Clinical trial NCT03774576
Conditions: Healthy Volunteers
Sponsor: Hoffmann-La Roche
Start date: 2018-12-17; Completion date: 2019-03-14
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the effect of multiple oral doses of itraconazole on the pharmacokinetics of RO7017773 in healthy volunteers.

Detailed description:

Arms: arm 1: Single dose of RO7017773 arm 2: Single dose of RO7017773 and multiple doses of itraconazole
Interventions: intervention 1: RO7017773 intervention 2: Itraconazole
Intervention descriptions: intervention 1: Single doses of RO7017773 intervention 2: Multiple doses of Itraconazole

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Non-Randomized, Open-Label, One Sequence, Two Period Cross-
Over Study to Investigate the Effect of CYP3A Inhibition on 
the Pharmacokinetics of RO7017773 in Healthy Participants 
NCT Number: 
NCT03774576 
Document Date: 
Protocol Version 3: 14-November-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The information contained in this document, especially any unpublished data, is the property of 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 Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7017773 —F. Hoffmann-La Roche Ltd
Protocol BP40822, Version 3
PROTOCOL
TITLE:
A NON-RANDOMIZED, OPEN-LABEL, ONE 
SEQUENCE, TWO-PERIOD CROSS-OVER STUDY 
TO INVESTIGATE THE EFFECT OF CYP3A 
INHIBITION ON THE PHARMACOKINETICS OF 
RO7017773 IN HEALTHY PARTICIPANTS
PROTOCOL NUMBER:
BP40822
VERSION:
3
EUDRACT NUMBER:
2018-002889-40
TEST PRODUCT:
RO7017773
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 15 August 2018
DATE AMENDED:
Version 2: 6 September 2018
Version 3: See electronic date stamp below
14-Nov-2018 15:11:36
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7017773—F. Hoffmann-La Roche Ltd
2/Protocol BP40822, Version 3
PROTOCOL ACCEPTANCE FORM
TITLE:
A NON-RANDOMIZED, OPEN-LABEL, ONE 
SEQUENCE, TWO-PERIOD CROSS-OVER STUDY 
TO INVESTIGATE THE EFFECT OF CYP3A 
INHIBITION ON THE PHARMACOKINETICS OF 
RO7017773 IN HEALTHY PARTICIPANTS
PROTOCOL NUMBER:
BP40822
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-002889-40
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 BP40822, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol BP40822 has been amended to incorporate the following changes based on 
health authority feedback:

The dose regimen and duration of itraconazole dosing was modified. Itraconazole 
will now be dosed 200 mg BID on Day 1 and 200 mg QD on Days 2 to 9.

Physiologically based pharmacokinetic (PBPK) predictions were updated to reflect 
the change in study design.

Exclusion criterion 10 was updated to remove text regarding inclusion of individuals 
with isolated bilirubin 1.5 ULN if bilirubin is fractionated and direct bilirubin 
35%.

A sentinel cohort was added and rationale to support dosing and potential dose 
adjustment based on review of safety, tolerability and pharmacokinetics was also 
added.

Study and individual stopping criteria were added to the protocol.
Additional minor changes and corrections have been made to improve clarity and 
consistency. Substantial new information appears in italics. 






RO7017773—F. Hoffmann-La Roche Ltd
6/Protocol BP40822, Version 3
 
 
 
 
Healthy participants will be admitted to the clinical unit on Day -1 of Period 1. An oral 
dose of 
RO7017773 will be administered alone, 30 minutes after 
starting a standardized breakfast on the morning of Day 1 of Period 1. Participants will 
be discharged on the morning of Day 4 after all assessments have been completed. 
They will return to the clinical unit for 3 ambulatory visits at Day 5, Day 6, and Day 8 for 
PK sampling and safety monitoring. 
After a wash-out period of 10 days, participants will be admitted to the clinical unit on 
Day -1 of Period 2 and will remain in-house until the morning of Day 1012. They will be 
administered 200 mg of itraconazole BID (12 hours apart) from on Day 1 and 200 mg of 
itraconazole QD from Day 2 to Day 8 9 in Period 2. Itraconazole will be administered as 
oral capsules containing 200 mg every 12 hours (BID), 30 minutes after starting a 
standardized breakfast in the morning and after a standardized dinner in the evening on 
Day 1 only and on Days 2 to 9 oral capsules containing 200 mg once a day (QD), 
30 minutes after starting a standardized breakfast in the morning. 
 
RO7017773 will be administered to 
each participant in combination with the morning dose of itraconazole. Participants will 
be discharged on the morning of Day 11 12 after all assessments have been completed. 
They will return to the clinical unit for 3 4 ambulatory visits at Day 13, Day 14, Day 15, 
and Day 15 16 for PK sampling and safety monitoring.  
Participants will visit the clinical research unit for a safety follow-up visit 15 to 20 days 
after the last dose of itraconazole.
 
 
 Similarly, safety data will be collected in Period 1 
and Period 2 in order to assess the effect of itraconazole on the safety profile of 
RO7017773.
4.1.1
Length of the Study
The total duration of the study for each participant will be up to 10 weeks, divided as 
follows (see also Section 1.3, Figure 1):

Screening: Up to 4 weeks

In-clinic and dosing Period 1: Day -1 to Day 4 with a single oral dose of 
 
RO7017773 administered on Day 1. 


RO7017773—F. Hoffmann-La Roche Ltd
7/Protocol BP40822, Version 3

Ambulatory visit Period 1: Day 5, 6 and 8 (PK sampling and safety monitoring)

Washout Period: Approximately 9 days to a maximum of 18 days (± 1 Day) (i.e., 
between Day 1 of Period 1 and Day -1 of Period 2).

In-clinic and dosing Period 2: Day -1 to Day 11 12 with multiple oral dose 
administrations of itraconazole (200 mg BID Day 1 and 200 mg QD Days 2 to Day 9) 
from Day 1 to Day 8 9 and 
RO7017773 with itraconazole 

Ambulatory visit Period 2: Day 13, Day 14, Day 15, and Day 15 16 (PK sampling 
and safety monitoring).

Follow-up visit: 15 to 20 days after the last dose of itraconazole.
4.2 Stopping Rules Criteria
4.2.1
Study Stopping Criteria
Dosing will be stopped at any time during the study if one of the following 
circumstances occurs in the participants, unless it is determined by the Investigator 
that the occurrence is not related to the administration of study drug:

One serious adverse event

Severe non-serious adverse events (i.e., considered at least related to 
RO7017773 administration) in two or more participants.
 
4.2.2
Individual Stopping Criteria
Dosing will be stopped at any time during the study in a given individual participant if 
compared to baseline one of the following circumstances occurs, unless it is determined 
by the Investigator that the occurrence is not related to the administration of the study 
drug:

a serious adverse event 

one (or more) severe adverse events (see Section 3.1 of Appendix 2 for definition 
of severity) 

clinically significant changes in vital signs or ECG, such as a QTcF > 480 ms (if 
confirmed by repeated measurement within 30 minutes) or QTcF change-from-
baseline > 60 ms (if confirmed by repeated measurement within 30 minutes)

an elevation of ALT > 3 x ULN, with an associated increase in bilirubin > 2 x 
ULN and with ALP ˃  2 ULN, in the absence of an alternative explanation




RO7017773—F. Hoffmann-La Roche Ltd
9/Protocol BP40822, Version 3
scenario for Cmax
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Doses of 200 mg QD or 200 mg BID of itraconazole are commonly used for DDI studies 
in healthy participants (CHMP, 2012). The itraconazole dosing regimen selected in this 
study (200 mg BID on Day 1 and QD on Days 2 to 9) reflects the higher therapeutic 
regimen for the treatment of itraconazole-sensitive fungal infections. Itraconazole will be 
administered with food to ensure maximum bioavailability. 
Multiple doses of 200 mg itraconazole BID on Day 1 and QD on Days 2 to 9 will be 
administered to maintain itraconazole exposure over the PK profile of the substrate 
RO7017773. To ensure that a close to maximal inhibition potential of itraconazole is 
reached as shown by PBPK simulations,
 
While 3 days is not 
sufficient for attainment of steady-state with itraconazole, 
 allows 
for some accumulation, with higher itraconazole and hydroxy-itraconazole exposure and 
therefore potentially greater degree of CYP3A inhibition, with consideration for safety 
concerns associated with a longer itraconazole run-in period. This strategy has been 
demonstrated in multiple drug-drug interaction studies to provide adequate CYP3A 
inhibition (Ke et al 2014; Liu et al 2015).
 
 
 
 
 


RO7017773—F. Hoffmann-La Roche Ltd
10/Protocol BP40822, Version 3
 
5.2 Exclusion Criteria
10. Alanine aminotransferase (ALT) and/or bilirubin 1.5 the upper limit of normal 
(ULN). (isolated bilirubin 1.5 ULN is acceptable if bilirubin is fractionated and 
direct bilirubin 35%).
5.3.1
Meals and Dietary Restrictions
On Day 1 of Period 1, study drug administration (RO7017773) will be performed 
30 minutes after starting a standardized breakfast. This breakfast should be consumed 
within 30 min or less. 
From On Day 1 to Day 8 of Period 2, itraconazole will be administered at a dose of 
200 mg every 12 hours (BID), 30 min after starting a standardized breakfast and after a 
standardized dinner in the evening. From Days 2 to Day 9 of Period 2, itraconazole will 
be administered at a dose of 200 mg once a day (QD), 30 min after starting a 
standardized breakfast. 
, 
 
RO7017773 will be administered to each participant in combination with the 
morning dose of itraconazole 
 
On the days of RO7017773 administration 
 a 
standard lunch will be provided 4 hours after dosing. On all other days of the in-house 
period, standard breakfast, lunch, dinner and snack will be provided at the times deemed 
convenient by the site, unless required for study drug administration.


RO7017773—F. Hoffmann-La Roche Ltd
11/Protocol BP40822, Version 3
6.1 Treatments Administered
Table 5
Summary of Treatments Administered
Study Treatment Name:
RO7017773
Itraconazole (Sporanox®)
Dosage Formulation:
Capsule
Capsule
Unit Dose Strength(s)/Dosage 
Level(s):
25 mg
100 mg
Dose:
200 mg BID and QD 
Route of Administration:
Oral
Oral
Dosing Instructions:
RO7017773 will be 
administered with water 
in the morning 30 
minutes after starting a 
standardized breakfast. 
Breakfast should be 
consumed within 30 
minutes or less. 
Itraconazole will be administered 
with water in the morning and in 
the evening (12 hours apart), 30 
minutes after starting a 
standardized breakfast and a 
standardized dinner on Day 1 
only. On Days 2 to 9 
itraconazole will be 
administered with water in the 
morning, 30 minutes after 
starting a standardized 
breakfast. Breakfast and dinner 
should be consumed within 30 
minutes or less.
Packaging and Labeling:
Study treatment will be 
provided in bottles. The 
IMP will be labeled as 
required per country 
requirements.
Marketed oral capsule(s) 
(100 mg) of itraconazole will be 
used during the study. 
Sporanox® will be sourced by the 
clinical site. 
Storage Conditions
Store at 2C to 8C, 
protect from light and 
moisture
Sporanox® capsules will be 
stored according to the SmPC.
Manufacturer
F. Hoffmann-La Roche 
Ltd.
Janssen-Cilag Ltd
6.3.1
Method of Treatment Assignment
The study is open-label. Up to 14 18 healthy participants will be enrolled in this study.
The participant numbers will be allocated sequentially in the order in which the 
participants are included. The subject numbers will be generated by the Sponsor or its 
designee and it will be sent to the Investigator. 




RO7017773—F. Hoffmann-La Roche Ltd
13/Protocol BP40822, Version 3
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
Protocol Amendment, Version 3: Rationale .................................................. 3
Protocol Amendment, Version 3: Summary of Changes............................... 4
1.
PROTOCOL SUMMARY............................................................................. 20
1.1
Synopsis................................................................................ 20
1.2
Schematic of Study Design.................................................... 25
1.3
Schedule of Activities ............................................................ 26
2.
INTRODUCTION ........................................................................................ 33
2.1
Study Rationale ..................................................................... 33
2.2
Background ........................................................................... 33
2.2.1
Background on RO7017773 .................................................. 34
34
2.2.1.2
Previous and Ongoing Clinical Studies.................................. 35
2.2.2
Background on Itraconazole.................................................. 38
2.3
Benefit/Risk Assessment....................................................... 38
3.
OBJECTIVES AND ENDPOINTS ............................................................... 40
4.
STUDY DESIGN......................................................................................... 42
4.1
Overall Design ....................................................................... 42
4.1.1
Length of the Study ............................................................... 43
4.2
Stopping Rules Criteria ............................................................ 44
4.2.1
Study Stopping Criteria............................................................ 44
4.2.2
Individual Stopping Criteria ..................................................... 44
4.3
Scientific Rationale for Study Design..................................... 45
4.3.1
Rationale for Study Population .............................................. 45
4.3.2
Rationale for Pharmacokinetic Assessments......................... 45
45
4.4
Dose Justification .................................................................. 46
4.5
End of Study Definition .......................................................... 47
5.
Study Population ................................................................... 47
5.1
Inclusion Criteria.................................................................... 48


RO7017773—F. Hoffmann-La Roche Ltd
14/Protocol BP40822, Version 3
5.2
Exclusion Criteria................................................................... 49
5.3
Lifestyle Considerations......................................................... 50
5.3.1
Meals and Dietary Restrictions.............................................. 50
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 51
5.3.3
Activity ................................................................................... 51
5.4
Screen Failures ..................................................................... 52
5.5
Recruitment Procedures........................................................ 52
6.
Treatments ............................................................................ 52
6.1
Treatments Administered....................................................... 53
6.2
Preparation/Handling/Storage/Accountability ........................ 54
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 55
6.3.1
Method of Treatment Assignment.......................................... 55
6.4
Treatment Compliance .......................................................... 55
6.5
Concomitant Therapy ............................................................ 55
6.5.1
Permitted Therapies .............................................................. 55
6.5.2
Prohibited Therapies ............................................................. 56
56
6.7
Treatment after the End of the Study..................................... 56
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 56
7.1
Discontinuation of Study Treatment....................................... 57
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 57
7.3
Lost to Follow-Up................................................................... 58
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 58
8.1
Efficacy Assessments............................................................ 58
8.2
Safety Assessments .............................................................. 59
8.2.1
Physical Examinations........................................................... 59
8.2.2
Vital Signs.............................................................................. 59
8.2.3
Electrocardiograms................................................................ 59
8.2.4
Clinical Safety Laboratory Assessments................................ 60
8.2.5
Suicidal Risk Monitoring ........................................................ 61


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15/Protocol BP40822, Version 3
8.2.6
Medical History and Demographic Data ................................ 61
8.3
Adverse Events and Serious Adverse Events ....................... 62
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 62
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 63
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 63
8.3.3.1
Investigator Follow-Up........................................................... 63
8.3.3.2
Sponsor Follow-Up ................................................................ 63
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 63
8.3.4.1
Emergency Medical Contacts................................................ 64
8.3.5
Pregnancy ............................................................................. 64
8.3.6
Non-Serious Adverse Events of Special Interest................... 64
8.3.7
Management of Specific Adverse Events .............................. 65
8.4
Treatment of Overdose.......................................................... 65
8.5
Pharmacokinetics .................................................................. 65
8.6
Pharmacodynamics ............................................................... 66
8.7
Genetics ................................................................................ 66
8.7.1
Clinical Genotyping................................................................ 66
8.8
Biomarkers ............................................................................ 66
8.9
Medical Resource Utilization and Health
Economics............................................................................. 66
8.10
Timing of Study Assessments ............................................... 66
8.10.1
Screening and Pre-Treatment Assessments ......................... 66
8.10.2
Assessments during Treatment............................................. 67
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 67
8.10.4
Follow-Up Assessments ........................................................ 67
9.
STATISTICAL CONSIDERATIONS ............................................................ 68
9.1
Statistical Hypotheses ........................................................... 68
9.2
Sample Size Determination ................................................... 68
9.3
Populations for Analyses ....................................................... 68


RO7017773—F. Hoffmann-La Roche Ltd
16/Protocol BP40822, Version 3
9.4
Statistical Analyses................................................................ 68
9.4.1
Demographics and Baseline Characteristics ......................... 68
9.4.2
Safety Analyses..................................................................... 68
9.4.3
Pharmacokinetic Analyses..................................................... 69
9.4.3.1
Pharmacokinetic Parameters................................................. 69
9.4.3.2
Statistical Analysis................................................................. 70
9.5
Interim Analyses .................................................................... 70
9.6
Summaries of Conduct of Study............................................ 71
10. REFERENCES ........................................................................................... 72
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.................................................................................... 73
LIST OF TABLES
Table 1
Schedule of Activities – Main Table ............................................ 27
Table 2
Schedule of Activities – Detailed Table Period 1......................... 29
Table 3
Schedule of Activities – Detailed Table Period 2......................... 31
Table 4
Objectives and Endpoints ........................................................... 41
Table 5
Summary of Treatments Administered........................................ 53
Table 6
Analysis Populations................................................................... 68
Table 7
Safety Statistical Analysis Methods ............................................ 69
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 25
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations.......... 74
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-Up and Reporting ............................................................ 81
Appendix 3
Procedures for Recording Adverse Events ................................ 89
Appendix 4
Clinical Laboratory Tests ........................................................... 94
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information.................................................................................. 96


RO7017773—F. Hoffmann-La Roche Ltd
17/Protocol BP40822, Version 3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ANOVA
Analysis of variance
ASD
Autism spectrum disorder
AST
Aspartate aminotransferase
AUC
Area under the curve
BID
bis in die (twice daily)
AUC0-inf
Area under the plasma concentration-time curve 
extrapolated to infinity
AUC0-last
Area under the plasma concentration-time curve up to 
the last measurable concentration
AUC0-t
Area under the plasma concentration-time curve from 
time 0 up to time t
AUC0-24h
Area under the plasma concentration-time curve from 
time 0 up to 24 hours
BMI
Body mass index
CDC
Center for Disease Control and Prevention
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence intervals
Cmax
Maximum plasma concentration
CL/F
Apparent oral clearance
CNS
Central nervous system
CRO
Contract research organization
CSR
Clinical study report
C-SSRS
Columbia Suicide-Severity Rating Scale
CTCAE
Common terminology criteria for adverse events
Ctrough
Trough (pre-dose) plasma concentration for 
itraconazole and its metabolites, e.g. 
hydroxy-itraconazole
CYP3A
Cytochrome P450 (CYP) 3A 
fmCYP3A4
Fraction metabolized CYP3A4
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram


RO7017773—F. Hoffmann-La Roche Ltd
18/Protocol BP40822, Version 3
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EFD
Embryo fetal development
Emax
Maximum effect
ESF
Eligibility screening form
EU
European Union
FDA
Food and Drug Administration
FE
Food effect
FSH
Follicle-stimulating hormone
GABA
Gamma-aminobutyric acid
GLP
Good Laboratory Practice
GABAA
Gamma-aminobutyric acid type A
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HR
Heart rate
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
IUD
Intrauterine device
LDH
Lactate dehydrogenase
LPLO
Last participant, last observation
MAD
Multiple ascending doses
NCI
National Cancer Institute
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter
PAM
Positive allosteric modulator
PBPK 
Physiologically based pharmacokinetic 
PET
Positron emission tomography
PK
Pharmacokinetic
PQ
PQ interval
PR
PR interval


RO7017773—F. Hoffmann-La Roche Ltd
19/Protocol BP40822, Version 3
PT
Prothrombin time
QRS
QRS interval
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RAUCo-inf
AUC ratios calculated as RO7017773 AUC0-inf Period 2
over RO7017773 AUCo-inf Period 1
RBC
Red blood cell
RCmax
Cmax ratio calculated as RO7017773 Cmax Period 2 over 
RO7017773 Cmax Period 1
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SBP
Systolic blood pressure
SE
Standard error
SmPC
Summary of Product Characteristics
SoA
Schedule of activities
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
Tmax
Time to reach maximum plasma concentration
T1/2
Apparent terminal half-life
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential


RO7017773—F. Hoffmann-La Roche Ltd
20/Protocol BP40822, Version 3
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A NON-RANDOMIZED, OPEN-LABEL, ONE SEQUENCE, TWO-
PERIOD CROSS-OVER STUDY TO INVESTIGATE THE EFFECT 
OF CYP3A INHIBITION ON THE PHARMACOKINETICS OF 
RO7017773 IN HEALTHY PARTICIPANTS
SHORT TITLE
OPEN-LABEL, ONE SEQUENCE, TWO-PERIOD CROSS-OVER 
DDI STUDY BETWEEN RO7017773 AND ITRACONAZOLE
PROTOCOL NUMBER:
BP40822
VERSION:
3
TEST PRODUCT:
RO7017773
PHASE:
I
RATIONALE
The aim of the study is to investigate the effect of multiple oral doses of itraconazole on the 
pharmacokinetics of RO7017773. Since CYP3A is one of the major metabolizing enzymes of 
RO7017773, CYP3A inhibitors are likely to increase the plasma exposure of RO7017773. 
Itraconazole is a strong CYP3A inhibitor and is commonly used as a prototypical CYP3A4 
inhibitor in drug-drug interaction (DDI) studies. 
This study will allow assessing the magnitude of increase in systemic exposure of RO7017773
when co-administered with CYP3A inhibitors like itraconazole. 




RO7017773—F. Hoffmann-La Roche Ltd
22/Protocol BP40822, Version 3

Follow-up visit: 15 to 20 days after the last dose of itraconazole.
The investigational medicinal product is: RO7017773, 25 mg capsules for oral administration. 
Length of Study
The total duration of the study for each participant will be up to 10 weeks. 
End of Study
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur approximately 2 weeks after the last participant’s last dose of 
itraconazole.
PARTICIPANT POPULATION
The participants of this study are healthy volunteers between 18 and 55 years of age, inclusive, 
who fulfill all the inclusion criteria and for whom none of the exclusion criteria apply. 
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Conference on Harmonisation Good Clinical Practice (ICH-GCP) 
guidelines and local regulations.
2.
Participants must be 18 to 55 years of age inclusive, at the time of signing the informed 
consent.
3.
Participants who are healthy as judged by the Investigator. Healthy status will be defined as 
the absence of evidence of any active or chronic disease following a detailed medical and 
surgical history, a complete physical examination, vital signs, 12-lead ECG, hematology, 
blood chemistry, serology and urinalysis.
4.
Body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive).
5.
Male and female participants.
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for male and/or female 
enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and 
the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
a)
Female participants:
Women of non-childbearing potential (WONCBP).
b)
Male participants:
During the treatment period and for at least 28 days after the last dose of the study 
treatment, agreement to: 
Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, 
such as a condom, with partners who are women of childbearing potential (WOCBP), or 
pregnant female partners, to avoid exposing the embryo to study treatment.
Refrain from donating sperm for at least 28 days after the last dose of the study drug.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Any condition or disease detected during the medical interview/physical examination that 
would render the participant unsuitable for the study, place the participant at undue risk or 
interfere with the participant’s ability to complete the study, as determined by the 
Investigator.


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2.
History or evidence of any medical condition potentially altering the absorption, metabolism,
or elimination of drugs. This includes a surgical history of the gastrointestinal tract affecting 
gastric motility or altering the gastrointestinal tract.
3.
History of convulsions (other than benign febrile convulsions of childhood) including 
epilepsy, or personal history of significant cerebral trauma or central nervous system (CNS)
infections (e.g., meningitis).
4.
History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic reactions.
5.
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.
6.
Abnormal blood pressure, i.e., systolic blood pressure (SBP) greater than 140 mmHg or 
less than 90 mmHg, and diastolic blood pressure (DBP) greater than 90 mmHg or less than 
50 mmHg.
7.
Abnormal pulse rate, resting pulse rate greater than 100 beats per minute (bpm) or less
than 40 bpm. 
8.
History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g., PQ/PR interval 220 ms, QT interval corrected for heart rate using the 
Fridericia’s correction factor [QTcF] 450 ms) 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).
9.
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 at any time during 
screening or on Day -1 to confirm eligibility.
10. Alanine aminotransferase (ALT) and/or bilirubin 1.5 the upper limit of normal (ULN).
11. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the 
exception of Gilbert's Syndrome or asymptomatic gallstones).
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 (results from the C-SSRS 
assessment should be taken into account).
13. Participants likely to need concomitant medication during the study period (including 
medication for dental conditions).
14. Participation in an investigational drug or device study within 90 days prior to screening, as 
calculated from the day of follow-up from the previous study, or more than 4 times a year.
15. Positive test for drugs of abuse or alcohol.
16. For women of non-childbearing potential (WONCBP), a positive pregnancy test.
17. Evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV 
antibodies.
18. Positive result for hepatitis B virus (HBV) or hepatitis C virus (HCV), presence of hepatitis B 
surface antigen (HBsAg) or positive HCV antibody test result at screening or within 
3 months prior to starting study treatment.
19. Dietary restrictions that would prohibit the consumption of standardized meals.
20. Use of any prohibited medications and/or food before study start and during the study.
21. Any suspicion or history of alcohol abuse and/or any suspicion of regular consumption of 
drugs of abuse or previous history of or treatment for a dependence disorder. 
22. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy 
that, in the opinion of the Investigator, contraindicates the participation in the study.
23. Participants who regularly smoke more than 5 cigarettes daily or equivalent and unable or 
unwilling not to smoke during the in-house period.
24. Participants who have donated over 500 mL of blood or blood products or had significant 
blood loss within 3 months prior to screening.
25. Participants under judicial supervision, guardianship, or curatorship.


RO7017773—F. Hoffmann-La Roche Ltd
24/Protocol BP40822, Version 3
26. Hypersensitivity to itraconazole, to any of the other excipients, or to any other triazole 
antifungal.
27. Any other known contraindications to itraconazole as stated in the Summary of Product 
Characteristics (SmPC).
NUMBER OF PARTICIPANTS
Fourteen to eighteen participants will be enrolled in order to obtain at least 12 evaluable 
participants.
CONCOMITANT MEDICATIONS
Permitted Therapies

Continuation of hormone-replacement therapy or other maintenance therapy is permitted 
throughout the study for participants who already use them.

Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours 
prior to dosing and after the in-house period, but should not exceed 4 g total during the 
week prior to dosing.
Prohibited Therapies
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 OTC medication (including herbal products, vitamins, minerals, energy 
drinks and dietary supplements). 

Any known inhibitor of CYP3A4 or P-glycoprotein taken within 2 weeks prior to the start of 
administration of the study drug (Period 1, Day 1) or within 5 times the elimination half-life of 
the medication prior to the start of study drug intake (whichever is longer) including but not 
limited to the following drugs: ketoconazole, fluconazole, erythromycin, clarithromycin, 
mifebradil, nefazodone, diltiazem, verapamil and cimetidine. 

Any known inducer of CYP3A4 or P-glycoprotein taken within 4 weeks prior to start of 
administration of study drug (Period 1 Day 1), including but not limited to the following drugs: 
rifampicin, rifabutin, glucocorticoids, carbamazepine, oxcarbazepine, phenytoin, 
phenobarbital, and St. John’s Wort.




RO7017773—F. Hoffmann-La Roche Ltd
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1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided in Table 1 to Table 3.


RO7017773—F. Hoffmann-La Roche Ltd
27/Protocol BP40822, Version 3
Table 1
Schedule of Activities – Main Table
PK = Pharmacokinetic
Day
Screening up to 
Day-28
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 8
Day -1 
Day 1 
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Assessments
Informed Consent
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
In house Period
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Discharge from the unit
x
x
Ambulatory Visit
x
x
x
x
x
x
x
Vital Signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-Lead ECG c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serology
x
Pregnancy Testd
x
x
Hormone Panel e
x
x
Alcohol Breath Test
x
x
x
Urine Drugs of Abuse
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
x
x
Coagulation
x
x
RO7017773 Administrationf
Itraconazole Administrationg
x
x
x
x
x
x
x
x
x
Standard Meal h
x
x i
x
x
x
x
x i
x
x
x
x
x
Itraconazole and 
metabolites PK sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical Genotyping
x
C-SSRS
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Treatment Period 1 & Washout period of 9 Days ± 1 Day up maximum of 18 Days
Treatment Period 2
Follow-up Visit      
(15 to 20 days after 
last itraconazole 


RO7017773—F. Hoffmann-La Roche Ltd
28/Protocol BP40822, Version 3
Table 1
Schedule of Activities – Main Table (cont.)
a)
Physical examination will include body weight at screening and follow-up, and height at screening when body mass index (BMI) will be derived.
b)
Vital signs will include blood pressure, pulse rate, and (at selected time points) body temperature. Vital sign measurements will be taken after 
the participant has rested in a supine position for at least 5 minutes.
c)
Triplicate 12‑lead ECG will be recorded after the participant has rested in a supine position for at least 10 minutes.
d)
Serum test at screening, urine test at Day -1.
e)
Hormonal panel for postmenopausal women only.
f)
The oral dose of RO7017773 will be given in the morning, 30 min after starting a standardized breakfast. 
g)
An oral dose of itraconazole will be given twice daily (2 x 200 mg) with 12 hours between the two doses and under fed conditions, i.e., 
30 minutes after starting a meal in the morning and the evening on Day 1 only. On Days 2 to 9, an oral dose of itraconazole will be given 
once daily (1 x 200 mg) under fed conditions, i.e., 30 minutes after starting a meal in the morning. 
h)
On the morning of study drug treatment, breakfast should be consumed within 30 min or less. On itraconazole administration days, the 
evening meal should be consumed within 30 min or less. 
i)
The same food conditions (in terms of meal constitution and time of administration) will apply on RO7017773 administration days.


RO7017773—F. Hoffmann-La Roche Ltd
29/Protocol BP40822, Version 3
Table 2
Schedule of Activities – Detailed Table Period 1
PK = Pharmacokinetic
Day
Vital Signs a
ECG-12 lead c 
Safety 
Laboratory 
Tests
RO7017773 
Administration
Standard 
Meal
Clinical 
Genotyping
xb
x
x e
x
xd
xb
x
x
x
x
x
x
xb
x
x
x
x
xb
x
Day 3
x
x
x
Day 4
x
x
Day 5
x
x
Day 6
Day 8
x
x
x
Day 1
Day 2


RO7017773—F. Hoffmann-La Roche Ltd
30/Protocol BP40822, Version 3
Table 2
Schedule of Activities – Detailed Table Period 1 (cont.)
a)
Blood pressure and pulse rate will be measured after the participant has rested in a supine position for at least 5 minutes.
b)
Body temperature to be measured.
c)
Triplicate 12‑lead ECG will be recorded after the participant has rested in a supine position for at least 10 minutes.
d)
The oral dose of RO7017773 will be given in the morning, 30 min after starting a standardized breakfast. 
e)
On the morning of study drug administration, breakfast should be consumed within 30 min or less. 


RO7017773—F. Hoffmann-La Roche Ltd
31/Protocol BP40822, Version 3
Table 3
Schedule of Activities – Detailed Table Period 2
PK = Pharmacokinetic
Day
Vital Signs a
ECG-12 lead d
Safety 
Laboratory 
Tests
Itraconazole 
Administration e
RO7017773 
Administration
Standard 
Meal g
Itraconazole & 
Metabolites PK 
Sample
x b
x
x
x
x
x
x
x
Day 2
x
x
x
Day 3
x
x
x b,c
xc
x
x
x
xc
x b
x
x
x
x
x
x
x
x
x
x
x
x b
x
x
x
x
x
x
x
x
x b
x
x
x
x
x
x
Day 6
x
x
x
x
x
Day 7
x
x
x
x
Day 8
x
x
x
x
x
Day 9
x
x
x
x
x
Day 10
x
x
Day 11
x
Day 12
x
x
x
Day 13
x
Day 14
x
Day 15
x
Day 16
x
x
x
x
Day 1
Day 4
Day 5


RO7017773—F. Hoffmann-La Roche Ltd
32/Protocol BP40822, Version 3
Table 3
Schedule of Activities – Detailed Table Period 2 (cont.)
a)
Blood pressure and pulse rate will be measured after the participant has rested in a supine position for at least 5 minutes.
b)
Body temperature to be measured.
d)
Triplicate 12‑lead ECG will be recorded after the participant has rested in a supine position for at least 10 minutes.
e)
An oral dose of itraconazole will be given twice daily (2 x 200 mg) with 12 hours between the two doses and under fed conditions, i.e., 30 
minutes after starting a meal in the morning and the evening on Day 1 only. On Days 2 to Day 9, an oral dose of itraconazole will be given 
once daily (1 x 200 mg) under fed conditions, i.e., 30 minutes after starting a meal in the morning.
g)
On the morning of study drug administration, breakfast should be consumed within 30 min or less. On itraconazole administration days, the 
evening meal should be consumed within 30 min or less. 


RO7017773—F. Hoffmann-La Roche Ltd
33/Protocol BP40822, Version 3
2.
INTRODUCTION
2.1
STUDY RATIONALE
RO7017773 is being developed for the treatment of the 2 core domains of Autism 
Spectrum Disorder (ASD): social communication deficits and repetitive and restrictive 
behaviors. RO7017773 has the potential to normalize GABAergic signaling in key brain 
regions implicated in ASD without the side effects of non-specific GABAA modulators 
(e.g., benzodiazepines). 
The aim of the study is to investigate the effect of multiple oral doses of itraconazole on 
the pharmacokinetics (PK) of RO7017773. 
 
CYP3A inhibitors are likely to increase the 
plasma exposure of RO7017773. Itraconazole, a potent and widely used triazole 
antifungal agent, is a strong CYP3A inhibitor and is a commonly used as a prototypical 
CYP3A inhibitor in drug-drug interaction (DDI) studies. 
This study will allow assessing the magnitude of increase in systemic exposure of 
RO7017773 when co-administered with CYP3A inhibitors like itraconazole.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
ASD is a complex, heterogeneous neurodevelopmental disorder characterized by 
impairments in social communication and interaction, as well as by repetitive behaviors 
and restricted interests (Diagnostic and Statistical Manual of Mental Disorders [DSM 5]).
The estimated prevalence of ASD in the United States is 1 in 68 children (CDC, 2014), 
and it is estimated that 1% of the world’s population have ASD (WHO, 2013).
No approved pharmacological treatment exists for the core social communication and 
social interaction deficits and repetitive behavior of ASD, and this disorder continues to 
be an area of high unmet medical need. Current treatments for associated symptoms of 
ASD may include antipsychotics (risperidone and aripiprazole) used for the treatment of 
irritability associated with ASD symptoms. Multiple lines of evidence suggest that an 
imbalance between excitatory/inhibitory neurotransmission in favor of excitation may 
arise from a dysfunction of the GABAergic signaling system (the main inhibitory 
neurotransmitter system in the brain) early in development; this imbalance represents a 
central characteristic of the neurobiology of autism, leading to some of the impairments 
observed in individuals with ASD. 


RO7017773—F. Hoffmann-La Roche Ltd
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2.2.1
Background on RO7017773
RO7017773 is a selective GABAA 5 subunit containing receptor positive allosteric 
modulator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




RO7017773—F. Hoffmann-La Roche Ltd
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.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RO7017773—F. Hoffmann-La Roche Ltd
37/Protocol BP40822, Version 3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RO7017773—F. Hoffmann-La Roche Ltd
38/Protocol BP40822, Version 3
 
2.2.2
Background on Itraconazole
Itraconazole is a potent and widely used triazole antifungal agent and a prototypic 
competitive inhibitor of CYP3A ([FDA, 1999; CHMP, 2012; Bjornsson et al 2003). It 
reduces the metabolism and increases exposure of drugs metabolized by the CYP3A4 
pathway. Itraconazole is available as oral capsules and the recommended doses in 
adults are 100 or 200 mg once daily (QD) or twice daily (BID) administered with food.
Itraconazole is generally well tolerated. Gastrointestinal disturbances are the most 
frequently reported AEs following the oral use of itraconazole. Nausea, vomiting, 
diarrhea, and abdominal pain have been commonly reported in patients undergoing 
treatment of systemic fungal infections. These AEs are dose-related and may be 
minimized by giving itraconazole with food. Rash was also observed in patients; 
however, rash tends to occur more frequently in immunocompromised patients receiving 
immunosuppressive medications. Itraconazole has been associated with rare cases of 
serious hepatotoxicity. Some of these cases had neither pre-existing liver disease nor a 
serious underlying medical condition and some of these cases developed within the first 
week of treatment. If clinical signs or symptoms develop that are consistent with liver 
disease, treatment should be discontinued and liver function testing performed. Other 
AEs include pruritus and angioedema, and rare cases of anaphylaxis have been 
reported. Fatigue, headache, dizziness, hypertension, decreased libido, impotence, 
visual disturbances and somnolence may also occur (SmPC).
A detailed description of the chemistry, pharmacology, efficacy and safety of
itraconazole is provided in the Summary of Product Characteristics (SmPC).
2.3
BENEFIT/RISK ASSESSMENT
This study is being conducted to evaluate the PK of RO7017773 with and without 
concomitant administration of itraconazole to investigate the effects of inhibition of 
CYP3A on RO7017773 exposure.  
In order to minimize the number of participants required in the study, a within-subject 
study design has been chosen and an open-label, one-sequence design was selected.
 
 
 
 
 
 
 




RO7017773—F. Hoffmann-La Roche Ltd
40/Protocol BP40822, Version 3
for periods of up to one year. Itraconazole doses of 200 mg QD or BID are also 
commonly used in DDI studies to ensure adequate CYP3A inhibition (Ke et al 2014; Liu 
et al 2015).
There is extensive clinical experience of the use of itraconazole and the potential clinical 
risks are well characterized. While some side effects occur frequently (e.g., headache, 
abdominal pain, and nausea), these generally do not require any medical intervention 
and side effects requiring treatment tend to occur rarely. There are a number of 
contraindications and precautions within the approved itraconazole prescribing 
information, but potential risks will be minimized by enrolling only healthy participants 
and specifically excluding people for whom the drug is contraindicated (e.g. history of 
heart failure). 
Itraconazole PK will be measured when given alone and concomitantly with RO7017773 
to ascertain that the PK concentrations of itraconazole ensure maximal CYP3A4 
inhibition. Participants will be kept in the clinical unit under continuous medical 
supervision and monitoring for 3 days after single administration of RO7017773 alone 
and one week after RO7017773 administration in combination with itraconazole. They 
will remain in the clinical unit up to 3 days after the administration of the last dose of 
itraconazole.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7017773 and itraconazole are 
provided in the Investigator’s Brochure and in the SmPC, respectively.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 4.


RO7017773—F. Hoffmann-La Roche Ltd
41/Protocol BP40822, Version 3
Table 4
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the effect of 
multiple oral doses of 
itraconazole on the 
pharmacokinetics (PK) of a 
single oral dose of RO7017773 
in healthy participants.

RO7017773 concentrations and 
RO7017773 PK parameters.
Secondary

To assess the safety and 
tolerability of a single oral dose 
of RO7017773 alone and in 
combination with multiple doses 
of itraconazole in healthy 
participants.

Incidence and severity of AEs.

Changes in vital signs, physical findings, 
ECG parameters, and clinical laboratory 
results during and after RO7017773 
administration alone and in combination 
with itraconazole. 

Change in suicide risk (using the 
Columbia Suicide Severity Rating Scale 
[C-SSRS]).

To assess the PK of itraconazole 
following multiple oral doses of 
itraconazole alone and in 
combination with a single oral 
dose of RO7017773 to ensure 
adequate CYP3A4 inhibition.

Concentrations and PK parameters for 
itraconazole and its metabolites.
Exploratory

To screen for the presence of 
RO7017773-derived 
metabolites.

PK concentrations of RO7017773-
derived metabolites, if appropriate.

To assess the relative 
abundance and PK parameters 
of any metabolite as appropriate.

PK parameters of RO7017773-derived 
metabolites, if appropriate.

To investigate whether genetic 
variants of drug-metabolizing 
enzymes (e.g. CYP3A4) can be 
related to the pharmacokinetic 
behavior or observations on the 
safety of RO7017773 in 
combination with itraconazole.

Clinical genotyping.


RO7017773—F. Hoffmann-La Roche Ltd
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4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2. 
This is a single-center, non-randomized, open-label, one-sequence, two-period 
crossover study in healthy male and female participants to investigate the effect of 
CYP3A inhibition on the PK of RO7017773 using concomitant administration of 
itraconazole as CYP3A inhibitor. 
In Period 1, participants will be administered a single oral dose of RO7017773 alone in 
fed state. In Period 2, after a wash-out period of 10 days, participants will receive 
multiple doses of itraconazole in fed state for 9 days and be administered 
 RO7017773
in combination with itraconazole 
.
 
 
 
 
 
 
 
 
 
 
Healthy participants will be admitted to the clinical unit on Day -1 of Period 1. An oral 
dose of 
RO7017773 will be administered alone, 30 minutes after
starting a standardized breakfast on the morning of Day 1 of Period 1. Participants will 
be discharged on the morning of Day 4 after all assessments have been completed. 
They will return to the clinical unit for 3 ambulatory visits at Day 5, Day 6, and Day 8 for 
PK sampling and safety monitoring. 


RO7017773—F. Hoffmann-La Roche Ltd
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After a wash-out period of 10 days, participants will be admitted to the clinical unit on 
Day -1 of Period 2 and will remain in-house until the morning of Day 12. They will be 
administered 200 mg of itraconazole BID (12 hours apart) on Day 1 and 200 mg of 
itraconazole QD from Day 2 to Day 9 in Period 2. Itraconazole will be administered as
oral capsules containing 200 mg every 12 hours (BID), 30 minutes after starting a 
standardized breakfast in the morning and after a standardized dinner in the evening on 
Day 1 only and on Days 2 to 9 oral capsules containing 200 mg once a day (QD), 30 
minutes after starting a standardized breakfast in the morning. On the morning 
 
 RO7017773 will be administered to each 
participant in combination with the morning dose of itraconazole. Participants will be 
discharged on the morning of Day 12 after all assessments have been completed. They 
will return to the clinical unit for 4 ambulatory visits at Day 13, Day 14, Day 15, and Day 
16 for PK sampling and safety monitoring.  
Participants will visit the clinical research unit for a safety follow-up visit 15 to 20 days 
after the last dose of itraconazole.
 
 
 Similarly, safety data will be collected in Period 1 and
Period 2 in order to assess the effect of itraconazole on the safety profile of RO7017773. 
4.1.1
Length of the Study
The total duration of the study for each participant will be up to 10 weeks, divided as 
follows (see also Section 1.3, Figure 1):

Screening: Up to 4 weeks

In-clinic and dosing Period 1: Day -1 to Day 4 with a single oral dose of 
 
RO7017773 administered on Day 1. 

Ambulatory visit Period 1: Day 5, 6 and 8 (PK sampling and safety monitoring)

Washout Period: Approximately 9 days to a maximum of 18 days (± 1 Day) (i.e., 
between Day 1 of Period 1 and Day -1 of Period 2).

In-clinic and dosing Period 2: Day -1 to Day 12 with multiple oral dose 
administrations of itraconazole (200 mg BID Day 1 and 200 mg QD Days 2 to Day 9) 
from Day 1 to Day 9 and co-administration of 
 
RO7017773 with itraconazole on the morning 
.

Ambulatory visit Period 2: Day 13, Day 14, Day 15, and Day 16 (PK sampling and 
safety monitoring).

Follow-up visit: 15 to 20 days after the last dose of itraconazole.




RO7017773—F. Hoffmann-La Roche Ltd
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4.3
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
Based on preclinical experiments, it is expected that there will be an effect of 
itraconazole, due to its inhibitory effect on the metabolism of RO7017773. To minimize 
the number of participants required, a two period crossover design has been selected. 
As the elimination of RO7017773 may be prolonged by itraconazole, an open-label, one-
sequence design has been selected. 
4.3.1
Rationale for Study Population
The participants of this study, healthy men and women of non-childbearing potential 
(WONCBP) aged 18 to 55 years (inclusive), have been chosen because of the absence 
of confounding diseases, which will permit a clearer and more consistent assessment of 
drug disposition and safety profile. In addition, healthy participants are unlikely to require 
concomitant medications which could interfere with the study drug or its PK.
4.3.2
Rationale for Pharmacokinetic Assessments
The investigation of the effect of multiple oral doses of itraconazole on the PK of a single 
oral dose of RO7017773 in healthy participants is the primary objective of the study. 
Pharmacokinetic assessments of RO7017773 will be performed in plasma. The timings 
of PK sample collection are based on PK modeling and on observed PK data collected 
in study BP40091 and are considered adequate to allow for a characterization of the 
absorption, distribution and elimination phases following a single oral dose 
administration of RO7017773. 
 
 
 
Plasma PK samples for itraconazole and its metabolite (hydroxy-itraconazole) will be 
collected to ensure that adequate exposure to itraconazole and its metabolites (e.g., 
hydroxy-itraconazole) is achieved.
Plasma PK samples may also be screened for exploratory RO7017773 metabolite 
identification with the use of non-validated methods to allow for an early identification of 
the metabolite(s) formed in vivo, and in particular to determine if any human-specific 
metabolite(s) are produced. In such circumstances, metabolite concentrations may be 
measured in residual pharmacokinetic plasma samples retrospectively, as appropriate.
 
 
 




RO7017773—F. Hoffmann-La Roche Ltd
47/Protocol BP40822, Version 3
 
 
 
Doses of 200 mg QD or 200 mg BID of itraconazole are commonly used for DDI studies 
in healthy participants (CHMP, 2012). The itraconazole dosing regimen selected in this 
study (200 mg BID on Day 1 and QD on Days 2 to 9) reflects the higher therapeutic
regimen for the treatment of itraconazole-sensitive fungal infections. Itraconazole will be 
administered with food to ensure maximum bioavailability. 
Multiple doses of 200 mg itraconazole BID on Day 1 and QD on Days 2 to 9 will be 
administered to maintain itraconazole exposure over the PK profile of the substrate 
RO7017773. To ensure that a close to maximal inhibition potential of itraconazole is 
reached as shown by PBPK simulations,
 
 While 3 days is not 
sufficient for attainment of steady-state with itraconazole, 
 allows 
for some accumulation, with higher itraconazole and hydroxy-itraconazole exposure and 
therefore potentially greater degree of CYP3A inhibition, with consideration for safety 
concerns associated with a longer itraconazole run-in period. This strategy has been 
demonstrated in multiple drug-drug interaction studies to provide adequate CYP3A 
inhibition (Ke et al 2014; Liu et al 2015).
 
 
 
 
 This duration of inhibition of CYP3A4 is 
considered sufficient to get a good overall estimate of the interaction between 
itraconazole and RO7017773.
4.5
END OF STUDY DEFINITION
The end of the study is defined as the date when the last participant last observation 
(LPLO) occurs. LPLO is expected to occur approximately 2 weeks after the last 
participant’s last dose of itraconazole.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.3.1.
The participants of this study are healthy volunteers between 18 and 55 years of age, 
inclusive, who fulfill all the inclusion criteria listed in Section 5.1 and for whom none of 
the exclusion criteria listed in Section 5.2 apply.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Conference on Harmonisation Good Clinical 
Practice (ICH-GCP) guidelines and local regulations.
Age
2.
Participants must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participants and Disease Characteristics
3.
Participants who are healthy as judged by the Investigator. Healthy status will be 
defined as the absence of evidence of any active or chronic disease following a 
detailed medical and surgical history, a complete physical examination, vital signs, 
12-lead ECG, hematology, blood chemistry, serology and urinalysis. 
Weight
4.
Body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive).
Sex
5.
Male and female participants.
The contraception and abstinence requirements are intended to prevent exposure of 
an embryo to the study treatment. The reliability of sexual abstinence for male 
and/or female enrollment eligibility needs to be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the participant. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
a)
Female participants

Women of non-childbearing potential (WONCBP), as defined in Appendix 5.
b)
Male participants: 
During the treatment period and for at least 28 days after the last dose of the 
study treatment, agree to:

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures, such as a condom, with partners who are women of childbearing 
potential (WOCBP, as defined in Section 1 of Appendix 5, or pregnant female
partners, to avoid exposing the embryo to study treatment.

Refrain from donating sperm for at least 28 days after the last dose of the study 
drug.


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5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Any condition or disease detected during the medical interview/physical examination 
that would render the participant unsuitable for the study, place the participant at 
undue risk or interfere with the participant’s ability to complete the study, as 
determined by the Investigator.
2.
History or evidence of any medical condition potentially altering the absorption, 
metabolism or elimination of drugs. This includes a surgical history of the 
gastrointestinal tract affecting gastric motility or altering the gastrointestinal tract.
3.
History of convulsions (other than benign febrile convulsions of childhood) including 
epilepsy, or personal history of significant cerebral trauma or central nervous system 
(CNS) infections (e.g., meningitis). 
4.
History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic 
reactions. 
5.
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.
6.
Abnormal blood pressure, i.e., systolic blood pressure (SBP) greater than 140 or 
less than 90 mmHg, and diastolic blood pressure (DBP) greater than 90 or less than 
50 mmHg.
7.
Abnormal pulse rate, resting pulse rate greater than 100 beats per minute (bpm) or 
less than 40 bpm. 
8.
History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g., PQ/PR interval 220 ms, QT interval corrected for heart rate 
using the Fridericia’s correction factor [QTcF] 450 ms) 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).
9.
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 at any time during screening or on Day -1 to confirm eligibility.
10. Alanine aminotransferase (ALT) and/or bilirubin 1.5 the upper limit of normal 
(ULN).
11. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's Syndrome or asymptomatic gallstones).
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 (results from the 
C-SSRS assessment should be taken into account).


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13. Participants likely to need concomitant medication during the study period (including 
medication 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-up from the previous study, or more 
than 4 times a year.
Diagnostic Assessments
15. Positive test for drugs of abuse or alcohol.
16. For women of non-childbearing potential (WONCBP), a positive pregnancy test.
17. Evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies.
18. Positive result for hepatitis B virus (HBV) or hepatitis C virus (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
19. Dietary restrictions that would prohibit the consumption of standardized meals.
20. Use of any prohibited medications and/or food before study start and during the 
study (see Section 6.5.2 and Section 5.3.1).
21. Any suspicion or history of alcohol abuse and/or any suspicion of regular 
consumption of drug of abuse or previous history of or treatment for a dependence 
disorder. 
22. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates the participation in the 
study. 
23. Participants who regularly smoke more than 5 cigarettes daily or equivalent and 
unable or unwilling not to smoke during the in-house period. 
24. Participants who have donated over 500 mL of blood or blood products or had 
significant blood loss within 3 months prior to screening. 
25. Participants under judicial supervision, guardianship or curatorship.
26. Hypersensitivity to itraconazole, to any of the other excipients, or to any other 
triazole antifungal.
27. Any other known contraindications to itraconazole as stated in the SmPC.
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 and for at least 8 hours prior to laboratory safety tests performed between 
Day-1 of Period 1 and the follow-up visit. 


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On Day 1 of Period 1, study drug administration (RO7017773) will be performed 
30 minutes after starting a standardized breakfast. This breakfast should be consumed 
within 30 min or less. 
On Day 1 of Period 2, itraconazole will be administered at a dose of 200 mg every 12 
hours (BID), 30 min after starting a standardized breakfast and after a standardized 
dinner in the evening. From Days 2 to Day 9 of Period 2, itraconazole will be 
administered at a dose of 200 mg once a day (QD), 30 min after starting a standardized 
breakfast. On the morning 
, an oral dose 
RO7017773 will be administered to each participant in combination with the morning 
dose of itraconazole 30 minutes after starting a standardized breakfast. This breakfast 
should be consumed within 30 minutes or less.
On the days of RO7017773 administration 
 a 
standard lunch will be provided 4 hours after dosing. On all other days of the in-house 
period, standard breakfast, lunch, dinner and snack will be provided at the times deemed 
convenient by the site, unless required for study drug administration.
Consumption of nutrients known to modulate CYP3A activity (e.g., grapefruit or 
grapefruit juice, Seville orange) will not be permitted within 2 weeks prior to first dosing 
until the safety follow up visit.
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 in-clinic period. During the 
participants’ ambulatory periods between screening and the follow-up visit, participants 
will be asked to limit their coffee or tea consumption to no more than 3 cups per day, and 
their consumption of methylxanthine-containing products (e.g. cola) to a maximum of 
1 liter per day.
Consumption of alcohol will not be allowed from 48 hours before dosing until the end of 
the participants’ in-clinic stays and participants will be asked to limit their alcohol 
consumption 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 2 ambulatory periods until follow-up. The 
use of tobacco will not be permitted from 48 hours before dosing until the end of the in-
clinic stay and participants will be asked to limit their tobacco use to a maximum of 
5 cigarettes a day or an equivalent amount of tobacco during the 2 ambulatory periods 
until follow-up.
5.3.3
Activity
Participants should refrain from strenuous exercise from 7 days prior to first admission 
until the follow-up visit. The level of activities should be kept as similar as possible on all 
study days until the follow-up visit. 


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5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study.
The Investigator will maintain a screening log to record details 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 
not be re-screened, unless agreed with the Sponsor. A repeat of a screening laboratory 
test because of uncertain or questionable results during screening is not considered a 
re-screening.
5.5
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using e.g., pre-screening 
enrollment logs, clinical database, and any Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) approved materials.
6.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.
All investigational medicinal products (IMPs) required for completion of this study
(RO7017773) will be provided by the Sponsor. Marketed oral capsules of itraconazole 
(Sporanox) will be sourced by the clinical site. 
All study drug administration will be at the study center under supervision of site staff.


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6.1
TREATMENTS ADMINISTERED
Table 5 summarizes the treatments administered.
Table 5
Summary of Treatments Administered
Study Treatment Name:
RO7017773
Itraconazole (Sporanox®)
Dosage Formulation:
Capsule
Capsule
Unit Dose Strength(s)/Dosage 
Level(s):
25 mg
100 mg
Dose:
200 mg BID and QD 
Route of Administration:
Oral
Oral
Dosing Instructions:
RO7017773 will be 
administered with water
in the morning 30 
minutes after starting a 
standardized breakfast. 
Breakfast should be 
consumed within 30 
minutes or less. 
Itraconazole will be administered 
with water in the morning and in 
the evening (12 hours apart), 30 
minutes after starting a 
standardized breakfast and a 
standardized dinner on Day 1 
only. On Days 2 to 9 
itraconazole will be 
administered with water in the 
morning, 30 minutes after 
starting a standardized 
breakfast. Breakfast and dinner 
should be consumed within 30 
minutes or less.
Packaging and Labeling:
Study treatment will be 
provided in bottles. The 
IMP will be labeled as 
required per country 
requirements.
Marketed oral capsule(s) 
(100 mg) of itraconazole will be 
used during the study. 
Sporanox® will be sourced by the 
clinical site. 
Storage Conditions
Store at 2C to 8C, 
protect from light and 
moisture
Sporanox® capsules will be 
stored according to the SmPC.
Manufacturer
F. Hoffmann-La Roche 
Ltd.
Janssen-Cilag Ltd
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
For itraconazole (Sporanox), see the SmPC for more details.
For RO7077713, see the Investigator’s Brochure and Pharmacy Manual (if available) for 
more details. 


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6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
Upon arrival of the IMPs at the site, the site pharmacy personnel will complete the 
following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment assignment schedule and e.g., IMP user
guidelines. 
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff.
The Investigator or delegate 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.


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Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual. 
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
The study is open-label. Up to 18 healthy participants will be enrolled in this study. The
participant numbers will be allocated sequentially in the order in which the participants 
are included. The subject numbers will be generated by the Sponsor or its designee and 
it will be sent to the Investigator. 
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment assignment. This individual will write the date 
dispensed and subject number on the study treatment label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study.
6.5
CONCOMITANT THERAPY
6.5.1
Permitted Therapies
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant 
from 4 weeks prior to screening until the follow-up visit must be recorded along with the 
reason for use, dates of administration (including start and end dates) and dosing
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).
Use of the following therapies is permitted, as specified below:

Continuation of hormone-replacement therapy or other maintenance therapy is 
permitted throughout the study for participants who already use them.

Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g/day up to 48 
hours prior to dosing and after the in-house period, but should not exceed 4 g total 
during the week prior to dosing.


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6.5.2
Prohibited Therapies
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 prior to study drug 
administration until follow-up, with the exception of medications to treat AEs and 
medications listed in Section 6.5.1, 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 OTC medication (including herbal products, vitamins, minerals, 
energy drinks and dietary supplements). 

Any known inhibitor of CYP3A4 or P-glycoprotein taken within 2 weeks prior to the 
start of the administration of study drug (Period 1 Day 1) or within 5 times the 
elimination half-life of the medication prior to the start of study drug intake (whichever 
is longer) including but not limited to the following drugs: ketoconazole, fluconazole, 
erythromycin, clarithromycin, mifebradil, nefazodone, diltiazem, verapamil and 
cimetidine. 

Any known inducer of CYP3A4 or P-glycoprotein taken within 4 weeks prior to start 
of administration of study drug (Period 1 Day 1), including but not limited to the 
following drugs: rifampicin, rifabutin, glucocorticoids, carbamazepine, oxcarbazepine, 
phenytoin, phenobarbital, and St. John’s Wort.
 
 
   
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7017773 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal.
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study specific procedures as outlined in this 
protocol.


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Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
See the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined (Section 6,
Appendix 3) or if the Investigator believes that it is in best interest of the participant.
Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for a study completion/early termination visit (see Section 8.10.3) and may undergo 
follow‑up assessments (see Section 8.10.4). The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. 
Participants who discontinue study treatment prematurely may be replaced in order to 
ensure obtaining 12 evaluable participants.
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.
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons may be replaced.
See SoA (Section 1.3 for data to be collected at the time of study discontinuation and at 
the follow-up visit, and for any further evaluations that need to be completed.


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7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant repeatedly 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 whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the Schedules of Activities 
(SoA; Section 1.3). Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-frame defined in the SoA 
(Section 1.3).
8.1
EFFICACY ASSESSMENTS
Efficacy parameters will not be evaluated in this study.


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8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological, neurological, and 
musculoskeletal systems in addition to head, eyes, ears, nose, throat, neck and lymph 
nodes. Height and weight will also be measured and recorded. The physical examination 
will NOT include pelvic, rectal or breast examinations.
Further examinations 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.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the Adverse Event eCRF.
8.2.2
Vital Signs
Vital signs will include temperature (tympanic), SBP and DBP, 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 (Section 1.3).
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-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures QRS complex, 
PR, 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 
10 minutes 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. 
ECGs should be performed prior to meals and blood draws as appropriate. 
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 eCRF or loaded electronically. QTcF and RR interval will be 
calculated automatically and recorded on the eCRF or loaded automatically. Changes in 
T‑wave and U‑wave morphology and overall ECG interpretation will be documented on 
the eCRF or 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 Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the separate 
laboratory manual and the SoA (Section 1.3).
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 significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to 
the normal range and/or an adequate explanation of the abnormality is found.


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
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., serious adverse event [SAE]
or AE or dose-modification), the results must be recorded in the eCRF.
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 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
Suicidal Risk Monitoring
RO7017773 is considered to be a CNS-active study treatment. There has been some 
concern that some CNS-active study treatments may be associated with an increased 
risk of suicidal ideation or behavior when given to some participants. Although this study 
treatment or other similar drugs in this class have not been shown to be associated with 
an increased risk of suicidal thinking or behavior when given to healthy participants, the 
Sponsor considers it important to monitor for such events before or during this clinical 
study.
Baseline assessment of suicidal ideation and behavior AND/OR treatment-emergent 
suicidal ideation and behavior will be monitored during the study using the C-SSRS.
C-SSRS assessments will be completed by the clinician.
8.2.6
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‑reported race/ethnicity, if acceptable 
by local regulations.


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8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious adverse 
events of special interest (NSAESI) and disease-related events and/or disease-related 
outcomes not qualifying as AEs or SAEs are discussed in Sections 8.3.6 and
Section 8.3.7.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity, and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3.
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other AE should not be reported.
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until 14 days after the last dose of study treatment. 
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for AEs after the end of the AE reporting period 
(14 days after the last dose of study treatment).
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study participation, 
the Investigator must promptly notify the Sponsor. For the procedures of reporting, see 
Appendix 2.


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8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all participant evaluation time-points.
8.3.3
Follow-Up of Adverse Events and 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 (Section 7.3), or the participant 
withdraws consent. Every effort should be made to follow all SAEs considered to be 
related to study treatment or trial-related procedures until a final outcome can be 
reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
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Investigator safety 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 Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical monitors is available 
24 hours a day 7 days a week. Medical monitors contact details will be available on a 
separate list generated by the study management team.
8.3.5
Pregnancy
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 28 
days after the last dose of study drug.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest 
NSAESIs are required to be reported by the Investigator to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Appendix 2 for reporting 
instructions).
NSAESIs for this study include the following:

Cases of an elevated ALT or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
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patient exposed to a medicinal product. This term applies only when a contamination 
of the study treatment is 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 treatment overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Section 5 and 
5.2 of Appendix 2 for further details).
Decisions regarding dose-interruptions or modifications of itraconazole will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant.
In the event of an overdose, the Investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Document the quantity of the excess dose, as well as the duration of the overdose
(for itraconazole only), in the eCRF.
PK samples collected per protocol may be used to further evaluate overdose or incorrect 
administration of itraconazole. 
8.5
PHARMACOKINETICS
Blood samples for the determination of plasma concentrations of RO7017773 will be 
collected as outlined in the SoA (see Section 1.3). Plasma RO7017773 concentrations 
will be measured by a specific and validated LC-MS/MS method. Plasma concentrations 
of RO7017773 metabolites may also be measured as appropriate using a specific assay. 
Blood samples for the determination of plasma concentrations of itraconazole and its 
metabolite (hydroxy-itraconazole) will be also collected as detailed in the SoA (see 
Section 1.3). Plasma concentrations of itraconazole and its metabolite (hydroxy-
itraconazole) will be measured by a specific and validated LC-MS/MS method.
PK parameters for RO7017773 and itraconazole and its metabolite will be read directly 
from the plasma concentration-time profiles or estimated using standard 
non-compartmental methods where appropriate. 


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If required, remaining PK samples may also be used for assay development/validation,
e.g., metabolites and measurement of exploratory biomarkers.
The blood samples will be destroyed up to 6 months after the date of final clinical study 
report (CSR). Details on sampling procedures, sample storage and shipment are given
in the Sample Handling Manual.
8.6
PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated in this study.
8.7
GENETICS
8.7.1
Clinical Genotyping
A blood sample will be collected for deoxyribonucleic acid (DNA) extraction according to 
the SoA (Section 1.3). If, however, the genetic blood sample is not collected during the 
scheduled visit, it may be collected at any time during the conduct of the clinical study.  
The DNA may be used to determine if alleles (e.g., at metabolic enzymes, transporters, 
receptors) affect the PK and/or safety of RO7017773.
Any remaining blood after the specified analyses may also be used for additional (assay) 
validation experiments.
Data arising from this study will be subject to the same confidentiality as the rest of the 
study.
The blood samples will be destroyed within 6 months after the date of final clinical study 
report (CSR). Details on sampling procedures, sample storage and shipment are given 
in the Sample Handling Manual.
8.8
BIOMARKERS
Biomarkers are not evaluated in this study.
8.9
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled participant and for participants who are not subsequently enrolled will be 
maintained at the study site.


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All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed at time-points indicated in 
the SoA (see Section 1.3), unless otherwise specified.
If possible and if the Sponsor agrees, any assessments identical to those planned in the 
protocol for the participants’ screening that have already been performed within the time
frames stipulated by the protocol for the screening exams may be used for the protocol 
in order to minimize the burden for the participants.
8.10.2
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 Subject Number and re-enroll 
in the study.
All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study or discontinue from the study early will be asked to 
return to the clinic 15 to 20 days after the last dose of study treatment for a follow‑up 
visit. 
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 8.3.1 and 8.3.3.




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Table 7
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results.
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
Columbia Suicide-
Severity Rating 
Scale (C-SSRS)
Individual data at will be presented in listings.
9.4.3
Pharmacokinetic Analyses
Analyses will be carried out on the PK analysis population.
9.4.3.1
Pharmacokinetic Parameters
The primary RO7017773 PK study variable will be the AUC (AUC0-inf if it can be derived, 
otherwise truncated as appropriate) and Cmax. All other PK parameters will be regarded 
as secondary.
The following PK parameters of RO7017773 and of itraconazole and its metabolites (e.g., 
hydroxy-itraconazole) will be read from the concentration versus time profiles or 
estimated using non-compartmental methods where appropriate:

Tmax : Time to maximum plasma concentration

Cmax : maximum observed plasma concentration

AUC0-t : area under the plasma concentration-time curve up to time t

AUC0-last : area under the plasma concentration-time curve up to the last measurable 
concentration

AUC0-inf: area under the plasma concentration-time curve extrapolated to infinity


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
T1/2 : apparent terminal half-life, computed as ln(2)/λz

CL/F: apparent oral clearance, calculated as Dose/AUC0-inf

RAUCo-inf : AUC ratios calculated as RO7017773 AUC0-inf Period 2 over RO7017773 
AUCo-inf Period 1 

RCmax: Cmax ratio calculated as RO7017773 Cmax Period 2  over RO7017773 CmaxPeriod 1 

Ctrough: trough (pre-dose) plasma concentration for itraconazole and its metabolites 
hydroxy-itraconazole.
Additional PK parameters may be reported as appropriate.
All pharmacokinetic concentration and calculated PK parameters for RO7017773, 
itraconazole and its metabolite will be presented in individual listings and summary 
tables (including descriptive summary statistics: mean, standard deviation, coefficient of 
variation, median, minimum, and maximum), and graphs (including concentration vs. 
time plots on linear and semi-logarithmic scales) as appropriate.
9.4.3.2
Statistical Analysis
The following linear statistical model will be applied to the log-transformed,
dose-normalized PK variables AUC (AUC0-∞if it can be derived, otherwise truncated as 
appropriate) and Cmax:
 =  + 
 +  + 
( = 1, 2, … , 12;  = 1,2)
where denotes the general mean of the transformed variables, 
 is the effect of the 
treatment (RO7017773 alone vs. RO7017773 together with Itraconazole), si is the 
random subject effect and ε is the random error (within subject variability). The random 
subject effect and the random error are assumed to be independent and normally 
distributed with zero means and variances and  respectively.
Least square means with corresponding 90% confidence intervals (CI) will be derived to 
compare the relative bioavailability of the different treatments.
Under this model the (geometric means) ratios 
( !"#$"""%&'()
( !"#$"""%)
and 
)*+( !"#$"""%&'()
)*+( !"#$"""%)
are obtained as 
,-.
,-/ = 01.21/ , i.e. by exponentiation of the corresponding estimated 
differences in the analysis of variance (ANOVA) model. 
9.5
INTERIM ANALYSES 
No interim analyses are planned for this study.


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9.6
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed. Data for study drug administration and concomitant 
medications will be listed. The number of participants who were enrolled, discontinued, 
and completed the study will be summarized and listed.


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10.
REFERENCES
Bjornsson TD, Callaghan JT, Einolf HJ, et al. Pharmaceutical Research and 
Manufacturers of America Drug Metabolism/Clinical Pharmacology Technical 
Working Group; FDA Center for Drug Evaluation and Research (CDER). The 
conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical 
Research and Manufacturers of America (PhRMA) perspective. Drug Metab 
Dispos. 2003; 31(7):815-32.
Columbia-Suicide Severity Rating Scale. Available at http://www.cssrs.columbia.edu/.
Committee for Human Medicinal Products (CHMP). Guideline on the investigation of 
drug interactions. June 2012.
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.
Investigator’s Brochure for RO7017773.
Ke AB, Zamek-Gliszczynski MJ, Higgins JW, et al. Itraconazole and clarithromycin as 
ketoconazole alternatives for clinical CYP3A inhibition studies. Clin Pharmacol 
Ther. 2014 May;95(5):473-6.
Liu L, Bello A, Dresser MJ, Heald D, et al. Best practices for the use of itraconazole as a 
replacement for ketoconazole in drug-drug interaction studies. J Clin Pharmacol. 
2015 Jun 4.
Sporanox(Itraconazole) SmPC, Janssen Cilag Ltd, July 2017.
U.S. Department of Health and Human Services. Food and Drug Administration. 
Guidance for Industry. In Vivo Drug Metabolism/Drug Interaction Studies – Study 
Design, Data Analysis, and Recommendations for Dosing and Labeling. November 
1999.
World Health Organization. Meeting report: autism spectrum disorders and other 
developmental disorders: from raising awareness to building capacity; World 
Health Organization, Geneva, Switzerland 16-18 September 2013.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
and Appendix 3 (procedures of recording), Appendix 5 (contraceptive guidance and 
collection of pregnancy information). Additional study-related appendices are in order of 
appearance in the protocol.


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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the 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 the study is initiated. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (Section 2.3.1 of this 
Appendix).
The Investigator should follow the requirements for reporting all adverse events 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.


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1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 
sample ICFs or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/EC submission. The final IRB/EC‑approved Consent 
Forms must be provided to the Sponsor for Health Authority submission purposes 
according to local requirements. Participants must be re-consented to the most current 
version of the ICF(s) during their participation in the study. A copy of the ICF(s) signed 
by all parties must be provided to the participant.
The 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 study file or in the site file and must be available for 
verification by study monitors at any time.


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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-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, 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 or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLO).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.


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A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data. Sites will be responsible for data entry into 
the electronic data capture (EDC) system. In the event of discrepant data, the CRO will 
request data clarification from the sites, which the sites will resolve electronically in the 
EDC system.
The CRO will produce a Data Management Plan or equivalent document that describes 
the quality checking to be performed on the data. Central laboratory data and/or other 
electronic data will be sent directly to the CRO, using the CRO's standard procedures to 
handle and process the electronic transfer of these 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.
2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.


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2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification to 
the Sponsor.
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.


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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.
3.
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor has contracted with 
CRO(s) who will be delegated responsibility for various aspects of this clinical trial.
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.


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


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
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
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 Appendix 3).

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.


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
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 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
The Investigator will then record all relevant AE/SAE information in the eCRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the 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 the Sponsor.
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
ASSESSMENT OF SEVERITY
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing 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 pre-defined 
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).


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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.
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 to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment (where 
applicable).

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
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 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 


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This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
5.
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)
Accidental overdoses or medication errors (see Appendix 2, Section 5.2 for details on 
reporting requirements).
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.


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5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
((Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), Investigators 
should record all case details that can be gathered on the paper Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and forward this form to the 
SAE Responsible within 24 hours after learning of the event.
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.
5.2
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR 
Accidental overdose and medication error (hereafter collectively referred to as "special
situations"), are defined as follows:

Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error: accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of the 
drug.


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Special situations are not in themselves adverse events, but may result in adverse 
events. All special situations associated with RO7017773, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
Special situations should be recorded as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For RO7017773 and itraconazole, each adverse event associated with a special 
situation should be recorded separately on the Adverse Event eCRF.  If the associated 
adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Appendix 2, 
Section 5.1). RO7017773, adverse events associated with special situations should be 
recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 


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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 documents:

RO7017773 Investigator's Brochure

Itraconazole Summary of Product Characteristics
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
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.


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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
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 
7.0 mEq/L should be recorded as “hyperkalemia”.


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
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 finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3 ULN in combination with total 
bilirubin 2 ULN.

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice.


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2, 
Section 5.1) and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event), either as a serious adverse event or a non-serious adverse event 
of special interest (see Section 8.3.6).
7.
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 
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 by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an 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”).
9.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration) 


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
o
The hospitalization was planned prior to the study or was scheduled during 
the study when elective surgery became necessary because of the expected 
normal progression of the disease.
o
The participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
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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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the local or central laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional repeat or unscheduled tests may be performed at any time during the study 
as determined for necessary safety reasons or technical issues with the samples.
Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose 
(fasting), urea, creatinine, protein, albumin, phosphate, 
calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, urate, LDH.
Coagulation

Prothrombin time (INR) and activated thromboplastin 
time (aPTT).
Viral Serology

HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, 
HIV-2 antibody), hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) antibody.
Lipids

Cholesterol, triglycerides.
Hormone

For post-menopausal women only to confirm post-
menopausal status: Estradiol and follicle-stimulating 
hormone (FSH).
Pregnancy Test

Serum or urine human chorionic gonadotropin (hCG) 
pregnancy test.
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood, nitrite, leukocyte
If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine will 
be sent to the laboratory for microscopy and/or 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.
Other Screening Tests

Urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).

Alcohol Breath test.
The results of each test will be provided electronically or captured in the CRF.


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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 participant listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.


RO7017773—F. Hoffmann-La Roche Ltd
96/Protocol BP40822, Version 3
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.

Women in the following categories are considered to be Women of Non-
Childbearing Potential (WONCBP)
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.


RO7017773—F. Hoffmann-La Roche Ltd
97/Protocol BP40822, Version 3
2.
CONTRACEPTION GUIDANCE

Female Participants
Table 1
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependenta
(Failure rate of 1% per year when used consistently and correctly)
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User-Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.
3.
PREGNANCY TESTING
For WONCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3 and Appendix 4 ). If 
a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing may also be performed according to local practice.


RO7017773—F. Hoffmann-La Roche Ltd
98/Protocol BP40822, Version 3
4.
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). This applies only to male participants who receive study 
treatment.
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.

Female participants who become pregnant
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in Appendix 2.


RO7017773—F. Hoffmann-La Roche Ltd
99/Protocol BP40822, Version 3
While the Investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment AND be withdrawn from the study.} 
5
ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female partner of a male 
participant exposed to study treatment should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5 of Appendix 2).

SAP_001.pdf: 
Official Title: 
A Non-Randomized, Open-Label, One Sequence, Two Period Cross-
Over Study to Investigate the Effect of CYP3A Inhibition on 
the Pharmacokinetics of RO7017773 in Healthy Participants 
NCT Number: 
NCT03774576 
Document Date: 
SAP Final Version: 23- April-2019 








CONFIDENTIAL 
 
BP40822 
BIOTRIAL BIOMETRICS – Statistical Analysis Plan – Final version – 18APR2019 
4/31 
TABLE OF CONTENTS 
 
1. 
Introduction .................................................................................................................... 8 
2. 
Study objectives ............................................................................................................... 8 
2.1. 
Primary objective ......................................................................................................... 8 
2.2. 
Secondary objectives ................................................................................................... 8 
2.3. 
Exploratory objectives ................................................................................................. 8 
3. 
Study methodology ......................................................................................................... 8 
4. 
Sample Size ..................................................................................................................... 9 
5. 
Changes to the planned analysis from protocol ............................................................ 9 
6. 
Statistical considerations ................................................................................................ 9 
7. 
Description of study subjects ........................................................................................ 11 
7.1. 
Definition of analysis sets .......................................................................................... 11 
7.2. 
Subject disposition ..................................................................................................... 11 
7.3. 
Protocol deviations .................................................................................................... 11 
8. 
Demographic data and baseline characteristics .......................................................... 12 
8.1. 
Demographic data ...................................................................................................... 12 
8.2. 
Other baseline characteristics .................................................................................... 12 
8.3. 
Medical and surgical history and procedures ............................................................ 12 
8.4. 
Previous and concomitant medications ..................................................................... 12 
8.5. 
Compliance ................................................................................................................ 12 
9. 
Pharmacokinetic data ................................................................................................... 13 
9.1. 
Generalities ................................................................................................................ 13 
9.2. 
Plasma concentrations and pharmacokinetic parameters .......................................... 14 
9.2.1. 
Plasma parameters .............................................................................................. 14 
9.2.2. 
Plasma pharmacokinetic analysis ....................................................................... 16 
10. 
Pharmacodynamics data .............................................................................................. 17 
11. 
Safety data ..................................................................................................................... 17 
11.1. Adverse events ........................................................................................................... 17 
11.2. Clinical laboratory data ............................................................................................. 18 
11.3. Other safety parameters ............................................................................................. 19 
11.3.1. 
Vital signs data ................................................................................................... 19 
11.3.2. 
Electrocardiogram data ...................................................................................... 20 
11.3.3. 
Physical examination .......................................................................................... 20 
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11.3.4. 
Alcohol breath test and urine drug of abuse ....................................................... 20 
11.3.5. 
Columbia-suicide severity rating scale .............................................................. 20 
11.3.6. 
Subjects’ habits .................................................................................................. 21 
12. 
Reporting conventions .................................................................................................. 21 
13. 
References ..................................................................................................................... 21 
14. 
Appendices .................................................................................................................... 22 
14.1. Appendix 1 - Flow chart and schedule of assessments of the study .......................... 22 
14.2. Appendix 2 - List of tables, listings and figures included in the clinical study report .. 
 
 ................................................................................................................................... 27 
 
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BIOTRIAL BIOMETRICS – Statistical Analysis Plan – Final version – 18APR2019 
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Unless specified otherwise, the calculation of percentages will be based on the number of 
observed values. Therefore, counts of missing values will be included in the denominator and 
displayed as a separate category if any. 
For the values measured outside of the treatment periods, data will be organised overall. 
For the values obtained during the treatment periods, data will be organised by treatment 
group: 
- 
For analyses of adverse events: 
- 
RO7017773 alone, 
- 
Itraconazole alone, 
- 
RO7017773 + itraconazole. 
- 
For the other safety and PK analyses: 
- 
RO7017773 alone, 
- 
RO7017773 + itraconazole. 
All safety listings will be sorted by subject and measurement time if applicable. 
All pharmacokinetics listings will be sorted by treatment group, subject and measurement 
time. 
All listings containing an evaluation date will display the study day defined as the day relative 
to the first administration of study drug: 
- 
Study day 1 will be defined as the day of the first administration date. 
- 
Study day -1 will be defined as the day prior to the first administration date. 
- 
There will be no study day 0. 
 
Handling of missing and retest values 
No management of missing values or values below/above a limit of detection/quantification 
will be performed, except for pharmacokinetic values (see section 9.1). 
For all parameters and for subjects with retest values, the last reliable value will be used for 
the measurement time before the first investigational medicinal product (IMP) administration 
in each period (provided it was measured before IMP administration in each period) and the 
first reliable value will be used for the measurement time after the first IMP administration in 
each period. 
 
Handling of incomplete dates 
No management of incomplete dates will be performed. The incomplete dates will be labelled 
as such in the listings. 
 
Baseline definition 
For all parameters, baseline will be defined as the last available measurement prior to the first 
IMP administration in each period.  
 
Duration 
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CONFIDENTIAL 
 
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BIOTRIAL BIOMETRICS – Statistical Analysis Plan – Final version – 18APR2019 
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Duration (in days, hh:mm) will be calculated by the difference between the start and stop date 
and time (e.g. duration of adverse event (AE) (days, hh:mm) = end of AE date and time – AE 
onset date and time). 
Duration (in days) will be calculated by the difference between the start and stop date + 1 
(e.g. duration of a medication (days) = end of medication date – onset of medication date + 1). 
 
Type I error rate 
Unless stated otherwise, statistical tests will be two-sided and will be carried out at the 5% 
level of significance. 
7. Description of study subjects 
7.1. Definition of analysis sets 
The following analysis sets will be defined: 
Included set (IS): all of the subjects included in the study. 
Safety set (SS): all participants who have been administered 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 analysis. 
Pharmacokinetic set (PKS): 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. 
The analysis sets will be precisely defined and validated during the data review meeting. 
The safety and pharmacokinetic sets will be analysed using subjects as treated. 
7.2. Subject disposition 
A summary table with the description of the number of included subjects, the number of 
subjects who completed the study and the number of subjects who discontinued the study, 
classified by main reason of withdrawal, will be prepared overall for the subjects in the 
included set. Corresponding individual listings will be provided. 
A summary table with the description of the number and percentage of subjects in each 
analysis set (Safety set and Pharmacokinetic Set) will be prepared overall. A specific listing 
of subjects excluded from safety and pharmacokinetic analyses will be provided with the 
reason(s) for exclusion. 
Listings with end of study status and study visit dates will also be generated. 
7.3. Protocol deviations 
A summary table with the number and percentage of subjects presenting deviations relating to 
inclusion/exclusion criteria will be prepared overall for the subjects in the included set. A 
summary table with the number and percentage of subjects presenting other protocol 
deviations (all deviations judged relevant during the data review meeting) will also be 
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CONFIDENTIAL 
 
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12/31 
prepared overall by status of the deviations (minor/major). The corresponding listings will be 
provided with the status of the deviations. 
8. Demographic data and baseline characteristics 
The analyses of the demographic and baseline characteristics will be performed on the safety 
set. 
8.1. Demographic data 
The subjects’ demographic characteristics (age, sex, ethnicity, height, weight and body mass 
index (BMI) recorded at screening) will be summarised overall, and listed. 
8.2. Other baseline characteristics 
Abnormal or positive results as well as all individual data for coagulation, immunology, 
serum/urine pregnancy tests (for females only) will be listed. 
Childbearing potential (for females only) and birth control method (for males only) as well as 
results for hormonology (for post-menopausal women only) and clinical genotyping will only 
be listed. 
8.3. Medical and surgical history and procedures 
Information on medical and surgical history recorded at the screening visit and procedures 
will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.1. 
A table with the number and percentage of subjects having at least one previous/ongoing 
medical history or one surgical history will be generated overall. Previous/ongoing medical 
history will be listed as well as prior surgeries and concomitant surgeries. 
8.4. Previous and concomitant medications 
Information on previous and concomitant medications will be coded according to the GNE 
Drug Thesaurus. 
A previous medication will be defined as a medication stopped prior to the date and time of 
the first administration of IMP. A concomitant medication will be defined as a medication 
that is taken by subjects any time during the treatment period (on or after the date and time of 
first IMP administration for each subject). If the date value does not allow allocation of a 
medication to the previous or concomitant category (missing or incomplete start or end date), 
this medication will be considered concomitant.  
A table with the number and percentage of subjects having taken at least one previous 
medication and a table with the number and percentage of subjects having taken at least one 
concomitant medication will be generated overall (overall and by medication class and 
medication drug name). Previous and concomitant medications will be listed separately.  
8.5. Compliance 
A listing with IMP administration dates and times will be generated. Time of meals intake 
will also be listed. 
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- 
By intensity, with the number and percentage of subjects with at least one TEAE and 
number of occurrences of a TEAE by treatment group, 
- 
By causality (to RO7017773 alone, to itraconazole alone and to both RO7017773 and 
itraconazole), with the number and percentage of subjects with at least one TEAE and 
number of occurrences of a TEAE by treatment group. 
If there are only a few adverse events (≤10), only a listing will be generated. 
All adverse events reported in the electronic Case Report Form (eCRF) will be listed with the 
SOC, the PT and the investigator's verbatim. All TEAEs will also be listed with the SOC and 
the PT. An additional listing will be provided for AEs leading to death and other serious and 
significant AEs (SAEs or AEs leading to study withdrawal). 
Note:  
i. 
In the descriptive tables, the number of subjects with at least one adverse event/TEAE 
for a given PT will also correspond to the number of adverse events/TEAEs whatever 
the number of occurrences during the studied period.  
ii. 
In case of a change of intensity or causality for an event during the same treatment 
period, the intensity will be the highest recorded intensity and the causality will be the 
highest likelihood recorded. 
iii. 
A treatment-emergent AE will be associated with the treatment group of the current 
period if this AE starts between the first IMP administration of the current period and 
the first IMP administration of the next period.  
11.2. Clinical laboratory data 
The following clinical laboratory parameters will be measured (see section 14.1): 
- 
at screening visit, 
- 
in Period 1: on Day -1, Day 3 and Day 8, 
- 
in Period 2: on Day -1, Day 4, Day 7, Day 10 and Day 16, 
- 
at follow-up visit. 
Haematology parameters will be listed and grouped as follows: 
- Red blood cells: erythrocytes (10^12/L), hematocrit (ratio) and hemoglobin (g/L). 
- White blood cells: basophils (10^9/L), eosinophils (10^9/L), leukocytes (10^9/L), 
lymphocytes (10^9/L), monocytes (10^9/L) and neutrophils (10^9/L). 
- Other parameters: platelets (10^9/L). 
Blood chemistry parameters will be listed and grouped as follows: 
- Liver function: alanine aminotransferase (IU/L), alkaline phosphatase (IU/L), aspartate 
aminotransferase (IU/L), bilirubin (µmol/L), direct bilirubin (µmol/L). 
- Renal chemistry: creatinine (µmol/L) and urea (mmol/L). 
- Electrolytes: bicarbonate (mmol/L), calcium (mmol/L), chloride (mmol/L), phosphate 
(mmol/L), potassium (mmol/L) and sodium (mmol/L). 
- Metabolism parameters: cholesterol (mmol/L), glucose (mmol/L), lactate dehydrogenase 
(IU/L), triglycerides (mmol/L) and urate (µmol/L). 
- Other proteins: albumin (g/L) and protein (g/L). 
Urinalysis parameters will be listed and grouped as follows: 
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11.3.2. Electrocardiogram data 
Standard 12-lead electrocardiogram (ECG) parameters (including heart rate (beats/min), PR 
interval (msec), RR interval (msec), QRS duration (msec), QT interval (msec) and Fridericia 
QTc interval (msec)) and ECG abnormalities will be recorded in triplicate (see section 14.1): 
- 
at screening visit, 
- 
in Period 1: on Day -1, Day 1 at pre-dose, H1, H2, H5, H6 and H8, Day 2, Day 3, Day 
4, Day 5 and Day 8, 
- 
in Period 2: on Day -1, Day 1, Day 4 at pre-dose, H1, H2, H5, H6, H8, Day 5, Day 6, 
Day 8, Day 9, Day 12 and Day 16, 
- 
at follow-up visit. 
The mean of the triplicate ECGs will serve as analysable data. 
Only interpretable ECGs will be analysed. 
Raw data and changes from baseline (except for ECG abnormalities) will be described by 
treatment group and measurement time.  
Values [raw data/ECG abnormalities and changes from baseline)] will be listed. 
11.3.3. Physical examination 
A complete physical examination will be measured (see section 14.1): 
- 
at screening visit, 
- 
in Period 1: on Day -1, 
- 
in Period 2: on Day -1 and Day 12, 
- 
at follow-up visit. 
Weight will be measured at screening and follow-up visits. 
Abnormal results as well as all individual data of physical examination will be listed. 
Raw data of weight and BMI will be described overall and listed. 
11.3.4. Alcohol breath test and urine drug of abuse 
Alcohol breath test and urine drug of abuse will be measured (see section 14.1): 
- 
at screening visit, 
- 
in Period 1: on Day -1, 
- 
in Period 2: on Day -1. 
Positive results as well as all individual data of alcohol breath test and urine drug of abuse 
will be listed. 
11.3.5. Columbia-suicide severity rating scale 
The Columbia-suicide severity rating scale (C-SSRS) will be measured (see section 14.1): 
- 
at screening visit, 
- 
in Period 1: on Day -1 and Day 4, 
- 
in Period 2: on Day -1, Day 3 and Day 11. 
The items of suicidal ideation, intensity of ideation and suicidal behavior will only be listed. 
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11.3.6. Subjects’ habits 
The subject’ habits (tobacco, caffeine, alcohol and grapefruit consumptions) will be measured 
(see section 14.1):  
- 
at screening visit (for tobacco consumption only), 
- 
in Period 1: on Day -1, Day 5, Day 6 and Day 8, 
- 
in Period 2: on Day -1, Day 13, Day 14, Day 15 and Day 16, 
- 
at follow-up visit. 
The subject’ habits will be summarised by treatment group and measurement time, and listed. 
12. Reporting conventions 
All tables, figures and listings are detailed in section 14.3. They will be prepared using SAS 
software as rtf files and the rtf files will be compiled as PDF files (one PDF file by main 
section). 
The footers will be presented as follows: --- STUDY BP40822 / <name of the program>.SAS 
/ <name of the output>.RTF / DDMMMYYYY HH:MM ---. 
Table and Listing Page Set Up Requirements: 
- 
Font Type = Courier New 
- 
Font Size = 8 pt (at a minimum) 
- 
Page Margins: Top=2 cm; Bottom=2 cm; Left=2 cm; Right=2 cm 
- 
Paper Size = A4 (21 cm x 29.7 cm) 
- 
Page Orientation: Landscape 
- 
Graphs: Portable Network Graphics (PNG) format 
Summary statistics will be presented as follows.  
Parameter (unit) 
Statistics 
/ Category 
Group X 
(N=xx) 
Quantitative variable (unit)* 
n 
xx 
 
Mean ± SD 
xx.xx ± xx.xx 
 
SEM 
xx.xx 
 
Median 
xx.xx 
 
Min ; Max 
xx.x ; xx.x 
Qualitative variable 
Class 1  n (%) xx (xx.x) 
 
Class 2  n (%) xx (xx.x) 
 
… 
… 
* All statistics, except the minimum and the maximum, will be provided with an additional 
decimal place compared to the variable itself. PK parameter coefficients of variation will be 
provided with one decimal place. 
13. References 
Not Applicable 
 
 
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Schedule of assessments 
- 
Main Table 
 
 
Day
Screening up to 
Day-28
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 8
Day -1 
Day 1 
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Assessments
Informed Consent
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
In house Period
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Discharge from the unit
x
x
Ambulatory Visit
x
x
x
x
x
x
x
Vital Signs b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-Lead ECG c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serology
x
Pregnancy Testd
x
x
Hormone Panel e
x
x
Alcohol Breath Test
x
x
x
Urine Drugs of Abuse
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
x
x
Coagulation
x
x
RO7017773 Administrationf
Itraconazole Administrationg
x
x
x
x
x
x
x
x
x
Standard Meal h
x
x i
x
x
x
x
x i
x
x
x
x
x
Itraconazole and 
metabolites PK sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical Genotyping
x
C-SSRS
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Treatment Period 1 & Washout period of 9 Days  1 Day up maximum of 18 Days
Treatment Period 2
Follow-up Visit      
(15 to 20 days after 
last itraconazole 
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BIOTRIAL BIOMETRICS – Statistical Analysis Plan – Final version – 18APR2019 
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- 
Detailed Table Period 2 
 
Day
Vital Signs a
ECG-12 lead d
Safety 
Laboratory 
Tests
Itraconazole 
Administration e
RO7017773 
Administration
Standard 
Meal g
Itraconazole & 
Metabolites PK 
Sample
x b
x
x
x
x
x
x
x
Day 2
x
x
x
Day 3
x
x
x b,c
xc
x
x
x
xc
x b
x
x
x
x
x
x
x
x
x
x
x
x b
x
x
x
x
x
x
x
x
x b
x
x
x
x
x
x
Day 6
x
x
x
x
x
Day 7
x
x
x
x
Day 8
x
x
x
x
x
Day 9
x
x
x
x
x
Day 10
x
x
Day 11
x
Day 12
x
x
x
Day 13
x
Day 14
x
Day 15
x
Day 16
x
x
x
x
Day 1
Day 4
Day 5
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