Conditions: Autism Spectrum Disorder
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: yes

Brief summary:
This is a single dose (SD), non-randomized, open-label, adaptive, parallel group study with the purpose of investigating the occupancy of alpha5-containing GABAA receptors by RO7017773 in healthy participants.

Detailed description:

Arms:
arm 1: The first two participants of the first cohort are anticipated to receive a single dose of RO7017773 orally. The doses to be tested in the subsequent cohorts of participants will be determined by review of PET scan, PK, and safety results from the previous dose level.

Interventions: intervention 1: RO7017773 intervention 2: [11C] Ro15-4513
Intervention descriptions: intervention 1: RO7017773 will be administered orally. The doses to be tested will be determined by review of PET scan, PK, and safety results from the previous dose level. intervention 2: At the start of each PET scan, participants will receive an intravenous dose of the radiolabeled tracer \[11C\]Ro15-4513.

Protocol document:
Prot_SAP_000.pdf: 
Official Title: A NON-RANDOMIZED OPEN LABEL, ADAPTIVE, 
PARALLEL GROUP, HUMAN POSITRON EMISSION 
TOMOGRAPHY (PET) STUDY TO ASSESS 
OCCUPANCY OF BRAIN α5-CONTAINING GABAA
RECEPTORS OF RO7017773 USING [11C] Ro15-4513 
FOLLOWING SINGLE ORAL DOSES IN HEALTHY 
PARTICIPANTS 
NCT Number:  NCT03507569 
Document Date:    Protocol
   
                    Version 1: 08 January 2018
                                Version 2: 08 March 2018 


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The information contained in this document, especially any unpublished data, is the property of 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 Committeeor 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.
RO7017773—F. Hoffmann-La Roche Ltd
Protocol BP40257, Version 2
PROTOCOL
TITLE:
A NON-RANDOMIZED OPEN LABEL, ADAPTIVE, 
PARALLEL GROUP, HUMAN POSITRON EMISSION 
TOMOGRAPHY (PET) STUDY TO ASSESS 
OCCUPANCY OF BRAIN 5-CONTAINING GABA
A 
RECEPTORS OF RO7017773 USING [11C] Ro15-4513 
FOLLOWING SINGLE ORAL DOSES IN HEALTHY 
PARTICIPANTS 
PROTOCOL NUMBER: BP40257
VERSION:
2
EUDRACT NUMBER: 
2017-004400-22
TEST PRODUCT: 
RO7017773
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1: 08 January 2018
DATE AMENDED
08-Mar-2018 20:34:07
 
Title
Approver's Name
Company Signatory
Date and Time (UTC)
Version 2: See electronic date stamp below


RO7017773—F. Hoffmann-La Roche Ltd
2/Protocol BP40257, Version 2
PROTOCOL ACCEPTANCE FORM
TITLE:
A NON-RANDOMIZED OPEN LABEL, ADAPTIVE, 
PARALLEL GROUP, HUMAN POSITRON EMISSION 
TOMOGRAPHY (PET) STUDY TO ASSESS 
OCCUPANCY OF BRAIN 5-CONTAINING GABA
A 
RECEPTORS OF RO7017773 USING [11C] RO15-4513 
FOLLOWING SINGLE ORAL DOSES IN HEALTHY 
PARTICIPANTS
PROTOCOL NUMBER: BP40257
VERSION NUMBER: 
2
EUDRACT NUMBER: 
2017-004400-22
TEST PRODUCT: 
RO7017773
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.


RO7017773—F. Hoffmann-La Roche Ltd
3/Protocol BP40257, Version 2
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE
Protocol BP40257 version 1 has been amended to incorporate the followingchanges:

 
 
 
 
 

 
 
 
 
.

 
 

 

 

 

 

.

 




RO7017773—F. Hoffmann-La Roche Ltd
4/Protocol BP40257, Version 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. 


RO7017773—F. Hoffmann-La Roche Ltd
5/Protocol BP40257, Version 2
PROTOCOL AMENDMENT, VERSION 2:


RO7017773—F. Hoffmann-La Roche Ltd
6/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
7/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
8/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
9/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
10/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
11/Protocol BP40257, Version 2


RO7017773—F. Hoffmann-La Roche Ltd
12/Protocol BP40257, Version 2
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM....................................................................2
1.
PROTOCOL SUMMARY.............................................................................18
1.1 
Synopsis................................................................................18
1.3 
Schedule of Activities............................................................24
2.
INTRODUCTION........................................................................................28
2.1 
Study Rationale.....................................................................28
2.2 
Background...........................................................................28
2.2.2 
Background on PET Tracer [11C]Ro15-4513.........................30
2.3 
Benefit/Risk Assessment.......................................................31
3.
OBJECTIVESAND ENDPOINTS...............................................................34
4.
STUDY DESIGN.........................................................................................35
4.1 
Overall Design.......................................................................35
4.1.1 
Length of the Study...............................................................36
4.1.2 
Selection of Dose Levels for Subsequent Cohorts 
and Timing of PET/CT Scans and PK Sampling S................36
4.1.3 
Communication Strategy.......................................................37
4.2 
Scientific Rationale for Study Design.....................................37
4.2.1 
Rationale for Study Population..............................................37
4.2.2 
Rationale for PK Sampling.....................................................37
4.2.4 
Rationale for PET Imaging.....................................................37
4.2.5 
Rationale for MRI Imaging.....................................................38
4.3 
Dose Justification..................................................................38
4.4 
End of Study Definition..........................................................39
5.
STUDY POPULATION................................................................................39
5.1 
Inclusion Criteria....................................................................40
5.2 
Exclusion Criteria...................................................................41
5.3 
Lifestyle Considerations.........................................................43


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5.3.1 
Meals and Dietary Restrictions..............................................43
5.3.2 
Caffeine, Alcohol, and Tobacco.............................................43
5.3.3  
Activity...................................................................................44
5.4 
Screen Failures.....................................................................44
5.5 
Recruitment Procedures........................................................44
6.
TREATMENTS............................................................................................44
6.1 
Treatments Administered.......................................................45
6.2 
Preparation/Handling/Storage/Accountability........................46
6.2.1 
PET Tracer [11C]Ro15-4513..................................................47
6.3 
Measures to Minimize Bias: Randomization and 
Blinding..................................................................................47
6.3.1  
Method of Treatment Assignment..........................................47
6.3.2 
Blinding..................................................................................47
6.4 
Treatment Compliance..........................................................47
6.5 
Concomitant Therapy............................................................47
6.5.1 
Permitted Therapy.................................................................47
6.5.2 
Prohibited Therapy................................................................48
6.6 
Dosage Modification..............................................................48
6.7 
Treatment after the End of the Study.....................................49
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL.................................49
7.1 
Discontinuation of Study Treatment.......................................49
7.2 
Participant Discontinuation/Withdrawal from the 
Study.....................................................................................49
7.3 
Lost to Follow-Up...................................................................50
8.
STUDY ASSESSMENTS AND PROCEDURES.........................................50
8.1 
Efficacy Assessments............................................................51
8.2 
Safety Assessments..............................................................51
8.2.1 
Physical Examinations...........................................................51
8.2.2 
Vital Signs..............................................................................51
8.2.3 
Electrocardiograms................................................................51
8.2.4 
Clinical Safety Laboratory Assessments................................52
8.2.5 
Medical History and Demographic Data................................53


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8.3 
Adverse Events and Serious Adverse Events.......................53
8.3.1 
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information.............................................................................53
8.3.2 
Method of Detecting Adverse Events and Serious 
Adverse Events.....................................................................54
8.3.3  
Follow-Up of Adverse Events and Serious 
Adverse Events.....................................................................54
8.3.3.1 
Investigator Follow-Up...........................................................54
8.3.3.2 
Sponsor Follow-Up................................................................55
8.3.4 
Regulatory Reporting Requirements for Serious 
Adverse Events.....................................................................55
8.3.4.1 
Emergency Medical Contacts................................................55
8.3.5 
Pregnancy.............................................................................55
8.3.6 
Non-Serious Adverse Events of Special Interest...................56
8.3.7 
Management of Specific Adverse Events..............................56
8.4 
Treatment of Overdose..........................................................56
8.5 
Pharmacokinetics..................................................................56
8.6 
Allen’s Test............................................................................57
8.7 
Arterial Blood Sampling.........................................................57
8.8 
Imaging..................................................................................57
8.8.1 
PET/CT Scans.......................................................................57
8.8.2 
Magnetic Resonance Imaging (MRI) Scans..........................58
8.9 
Biomarkers............................................................................58
8.10 
Health Economics/Medical Resource Utilization 
and Health Economics...........................................................58
8.11 
Timing of Study Assessments...............................................58
8.11.1 
Screening and Pre-Treatment Assessments.........................58
8.11.2 
Assessments During Treatment............................................59
8.11.3 
Assessments at Study Completion/Early 
Termination Visit....................................................................59
8.11.4 
Follow-Up Assessments........................................................59
9.
STATISTICAL CONSIDERATIONS............................................................59
9.1 
Statistical Hypotheses...........................................................59
9.2 
Sample Size Determination...................................................59


RO7017773—F. Hoffmann-La Roche Ltd
15/Protocol BP40257, Version 2
9.3 
Populations for Analyses.......................................................60
9.4 
Statistical Analyses................................................................60
9.4.1 
Demographics and Baseline Characteristics.........................60
9.4.2 
Safety Analyses.....................................................................60
9.4.3 
Pharmacokinetic Analyses.....................................................61
9.4.4 
Pharmacodynamic Analyses.................................................61
9.4.5 
Pharmacokinetic/Pharmacodynamic Relationship.................62
9.5 
Summaries of Conduct of Study............................................62
10. REFERENCES...........................................................................................63
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS....................................................................................64
LIST OF TABLES
Table1 
Schedule of Activities –Main Table ................................................25
Table2 
Schedule of Activities –Imaging Session 2, Detailed Table................27
Table4 
Objectives and Endpoints...........................................................34
Table6 
Summary of Treatment Administered and PET Ligand...............45
Table7 
Analysis Populations...................................................................60
Table8 
Safety Statistical Analysis Methods............................................61
LIST OF FIGURES
LIST OF APPENDICES
Appendix1 
Regulatory, Ethical, and Study Oversight Considerations..........65
Appendix2 
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-Up andReporting.............................................................71
Appendix3 
Procedures for Recording Adverse Events................................77
Appendix4 
Clinical Laboratory Tests...........................................................81
Appendix5 
Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................83


RO7017773—F. Hoffmann-La Roche Ltd
16/Protocol BP40257, Version 2
LIST OF ABBREVIATIONS AND DEFINITIONS OFTERMS
Abbreviation
Definition
ADP
Adenosine diphosphate
AE
Adverse event
aPTT
Activated partial thromboplastin time
ASD
Autism Spectrum Disorder
AUC
Area under the curve
BP
Blood pressure
CL
Clearance
CNS
Central nervous system
CRO
Contract research organization
CSR
Clinical study report
CT
Computed tomography
CYP
Cytochrome
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EU
European Commission
FSH
Follicle-stimulating hormone
GLP
Good Laboratory Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICRP
International Committee for RadiologicalProtection
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational new drug (application)
INR
International normalized ratio
IRB
Institutional review board
IV
Intravenous
LPLO
Last participant, last observation
MAD
Multiple-ascendingdoses
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose


RO7017773—F. Hoffmann-La Roche Ltd
17/Protocol BP40257, Version 2
NOAC
Non-vitamin K antagonist oral anticoagulant
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter
PAM
Positive allosteric modulator
PD
Pharmacodynamic
PK
Pharmacokinetic
QRS
QRS complex
QT
QT interval
QTc
QTca
QT corrected for heart rate
Individual probabilistic correctedQT
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RO
Receptor occupancy
ROI
Region of interest
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SoA
Schedule of activities
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TQT
Thorough QT
ULN
Upper limit of normal
V
Volume
V/F
Apparent volume ofdistribution
VPA
Valproic acid
WBC
White blood cell










RO7017773—F. Hoffmann-La Roche Ltd
22/Protocol BP40257, Version 2
9.
Abnormal pulse rate, resting pulse rate greater than 100 or less than 40 bpm. 
10. History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g., PQ/PR interval 210 ms , QTcF 450 ms (470 ms females) or 
cardiovascular disease (e.g., cardiac insufficiency, coronary artery disease, cardiomyopathy, 
congestive heart failure, family history of congenital long QT syndrome, family history of 
sudden death).
11. Clinically significant abnormalities in laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or 
questionable results, tests performed during screening may be repeated before 
randomization to confirm eligibility.
12. Participants who, in the Investigator
's judgment, pose a suicidal or homicidal risk, or any 
participant with a history of suicidal or homicidal attempts.
Prior/Concomitant Therapy
13. Participants likely to need concomitant medication during the study period (including for 
dental conditions).
Prior/Concurrent Clinical Study Experience
14. Participation in an investigational drug or device study within 90 days prior to screening, as 
calculated from the day of follow-upfrom the previous study, or more than 4 times a year.
15. Previous inclusion in a research and/or medical protocol involving PET or radiological 
investigations (within the last 12 months).
Diagnostic Assessments
16. Positive test for drugs of abuse or alcohol.
17. For WONCBP, a positive pregnancy test.
18. Show evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV 
antibodies.
19. Positive resulton hepatitis B (HBV) or hepatitis C (HCV), presence of hepatitis B surface 
antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months 
prior to starting study treatment.
Other Exclusions
20. Dietary restrictions that would prohibit the consumption of standardized meals.
21. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of drug of 
abuse or previous history of or treatment for a dependence disorder.
22. Participants who regularly smoke more than 5 cigarettes daily or equivalent and unable or 
unwilling not to smoke during the in-house period.
23. Participants who have donated over 500 mL of blood or blood products or had significant 
blood loss within 3 months prior to screening.
24. Participants under judicial supervision, guardianship or curatorship.
25. Presence of a cardiac pacemaker or other electronic device; ferromagnetic metal foreign 
bodies in vulnerable positions; presence of certain tattoos that might make it unsafe for an 
MRI; participant working as a machinist, welder or metal worker; claustrophobia; as 
assessed by a standard pre MRI questionnaire.
26. Occupational radiation exposure or radiation exposure Exposure to ionising radiation infrom
medical diagnostic or treatmentsresearchover the past 12 months, that would result in a dose in 
excess of 10 mSvwhich when combined with the planned exposure fromthis studywould result in 
an effective dose in excess of 10 mSv.
27. Contraindication for arterial cannulation; Allen’s test indicating potential risk in placement of 
the arterial cannula.
NUMBER OF PARTICIPANTS
It is anticipated that a maximum of 15 participants will be enrolled in the study. At each 
anticipated dose level, up to 2 to 3 participants maybe enrolledwith 2 participants per cohort.




RO7017773—F. Hoffmann-La Roche Ltd
24/Protocol BP40257, Version 2
1.3 
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided inTable1andTable2.


RO7017773—F. Hoffmann-La Roche Ltd
25/Protocol BP40257, Version 2
Table1
Schedule of Activities –Main Table
a)
For each participant, imaging session 2 (on-treatmentPET/CT scans) will occur 
approximately 7 days after imaging session 1 (baseline scan).
b)
Safety and follow-up visit to be done 5 to 10 days after the RO7017773 administration.
c)
Height at screening only, when body mass index (BMI)will be derived.
d)
Vital signs will include blood pressure, pulse rate and body temperature. Temperature will be 
recorded on Day 1 of imaging session 2only. All measurements will be taken after the 
participant has rested in a supine position for at least 5 minutes.
Visit
Screen
ing
Fo
l
low U
p 
V
is
it
b
Day(s) (relative to PET scans)
Up to
-28 
-1 
1 
-1 
1  
2  
3 
5-10 days
Informed Consent
x
Medical History 
x
Physical Examination
x
x
Height & weight
c
x  
x
x
x
Admission
x
x
In-house Period
x  
x  
x  
x  
x  
x
Discharge
x
x
Vital Signs 
d
x  
x
x
e
x  
5  
x  
x  
x
ECG-12 lead 
f
x  
x
x
e
4
g
4  
x  
x  
x
Serology
x
Pregnancy Test 
h
x  
x
x
x
Hormone Panel 
i
x
Alcohol Breath Test
x  
x
x
Urine Drugs of abuse
x  
x
x
Urinalysis
x  
x
x
x
Blood Chemistry
x  
x
x
x
Hematology
x  
x
x
x
Coagulation
x
Standardised  meal
x  
x  
x  
x  
x  
x
MRI Scan
 j
x
Allen
's test 
x  
x  
x  
x  
x
Administration of RO7017773
l
x
Injection [
11C]Ro015-4513
x
2
Arterial blood sampling for 
[
11C]Ro015-4513 radioactivity 
measurement 
x
x
Previous and Concomitant 
Treatments
x  
x  
x  
x  
x  
x  
x  
x
Adverse Events
x  
x  
x  
x  
x  
x  
x  
x
Imag
ing Sess
ion 2 (on-treatment)
a
Imag
ing Sess
ion 1 
(base
l
ine)


RO7017773—F. Hoffmann-La Roche Ltd
26/Protocol BP40257, Version 2
Table1
Schedule of Activities –Main Table(cont.)
e)
Prior to the PET scan and before discharge from the unit.
f)
Triplicate 12-leadECGs will be collected after the participanthas rested in a supine position 
for at least 10 minutes.
g)
ECGs will be time-matchedon Day 1and Day-1of imaging session 2 (see Detailed table).
h)
Pregnancy test for females of childbearing potential only. Serum test at screening, urine test 
at Day 1 of imaging session 1 and 2 and follow-up.The screening pregnancy test can be 
used for the MRI scan if done on the day of the MRI scanotherwise an additional urine test 
on day of MRI scan will be performed.
i)
Hormonal panelis for post-menopausalwomen only.
j)
Participants will complete an MRI questionnaire before the scan, to exclude unsuitable and 
unwilling participants. The structural MRI scan may be done at a separate visit, provided the 
results are available before the baseline PET scan.The MRI scan should be performed 
within 60 days of screening.
l)
RO7017773 will be administered orally with water, in the morning of Day 1 of imaging 
session 2 after an overnight fast of at least 10 hours. Water will be allowed ad libitum until 1 
hour prior to dosingand from 1 hour post-dosing.Occasionally, a technical failure (such as 
unsuccessful tracer synthesis) or study logistical requirements may require one or both on-treatment 
PET scans to be rescheduled.


RO7017773—F. Hoffmann-La Roche Ltd
27/Protocol BP40257, Version 2
Table2
Schedule of Activities –Imaging Session 2, Detailed Table
Times relative to RO 
administration
Predose 
equivalent
2h  
6h  
11h
Predose 0h  
2h  
3.5h  4.5h  
5h 
6h 
9h  10.5h
Administration of 
RO7017773
X
Injection [
11C]Ro015-4513
X
X
Vital Signs (blood pressure 
and pulse rate)
X
X
X
X
Temperature
X
X
X
ECG-12 lead 
X 
X 
X  
X  
X
X
X
Day -1
Imag
ing Sess
ion 2 (on-treatment)
Day 1
11h
X
X


RO7017773—F. Hoffmann-La Roche Ltd
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2. 
INTRODUCTION
 
 
2.1 
STUDY RATIONALE
This study aims to quantify the level of receptor occupancy of RO7017773 using PET 
tracer [
11C]Ro15-4513 after varyingsingle oral doses of RO7017773. The measurement 
of brain receptor occupancy (RO) obtainedusing positron emission tomography (PET) is 
critically important to characterize PK-ROrelationship and 
 
 
 
. Each participant will undergo a baseline 
PET/CT scan and two on-treatment PET/CT scans, allowing the extent and duration of 
brain GABAA-α5 receptor occupancy of varying single oral doses of RO7017773 in 
healthy volunteers to be measured using the [11C]Ro15-4513PET tracer. The study will 
estimate the doses of RO7017773 which displaces the binding of the radiolabeled
GABAA5 ligand [11C]Ro15-4513to the receptors in the brain.
The rationale for the study design is providedin Section4.2.
2.2 
BACKGROUND
 
 
 
 
 
 
 
 
 
 


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2.2.1 
Background on RO7017773
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A detailed description of the chemistry, pharmacology, efficacyand safety of 
RO7017773 is provided in the Investigator’s Brochure (RO7017773 Investigator’s 
Brochure).
2.2.2  
Background on PET Tracer [
11C]Ro15-4513
In this study, thePET ligand[
11C]Ro15-4513 (non-InvestigationalMedicinal Product 
[NIMP]) will be given to participants at the start ofeach PET/CT scan, to quantify the 
level of receptor occupancy at 5-containing GABAAreceptors after single oral dosesof 
RO7017773.
[
11C]Ro15-4513is a partially selective ligandforthe GABA
A5 receptor subtype with
relatively higher in vitro affinity for the 5 subunit-containing GABAAreceptor than for
other subunits. Ro15-4513 has 10-20-fold higher in vitro affinity for 5 subunit-
containing GABAAreceptors(Ki=0.7 nmol/l) compared with 1, 2, and 3 subunit-
containing receptors(Ki=7–10 nmol/l).
 
 


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 In previous PET studies, binding of [
11C]Ro15-4513 was predominantly 
seen in the hippocampus, amygdala, anteriorcingulate cortex, and insular cortex, 
consistent with the evidencethat it is selectivelylabelling GABA
Areceptors containing 
the5 subunit (Myers et al 2017). Noadverse effects of the PET tracer have been 
reported to date.
2.3 
BENEFIT/RISK ASSESSMENT
This will be the first study assessing GABAA5 receptor occupancy following single 
doses of RO7017773 in healthy participants. Each participantwill undergo a baseline 
PET/CT scanand two on-treatmentPET/CT scans, allowing the extent and duration of 
brain GABAA-5 receptor occupancy of varying single oral doses of RO7017773 in 
healthy participants to be measured using the [11C]Ro15-4513 PET tracer.This 
information will be used for
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




RO7017773—F. Hoffmann-La Roche Ltd
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supervised by clinical personnel. Safety and tolerability will be monitored closely; 
tolerability will be assessed by recording adverseevents and close observation of the 
participants. In addition, laboratory safety parameters will be monitored as well as vital 
signs (blood pressure, temperatureandpulse rate) and ECGs be recorded.
The PET tracer [11C]Ro15-4513 has been used in previous studies in healthy 
participants to quantify the level of occupancy at 5 containing GABAAreceptorsafter a 
single dose of study drug. 
 
 
 The amount of tracer 
that will be given to an individualfor a PET/CT scanwill be less than10 g.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RO7017773—F. Hoffmann-La Roche Ltd
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Magnetic resonance images (MRI) delineating brain anatomywill be acquired in this 
study to aid PET image analysis. There are no known risks to participants associated 
withMRI scanning, provided that they have no contraindications to MRI as listed in the
exclusion criteria. Potential risks associated with metallic implants will be mitigatedby 
administration of a questionnaire and careful screening.
Clinically appropriate strategies to minimize risk to participants have been built into the 
protocol through the means of eligibility criteria, monitoring strategies, and management 
guidelines. Furthermore, 
 
be available prior to initiating the PET study at the respective dose levels.
The potential risks for any healthy participants due to the treatment of RO7017773 or 
study-related procedures are considered minimal and are outweighed by the potential to 
develop a new treatment for ASD. Further information about the known and expected 
benefits in the context of potential risks and reasonably expected adverse events of 
RO7017773 is provided in the Investigator’s Brochure (RO7017773 Investigator’s 
Brochure).
3. 
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table4.
Table4
Objectives and Endpoints
Objectives
Endpoints
Primary
 To assess the relationship between 
RO7017773 plasma concentration and 
brain occupancy of GABAAreceptor 
subtypes (containing the5 subunit)after 
single oral doses of RO7017773 using 
[
11C]Ro15-4513PET tracer.
 Occupancy of brain 5-containing GABAA
receptors by RO7017773 in selected 
regions of interest (ROIs).

RO7017773 plasma concentrations.
Secondary
To assessthe safety and tolerability of 
single oral doses of RO7017773.
Incidence and severity of AE.
Changes in vital signs, physical findings, 
ECG parameters, and clinical laboratory 
results during and following RO7017773 
administration.




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will receive no more than 2 doses of RO7017773, and 3 doses of the radiolabeled ligand,
[
11C]Ro15-4513, throughout the study. Participants will attend the clinical research unit 
for a safety follow-up visit 5 to 10 days after the last dose of RO7017773.
 
 
 
 
.
This study will have an adaptive design to adequately evaluate the exposure versus RO 
relationship. 
 
 
 
 
 
 The doses will be selected in order to obtain a wide 
enough range of receptor occupancies to allow adequate model parameter estimation of the 
RO7017773 exposure-RO relationshipbased on RO7017773 concentrations that will span 
as much of the occupancy range as possible.
4.1.1  
Length of the Study
The total duration of the study for each participant will be up to 8weeks divided as 
follows:

Screening: Up to 4weeks

Imaging Session 1 (baseline PET/CT scan): Day 1 to Day 1

Imaging Session 2 (on-treatmentPET/CT scan): Day -1
1)to 

Safety follow-up: 5 to 10 Days after last dose.
1)Admission for imaging session 2 will be at least 6days after the baseline PET/CT scan
if arterial sampling required.
4.1.2 
Selection of Dose Levels for Subsequent Cohorts and Timing 
of PET/CT scans and PK sampling S
The choice of the next dose level(s) will be made following review, by the Investigator,
the PET specialistand Sponsor, of RO data at the previous dose level(s), and all 
availablePK, PK-RO data, safetyand tolerability dataas outlined inAppendix6and in 
Section4.3.
If a dose level causes any safety concerns, the same or a higher dose level will not be
tested in any other participants (see Section2.3).


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4.1.3 
Communication Strategy
There will be review of available safety, PK and occupancy data (see Section4.1.2) prior 
to initiation of the next dose. A Dose Selection Meeting will be conducted between the 
Sponsor study team, the PET specialist and Investigator prior to dosing of the next 
cohort. There will be at least one week between each dose level in order to permit 
adequate time for collation and review of emerging data before the next dose is 
administered.
4.2 
SCIENTIFIC RATIONALE FOR STUDYDESIGN
The study rationale is provided in Section2.1.
4.2.1 
Rationale for Study Population
The participants of this study arehealthymale and female(women of non-childbearing 
potential)participantsaged 23to 55years(inclusive), chosen because of the absence of 
confounding diseases, which will enablea clearer and more consistent assessment of 
drug disposition,biological activityand safety profile. In addition, healthy participantsare 
unlikely to require concomitant medicationswhich could interferewith study drugs.
4.2.2 
Rationale for PK sampling
Blood samples for determination of RO7017773 in plasma will be collected prior and just 
after each on-treatmentPET/CT scans to inform the PK-RO model.
4.2.4 
Rationale for PET Imaging
PET is a non-invasiveimaging technique based on the external detection and recording 
of the decay of positronemitters incorporated in biological molecules introduced in a 
participant. Molecules of biological interest are labeled with short-lived positron emitter 
isotopes of biological nuclei (in this study [11C]), providing radioligands with high specific 
activity and preserved biochemical properties. The PET instruments make it possible to 


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obtain time varying three-dimensional maps of the absolute radioactivity concentration 
distribution. By applying ligand kinetic principles to these PET data, it is then possible to 
estimate absolute values of the physiological parameters that determine the interactions 
and fate of the labeled molecule. In humans, radioligands are usually administered in 
minute amounts (typical mass dose is the low μg range).Because of the low radiation 
doses that are necessary (10 mSv), PET can be safely used for clinical research 
purposes.
4.2.5 
Rationale for MRI Imaging
Astructural MRI scan of the brain will be acquired for each participantto provide an 
anatomical imageto aid PET image analysis.
4.3 
DOSE JUSTIFICATION
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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The participants of this study are healthy volunteers between 23 and 55 years of age, 
inclusive, who fulfill all the inclusion criteria listed in Section5.1.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1 
INCLUSION CRITERIA
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to ICH and local regulations.
Age
2.
Healthy participants aged 23to 55 years of age, inclusive, at the time of signing the 
informed consent. 
Type of Participants and Disease Characteristics
3.
Healthy, as judged by the Investigator.
Healthy status is defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination 
including vital signs, 12-lead ECG, hematology, blood chemistry, serology and 
urinalysis.
Weight
4.
Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive at screening.
Sex
5.
Male and femaleparticipants
a) Female Participants
 




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4.
History of convulsions (other than benign febrile convulsions of childhood) including 
epilepsy, or personal history of significant cerebral trauma or CNS infections (e.g.,
meningitis).
5.
Clinically significant abnormal finding from the MRI performed after the initial 
screening examination.
6.
A history of clinically significant hypersensitivity (e.g.,drugs, excipients) or allergic 
reactions.
7.
Any major illness within one month before the screening examination or any febrile 
illness within one week prior to screening and up to first study drug administration.
8.
Abnormal blood pressure, i.e, systolic blood pressure (SBP) greater than 140 or less 
than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 
mm Hg.
9.
Abnormal pulse rate, resting pulse rate greater than 100 or less than 40 bpm. 
10. History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g.,PQ/PR interval 210 ms , QTcF 450 ms (470 ms females)
or cardiovascular disease (e.g.,cardiac insufficiency, coronary artery disease, 
cardiomyopathy, congestive heart failure, family history of congenital long QT 
syndrome, family history of sudden death).
11. Clinically significant abnormalities in laboratory test results (including hepatic and 
renal panels, complete blood count, chemistry panel and urinalysis).In the case of 
uncertain or questionable results, tests performed during screening may be 
repeated before randomization to confirm eligibility.
12. Participantswho, in the Investigator
's judgment, pose a suicidal or homicidal risk, or 
anyparticipantwith a history of suicidal or homicidal attempts.
Prior/Concomitant Therapy
13. Participants likely to need concomitant medication during the study period (including 
for dental conditions).
Prior/Concurrent Clinical Study Experience
14. Participation in an investigational drug or device study within 90 days prior to 
screening, as calculated from the day of follow-upfrom the previous study, or more 
than 4 times a year.
15. Previous inclusion in a research and/or medical protocol involving PET or 
radiological investigations (within the last 12 months).
Diagnostic Assessments
16. Positive test for drugs of abuse or alcohol.
17. For WONCBP, a positive pregnancy test.
18. Show evidence of human immunodeficiency virus (HIV) infection and/or positive 
human HIV antibodies.


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19. Positive result onhepatitis B(HBV) or hepatitis C(HCV), presence of hepatitis B 
surface antigen (HBsAg)or positive hepatitis C antibody test result at screening or 
within 3 months prior to starting study treatment.
Other Exclusions
20. Dietary restrictions that would prohibit the consumption of standardized meals.
21. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of 
drug of abuseor previous history of or treatment for a dependence disorder.
22. Participants who regularly smoke more than 5 cigarettes daily or equivalent and 
unable or unwilling not to smoke during the in-houseperiod(see Section5.3.2).
23. Participants who havedonatedover 500 mL of blood or blood products or had 
significant blood loss within 3 months prior to screening.
24. Participants under judicial supervision, guardianship or curatorship.
25. Presence of a cardiac pacemaker or other electronic device; ferromagnetic metal 
foreign bodies in vulnerable positions; presence of certain tattoos that might make it 
unsafe for an MRI; participantworking as a machinist, welder or metal worker; 
claustrophobia; as assessed by a standard pre MRI questionnaire.
26. Occupational radiation exposure or radiation Exposure exposure from medical diagnostic 
or treatments to ionising radiation in medical researchover the past 12 months, that 
would result in a dose in excess of 10 mSvwhich when combined with theplanned 
exposure fromthis studywould result in an effective dose in excess of 10 mSv.
27. Contraindication for arterialcannulation; Allen’s test indicating potential risk in 
placement of the arterial cannula.
5.3 
LIFESTYLE CONSIDERATIONS
5.3.1 
Meals and Dietary Restrictions
Participants will have to be fasted for at least 4 hours prior to laboratory safety tests at 
screening. 
 
 
5.3.2 
Caffeine, Alcohol, and Tobacco
The consumption of food and beverages containing caffeine or other 
methylxanthine-containing products (e.g., tea, coffee, caffeinated soft drinks, cola, 
chocolate) will not be permitted from 48 hours before dosing until the end of the 
residential period. During the period from screening to the follow-up visit when 
participants are not resident in the unit, participants will be asked to limit coffee or tea 
consumption to no more than 3 cups per day, and methylxanthine-containing products 
(e.g. cola and chocolate) must be limited to a maximum of 1liter per day.


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Consumption of alcohol will not be allowed from 48 hours before dosing until the end of 
the residential period and participants will be asked to limit alcohol to a maximum of 2 
units/day (1 unit equates to approximately 330 mL beer, 125 mL of wine or 25 mL of 
spirits) during the out-clinic period until follow-up. The use of tobacco will not be 
permitted from 48 hours before dosing until the end of the residential period and 
participants will be asked to limit tobacco use to a maximum of 5 cigarettes a day or 
equivalent amount of tobacco during the out-clinic period until follow-up.
5.3.3 
Activity
Light ambulatory activities will be permitted, with the level of activities kept as similar as 
possible on all days in the clinical research unit.
After the participants leave the unit they will be asked to refrain from strenuous physical 
activity until the end of their participation in the study.
5.4 
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized to study treatment/entered in the study.
The Investigator will maintain a screening log to recorddetails of all participants 
screened and to confirm eligibility or record reasons for screening failure.
Individuals who do not meet the criteria for participation in this study (screen failure)will 
notbe re-screenedunless agreed with the Sponsor. A repeat of a screening laboratory 
test because of a borderline result is not considered a re-screening.
5.5 
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, clinical database and IEC/IRB approved newspaper/radio/social-media
advertisements prior to consenting to take place on this study.
6. 
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo,or medical device(s)intended to be administeredto a study participant 
according to the study protocol.
All IMPs required for completion of this study (RO7017773) will be provided by the 
Sponsor. All study drug administration will be administered at the study center under 
supervision of site staff.Theradiolabeled PET tracer [
11C]Ro15-4513 is considered as 
non-IMP.
At the start of each PET/CT scan, participants will receive an IVdose of [
11C]Ro15-4513.


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6.1 
TREATMENTS ADMINISTERED
Table6summarizes the treatments administeredin the study.
Table6
Summary of Treatment Administered and PET Ligand
Study Treatment 
Name:
RO7017773
[
11C]Ro15-4513
Dosage 
Formulation:
Capsule
Sterile solution for IV injection
Unit Dose 
Strength(s)/Dosage 
Level(s):
Not applicable.
Dose:
Will not exceed 10 g for each 
PET/CT scan (maximum activity 
370 MBq).
Route of 
Administration:
Oral
Intravenous
Dosing Instructions:
 
 
 
 
 
An appropriate aliquot of 
[
11C]Ro15-4513concentrate for 
injection is to be diluted with up to 
20 mL Sodium chloride for 
injection immediately prior to the IV 
administration.
The injection with [
11C]Ro15-4513
occurs simultaneously withthe 
start of the PET/CT scan.
Packaging and 
Labeling:
Study treatment will be provided in 
bottles. Each bottle will be labeled
according to thecountry 
requirements.
Radiolabeled [11C]Ro15-4513
solution for injection packaging will 
be overseen locally according to 
GMP and site SOPs.
Storage Conditions
  
[
11C]Ro15-4513solution for 
injection is prepared immediately 
prior to administration.
Manufacturer 
F. Hoffmann-La Roche Ltd
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section6.6or Section7, respectively. See Section5.3.1for study food 
restrictions. Details on the synthesis of [
11C]Ro15-4513and the preparation of the 
concentrate for injection are given in the “Quality documentation for the PET tracer 
[
11C]Ro15-4513” (see the Pharmacy Manual). 
Please see the RO7017773 Investigator’s Brochureand Pharmacy Manual formore 
details.


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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drugRO7017773packaging will be overseen by the Roche clinical trial supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
Upon arrival of the IMPsat the site, site personnel will complete the following:

Check the IMP (RO7017773) for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report anydeviations or product complaints to the Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule and Pharmacy Manual.
The Investigator or delegate must confirm that the appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are to be reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff.
The Investigator, Institution, or the Head of the Medical Institution (where applicable)is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records).
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual.


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6.2.1 
PET Tracer [
11C]Ro15-4513
The radiolabeled PET tracer [
11C]Ro15-4513 will be synthesized from the precursor by a 
qualified person. The preparation of the concentrate for injection will be performed 
according to the “Quality documentation for the PET tracer [
11C]Ro15-4513” (see 
Pharmacy Manual) immediately prior to the administration. Radiolabeled [
11C]Ro15-4513 
solution for injection packaging will be overseen locally according to GMP and site SOPs.
6.3 
MEASURES TO MINIMIZEBIAS: RANDOMIZATION AND 
BLINDING
6.3.1 
Method of Treatment Assignment
The study is open‑label. Up to 15 healthyparticipants will be enrolled in this study. The 
participant numbers will be allocated sequentially in the order in which the participants 
are enrolled. The randomization numbers will be generated by the Sponsor or its 
designeeand it will be sent to the Investigator.
6.3.2 
Blinding
This is an openlabel study, blinding procedures are not applicable.
6.4 
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule.This individual will write the date 
dispensed and participant number on the study treatment vial label and on the Drug 
Accountability Record. This individual will also record the study treatmentnumber 
received by each participant duringthe study.
6.5 
CONCOMITANT THERAPY
6.5.1 
Permitted Therapy
Any medication or vaccine (including over-the-counter[OTC]or prescription medicines,
approved dietary and herbal supplements, nutritional supplements) and any non-
medication interventions (e.g.,individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, and rehabilitative therapy)used by a participant from 4 
weeks prior to screening until the follow-up visitmust be recorded along with reason for 
use, dates of administration (including start and end dates) and dosage information 
(including dose and frequency).
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF.


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Use of the following therapies is permitted, as specified below:

 
 

Acetaminophen/paracetamol is allowed up to a maximum dose of 2g/day upto 
48hours prior to dosing and after the in-house period, but should not exceed 4g 
total during the week prior to dosing.
6.5.2 
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be
recorded on the appropriate eCRF.
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor. 
Use of the following therapies is prohibited during the study and for at least 30 days or at 
least 5 half-lives of the medication prior to initiation of study treatment (whichever is 
longer), unless otherwise specified below:

Any prescribed or over-the-counter medication (including herbal products, vitamin, 
mineral, energy drinks and dietary supplements), unless specified in Section6.5.1.

 

 
 
 
 
 

 
 
 

Acetylsalicylic acid and other anti-platelet and anti-coagulation medication,e.g., 
adenosine diphosphate (ADP) receptor inhibitors, heparin, warfarin and non-vitamin 
K antagonist oral anticoagulants (NOACs).
6.6 
DOSAGE MODIFICATION
The study is adaptive in nature to adequately evaluate the exposure versus RO 
relationship. The subsequent dose levels will be selected based on the evaluation of the 


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PK-ROrelationship and safety and tolerability data. The maximum daily dose will not 
exceed the highest tolerable and safe dose in the SAD part of study   
 
(Section4.3).
6.7 
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provideRO7017773 or other study interventions to 
participants after conclusion of the study. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND
PARTICIPANTDISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Appendix1Study Governance 
Considerations Study.
7.1 
DISCONTINUATION OF STUDYTREATMENT
Seethe SoA (Section1.3)for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determines,may jeopardize the 
participant’s safety if he/she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will remain as part of the overall research data.


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Participants who withdraw from the study for safety reasons will not be replaced. 
Participantswho withdraw from the study for other reasonsmay be replacedto ensure 
adequatenumbers of evaluable participants.Replacement of participants for other 
reasonswill be discussed between the Investigator and the Sponsor, based on existing 
data.
See SoA (Section1.3) for data to be collected at the time of study discontinuation and at 
safety and follow-upvisits,and for any further evaluations that need to be completed.
7.3 
LOST TO FOLLOW-UP
A participantwill be considered lost to follow-up if the participantrepeatedly fails to
return for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whetheror not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documentedin the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix1.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-pointsare summarized in the Schedules of Activities 
(SoA; Section1.3).Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g.,blood count)and obtained before signing of theInformed Consent Form (ICF)may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-framedefined in the SoA.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
withthe samples.


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8.1 
EFFICACY ASSESSMENTS
Efficacy parameters will not be evaluated in this study.
8.2 
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are providedin the SoA (Section1.3).
8.2.1 
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological, 
musculoskeletal in addition to head, eyes, ears, nose, throat, neck and lymph nodes
systems. Height and weight will also be measured and recorded. Further examination of 
other body systems may be performed in case of evocative symptoms at the 
Investigator’s discretion.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
The physical examination will NOT include pelvic, rectal or breast examinations.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as adverse events on theAdverse Event eCRF.
8.2.2 
Vital Signs
Vital signs will include temperature (tympanic), systolic and diastolic blood pressure and 
pulse rate. They will be taken before blood collection and will be measured in a supine 
position after at least 5 minutes rest at the time point specified in the SoA tables 
(Section1.3).
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
When possible, the same arm should be used for all blood pressure measurements.
8.2.3 
Electrocardiograms
Triplicate 12-leadECG will be obtained as outlined in the SoA (see Section1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.
At each time point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 5 minutes.


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To minimize variability, it is important that participants be in a resting position for at least 
10minutes prior to each ECG evaluation. Body position should be consistently
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre ECG 
resting period and during ECG recording. In some cases, it may be appropriate to repeat 
abnormal ECGs to rule out improper lead placement as contributing to the ECG 
abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRFor loaded electronically. QTcF(Fridericia’s correction) and RR 
will be calculated automatically and recordedon the eCRF or loaded electronically. 
Changes in T-wave and U-wave morphology and overall ECG interpretation willbe 
documented on the eCRFor loaded electronically. T-wave information will be captured 
as normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
8.2.4 
Clinical Safety LaboratoryAssessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix4and these assessments must be conducted in accordance with the separate 
laboratorymanual and the SoA (Section1.3).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant
's condition.

In the event of unexplained abnormal clinically significantlaboratory test values, the 
tests should be repeated immediately and followed up until they have returned to 
the normal range and/or an adequate explanation of the abnormality is found.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified.

If laboratory values from non-protocol specified laboratory assessments performed 
at the local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or 
dose-modification) then, the results must be recorded in the CRF.


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Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety.
Where the clinical significance of abnormal 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.
8.2.5 
Medical History and Demographic Data
Medical history includes clinically significant diseases and all medications (e.g., 
prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional supplements) 
used by the participant within 30 days prior to the screening visit.
Demographic data will include age, sex, and self-reportedrace/ethnicity.
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or serious adverse event (SAE) can be found inAppendix2.
The non-seriousadverse events of special interest and disease-related events and/or 
disease-related outcomes not qualifying as AEs or SAEs are discussed in Section8.3.6.
The Investigator and any qualified designees are responsiblefor ensuring that all 
adverse events (including assessment of seriousness, severity and causality; see
Appendix2) arerecorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Appendix2.
Procedures used for recording adverse events are provided inAppendix3.
8.3.1  
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix2.
Investigators will seek information on adverse events at each participant’s contact. All 
adverse events, whether reported by theparticipant or noted by study personnel, will be 
recorded in the participant’s medical record and on the Adverse Event eCRF as follows:


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After informed consent has been obtainedbut prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (e.g., serious adverse eventsrelated to invasive procedures such as biopsies).
Any other adverse event should not be reported.
After initiation of study treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until 14 days after the last dose of study treatment. 
Post-study adverse events and serious adverseevents:The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period {14 days after the last dose of study treatment}.
However, if the Investigator learns of any SAE (including a death) or other adverse 
events of concern that are believed to be related to prior treatment with study treatment, 
at any time after a participant has been discharged from the study, and the Investigator
considers the event to be reasonably related to the study treatment or study participation, 
the Investigator must promptly notify the Sponsor.For the procedure of reporting, see
Appendix2.
8.3.2 
Methodof Detecting Adverse Eventsand Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodologyof non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation time-points.
8.3.3 
Follow-Up of AdverseEventsand Serious Adverse Events
8.3.3.1 
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 event is 
otherwise explained, the participant is lost to follow-up(Section7.3),or the participant 
withdraws consent. Every effort should be made to follow all serious adverse events 
considered to be related to study treatment 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 EventeCRF and in the participant’s medical record to facilitate source 
data verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided inSection8.3.5.


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8.3.3.2 
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 visitto obtain additional case detailsand outcome information 
(e.g.,from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will complywith country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigatorsafety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then,file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB and EC, see Appendix2.
8.3.4.1 
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical monitors is available 
24hours a day 7 days a week. Medical monitors contact details will be available on a 
separate list generated by the study management team.
8.3.5 
Pregnancy
 
Male participantswill be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 90
days after the last dose of study drug.


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If a pregnancy is reported, the Investigator should inform the Sponsor within 24hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
inAppendix5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs(Appendix5).
8.3.6 
Non-SeriousAdverse Events of Special Interest
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Appendix2for reporting instructions)
Non-serious adverse events of special interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Appendix3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiformencephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participantexposed to a medicinal product. This term applies only
when a contamination of the study treatmentis suspected.
8.3.7 
Management of Specific Adverse Events
Treatment of specific AEs will be considered on a case-by-case basis according to local 
standard of care.
8.4 
TREATMENT OF OVERDOSE
Study treatmentoverdose 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 
treatmentis not an adverse event unless it results in untoward medical effects(see 
Section7of Appendix3for further details).
8.5 
PHARMACOKINETICS
Plasma concentrations of RO7017773 will be measured by a specific and validated LC-
MS/MS method.
The PK samples will be taken as outlined in the Schedules of Activities tables (see 
Section1.3).If required, remaining PK samples may also be used for assay 
development/validation experiments.


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The blood samples will be destroyed within 6 months after the date of final CSR. Details 
on sampling procedures, sample storage and shipment are given in the Sample
Handling Manual.
8.8 
IMAGING 
8.8.1 
PET/CT Scans
Dynamic PET/CT scans will be performed at   
 using a PET/CTscanner. 
A venous cannula will be inserted into the forearm or antecubital vein for injecting the 
PET tracer. Participantswillbe placed in the PET/CT scanner and appropriate devices 
(e.g., foam padding) will be usedto decrease movement during the scan and to 
standardize the orientation of the head.
 


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Motion tracking software and hardware (e.g. lightweight goggles) may be used for 
accurate monitoring of any residual head movement. The participant will be monitored 
continuously by a qualified PET technician.
A low-dose CT scan will beperformedbefore each injection of the radioligandto correct 
for the attenuation of emitted radiation. Afterthe low-dose CT scan,participantswill then
receive an intravenous bolus injection of up to 370 MBq of the [
11C]Ro15-4513
radioligand. Dynamic emission data will be recorded for up to about 90 min after
injection of the radioligand.
8.8.2  
Magnetic Resonance Imaging (MRI) Scans
Structural MRI acquisition will beperformed at   
 using a 3 Tesla   
 clinical 
MRI system (
, Germany), andwill consist of a structural 
scanning protocol. MRI scans will be evaluated by aradiologist to exclude any 
participants with major pathology or abnormalities. Aradiologist will provide a report of 
each MRI scan to the investigator.
For each participant,a MRI scan will be acquired after initial screening, but prior to the 
PET/CT scan.
The MRI scan will be used as an eligibility criterionand also co-registered with the 
subsequent PET/CT scans and used for anatomical localization.
Only participanteligibility following the MRI will be captured on the eCRF where date, 
time, and categorization in normal/abnormal will be recorded. Any additional data willnot 
be required and will remain at the site.
8.9 
BIOMARKERS
Biomarkers are not evaluated in this study.
8.10 
HEALTH ECONOMICS/MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
8.11 
TIMING OF STUDY ASSESSMENTS
8.11.1 
Screening and Pre-treatmentAssessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 


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screening log to record detailsof all participants screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened participantwith regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed at the time-points indicated 
in the SoA (see Section1.3), unless otherwise specified.
8.11.2 
Assessments During Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and
re-enroll in the study.
All assessments must be performed as per SoA (see Section1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
8.11.3 
Assessments at Study Completion/Early Termination Visit
Participants who complete the study (defined as) or discontinue from the study early will 
be asked to return to the clinic days after the last dose of study drug for a follow‑up visit. 
The visit at which response assessment shows progressive disease may beused as the 
study completion/early termination visit.
8.11.4 
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections8.3.1and 8.3.3.
9. 
STATISTICAL CONSIDERATIONS
9.1 
STATISTICAL HYPOTHESES
The studyis an exploratory one, and there are no null hypotheses to be tested.
9.2 
SAMPLE SIZE DETERMINATION
It is anticipated that a maximum of 15 participants will be enrolled in the study. At each 
anticipated dose level, up to 2 to 3 participants maybe enrolledwith 2 participants per 
cohort.
The sample size is chosen for practical and feasibility reasons and is within the range 
generally accepted for PET studies. It isconsidered adequate to allow modelling of the 
relationship between RO7017773 plasma concentrations and the occupancy of 
5-containing GABAAreceptors.


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9.3 
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table7.
Table7
Analysis Populations
Population
Description
Safety
All participants randomized to study treatment and who 
received at least one dose of the study treatment, whether 
prematurely withdrawn from the study or not, will be included 
in the safety analy
sis. 
PK
All participants who have received at least one dose of study 
treatment and who have data from at least one post-dose 
sample will be included in the PK analysis population. 
Participants will be excluded from the PK analysis population if 
they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol, or if data are 
unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the 
reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure.
PK/PD
All participants who received at least oneon-treatment 
PET/CT scan. Participants will be excluded from the PK/PD 
analysis population if they significantly violate the inclusion or 
exclusion criteria or deviate significantlyfrom the protocol. 
Participants will also be excluded if unavailable or incomplete 
data significantly affect the PK/PD analysis. Excluded cases 
will be documented together with the reason for exclusion. All 
decisions on exclusions from the analysis will be made before 
database lock.
9.4 
STATISTICALANALYSES
9.4.1 
Demographics and Baseline Characteristics
Demographic and other baseline characteristics of the safety analysis population will be 
listed.
9.4.2 
Safety Analyses
All safety analyses will be based on the safety analysis population.


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Table8
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events 
The original terms recorded on the eCRF by the Investigator for adverse 
events willbe coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units;Système International d’Unités) by 
individual listings with flagging of abnormal results.
Vital signs 
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging ofabnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
9.4.3 
Pharmacokinetic Analyses
PK concentration data will be summarized using the PK Population, see Table7.
Individual plasma concentrations of RO7017773will be listed and summarized. Formal 
PK analysis will not be done.
9.4.4 
Pharmacodynamic Analyses
Pharmacodynamic analysis will be done using the PK/PD Analysis Population, see 
Table7.
Occupancy of 5-containing GABAAreceptors by RO7017773will be calculated for 
target ROIs. ROIs will be regions with strong [
11C]Ro15-4513 signal (i.e. regions with 
relatively high density of GABA
A5 and appreciable size) and including, but not limited to 
the amygdala, hippocampus, insular cortex, anterior cingulate, and ventral striatum.
Structural MRI image will be co-registered to a standard reference space.  A template 
brain image and associated atlas will be nonlinearly warped to each participant’s MRI to 
enable automated definition of ROIs. Dynamic PET images will be registered to each 
participant’s MRI scan and corrected for motion using a frame-to-frameregistration
process with a normalized mutual information cost function. ROIs defined on theMRI 
images will be applied to the dynamic PET data to derive regional time-activity curves 
(TACs) for ROIs. The total volume of distribution (VT) for each ROI will be derived and 
used to calculate RO by RO7017773:


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RO and regional VTdata will be presented by listings and no formal statisticalanalysis 
will be performed.
Additional PD analyses will be conducted as appropriate.
9.4.5 
Pharmacokinetic/pharmacodynamic Relationship
 
 
9.5 
SUMMARIES OF CONDUCTOF STUDY
All protocol deviations will be listed. Data for study drug administration and concomitant 
medication will be listed. The number of participants who were randomized, discontinued 
and completed the study will be summarized and listed.


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10. 
REFERENCES
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal 
Investigators,Centers for Disease Control and Prevention (CDC). Prevalence of 
autism spectrum disorder among children aged 8 years -autism and 
developmental disabilities monitoring network, 11 sites, United States, 2010. 
MMWR Surveill Summ 2014;63:1-21.
Final ClinicalStudy Report –BP25129 -A two-part single-center, randomized, double-
blind, single ascending dose, placebo-controlled, parallel study to investigate 
safety, tolerability, pharmacokinetics and pharmacodynamics of RO5186582 in 
healthy young male subjects.–Report No. 1039850, September2011.
Final Clinical Study Report –BP29784 -A single-centre, non-randomised, open label, 
positron emission tomography imaging study to assess occupancy of α5-
containing GABAA receptors by RO5186582 in healthy volunteers of Japanese 
origin.–Report No. HMR trial code 15-003, August 2016.
Final Clinical Study Report –BP25611 -A single-center, double blind molecular and 
functional imaging study to assess GABAA alpha5 receptor expression, occupancy 
and functional connectivity in the brains of individuals with Down Syndrome and 
healthy controls–Report No. 1057675, August 2014.
Investigator’s Brochure RO7017773.
Myers, Jim FM, Comley, Robert A, Gunn, Roger N, Quantification of [11C]Ro15-4513 
GABAAα5 specific binding and regional selectivity in humans. Journal of Cerebral 
Blood Flow & Metabolism, 2017, 37; 6: 2137-2148.
Positron emission tomography (PET) study in baboon to investigate brain GABAA α5 
receptor occupancy of RO7017773 using [
11C]RO0154513. Roche Report (RDR) 
1080714; in preparation.
WHO (World Health Organization).Autism spectrum disorders and other developmental 
disorders: From raising awareness to building capacity. Meeting Report 16-18 
September 2013, Geneva, Switzerland.


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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
The following section includes standard appendices such as Appendix1(for regulatory, 
ethical and study oversight considerations), Appendix2(for AE definitions, reporting), 
Appendix3(procedures of recording), and Appendix5(contraceptive guidance and 
collection of pregnancy information). Additional study-related appendices are listed in 
order of appearance in the protocol.


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Appendix1
Regulatory, Ethical, and Study Oversight Considerations
1. 
REGULATORY AND ETHICAL CONSIDERATIONS
1.1. 
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
1.2. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the participant (e.g. 
advertisements, diaries etc), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before thestudy is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (Section2.3.1 of this 
Appendix).
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.
1.3. 
INFORMED CONSENT
The Sponsor’s MasterInformed Consent Form (and ancillary sample ICFssuch 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. 
Participants must be informed that their participation is voluntary. Participants will be 
requiredto sign a statement ofinformed consent that meets the requirements of 21 CFR
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA)requirements, where applicable, and the IRB/IEC or study center.The Sponsor 


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or its designee must review and approve any proposed deviations from the Sponsor
's 
sample ICFsor any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/EC submission. The final IRB/EC‑approved Consent 
Forms must be provided to the Sponsor for Health Authority submission purposes 
according to local requirements.Participants must be re-consented to the most current 
version of the ICF(s)during their participation in the study. A copy of the ICF(s)signed 
by all parties must be provided to the participant or the participant’s legally authorized 
representative.
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative before his or her participation in the study. The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the study.
The 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 
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants 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 participant 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 participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s studyfile or in the site file and must be available for 
verification by study monitors at any time.
1.4. 
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-relateddata will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 


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Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
1.5. 
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification ordisclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV).
2. 
DATA HANDLING AND RECORD
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1. 
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
2.1.2. 
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 


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instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical 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 ofrecords described below.
To facilitatesource data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4. 
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making thechange, and date of the change.
2.2. 
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of thisstudy 
must be retained by the Investigator for at least 15 years after studycompletion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period withoutthe written approval of the Sponsor. 
No records may be transferred to another location or party without written notification to 
the Sponsor.
2.3. 
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.


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2.3.1. 
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2. 
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
informationand 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.
2.3.3. 
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ 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.


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2.4  
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or 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 participants.

Participant 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.
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor
's procedures, or GCP guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.


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Appendix2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1. 
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse eventis any 
untoward medical occurrence in a participantor clinical investigation participant
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An adverse eventcan therefore be:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated withthe use of a medicinal product, 
whether or not considered related to the medicinal product.
Events Meetingthe AE Definition:

Any deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 
or other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to 
a change in study treatment or concomitant treatment or discontinuation from study 
treatment.

Exacerbation of a chronic or intermittentpreexistingcondition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies).
EventsNOTMeetingthe AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexistingdisease(s) or condition(s) present 
or detected at the start of the study that do not worsen.


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2. 
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexistingcondition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition isnot intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.

Other significant events:
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
3. 
RECORDING OF ADVERSEEVENT AND/OR SERIOUS
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progressnotes, laboratory reports, and diagnostics reports) 
related to the event.
The Investigator will then record all relevant AE/SAE information in the CRF.
It is notacceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitorin lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor.
TheInvestigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1. 
ASSESSMENT OF SEVERITY
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table1(as a 
guidance for assessing adverse event severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a predefined
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor
immediately (i.e., no more than 24 hours after learning of the event.


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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 above).
3.2. 
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related tothe study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factorsin the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For participant receiving combination therapy,causality will be assessed individually for 
each protocol-mandated therapy.
4. 
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsortoelucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsorwith a copy of any post-mortem findings 
including histopathology
New or updated information will berecorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within24 hours of 
receipt of the information.


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5. 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events

Non-serious adverse events of special interest(NSAESI)

Pregnancies(see Section8.3.5)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.1  
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTSAND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
Eventsthat Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandatedintervention 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).
Events that Occur after Study TreatmentInitiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section8.3.6) that occur after initiation of study treatment (Section8.3.1),investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 


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Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need tobe entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period, if the event is believed to be related to prior study
treatment the event should be reported directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or 
email address provided to investigators.
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document{s}:

RO7017773 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.


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Appendix3
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.
1. 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
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.
2. 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time-points. Such events should only be recorded once on the 


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Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between participant evaluation 
time-points and subsequently recurs. Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF.
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 upper limit of normal [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 
7.0mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


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5. 
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g.,high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6. 
ABNORMAL LIVER FUNCTION TESTS
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (seeAppendix2, 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 (seeSection8.3.6).
7. 
OVERDOSE
Any study treatmentoverdose or incorrect administration of study treatmentshould be 
noted on the Study treatmentAdministration eCRF.
All adverse events associated with an overdose or incorrect administration of study 
treatmentshould be recorded on the Adverse Event eCRF. If the associatedadverse 
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 Appendix2, 5.1).
8. 
DEATHS
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 


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concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced bythe established cause of death.The term"sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
9. 
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g.,“more frequent headaches”).
10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix2).
The following hospitalization scenarios are not considered to be serious adverse events: 

Plannedhospitalization required by the protocol {(e.g., for study drug administration 
or insertion of access device for study drug administration)}. 

Hospitalizationfor a pre-existingcondition, provided that all of the following criteria 
are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease. 
o The healthy volunteer has not suffered an adverse event. 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.


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Appendix4
Clinical Laboratory Tests
The tests detailed in Table1 will be performedby the local or central laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections5.1andSection5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
Table1
Protocol-Required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes).
Clinical Chemistry
Sodium, potassium, chloride, bicarbonate, glucose 
(fasting), urea, creatinine, total protein, albumin, 
phosphate, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, gamma-glutamyl-transferase 
(g-GT), creatine phosphokinase (CPK), LDH.
Coagulation
Prothrombin time (INR) and activated thromboplastin 
time (aPTT).
Viral Serology
HIV (specific tests HIV1 antibody, HIV-1/2 antibody, 
HIV-2 antibody), hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) antibody.
Hormone
For post-menopausal female only to confirm post-
menopausal status: follicle stimulating hormone (FSH) 
and estradiol.
Pregnancy Test
Serum or urinehuman chorionic gonadotropin (hCG) 
pregnancy test (as needed
 
Urinalysis
Specific gravity
Dipstick: pH, glucose, protein, blood, nitrite, leukocyte 
If there is a positive result (confirmed by a positive 
repeated sample), urine will be sent to the laboratory 
for microscopy and if necessary a urine culture. If there 
is an explanation for the positive dipstick results (e.g., 
menses), it should be recorded and there is no need to 
perform microscopy and culture.
Microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.
Other Screening Tests
Urine drug screen (to include at minimum: 
amphetamines, methamphetamines, barbiturates, 
cocaine, opiates, methadone, cannabinoids and 
benzodiazepines)
Alcohol breath test.


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The results of each test will be provided electronically orcaptured inthe eCRF.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

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.

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 participantlistings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participantlistings 
as “HH” for very high or “LL” for very low.


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3. 
PREGNANCY TESTING
For WONCBP enrolled in the study,blood sample and urine pregnancytests will be 
performed according to Schedule of Activity tables (see Section1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected andaccording to local practice.


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4. 
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant isin this study(see 
Section8.3.5Pregnancy). This applies only to male participants who receive 
RO7017773.
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment.The
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Formand submit it to the Sponsorwithin24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner wouldneed to sign an Authorization for 
Useand Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.Ifthe authorization has been signed, the Investigator shouldupdate the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician.The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor.Monitoring of the participant’s partner should
continue until conclusion of the pregnancy.Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.


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5 
ABORTIONS
Any spontaneous abortion should be classifiedas 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 5of Appendix2).
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 5of Appendix2).
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.
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant orfemale 
partner of a male participantexposed to study treatmentshould 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 5of Appendix2. 


RO7017773—F. Hoffmann-La Roche Ltd
87/Protocol BP40257, Version 2