis) at Screening or on Day -1. Abnormal renal 
function including serum creatinine ULN (Local Lab) or calculated creatinine clearance 
70 mL/min (using the Cockcroft Gault formula).
12. Participation in an investigational drug or device study within 90 days prior to Screening or 5 
times the half-life of the investigational drug (whichever is longer).
13. Donation of blood over 500 mL within three months prior to Screening.
14. Concomitant disease or condition (including allergic reactions against any drug, or multiple 
allergies) that could interfere with, or treatment of which might interfere with, the conduct of 
the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the 
healthy subject in this study.
15. Any major illness within the one month preceding the Screening visit, or any febrile illness 
within the two weeks preceding the Screening visit.
16. Alcohol consumption of more than 2 standard drinks per day on average; 1 standard drink 
equals 10 grams of alcohol, and/or drug abuse within one year of randomization.
17. Hypersensitivity to the excipients of the study drug.
18. HVs under judicial supervision, guardianship or curatorship.


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LENGTH OF STUDY
The total duration of the study for each HV will be up to 16 weeks, divided as follows:
Screening: Up to 4 weeks;
In Clinic period: Days 1 to 3;
Safety Follow--up: up to at least Day 85
END OF STUDY
The end of the study is defined as the date the last subject’s (HV’s) last observation (LSLO) 
occurs. LSLO is expected to occur at the safety follow-up visit of the last HV enrolled.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events, including adverse events of special interest (see 
Section 5.1.3).

Incidence of laboratory abnormalities based on hematology, blood chemistry, coagulation 
and urinalysis test results (see Section 4.6.1.5).

ECGs (see Section 4.6.1.4).

Vital signs, including blood pressure, pulse rate and temperature (Section 4.6.1.3).
PHARMACOKINETIC OUTCOME MEASURES
The PK evaluations for this study are as follows:
Blood and urine samples will be collected to evaluate the RO7062931 and, if applicable, 
metabolite(s) PK, as specified in the Schedule of Assessment tables (see Appendix 1 and 
Appendix 2). Plasma and urine concentrations will be measured by specific validated methods.
The following plasma and urine PK parameters will be calculated for RO7062931 (and its 
metabolites, as appropriate), when possible, using non-compartmental methods:

Cmax: maximum plasma concentration.

tmax: time to reach the maximum plasma concentration.

AUC0-inf: area under the plasma concentration-time curve from time zero to infinity.

AUC0-last: area under the plasma concentration-time curve from time zero until the last 
quantifiable time-point.

Additional PK parameters may be calculated from available data including:
k (terminal elimination rate constant), 
t1/2 (terminal elimination half-life), 
CL/F (apparent clearance) and 
Vz/F (apparent volume of distribution).

Urine PK parameters may be calculated with available data including:
Ae: cumulative amount of drug excreted in urine over a 24 hour period or over defined time 
periods linked to the pools of urine collected.
OTHER OUTCOME MEASURES

Kidney biomarkers including urine α1-microglobulin, β2-microglobulin and KIM-1.

Liver biomarkers including, miRNA122 and GLDH.

Assessments for inflammatory markers (complement, C-Reactive Protein [CRP], 
erythrocyte sedimentation rate [ESR], gamma globulin and the following inflammatory 
biomarkers [interleukin (IL)-6, IL-8, IL12, mast cell protease (MCP1), tumor necrosis factor 
(TNF), drug-induced autoantibodies and anti-drug antibodies (ADA).


RO7062931—F. Hoffmann-La Roche Ltd
25/Protocol YP39432, Version 2
INVESTIGATIONAL MEDICINAL PRODUCT(S)
The investigational medicinal products (IMPs) in this study are RO7062931 and placebo, and 
will be provided by the Sponsor. 
All RO7062931 doses and placebo will be administered at the study clinic in the morning by 
investigational staff and should be administered in the fasted state either two hours before or 
two hours after a morning meal. Subcutaneous doses will be administered at an appropriate 
site (for example the abdomen or upper thigh).
PROCEDURES
A Schedule of Assessments (SoA) is provided. 
STATISTICAL METHODS
All HVs on placebo will be pooled as one treatment group.
SAFETY ANALYSES
All HVs who have received 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 adverse 
events, injection site reactions (ISRs), reason for withdrawal from study, laboratory data, ECG, 
concomitant medications, vital signs and physical examination results will be listed and 
summarized descriptively by treatment and dose level. All placebo patients will be pooled as 
one treatment group. Marked abnormalities will be flagged for laboratory data.
As appropriate, listings, summary tables and graphs (study subject plot and/or mean plots) will 
be provided for safety and tolerability assessments.
PHARMACOKINETIC ANALYSES
Study subjects will be excluded from the pharmacokinetic (PK) analysis population if they 
significantly violate the eligibility criteria or the protocol, or if data are unavailable or 
incomplete which may influence the PK analysis. 
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Summary descriptive statistics of plasma PK parameters, 
including Cmax, Tmax, AUCinf, AUClast and t1/2, for RO7062931 and any metabolites when 
available, will be presented by cohort including means, geometric means, standard deviations
(SD), coefficients of variation (CV), medians and ranges. Note: the geometric mean and 
associated CV% will be used to describe Cmax, AUCinf, AUClast. Listings, summary tables and 
graphs (individual plots and/or mean plots) by treatment group will be provided. Descriptive 
statistics of urine PK parameters for RO7062931 and any metabolites will be presented, where 
available. PK data from this study may be pooled with data from other studies to develop a 
population PK model.
The Power model method will be used to aid assessment of dose-proportionality, as a departure 
from dose-proportionality could be an indication 
. For 
each of the PK parameters, AUC and Cmax, a regression model will be fitted where the log 
transformed PK parameter is fitted as the response variable and log-transformed dose, treated 
as a continuous data, fitted as a fixed effect. The estimate of the regression coefficient for log 
dose and the intercept and associated 90% Confidence Intervals for each will be presented. 
Urinary PK parameters will also be used 
. In addition to the 
summaries described above for the urinary PK parameters, a two-parameter logistic regression 
model can be used to model the relationship between the dose and the probability of observing 
drug concentration in the urine. Where p is the probability of observing concentration in the 
urine at a given dose, is the log of the odds for p at the reference dose (i.e., equals to 
0.3 mg/kg, the starting dose of SAD) and is the change in log odds for an e1-fold increase in 
dose (detailed discussion can be found in Neuenschwander et al 2008).
These analyses will be carried out initially at the end of the second cohort and at the end of
each subsequent cohort
.


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OTHER ANALYSES
The immunogenicity analyses, if applicable, will include subjects with a pre-dose and one 
post-dose ADA assessment, with subjects grouped according to treatment received.
The kidney and liver biomarkers (see Section 4.6.1.8) will be explored graphically. Plots will 
include longitudinal plots for both actual result and change from baseline. Longitudinal plots 
will include individual subject responses by dose, as well as mean/median plots. Box and 
whisker plots may also be used to detect outliers. At minimum, any data that is collected as 
detailed in Section 4.6.1.7, and is available at the time of database closure will be listed and 
summarized using descriptive statistics. Data may also be explored graphically.
SAMPLE SIZE JUSTIFICATION
The planned sample size of 8 active per cohort was chosen not only to allow adequate 
assessment of safety and tolerability but also to increase the precision of the estimates of mean 
PK and urinary parameters, as comparisons of these parameters across doses will be used in 
part 
.
Up to 50 HVs will be included in this study. Up to 5 cohorts of 10 HVs (8 on active and 2 on 
placebo per dose level) are planned with the fifth and last cohort being optional and based on 
the analysis of emerging PK and safety data from this study and available data from study 
BP39405.
CONCOMITANT MEDICATIONS
Restrictions apply to healthy volunteers regarding prescribed or over-the-counter (OTC) 
medication, vitamins, fish oils, protein powders, including herbal remedies, taken within 2 weeks 
prior to study drug administration (with the exception of hormone replacement therapy [HRT], 
which is allowed throughout the study). Paracetamol (up to 1 g per day) will be allowed. 
There are no other concomitant treatment restrictions at this time as no drug-drug interactions 
are foreseen for RO7062931.
In the event that a HV requires additional medication during the course of the trial, this may 
be allowed after consultation with the Investigator and Sponsor.
Medications used to treat an AE may only be prescribed after consultation with the Sponsor 
(with the exception of paracetamol), unless there is a medical need to ensure the well-being of 
the subject that should not be delayed. 
It is unlikely that food will have an impact on the PK of RO7062931, however, RO7062931 
should be administered in a fasted state (i.e., 2 hours before, or, 2 hours after a meal).


RO7062931—F. Hoffmann-La Roche Ltd
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AAV
Adeno-associated virus
AAV-HBV
Adeno-associated virus carrying a replicable hepatitis B 
virus genome
ADAs
Anti-drug antibodies
AE
Adverse events
Ae
Cumulative amount of drug excreted in urine over a 
24-hour period
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase 
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
cccDNA
Covalently closed circular DNA 
CHB
Chronic hepatitis B virus
CL
Clearance
CL/F
Apparent clearance
CNS
Central nervous system
CRO
Contract research organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP
Cytochrome
DBP
Diastolic blood pressure
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
dsDNA
Double stranded DNA
EC
Ethics Committee
ECG
Electrocardiograms
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EEA
European Economic Area
ESF
Eligibility Screening Form


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Abbreviation
Definition
ESR
Erythrocyte sedimentation rate
EU
European Commission
FDA
Food and Drug Administration
FIH
First-in-human
FSH
Follicle-stimulating hormone
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GLDH
Glutamate-dehydrogenase
GLP
Good Laboratory Practice
HAV
Hepatitis A virus
HBeAg
HBV envelop antigen
HBV
Hepatitis B virus
β-HCG
beta-human chorionic gonadotropin
HCV
Hepatitis C
HDL
High density lipoproteins
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormone replacement therapy
HV
Healthy volunteer
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IL
Interleukin
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IRR
Injection Related Reactions
ISRs
Injection site reactions
k
Terminal elimination rate constant
KIM-1
Kidney injury molecule-1
LDH
Lactate dehydrogenase
LDL
Low density lipoproteins
LH
Luteinizing hormone
LLN
Lower limit of normal
LNA
Locked nucleic acid


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Abbreviation
Definition
LSLO
Last study subject, last observation
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCP
Mast cell protease
miRNA
Micro RNA
msec
Milliseconds
MTD
Maximum tolerated dose
NGAL
Neutrophil gelatinase-associated lipocalin 
NHP
Non-human primate
NOAEL
No-observed-adverse-event level
OTC
Over-the-counter
PD
Pharmacodynamic
PEG-IFN
Pegylated IFN
PK
Pharmacokinetic
PT
Prothrombin time
QRS
QRS complex
QT
QT interval
RBC
Red blood cell
RNA
Ribonucleic acid
SAD
Single ascending dose
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SoA
Schedule of assessments
ssDNA
Single stranded DNA
SSO
Single stranded oligodeoxyribonucleotide
TNF
Tumor necrosis factor
ULN
Upper limit of normal
V
Volume
VZ/F
Apparent volume of distribution
WBC
White blood cell


RO7062931—F. Hoffmann-La Roche Ltd
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1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
Hepatitis B virus (HBV) infection is a major cause of both acute hepatitis and chronic 
liver diseases, including cirrhosis and hepatocellular carcinoma. Approximately two 
billion people worldwide have serological evidence of past or present HBV infection, and 
around 240 million people are chronic hepatitis B surface antigen (HBsAg) carriers, 
among which around 38% of the patient population reside in China (WHO 2015). An 
estimated 686,000 people die each year due to the acute or chronic consequences of 
hepatitis B (WHO 2016; EASL 2012).
Antiviral therapy of chronic hepatitis B virus (CHB) aims to improve quality of life and 
survival of the patients by preventing progression of liver damage to cirrhosis, 
decompensated liver disease, hepatocellular carcinoma, and death. Sustained 
suppression of HBV replication is associated with biochemical remission, histological 
improvement and delayed disease progression (EASL 2009).
Chronic HBV infection is a dynamic process with several stages, during which CHB may 
be present either as HBV e antigen (HBeAg)-positive or HBeAg-negative. Current 
guidelines specify the ideal endpoint of therapy for CHB patients as the loss of HBsAg 
with or without HBsAg seroconversion (EASL 2012). For HBeAg-positive patients, 
HBeAg seroconversion is indicative of better prognoses, including lower rates of 
cirrhosis and slower disease progression. Other clinically meaningful endpoints, 
irrespective of HBeAg status, are HBV DNA suppression and alanine aminotransferase 
(ALT) normalization, which indicate the virological and biochemical responses to 
therapies, respectively. 
Currently, there are two types of drugs available for the treatment of CHB: 
subcutaneously administered interferon preparations (IFN; conventional or pegylated 
IFN [PEG-IFN]) and orally administered nucleoside/nucleotide analogues (NUC), 
including adefovir, telbivudine, tenofovir, entecavir, and lamivudine. Although 
nucleos(t)ide treatment is highly effective at normalizing liver enzymes (biochemical 
response) and in lowering the HBV DNA level to undetectable levels (virological 
response), chronic HBV infection cannot be completely eradicated with currently 
approved therapeutics due to the persistence of HBV covalently closed circular DNA 
(cccDNA) in the nucleus of infected hepatocytes (Lucifora et al 2014). Signs of infection 
return to pre-treatment levels (relapse) if nucleos(t)ides are discontinued in the majority 
of cases. Therefore, few individuals achieve a functional or clinical cure with current 
therapies (sustained HBsAg and HBV DNA loss with or without HBsAg seroconversion 
occurs in15% after five years following treatment discontinuation). Moreover, PEG-IFN 
is associated with significant safety and tolerability risks, while NUC analogues 
frequently require prolonged or indefinite therapy and some are associated with high risk 
of resistance.


 
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31/Protocol YP39432, Version 2 
1.2 
BACKGROUND ON RO7062931 
RO7062931is a N-Acetylgalactosamine (GalNAc)-targeted locked nucleic acid 
(LNA)-containing single stranded oligodeoxyribonucleotide (SSO), complementary to 
HBV genome-derived mRNA species, intended for the treatment of CHB infections. 
Chronicity in CHB is believed to be perpetuated, at least in part, by protein products 
expressed from the HBV genome which are derived from translation of four mRNA 
species transcribed from the cccDNA template located in the nucleus of infected 
hepatocytes. 
 
 
 
 
 
 
See the RO7062931 Investigator Brochure (IB) for details on non-clinical and clinical 
studies. 
1.2.1 
Previous Non-Clinical Studies 
RO7062931 has shown potent antiviral activity through the inhibition of 
, 
. RO7062931 is 
 active in vitro against 
 
. In mice infected with a 
recombinant adeno-associated virus (AAV) carrying a replicable HBV genome 
(AAV-HBV), administration of RO7062931 reduced 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
RO7062931—F. Hoffmann-La Roche Ltd 
33/Protocol YP39432, Version 2 
 
 
 
 
1.2.2 
Previous Clinical Studies 
Study BP39405, the first-in-human (FIH) study with RO7062931, was initiated in January 
2017. In this ongoing study, as of 8 November, 2017, 60 healthy subjects (including 15 
Asian healthy subjects) had received a single dose of RO7062931 or placebo at various 
dose levels from 0.1, 0.3, 1.0, 2.0, 3.0 to 4.0 mg/kg. As of 8th November 2017, two HBV 
patients had been randomized in Part 2a of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
1.3.1 
Study Rationale 
Study BP39405 is the first clinical study with RO7062931 designed to assess: the safety, 
tolerability and pharmacokinetics (PK) of subcutaneously administered single ascending 
doses (SAD) in healthy volunteers (HVs; Part 1); and safety, tolerability, PK, and 
pharmacodynamic (PD) effects of subcutaneously administered multiple doses to CHB 
patients (Part 2). Study YP39432 will assess the safety, tolerability and PK of single 


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doses of RO7062931 in healthy Chinese volunteers, This initial evaluation will be 
important to inform future clinical studies in Chinese subjects.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be conducted in healthy Chinese volunteers and results from this study 
will be compared with the global study, BP39405, to determine if there may be any 
detectable differences between Caucasian and Asian healthy volunteers in safety, 
tolerability and pharmacokinetics. For the healthy volunteers, no therapeutic benefit is 
anticipated. However, data from these healthy volunteers is expected to provide a
clearer and more consistent assessment of safety and PK to allow better design of 
therapeutic studies in HBV patients. 
1.3.2
Benefit–Risk Assessment
Limited clinical experience with RO7062931 currently exists. The evaluation of the
potential risks of drug administration and the specific tests, observations, and 
precautions required for this clinical study with RO7062931 will be based on information 
from non-clinical toxicology and safety pharmacology studies as well as available data 
from the FIH study BP39405. Safety and tolerability will be carefully assessed, and HVs
will be closely monitored. All dose levels to be included in this study will be within the 
dose-range which has been demonstrated to be safe and well-tolerated in the FIH study 
(BP39405). The study will be done under a controlled setting, with tight clinical and 
laboratory monitoring to minimize potential risks to the participants. Dose-escalation 


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decisions will be made based on the safety/tolerability and PK observations from the 
previous cohorts and the ongoing study BP39405.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objective of this study is:

To assess the safety and tolerability of RO7062931 compared to placebo after 
single-ascending doses in healthy Chinese volunteers.
2.2
SECONDARY OBJECTIVES
The secondary objective for this study is:

To assess plasma and urine PK of RO7062931 and, if applicable metabolite(s), after 
single-ascending doses in healthy Chinese volunteers.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This study is randomized, Sponsor-open, Investigator-blind and subject-blind. Up to five
ascending dose-levels (cohorts) will be explored within the dose-range shown to be safe 
and well-tolerated in Study BP39405. The planned doses for the first four cohorts will be 
0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg and 3.0 mg/kg, respectively (see Figure 1). The 
planned dose-levels may be modified and an additional (optional, 4.0 mg/kg) cohort
enrolled based on emerging results from ongoing preclinical and clinical studies 
(including this study).
It is planned to enroll 10 HVs in each cohort; eight HVs will receive RO7062931 and two 
will receive placebo. Sentinel dosing will be employed in each cohort, where two 
subjects will be dosed on Day 1, of which at least one HV will receive RO7062931 in 
order to monitor for potential acute reactions. The remaining 8 subjects will be dosed on
the following day (24 hours after the initial administrations) following satisfactory safety 
assessment of the first two HVs by the Investigator. The sentinel dosing requirements 
may be modified based on the data from Study BP39405.


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Figure 1
Study Design
The total duration of the study for each HV will be up to 16 weeks divided as follows:

Screening: Up to 4 weeks;

In-Clinic period: Days -1 to 3;

Safety Follow-up: up to at least Day 85
3.1.2
Dose- Escalation Decisions
Dose-escalation/review meetings will be conducted by the Investigator, the Medical 
Monitor, and the Sponsor Clinical Team prior to each RO7062931 dose-escalation (see 
Section 3.1.2.1). The actual doses may be modified based on emerging data from this 
study, and emerging results from ongoing preclinical studies and Study BP39405.
Escalation to the next dose cohort will be based primarily on the review of safety and 
tolerability information (including adverse events, electrocardiograms [ECGs], vital signs, 
clinical laboratory test results) collected up to 28 days post-dose (Day 29 2 Days) and, 
all available PK data collected at least 7 days post-dose in a minimum of 8 subjects
(receiving active drug or placebo) within the previous cohort. The decision to escalate 
the dose will be made by mutual agreement between the Sponsor and the Investigator.
3.1.2.1
Dose-Escalation Decision Criteria 
This study uses a dose-escalation schedule that may be modified if: 

Events emerge that the Sponsor and/or Investigator consider indicators that the 
planned dose-escalation step would result in unacceptable risks for the safety of the 
HVs.


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
The Sponsor and Investigator agree to do so and neither considers that the 
proposed subsequent dose level poses an unacceptable risk to the study subjects.
Single doses will not be escalated if the dose-escalation stopping criteria are met (see 
Section 3.1.2.2 below) but may exceed the dose level of 4.0 mg/kg (see Section 3.2.1) 
only if anticipated to be safe and necessary to generate additional PK data in support of 
dosing regimens for use in patients. 
3.1.2.2
Dose-Escalation Stopping Criteria
Dose-escalation will not be implemented as planned if one of the criteria below is 
fulfilled, unless it is obvious that the occurrence is not considered to be related to 
RO7062931. 
Dose-escalation will be stopped if at a dose level, more than 2 of 8 HVs receiving 
RO7062931 experience the following:

Severe or clinically significant (as defined by the Investigator) RO7062931-related
adverse events of the same character, or

Clinically significant RO7062931-related laboratory abnormality of the same 
character, or

Clinically significant RO7062931-related changes in vital signs or ECGs of the same 
character (e.g., QTcF500 msec, or60 msec longer than the pre-dose baseline, 
within the first 48 hours post-dose).

Within two consecutive dose cohorts, four occurrences (in 4 HVs) of any of the 
above conditions in HVs receiving active drug.

Other findings (regardless of the incidence rates) that at the joint discretion of the 
Sponsor and the Investigator indicate that dose-escalation should be halted.
Additionally, planned dose-escalation may be stopped by mutual agreement between 
the Sponsor and Investigator, 
 
 
In case the dose-escalation is stopped, lower doses within the tolerated dose-range
could be investigated or a dose repeated in the subsequent cohorts by mutual 
agreement between the Sponsor and Investigator, in order to increase the amount of 
data within this tolerated dose-range.
Any serious adverse event considered related to study drug will lead to an immediate 
halt of study drug dosing, dose escalation and enrollment of new subjects until a 
thorough investigation has been conducted by the Sponsor’s Clinical Team and the 
Principal Investigator. The sponsor or designee will notify all investigators and 
IRBs/EC regarding the outcome of such investigation, and the study will only continue 
if agreed by the IRBs/EC.
Due to the exploratory nature of this clinical study, its conduct can be discontinued at 
any time at the discretion of the Sponsor (see Section 4.7).


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3.1.3
Communication Strategy
After each HV receives RO7062931 (or placebo), the Investigator(s) must confirm to the 
Sponsor that the HV has been dosed and provide a brief summary of the status of the 
subject in terms of safety and tolerability to RO7062931/placebo (this will be 
communicated by email and/or telephone). The Investigator(s) will provide a safety 
assessment feedback of the first two sentinel dosing HVs of each cohort prior to dosing 
the remaining HVs enrolled in the cohort.
In case of a safety concern, the Investigator will contact the Sponsor immediately to 
discuss study subject status and action taken/to be taken. In addition, after each cohort 
has been completed, the Sponsor will organize a teleconference with the Investigator to 
discuss the safety and tolerability of RO7062931 and to discuss eventual next cohort(s) 
or continuation. During these teleconferences, adverse events (with severity assessed 
as given in Table 1) in addition to available safety laboratory results, vital signs, ECGs, 
will be discussed along with the results of the available PK data, and any other available 
data that may assist the dose-escalation decision process. The decision of these 
meetings will be documented in writing.
In addition to these communications, the Sponsor and Investigator(s) will be in regular 
contact throughout the study by email/telephone as per normal interactions during the 
conduct of a clinical study and the Sponsor will arrange regular teleconferences and 
meetings to discuss study status.
3.1.4
End of Study
The end of the study is defined as the date the last subject’s (HV’s) last observation 
(LSLO) occurs. LSLO is expected to occur at the safety follow-up visit of the last HV
enrolled.
3.2
RATIONALE FOR STUDY DESIGN
Safety and PK of single RO7062931 doses will be characterized in HVs to determine the 
best liver-targeted dose to be evaluated in future studies in Chinese patients with CHB.
3.2.1
Rationale for Dosage Selection
The anticipated dose levels for this study are 0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg and 
3.0 mg/kg for Cohorts 1-4. In addition, based on the PK and safety evaluation of the top
dose cohort and the available data from FIH Study BP39405, an optional fifth cohort 
(4.0 mg/kg) may be enrolled. All dose levels in this study will be within the dose range 
which has been demonstrated to be safe and well tolerated in the BP39405 study.
Doses up to 4.0 mg/kg are anticipated to be safe in humans 
 
 


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Data from the ongoing BP39405 study have shown that single doses of RO7062931 
from 0.1 to 4.0 mg/kg were considered safe and well tolerated in healthy humans 
(Section 1.2.2). The planned starting dose of 0.3 mg/kg is higher than was used for the 
first EIH study, BP39405. The 0.3 mg/kg dose is chosen to minimize additional testing in 
Chinese HVs of doses that may not provide information. This starting dose would have a 
safety margin 10-fold to the most sensitive species evaluated in GLP toxicology 
studies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.2
Rationale for Study Population
Chinese healthy male and post-menopausal or surgically sterile female HVs of 18 to 
60 years of age, inclusive, have been selected for this study, for the following reasons:

A dedicated study in HVs is expected to provide a more consistent and robust 
assessment of safety, PK parameters and pharmacological effect in the absence of 
potentially confounding disease and medications.

Unexpected adverse events or toxicities are usually better identified and easier to 
treat in HVs without co-morbid diseases or concomitant medications. At the dose 
and regimen selected, HVs have lower risk of developing clinically significant 
sequelae from potential temporary adverse events.

The rate of incidental or sporadic findings that may interfere with the assessment of 
basic safety parameters or with meeting study objectives is likely to be lower in 
healthy individuals than in patients.


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
The doses to be explored in this study, will have already been declared as safe and 
well tolerated in the BP39405 study.
3.2.3
Rationale for Control Group
This Phase I study is designed to be adequate and well-controlled. Randomization to 
RO7062931 or placebo will occur in a 4:1 ratio within each of the up to 4 cohorts 
planned. This is considered sufficient to allow for comparisons of safety and tolerability 
of active drug to placebo both within and across cohorts.
3.2.4
Rationale for Biomarker Assessments
Complementary liver biomarkers, attempting to further characterize potential hepatic 
effects may include microRNA-122 (miRNA-122) and glutamate dehydrogenase (GLDH).
According to Hornby et al 2014, miRNA-122, a liver-enriched miRNA, has demonstrated 
its use both in animal and human studies as a sensitive and specific biomarker of drug 
induced liver injury (DILI) and may be elevated earlier than ALT. In addition, it has also 
been used as a marker of viral hepatitis; Zhang et al 2010 reported that plasma 
miRNA-122 levels change in patients infected with HBV showing a disease–severity 
relationship and a strong correlation with plasma ALT activity. 
In the pre-clinical studies (monkey and rat GLP studies) with RO7062931, increased 
levels of 1-microglobulin, kidney injury molecule (KIM)-1, neutrophil gelatinase-
associated lipocalin (NGAL) and 2-microglobulin were observed. In a first-in-human
study, the treatment with the LNA antisense oligonucleotide SPC5001 (Poelgeest et al 
2015) was associated with acute renal tubular toxicity at the highest dose tested. 
Therefore, urine kidney biomarkers 1-microglobulin, 2-microglobulin and KIM-1 will be 
included in this study to evaluate potential acute kidney effects.
Based on non-clinical data (and class effect [Kynamro Solution for injection 189 mg, 
CHMP-EMA Assessment Report 2013]) RO7062931 is considered to be of low risk for 
acute reactions; however, cytokines and complement activation will be measured and 
sentinel dosing will be implemented.
3.3
OUTCOME MEASURES 
3.3.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events, including adverse events of special 
interest (see Section 5.1.3).

Incidence of laboratory abnormalities based on hematology, blood chemistry, 
coagulation and urinalysis test results (see Section 4.6.1.5).

ECGs (see Section 4.6.1.4).

Vital signs, including blood pressure, pulse rate and temperature (see 
Section 4.6.1.3).


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3.3.2
Pharmacokinetic Outcome Measures
The PK evaluations for this study are as follows:
Blood and urine samples will be collected to evaluate the RO7062931 and if applicable 
metabolite(s) PK, as specified in the Schedule of Assessment tables (see Appendix 1
and Appendix 2). Plasma and urine concentrations will be measured by specific 
validated methods.
The following plasma and urine PK parameters will be calculated for RO7062931 (and 
its metabolites, as appropriate), when possible, using non-compartmental methods:

Cmax: maximum plasma concentration.

tmax: time to reach the maximum plasma concentration.

AUC0-inf: area under the plasma concentration-time curve from time zero to infinity.

AUC0-last: area under the plasma concentration-time curve from time zero until the 
last quantifiable time-point.

Additional PK parameters may be calculated from available data including:
k (terminal elimination rate constant), 
t1/2 (terminal elimination half-life), 
CL/F (apparent clearance) and 
Vz/F (apparent volume of distribution).

Urine PK parameters may be calculated with available data including:

Ae: cumulative amount of drug excreted in urine over a 24 hour period or over 
defined time periods linked to the pools of urine collected.
3.3.3
Other outcome measures

Kidney biomarkers including urine α1-microglobulin, β2-microglobulin and KIM-1.

Liver biomarkers including, miRNA122 and GLDH.

Assessments for inflammatory markers (complement, C-Reactive Protein [CRP], 
erythrocyte sedimentation rate [ESR], gamma globulin and the following 
inflammatory biomarkers [interleukin (IL)-6, IL-8, IL12, mast cell protease (MCP1), 
tumor necrosis factor (TNF), drug induced autoantibodies and anti-drug
antibodies (ADA).
4.
MATERIALS AND METHODS
4.1
CENTER
An 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.


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4.2
STUDY POPULATION
Healthy volunteers must satisfy all inclusion and exclusion criteria to be enrolled into the 
study. Under no circumstances are subjects who enroll in this study permitted to be 
re-randomized to another cohort of this study.
Study subjects who drop out of the study for non-safety reasons may be replaced to 
ensure sufficient data to characterize the safety, tolerability, and PK and/or to make 
dose-escalation decisions. Study subjects who withdraw from the study due to poor 
tolerability or for study drug-related adverse events will not be replaced.
4.2.1
Recruitment Procedures 
HVs will be identified for potential recruitment using pre-screening enrollment logs, 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) approved 
newspaper/radio advertisements and mailing lists prior to consenting to take place on 
this study.
4.2.2
Inclusion Criteria
HVs must meet the following criteria for study entry:
1.
Chinese healthy male and female (of non-childbearing potential) volunteers. Healthy 
status is defined by absence of evidence of any active or chronic disease following a 
detailed medical and surgical history, concomitant drug use (including hormonal 
supplements), a complete physical examination including vital signs, 12-lead ECG, 
hematology, blood chemistry, serology and urinalysis.
2.
18 to 60 years of age, inclusive.
3.
A Body Mass Index (BMI) between 19 to 27 kg/m2 inclusive and a body weight of at 
least 45 kg.
4.
Women should be of non-childbearing potential. These include those who have 
undergone surgical sterilization (removal of ovaries and/or uterus) or are 
post-menopausal (12 continuous months of amenorrhea with no identified cause 
other than menopause, confirmed by follicle-stimulating hormone [FSH] ≥LLN 
(Local Lab), or amenorrhea for at least 24 months if on hormone replacement 
therapy [HRT]).
All males must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agree to refrain from donating sperm, as defined 
below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom up to 105 days after the last 
RO7062931 dose to avoid exposing the embryo to the study drug. Men must 
refrain from donating sperm during this same period.


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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 HV. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
5.
Able to participate and willing to give written informed consent and to comply with 
the study restrictions.
6.
Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on 
Day 1 and agree to remain as non-smoker during the study.
4.2.3
Exclusion Criteria
HVs who meet any of the following criteria will be excluded from study entry:
1.
Women who are lactating.
2.
Any suspicion or history of alcohol and/or other substance abuse or dependence in 
the past 6 months.
3.
Positive urine drug and alcohol screen (barbiturates, benzodiazepines, methadone, 
amphetamines, methamphetamines, opiates, cocaine, cannabinoids and alcohol), or 
positive cotinine test at Screening or Day -1.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency 
virus (HIV)-1 and -2 at Screening.
5.
Confirmed (e.g., two consecutive triplicate measurements) average systolic blood 
pressure (SBP)140 or90 mmHg, and diastolic blood pressure (DBP)90 
or45 mmHg at Screening or Day -1.
6.
Confirmed (e.g., two consecutive triplicate measurements) average resting pulse 
rate > 90 or < 45 beats per minute (bpm) at Screening or Day -1.
7.
A personal history of unexplained blackouts or faints, or known risk factors for 
Torsade de Pointes (e.g., hypokalemia, heart failure). Clinically significant abnormal 
ECG, including arrhythmias or marked QT abnormalities (QTcF < 300 msec 
or450 msec at Screening or Day -1).
8.
ECG morphology at Screening or Day -1 that renders measurement of QT interval 
imprecise (e.g., neuromuscular artifact that cannot be readily eliminated, indistinct 
QRS onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves, 
arrhythmias, etc.).
9.
Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right 
or left bundle branch block, Wolff-Parkinson-White syndrome, or cardiac pacemaker.
10. Personal or family history of congenital long QT syndrome or sudden death.
11. Any out of range findings in liver function tests, INR and renal function tests or 
any clinically significant abnormalities (as judged by the Investigator) in the physical 
examination and in the remaining laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel and urinalysis) at Screening or on 
Day-1. Abnormal renal function including serum creatinine ULN (Local Lab) or 
calculated creatinine clearance 70 mL/min (using the Cockcroft Gault formula).


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12. Participation in an investigational drug or device study within 90 days prior to 
Screening or 5 times the half-life of the investigational drug (whichever is longer).
13. Donation of blood over 500 mL within three months prior to Screening.
14. Concomitant disease or condition (including allergic reactions against any drug, or 
multiple allergies) that could interfere with, or treatment of which might interfere with, 
the conduct of the study, or that would, in the opinion of the Investigator, pose an 
unacceptable risk to the healthy subject in this study.
15. Any major illness within the one month preceding the Screening visit, or any febrile 
illness within the two weeks preceding the Screening visit.
16. Alcohol consumption of more than 2 standard drinks per day on average; 1 standard 
drink equals 10 grams of alcohol (for further guidance please see Appendix 3)
and/or drug abuse within one year of randomization.
17. Hypersensitivity to the excipients of the study drug.
18. HVs under judicial supervision, guardianship or curatorship.
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This study is Sponsor-open, Investigator-blinded and subject-blinded. This means that 
the study subjects will be blinded, the Investigator(s), site staff observing the subjects 
will be blinded and the Sponsor will be unblinded. Additionally, the site pharmacist and 
the study drug administrator will be unblinded. Members of the Sponsor’s study team 
who do not have direct contact with the Investigator or study site staff will be unblinded. 
This does not include any Contract Research Organisations (CROs) and any Sponsor 
staff in direct contact with the Investigators and the study sites, who will remain blinded.
Ten HVs will be randomized to active drug or placebo in each dose cohort/level in a 4:1 
ratio. The randomization numbers will be generated by the Sponsor or its designee. The 
randomized treatment assignment will be allocated from the list sequentially to subjects 
in the order in which they are enrolled. For each dose cohort, the randomization will be 
designed such that of the first 2 HVs, one will receive active drug, and the other will 
receive placebo. The remaining 8 HVs in the cohort will be randomized such that 7 
receive active drug and 1 receives placebo. The treatment allocation will be managed by 
the unblinded Pharmacist and will be based on the randomization assignment list. An 
unblinded study drug administrator will administer the drug to the subject. Drug 
administration to a subject will be performed in isolation of other subjects.  
To allow informed recommendations or decisions regarding the dose selection, an 
integrated assessment of the safety, tolerability and available PK data will be made prior 
to each dose decision (see Sections 3.1.2 to 3.1.3). If required, unblinded data 
(individual as well as at group level) may also be presented to the Drug Safety 
Committee or other experts of the Sponsor.


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4.4
STUDY TREATMENT
4.4.1
Formulation, Packaging, and Handling
4.4.1.1
RO7062931 and Placebo
RO7062931 and placebo investigational medicinal products (IMPs) to be used in the 
study will be provided by Roche. 
The drug substance RO7062931 is colorless to yellow, brownish yellow or greenish 
yellow sterile liquid for injection provided in single-use vials. As the formulation 
contains no preservatives, it should be diluted under appropriate aseptic conditions. An 
in-line filter must be used prior to administration (see Pharmacy Manual for further 
details).
Placebo vials are manufactured containing the same inactive ingredients (sodium 
chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate) but no 
active substance.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations. Study drug packaging will be overseen by the Roche 
clinical trial supplies department and bear a label with the identification required by local 
law, the protocol number, drug identification and dosage. Study drug should be stored 
under the recommended storage conditions (2-8°C, protected from light. For further 
details see the product label). 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery.
For further details, see the RO7062931 Investigator’s Brochure and Pharmacy Manual.
4.4.2
Dosage, Administration and Compliance
4.4.2.1
RO7062931 and Placebo
The qualified individual responsible for dispensing the study drug will be unblinded and 
will prepare the correct dose according to the randomization schedule. This individual 
will write the date dispensed, study subject number and initials on the study drug vial 
label and on the Drug Accountability Record. This individual will also record the study 
drug (e.g., batch number) received by each subject during the study.
SC doses will be administered at an appropriate site, for example the abdomen or upper 
thigh. All RO7062931 doses and placebo will be administered at the study clinic in the 
morning by investigational staff and should be administered in the fasted state either two 
hours before or two hours after a morning meal.


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4.4.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO7062931 and placebo) will be provided 
by the Sponsor. The investigational site will acknowledge receipt of IMPs, to confirm the 
shipment condition and content. Any damaged shipments will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
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 HV to whom the study drug was dispensed (for example, 
HV’s 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 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Written documentation of destruction must contain the following:

Identity [e.g., batch number] of investigational product[s] destroyed

Quantity of investigational product[s] destroyed

Date of destruction

Method of destruction

Name and signature of responsible person [or company] who destroyed 
investigational product[s].
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.


RO7062931—F. Hoffmann-La Roche Ltd
47/Protocol YP39432, Version 2
4.5
CONCOMITANT THERAPY AND FOOD
4.5.1
Permitted Therapy 
Patients will be permitted to use the following therapies during the study:

Hormone-replacement therapy

Paracetamol (up to 1 g per day)

Medications used to treat an AE may only be prescribed after consultation with the 
Sponsor (with the exception of 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).
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
4.5.2
Prohibited Therapy
Use of any prescribed or over-the-counter (OTC) medication, vitamins, fish oils, 
protein powders, including herbal remedies; taken within 2 weeks prior to first study 
drug administration, with the exceptions of therapies listed in Section 4.5.1. However, 
in the event that a HV requires additional medication during the course of the trial, 
this may be allowed after consultation with the Investigator and Sponsor.
There are no other concomitant treatment restrictions at this time as no drug-drug
interactions are foreseen for RO7062931.
4.5.3
Prohibited Food
There are no prohibited foods.
It is unlikely that food will have an impact on the PK of RO7062931, however, 
RO7062931 should be administered in a fasted state (i.e., 2 hours before, or, 2 hours 
after a meal).
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the Schedule of 
Assessments tables as outlined in Appendix 1 and Appendix 2. At time-points when 
several assessments coincide, the following sequence should be followed with the PK 
blood sample to be taken first at the nominal time-point:

Urine collection

Vital signs

ECGs

PK, safety blood sampling


RO7062931—F. Hoffmann-La Roche Ltd
48/Protocol YP39432, Version 2

Study drug administration
4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, i.e., surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse, and all medications (e.g., 
prescription drugs, OTC, herbal or homeopathic remedies, nutritional supplements) used 
by the study subject within 30 days prior to the Screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.6.1.2
Physical Examinations
A complete physical examination should be performed at baseline and include an 
evaluation of the head, eyes, ears, nose, throat, neck and lymph nodes, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems. Further examination of other body systems may be performed in 
case of evocative symptoms at the Investigator’s discretion.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in healthy volunteer’s notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
Body weight will be recorded at Screening and during the study. Height will be recorded 
at the Screening visit only. BMI will be calculated at Screening.
4.6.1.3
Vital Signs
Vital signs will be obtained after the subject has been resting in a supine position for at 
least 10 minutes. 
Blood pressure (BP; systolic and diastolic), pulse rate and body temperature (tympanic) 
will be recorded at the time-points specified in the Schedule of Assessments tables (see 
Appendix 1 and Appendix 2). Blood pressure and pulse rate will be performed in 
triplicate (can be as short as 20 seconds to 1-minute interval between measurements)
and recorded in eCRF. Vital signs should be measured prior to blood draw. When
possible, the same arm should be used for all blood pressure measurements.
Blood pressure and pulse rate should be obtained in a quiet room at a comfortable 
temperature, with the subject's arm unconstrained by clothing or other material. Where 
possible all measurements will be obtained from the same arm and, with the same cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (the “ideal” cuff should have a bladder length that is 80% and a width that is at 


RO7062931—F. Hoffmann-La Roche Ltd
49/Protocol YP39432, Version 2
least 40% of arm circumference [a length-to-width ratio of 2:1]). The study subject should 
be asked to remove all clothing that covers the location of cuff placement.
4.6.1.4
Electrocardiograms
ECGs will be collected after the study subject has been in a supine position for at least 
10 minutes prior to each ECG evaluation. At the specified time-points (see the Schedule 
of Assessments tables; Appendix 1 and Appendix 2), 12-lead ECGs will be obtained in 
triplicate, i.e., three consecutive interpretable 12-lead ECGs within a 2-5-minutes, and 
recorded in eCRF. Triplicate recordings should be taken for any unscheduled ECG.
All ECG recordings must be performed using a standard digital high-quality, high-fidelity 
ECG machine equipped with computer-based interval measurements. Automated ECG 
intervals (PR [PQ], QRS, QT, QTcF [to be derived in eCRF]) and heart rate (HR) will be 
captured or calculated, and the changes in T-wave and U-wave morphology will be 
documented. Changes in T-wave and U-wave morphology and overall ECG 
interpretation will be documented on the eCRF. T-wave information will be captured as 
normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic ECG tracings must be appropriately kept by the 
study center and must fulfill all applicable archiving requirements. The ECG intervals and 
interpretation will be recorded on the eCRF or may be sent electronically. If considered 
appropriate by Roche, ECGs may be analyzed retrospectively at a central laboratory.
The following are requirements for ECG assessments:
1.
Digital ECG recordings, storage and analysis.
2.
Three useful recordings must be collected without artefacts, per time-point. 
3.
Body position should also be consistently maintained for each ECG performed. In 
particular, changes in HR should be avoided. The absence of any environmental 
distractions (television, radio, conversation) during the pre-ECG rest and the ECG 
recording in the clinic must be emphasized.
4.
Avoid (if the schedule of assessment allows) ECG recordings within 3 hours after 
meals.
5.
Strictly match timing and conditions of ECG recording to baseline. Conditions to be 
standardized include food intake, activity level, stressors, and room temperature.
6.
If possible, the same machine, brand and model, should be used for the same study 
subject throughout the study.
7.
ECGs should be 12-lead, recorded at 25 mm/sec for at least 10 seconds.
8.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper 
lead placement as contributing to the ECG abnormality.


RO7062931—F. Hoffmann-La Roche Ltd
50/Protocol YP39432, Version 2
9.
ECG machines should have periodic calibration and service records (minimum once 
a year).
10. If any QT/QTc values500 msec or increases from pre-dose on Day 1 
QTc60 msec (as provided by the machine), the site should repeat the ECG within 
the next 5 minutes and notify the Sponsor. If confirmed, ECG recordings should be 
repeated at least hourly until two successive ECGs show QTc values below the 
threshold value that triggered the repeated measurement.
4.6.1.5
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 HV safety. Where the clinical significance of abnormal lab 
results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse, e.g., previous occasional intake of a medication or 
food containing for example codeine, benzodiazepines or opiates, the test could be 
repeated to confirm washout.
Additional blood and urine safety samples will also be collected at the time of a serious 
adverse event.
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. The following blood and urine 
samples will be collected:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), mean 
corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration 
(MCHC).

Blood chemistry: ALT, AST, total and indirect bilirubin, alkaline phosphatase (ALP), 
blood urea nitrogen (BUN), gamma-glutamyl transferase (GGT) (at Screening only), 
creatine phosphokinase (at Screening only), total protein, albumin, creatinine and
calculated creatinine clearance using Cockcroft Gault formula, glomerular filtration
rate (GFR) calculated, uric acid, cystatin c, fasting glucose, total cholesterol, low 
density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, 
triglycerides, sodium, chloride, potassium, calcium, magnesium, phosphate and 
bicarbonate. 


RO7062931—F. Hoffmann-La Roche Ltd
51/Protocol YP39432, Version 2

Coagulation: prothrombin time (PT), International Normalized Ratio (INR), activated 
partial thromboplastin time (aPTT).

Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocytes, specific gravity and pH. All urine 
samples will also be sent to the laboratory to perform microscopy to examine urine 
sediment for casts and cells. If there is a clinically significant positive dipstick result, 
(i.e., confirmed by a positive repeated sample), urine will be sent to the laboratory 
for culture. If there is an explanation for the positive dipstick result, e.g., menses, it 
should be recorded. Urine color may be evaluated from urinalysis or urine PK 
samples if considered necessary.

Viral serology: HIV-1 Antibody, HIV-2 Antibody, hepatitis A virus (HAV IgM 
Antibody), HBV (surface antigen, HBsAg), hepatitis C virus (HCV RNA or HCV 
antibody).

Pregnancy test
For all women enrolled in the study: Blood sample for determining beta-human 
chorionic gonadotropin (-HCG) at Screening. Urine pregnancy tests will be 
performed at specified subsequent visits. If a urine pregnancy test is positive, it 
must be confirmed by a blood pregnancy test.

Hormones: FSH (females only to confirm post-menopausal status, performed at 
Screening only).

Drugs of abuse (urine): Cannabinoids, amphetamines, methamphetamines, opiates, 
methadone, cocaine, benzodiazepines, and barbiturates.

Alcohol breath or blood test will be performed.
4.6.1.6
Pharmacokinetic Assessments 
PK samples are mandatory. Blood and urine samples will be collected to evaluate the 
PK of RO7062931 and metabolites, if applicable, from all HV cohorts, as specified in the 
Schedule of Assessments (see Appendix 1 and Appendix 2). When the PK assessment 
is scheduled for the same nominal time as another scheduled assessment, the PK blood 
samples should be taken as close as possible to the scheduled time. The volume of 
each urine sample at each interval will be measured by the site staff and recorded in 
eCRF. The actual date and time of each blood sample collection, the start and end date 
and time for each urine sample collection will be recorded in eCRF. RO7062931 levels 
will be analyzed by using validated assays.
Additional PK sample will also be collected at the time of a serious adverse event. 
 
 
PK parameters will be estimated using standard non-compartmental methods 
for RO7062931/ metabolites.


RO7062931—F. Hoffmann-La Roche Ltd
52/Protocol YP39432, Version 2
A decision to stop PK sampling earlier or to collect more samples than currently 
proposed scheduled times will be based on the PK profile of the study drug. Timing of 
PK sampling may change based on emerging PK results after agreement with the 
Sponsor and the Investigator. Details on sampling procedures, sample storage and 
shipment are given in the lab manual.
PK samples will be stored for up to 2 years for the protocol assessments, unless 
otherwise indicated. Samples will be destroyed no later than 2 years after the date of 
final closure of the clinical database, unless regulatory authorities require specimens to 
be maintained for a longer time period. If required, the residual of the PK samples taken 
during the study (any time-point) can be used for additional analysis (including assay 
validations and immunogenicity analyses).
Samples for laboratory tests as specified above will be sent to one or several central 
laboratories or to the Sponsor for analysis. For sampling procedures, storage conditions, 
and shipment instructions, see the separate laboratory manual.
4.6.1.7
Assessments for Inflammatory Markers, Drug-Induced 
Autoantibodies and Anti-Drug Antibodies (ADA)
Samples for laboratory tests as specified below will be sent to one or several central 
laboratories or to the Sponsor for analysis. Based on analysis of the data in this study 
and other studies, any sample type not considered to be critical for safety evaluation 
may be stopped at any time if the data from the samples collected does not produce 
useful information. For sampling procedures, storage conditions, and shipment 
instructions, see the separate laboratory manual.
The timing of sampling and parameter may change based on emerging results and after 
agreement with the Sponsor and the Investigator.
The following separate assessments will take place in this study: 

For inflammatory markers

For development of drug-induced autoantibodies

For development of anti-drug antibodies (ADAs)
Inflammatory Markers
Blood samples for assessing inflammatory markers will be obtained for all HVs at 
pre-specified time-points (see the Schedule of Assessments; Appendix 1 and 
Appendix 2). In addition, in case an immune-driven adverse event/ an adverse event
suggestive of immunological involvement occurs, an unscheduled sample will be 
collected as close to the onset of the adverse event as possible. Blood samples (both 
planned and unscheduled) will be taken to assess: complement, C-Reactive Protein 
(CRP), erythrocyte sedimentation rate (ESR), gamma globulin and the following 
inflammatory biomarkers (interleukin [IL]-6, IL-8, IL12, mast cell protease [MCP1], tumor
necrosis factor [TNF]).


RO7062931—F. Hoffmann-La Roche Ltd
53/Protocol YP39432, Version 2
Drug-Induced Auto-antibodies
Blood samples for assessing drug-induced autoantibodies will be obtained for all study 
subjects before dosing, at baseline (see the Schedule of Assessments; Appendix 1 and 
Appendix 2). In addition, in case an autoimmune driven adverse event/ an adverse event
suggestive of autoimmunological involvement occurs, an unscheduled sample will be 
collected as close to the onset of the adverse event as is possible. The panel of 
autoantibodies to be assessed will be: anti-nuclear antibodies, anti-double-stranded 
DNA (dsDNA) antibodies, anti-histone antibodies, anti-single stranded DNA (ssDNA)
antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibodies, rheumatoid 
factor. 
ADA Assessment
Blood samples will be collected from all subjects at each time-point as specified in the 
Schedule of Assessments tables (Appendix 1 and Appendix 2). All ADA blood samples 
should be collected prior to dosing of investigational drug. ADA blood samples will be 
stored and will only be analyzed in case there is an immune-driven adverse event / an 
adverse event suggestive of immunological, anti-drug involvement or in case of an 
atypical PK result. If required, the residual of the ADA samples taken during the study 
(any time-point) can be used for additional analysis (including assay validations and 
immunogenicity analyses).
Unless otherwise indicated for the above samples, the collected samples will be stored 
for up to 5 years for the protocol assessments. 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
Other Assessments
The following urinary kidney biomarkers will be analyzed from urine samples:  
α1-microglobulin, β2-microglobulin, and KIM-1. Each biomarker will be normalized to 
urine creatinine.
The following liver biomarkers will be analyzed from blood samples: miRNA122 and
GLDH.
The timing of sampling and parameter may change based on emerging results and after 
agreement with the Sponsor and the Investigator.
Based on analysis of the data in this study and other studies, any sample type not 
considered to be critical for safety evaluation may be stopped at any time if the data from 
the samples collected does not produce useful information.
Samples as specified above will be sent to one or several central laboratories or to the 
Sponsor for analysis. For sampling procedures, storage conditions, and shipment 
instructions, see the separate laboratory manual.


RO7062931—F. Hoffmann-La Roche Ltd
54/Protocol YP39432, Version 2
4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Predosing 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 HVs and for HVs who are not subsequently enrolled will be maintained at the 
study site.
All screening and pre-dosing assessments must be completed and reviewed to confirm 
that HVs meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all HVs screened and to confirm eligibility or record reasons for 
screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened HV with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
If a HV fails an inclusion/exclusion criterion due to a transient and non-clinically 
significant condition at screening, the Investigator may repeat the relevant screening 
assessment(s) within 28 days of the screening period. If the HV fails a second time, they 
will be classed as a screen failure and cannot be re-screened. Re-screening is allowed 
for HV who were screened in the study and met study inclusion/exclusion criteria but 
failed to be randomized within 28 days after the start of screening period. In order to 
re-screen such a HV, all inclusion and exclusion criteria should be re-evaluated and all 
applicable screening assessments repeated if done more than 28 days before
randomization.
4.6.2.2
Assessments during Drug administration
Under no circumstances will HVs who enroll in this study and have received RO7062931 
or placebo as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments must be performed as listed in the Schedule of Assessments 
(Appendix 1 and Appendix 2).
4.6.2.3
Follow-Up Assessments and Study Completion
HVs who complete the study, or who discontinue from the study early, will be 
encouraged to attend the clinic for long term follow up as per the SOA in Appendix 1.
Blood sample for PK and safety lab assessment will be collected in the event of early 
termination. Adverse events should be followed as outlined in Section 5.5.


RO7062931—F. Hoffmann-La Roche Ltd
55/Protocol YP39432, Version 2
4.7
HEALTHY VOLUNTEER, STUDY, AND SITE DISCONTINUATION
4.7.1
Healthy Volunteer Discontinuation
The Investigator has the right to withdraw a HV from the study at any time. In addition, 
HVs have the right to voluntarily 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:

HV withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the HV’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the HV.

HV non-compliance.
Healthy volunteers who discontinue early for non-safety reasons may be replaced. 
The decision to replace a subject will be made by a mutual agreement between the 
Sponsor and Investigator.
4.7.1.1
Withdrawal from Study
Every effort should be made to obtain information on HVs who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
HVs will not be followed for any reason after consent has been withdrawn.
When a HV voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless the HV
specifically requests for these to be discarded or local laws require their immediate 
destruction.
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 HVs.

Clinically significant changes in safety parameters considered to be related to 
RO7062931 and not considered acceptable by the Investigator and/or Sponsor.

HV enrollment is unsatisfactory.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.


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RO7062931—F. Hoffmann-La Roche Ltd
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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.

Severe injection site reactions.

Renal adverse events defined as serum creatinine 1.5upper limit of normal (ULN)
or increase of50% from baseline.
5.2
SAFETY PLAN
Measures will be taken to ensure the safety of the HVs participating in this trial; in 
particular, the use of appropriate inclusion and exclusion criteria and close monitoring of 
the study subjects. HVs will be monitored by adverse event monitoring, vital sign 
monitoring, ECG monitoring, and hematology and clinical chemistry parameters.
The Investigator has the right to withdraw a HV for safety reasons at any time. Also, the 
Investigator and Sponsor may terminate a particular cohort or the study as whole at any 
time if considered warranted for safety reasons. For example, a particular cohort may be 
terminated in case of safety related drop-outs if the safety events were similar in nature.
ALT elevations of 2-3 times the baseline value that are self-limited, are likely to reflect 
drug toxicity. Progressive increases, or ALT elevations associated with increases in 
bilirubin and alkaline phosphatase, should be treated as adverse events. 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4-5.6.
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each study subject contact. All 
adverse events, whether reported by the HV or noted by study personnel, will be 
recorded in the HV’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.


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After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the last follow-up visit.
After the last follow-up visit, Investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be related to prior  study 
drug administration (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 1 provides guidance for assessing adverse event severity in the study.
Table 1
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 HV, 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 HV or use of concomitant medications known to 
increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.


 
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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 
Injection-Site Reactions 
Adverse events that occur during or after study drug administration and are judged to be 
related to the SC study drug injection should be captured as a diagnosis (e.g., “injection 
reaction" on the Adverse Event eCRF. If possible, avoid ambiguous terms (such as 
"systemic reaction"). Associated signs and symptoms should be recorded on the 
dedicated Injection Reaction eCRF. Grading of pre-defined injection site reaction 
symptoms is described in Appendix 4. If a subject experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on 
the Adverse Event eCRF, with signs and symptoms also recorded separately on the 
dedicated Injection Reaction eCRF. 
Other Adverse Events  
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


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
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 
HV 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.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), only 
the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.


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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 medical intervention or a change in concomitant therapy

Clinically significant in the Investigator’s judgment
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).


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5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a 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 pre-existing medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”).
5.3.5.9
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization should be documented and reported as 
a serious adverse event (per the definition of serious adverse events 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 study.
The following hospital scenarios are not considered to be serious adverse events, but 
should be reported as adverse events instead.

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.


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5.3.5.10
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 5.4.2).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
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 will be available on a 
separate list generated by the study management team.


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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 Serious Adverse Event
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 Sections 5.1.2 and 5.1.3) that occur after initiation of study drug, investigators 
should record all case details that can be gathered 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 Serious Adverse Event 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.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Healthy Volunteers
Female subjects of childbearing potential will not be allowed to take part in this study.  
Although highly unlikely, female subjects will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 105 days after the last 
dose of study drug. 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 study 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 subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
105 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed by the Investigator and submitted to the Sponsor within 24 hours 
after learning of the pregnancy. Attempts should be made to collect and report details of 


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the course and outcome of any pregnancy in the partner of a male HV 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 HV 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 5.4.2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female HV or female partner of a
male HV exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.5
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 HV is 
lost to follow-up, or the HV 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 records 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.


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All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as after the last follow-up visit). 
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 administration, the event should be reported directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the Serious Adverse Event 
Reporting Form using the fax number or email address provided to Investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to Investigators, IRBs, ECs, and 
applicable Health Authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO7062931 Investigator'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
6.1
DETERMINATION OF SAMPLE SIZE
The planned sample size of 8 active per cohort was chosen not only to allow adequate 
assessment of safety and tolerability but also to increase the precision of the estimates 


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of mean PK and urinary parameters, as comparisons of these parameters across doses 
will be used in part 
. 
Up to 50 HVs will be included in this study. Up to 5 cohorts of 10 HVs (8 on active and 2 
on placebo per dose level) are planned with the fifth and last cohort being optional and 
based on the analysis of emerging PK and safety data from this study and available data
from study BP39405.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations and discontinuations from the study will be 
summarized by treatment and dose level. The number of HVs who were randomized, 
discontinued and completed the study will be summarized. Reasons for premature study 
withdrawal will be listed and summarized by treatment and dose level. Demographic and 
other baseline characteristics will be summarized with descriptive statistics by treatment 
and dose level. All HVs on placebo will be pooled as one treatment group.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All HVs who have received 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
HVs will be excluded from the PK analysis population if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from the protocol or if data are 
unavailable or incomplete which may influence the PK analysis. Excluded cases will be 
documented together with the reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure.
6.3.3
Immunogenicity Analysis Population
The immunogenicity analyses, if applicable, will include subjects with a pre-dose and
one post-dose ADA assessment, with subjects grouped according to treatment received.
The relationship between ADA status and safety and PK endpoints will be analyzed and 
reported descriptively via subgroup analyses.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Descriptive statistics will be generated for demographics, including sex, self-reported 
race, ethnicity, age.
Data for study drug administration and concomitant medication will be listed. The 
number of subjects who were randomized, completed treatment period, discontinued 
study and completed the study (including follow-up period) will be summarized by 
treatment and dose level. All placebo patients will be pooled as one treatment group.


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6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
The safety data, including adverse events, injection site reactions (ISRs), reason for 
withdrawal from study, laboratory data, ECG, concomitant medications, vital signs and 
physical examination results will be listed and summarized descriptively by treatment 
and dose level. All placebo patients will be pooled as one treatment group. Marked 
abnormalities will be flagged for laboratory data.
As appropriate, listings, summary tables and graphs (study subject plot and/or mean 
plots) will be provided for safety and tolerability assessments.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor by assigning preferred terms. Adverse events will be 
summarized by mapped term and appropriate thesaurus level.
Adverse events will be described by individual listings and frequency tables broken down 
by body system.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Study subject listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing. Laboratory test values will be presented by listings and descriptive summary 
statistics.
6.5.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
6.5.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in study subject listings of laboratory data.


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In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a study subject, the midpoint of the standard reference range will be used 
as the study subject baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the study subject
listings as “HH” for very high or “LL” for very low.
6.5.3
Vital Signs
Vital signs data will be presented by individual listings. In addition, tabular summaries 
will be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be reported as summary descriptive statistics for the actual values and 
changes from baseline will be tabulated by nominal time for HR, QRS duration, PR and 
QTcF. For multiple measurements taken at a nominal time-point, the average of these 
measurements will be used as the value at that nominal time-point in all summaries. In 
addition, QTcF will be categorized at each time-point as450 msec, 450-480 msec, 
480-500 msec and 500 msec and summarized. Similarly, a summary will be provided 
of the QTcF changes from baseline at each time-point categorized as 30 msec, 
30-60 msec, and 60 msec. Changes of the overall ECG interpretation, T-wave and 
U-wave morphology will be summarized.
6.5.5
Concomitant Medications
The original terms recorded on the study subjects’ eCRF by the Investigator for 
concomitant medications will be standardized by the Sponsor by assigning preferred 
terms.
Concomitant medications will be presented in summary tables and listings.
6.6
PHARMACOKINETIC ANALYSES
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Summary descriptive statistics of plasma PK parameters, 
including Cmax, Tmax, AUCinf, AUClast, and t1/2 for RO7062931 and any metabolites when 
available, will be presented by cohort including means, geometric means, standard 
deviations (SD), coefficients of variation (CV), medians and ranges. Note: the geometric 
mean and associated CV% will be used to describe Cmax, AUCinf, AUClast. Listings, 
summary tables and graphs (individual plots and/or mean plots) by treatment group will 
be provided. Descriptive statistics of urine PK parameters for RO7062931 and any 
metabolites will be presented, where available. PK data from this study may be pooled 
with data from other studies to develop a population PK model. 




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A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Central laboratory data and 
electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an online 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 HV enrolled, an eCRF must be 
completed and electronically signed by the principal Investigator or authorized delegate 
from the study staff. If a HV withdraws from the study, the reason must be noted on the 
eCRF. If a HV is withdrawn from the study because of a treatment‑limiting adverse 
event, thorough efforts should be made to clearly document the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which subjects’ 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, 


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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, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer. After that period of time, 
the documents may be destroyed, subject to local regulations. No records may be 
disposed of without the written approval of the Sponsor. Written notification should be 
provided to the Sponsor prior to transferring any records to another party or moving 
them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 


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ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms 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 subject before his or her 
participation in the study. The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each subject shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the subject. All signed and 
dated Consent Forms must remain in each subject’s study file or in the site file and must 
be available for verification by study monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. In 
addition, any subject recruitment materials must be approved by the IRB/EC.


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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 safety reports or other 
safety‑related communications from the Sponsor. Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
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 patient, 
unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LSLO).
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 


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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, subject’ 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 
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.


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9.5
PROTOCOL AMENDMENTS
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.


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10.
REFERENCES
Committee for Medicinal Products for Human Use (CHMP). Assessment Report: 
Kynamro Solution for injection 189 mg. European Medicines Agency (EMA) 2013.
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B. J Hepatol. 2009;50:227-242.
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–185.
Investigator’s Brochure RO7062931.
Hornby RJ, Lewis PS, Dear J, et al. MicroRNAs as potential circulating biomarkers of 
drug-induced liver injury: key current and future issues for translation to humans. 
Expert Rev Clin Pharmacol. 2014;7(3):349-362.
Lucifora J, Xia Y, Reisinger F. Specific and non-hepatotoxic degradation of nuclear 
hepatitis B virus cccDNA. Science. 2014; 343(6176):1221-1228.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008;27(13):2420-2439.
Poelgeest EP, Hodges MR, Moerland M, et al. Antisense-mediated reduction of 
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9): a first-in-human 
randomized, placebo-controlled trial. Br J Clin Pharmaco.l 2015; 80(6):1350-1361.
World Health Organization (WHO). New Hepatitis B treatment guidelines released in 
China. 2015;
http://www.wpro.who.int/china/mediacentre/releases/2015/20150515/en/
WHO Fact Sheet N°204, updated July 2016. 
(http://www.who.int/mediacentre/factsheets/fs204/en/index.html)
Zhang Y, Jia Y, Zheng R, et al. Plasma microRNA-122 as a biomarker for viral-, alcohol-, 
and chemical-related hepatic diseases. Clin Chem. 2010;1(12):1830-1838.


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Appendix 1 Schedule of Assessments – Main table
Protocol Activity
Screening
Scheduled Time
Day -28 to -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 8
Day 15
Day 29
Day 85e
Visit Window
(± 1 day)
(± 2 days)
(± 7 days)
Informed Consent
x
Inclusion + Exclusion Criteria
x
x
Demography
x
Medical History
x
Physical Examinationh
x
x
x
x
x
x
Vital Signs
x
x
5
x
x
x
x
x
x
x
x
x
ECG-12 lead
x
x
5
x
x
x
x
x
Hematologya
x
x
x
x
x
x
x
Blood Chemistrya
x
x
x
x
x
x
x
Urinalysisa
x
x
x
x
x
x
x
Serology
x
Coagulationa
x
x
x
x
x
x
x
Inflammatory markersg
3
x
x
Drug-induced antibodiesi
xd
x
x
x
ADAf
xd
x
x
x
Urine kidney biomarkers
xd
x
x
x
x
x
Blood liver biomarkers
x
x
x
x
x
x
Pregnancy Testb
x
x
x
x
FSHc
x
Substance Use
x
x
Admission
x
Discharge
x
Ambulatory Visit
x
x
x
x
x
x
x
x
Randomisation
x
x
Medication
x
Blood PK Samplea
12
3
x
x
x
x
x
Urine PK Samplej
4
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
Treatments
x
x
x
x
x
x
x
x
x
x
x
x
Period 1
Follow Up


 
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Appendix 1 Schedule of Assessments – Main table (cont.) 
 
a) 
Timing of PK sampling may change based on PK results from the FIH (BP39405) study, blood sample for PK and safety laboratory assessments will be 
collected in the event of a SAE or at early termination. 
b) 
Blood for beta-human chorionic gonadotropin (β-HCG) for pregnancy test at Screening, urine on all other occasions. 
c) 
FSH only for females and to confirm post-menopausal. 
d) 
Pre-dose. 
e) 
If necessary, subjects may be asked to return for additional follow-up visits. 
f) 
For ADA samples will be stored and will only be analyzed in case an immune driven AE/AE suggestive of inflammatory involvement occurs or in case of an 
atypical PK result. 
g) 
In case an immune driven AE/AE suggestive of immunological involvement occurs, an unscheduled sample will be collected and analyzed. 
h) 
Complete physical examination, is required at Screening and Day   1. At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed at the discretion of the Investigator.  
i) 
In case an autoimmune driven AE/AE suggestive of autoimmunological involvement occurs, an unscheduled sample will be collected and analysed.  
j) 
Urine collection periods [0-4], [4-8], [8-12] and [12-24] hours post-dose. 
 
 


 
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Appendix 2 Schedule of Assessments – Detailed table 
Period
Day
Scheduled 
Time (h)
Administration 
of Study 
Medication
Vital 
Signs
ECG-12 
lead
Inflammatory 
markers
Drug-
induced 
antibodies
ADA
Urine 
kidney 
biomarkers
Blood liver 
biomarkers
Blood PK 
Sample
Urine PK 
Samplea
Screening
Day -28 to -2
x
x
Day -1
x
x
x
Predose
x
x
x
x
x
x
x
0
x
x
0.25
x
0.5
x
1
x
x
x
1.5
x
2
x
3
x
x
4
x
x
x
x
6
x
8
x
x
x
x
12
x
x
x
x
x
18
x
24
x
x
x
x
x
x
x
30
x
36
x
Day 3
48
x
x
x
Day 4
72
x
x
Day 5
96
x
x
Day 6
120
x
x
Day 8
168
x
x
x
x
x
x
Day 15
(± 1 day)
x
x
x
x
x
Day 29
(± 2 days)
x
x
x
x
x
x
Day 85
(± 7 days)
x
x
x
x
x
x
Period 1
Day 1
Day 2
Follow up 
Visit
 
a) 
Urine collection periods [0-4], [4-8], [8-12] and [12-24] hours post-dose. 


 
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Appendix 3  
Alcohol Unit Calculation - Examples 
From Australian Department of Health (Population Health Division) 
http://www.alcohol.gov.au/internet/alcohol/publishing.nsf/Content/standard 
 


 
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Appendix 3  
Alcohol Unit Calculation - Examples (cont.) 
 
 
 
 


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