Clinical trial NCT04299464
Conditions: Autism Spectrum Disorder (ASD)
Sponsor: Hoffmann-La Roche
Start date: 2021-03-31; Completion date: 2024-05-15
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will investigate the efficacy, safety, tolerability, and pharmacokinetics of RO7017773 in participants aged 15-45 years who have been diagnosed with ASD with a score of \>/=50 on the Wechsler Abreviated Scale of Intelligence (WASI-II).

Detailed description:

Arms: arm 1: Participants will receive placebo matched to RO7017773 for approximately 12 weeks. arm 2: Participants will receive a fixed low dose of RO7017773 for approximately 12 weeks. arm 3: Participants will receive a fixed high dose of RO7017773 for approximately 12 weeks.
Interventions: intervention 1: Placebo intervention 2: RO7017773
Intervention descriptions: intervention 1: Participants will receive oral placebo for approximately 12 weeks. intervention 2: Participants will receive oral RO7017773 for approximately 12 weeks.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase II Multicenter, Randomized, Double-Blind, 12-Week 
Treatment, 3-Arm, Parallel-Group, Placebo-Controlled Study to 
Investigate the Efficacy, Safety and Tolerability of RO7017773 in 
Participants Aged 15 to 45 Years With Autism Spectrum Disorder 
(ASD) 
NCT Number: 
NCT04299464 
Document Date: 
Protocol Version 5: 02-June-2022 
 
 
 


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The information contained in this document, especially any unpublished data, is the property of 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 BP41316, Version 5 
PROTOCOL 
TITLE: 
A PHASE II MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, 12-WEEK TREATMENT, 3-ARM, 
PARALLEL-GROUP, PLACEBO-CONTROLLED 
STUDY TO INVESTIGATE THE EFFICACY, SAFETY 
AND TOLERABILITY OF RO7017773 IN 
PARTICIPANTS AGED 15 TO 45 YEARS WITH 
AUTISM SPECTRUM DISORDER (ASD) 
PROTOCOL NUMBER: 
BP41316 
VERSION: 
5 
EUDRACT NUMBER: 
2019-003524-20 
IND NUMBER: 
141893 
TEST PRODUCT: 
RO7017773  
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1: 23 Nov 2019
DATE AMENDED: 
Version 2: 15 May 2020
Version 3: 18 February 2021
Version 4: 25 October 2021
Version 5: See electronic signature and date
stamp on the final page of this 
document 




RO7017773—F. Hoffmann-La Roche Ltd 
3/Protocol BP41316, Version 5 
PROTOCOL AMENDMENT, VERSION 5 
RATIONALE 
Protocol BP41316 has been amended to reduce the study burden for participants and 
their caregivers, reduce the duration of study visits, and provide additional flexibility to 
schedule study visits and perform specific study assessments remotely. Changes to the 
protocol, along with a rationale for each change, are summarized below: 
•
Changes to reduce the study burden
–
In Table 1, administration of Pediatric Quality of Life InventoryTM (PedsQL)
Family Impact Module has been removed to reduce study burden for
participants and caregivers. Section 3 (Objectives and Endpoints) has been
updated accordingly and Section 8.1.5.10 (Pediatric Quality of Life Inventory
[PedsQL] Version 2.0 Family Impact Scale) in the previous version of the
protocol has been removed.
–
A new table (Table 2 Visit Scheduling Details) has been added to provide more
flexibility for participants, to enhance study feasibility, and to reduce burden for
caregivers by extending screening period in case of logistic reasons and
allowing split visits for any day within visit time windows.
–
To provide more flexibility, footnote d has been added to Table 3 to clarify that
completion of in-clinic assessments can be done either at baseline or on Day 1.
–
Sections 1.3 (Schedule of Activities), 3 (Objectives and Endpoints), 4.2.3.2
(Rationale for Response Biomarkers), and 8.7.1.4 (Response Biomarkers: Eye-
Tracking and EEG Biomarkers) have been updated to remove part of the
electroencephalogram (EEG)/electrooculogram (EOG) assessments in order to
reduce the duration of the trial’s visits. Auditory EEG tasks have been removed
from Pre-Baseline and Week 12 visits, and the saccadic peak velocity (SPV)
task has been removed from Week 12.
–
Section 1.3 (Schedule of Activities) and Section 8.7.1.1 (Digital Biomarkers)
have been updated to reduce the time that participants and their support person
need to spend on the digital biomarker assessments, including the following
changes: (1) removal of surveys from the smartphone app, except the EuroQol
5 Dimension 5-Level Questionnaire (EQ-5D-5L); (2) removal of one of the four
active tasks from the smartphone app; (3) use of the beacons is optional; and
(4) reduction of the frequency of at-home active tests from 7 per week
(i.e., once every day) to 3 per week (i.e., all tests once per week).
–
To reduce the burden on support person, Section 4.1 (Study Design),
Section 5.1 (inclusion criterion #2), and Appendix 1, Section 2.1.2.2 (Remote
Administration of Electronic Clinical Outcome Assessments) have been
updated to clarify that for support persons of high-functioning adult participants,
no on-site visits are necessary after the screening visit if all electronic clinical
outcome assessments (eCOA), interview, and forms are performed remotely.


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–
To reduce the duration of site visits and increase flexibility for both sites and
study participants, Appendix 1, Section 2.1.2.2 (Remote Administration of
Electronic Clinical Outcome Assessments) has been updated to clarify that all
caregiver- and patient-reported scales, forms, and interviews including the
Vineland-3, Children’s Yale-Brown Obsessive Compulsive Scale modified for
ASD (CY-BOCS-ASD), and Clinical Global Impression (CGI) assessments may
be administered remotely at the participants’ home.
•
Changes related to pharmacokinetics
–
Footnote #11 in Table 1 and Section 8.5 (Pharmacokinetics) have been
updated following review of the initial pharmacokinetic (PK) data from 13 high-
functioning adult participants. In high- and low-functioning adult participants, the
PK sampling has been reduced on Day 1. Additionally, in low-functioning adult
participants only, the Week 2, 6-hour PK sample is optional. In adolescents, all
PK samples on Day 1 still remain mandatory until the 2nd Internal Monitoring
Committee (IMC) + Scientific Oversight Committee (SOC) review.
–
Section 8.5. (Pharmacokinetics) and footnote #10 in Table 1 has been updated
to ensure that study drug is administered with breakfast/some food on Day 1
and Day 14 to ensure accurate capturing of the peak concentrations of
RO7017773 as emerging PK data suggests a tmax of approximately 2 hours
following a light meal.
–
Footnote #8 in Table 1 has been updated with regards to postdose ECG
measurements on Day 1 and Day 14; ECG assessments at 4 hours postdose
on these days were removed as the emerging PK data suggests a tmax of
approximately 2 hours corresponding to highest plasma concentrations for
RO7017773 following a light meal. Therefore, ECG assessments will be
reduced to one timepoint postdose (2 hours) to capture peak effect on ECG
parameters.
•
Changes to eligibility criteria
–
Section 5.1 (Inclusion Criteria) has been updated to remove the Clinical Global
Impression-Severity (CGI-S) scale as an inclusion criterion. This additional
criterion is not necessary to select the target study population as both core
symptoms are enriched by more specific severity-based inclusion criteria.
Section 5.4 (Screen Failures) has also been updated accordingly.
–
Inclusion criterion #8 (Section 5.1 Inclusion Criteria) and Section 8.1.4.1
(Wechsler Abbreviated Scale of Intelligence, Second Edition) have been
updated regarding the possibility to use previous intelligence quotient (IQ)
assessments for adult participants.
–
Section 5.2 (Exclusion Criteria) has been updated to clarify the eligibility of
subjects with syndromic forms of autism spectrum disorder (ASD) and genetic
alterations strongly associated with ASD.
–
Sections 5.1 (Inclusion Criteria) and 4.2.1 (Rationale for Study Population) have
been updated to lower the inclusion threshold for the CY-BOCS-ASD to a total
score of at least 8 on the basis of new data indicating that an inclusion


RO7017773—F. Hoffmann-La Roche Ltd 
5/Protocol BP41316, Version 5 
threshold of 8 is sufficient to recruit a study population with elevated levels of 
restricted and repetitive behaviors. With this change, the Sponsor aims to avoid 
exclusion of subjects with sufficiently high levels of restricted and repetitive 
behaviors that are suitable to monitor these behaviors in the context of this 
study. Section 5.4 (Screen Failures) has also been updated to clarify that 
participants who meet the updated inclusion threshold are eligible to 
re-screening. 

Other changes
–
Table 1 has been updated to move the administration of the initial CGI-S clinical
interview from screening to pre-baseline. Section 8.1.5.4 and Table 9 have
been updated accordingly.
–
It has been clarified that follow-up period will start from the Week 12 visit
(Table 1).
–
Footnote #33 in Table 1 has been updated to clarify that the mandatory hair
sample will only be collected from participants who have sufficient hair.
Section 8.8.1 (Mandatory Samples) has also been updated accordingly.
–
Section 6.5.3 (Prohibited Therapy) has been updated to state explicitly that
topiramate, felbamate, zonisamide, and pregabalin are prohibited in this study.
Appendix 6 has been updated accordingly.
–
Section 8.1.5.10 (Neurocognitive Battery) and footnote #3 in Table 9 have been
updated to clarify that for low-functioning participants, the selection of attention
tasks from the neurocognitive battery should be prioritized and performed first.
–
Section 8.7.1.4 (Response Biomarkers: Eye-Tracking and Task EEG
Biomarkers) has been updated to clarify that for low-functioning participants,
response biomarker assessments may be skipped if they are not able to
complete the full set of assessments.
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol. 






RO7017773—F. Hoffmann-La Roche Ltd 
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7.1 
Discontinuation of Study Treatment ......................................... 75 
7.1.1 
Temporary Interruption ............................................................ 75 
7.2 
Participant Discontinuation/Withdrawal from the Study ........... 76 
7.3 
Lost to Follow-Up ..................................................................... 76 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 77 
8.1 
Efficacy Assessments .............................................................. 77 
8.1.1 
Requirements for Support Persons .......................................... 81 
8.1.2 
Instructions for Support Person ............................................... 82 
8.1.3 
Administration of Participant-Reported Scales to Illiterate 
Participants .............................................................................. 83 
8.1.4 
Screening Assessments .......................................................... 83 
8.1.4.1 
Wechsler Abbreviated Scale of Intelligence, Second 
Edition (WASI-II) ...................................................................... 83 
8.1.4.2 
Autism Diagnostic Observation Schedule, Second Edition 
(ADOS-2) ................................................................................. 83 
8.1.4.3 
Social Responsiveness Scale, Second Edition (SRS-2) .......... 84 
8.1.4.4 
Children’s Yale-Brown Obsessive Compulsive Scale 
Modified for ASD (CY-BOCS-ASD) ......................................... 84 
8.1.5 
Clinical Outcome Assessments ............................................... 85 
8.1.5.1 
Vineland Adaptive Behavior Scale, Third Edition 
(VinelandTM-3) .......................................................................... 85 
8.1.5.2 
Repetitive Behavior Scale-Revised (RBS-R) ........................... 86 
8.1.5.3 
Caregiver-Reported Routines Inventory (CRRI) ...................... 86 
8.1.5.4 
Clinical Global Impression-Severity (CGI-S) and 
Improvement (CGI-I) Scales .................................................... 86 
8.1.5.5 
Beck Anxiety Inventory (BAI) ................................................... 87 
8.1.5.6 
Parent-Rated Anxiety Scale-ASD (PRAS-ASD) ....................... 87 
8.1.5.7 
The Adolescent/Adult Sensory Profile ..................................... 87 
8.1.5.8 
Short Sensory Profile 2 (SSP-2) .............................................. 88 
8.1.5.9 
Pediatric Quality of Life Inventory (PedsQL) Version 4.0 
Generic Core Scale and Cognitive Functioning Scale ............. 88 
8.1.5.10 
Neurocognitive Battery ............................................................ 89 
8.1.5.11 
Karolinska Sleepiness Scale (KSS) ......................................... 92 
8.1.5.12 
Epworth Sleepiness Scale (ESS) ............................................. 92 
8.1.5.13 
ESS for Children and Adolescents (ESS-CHAD) ..................... 93 


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8.1.5.14 
Sudden Onset of Sleep Questionnaire .................................... 93 
8.1.5.15 
Patient-Reported Outcomes Measurements Information 
System (PROMIS) Sleep Disturbance Questionnaire Short 
Form ........................................................................................ 93 
8.1.5.16 
Patient-Reported Outcomes Measurements Information 
System (PROMIS) Sleep-Related Impairment 
Questionnaire Short Form ....................................................... 94 
8.1.5.17 
Entry and Exit Questions ......................................................... 94 
8.1.6 
Other Assessments ................................................................. 94 
8.2 
Safety Assessments ................................................................ 94 
8.2.1 
Medical History, Demographic Data, and Support Person 
Information ............................................................................... 95 
8.2.2 
Physical Examinations ............................................................. 95 
8.2.3 
Vital Signs ................................................................................ 96 
8.2.4 
Electrocardiograms .................................................................. 96 
8.2.5 
Clinical Safety Laboratory Assessments .................................. 97 
8.2.6 
Suicidal Risk Monitoring .......................................................... 98 
8.2.7 
Cognitive Assessments and Measures of Somnolence or 
Sudden Onset of Sleep ............................................................ 98 
8.3 
Adverse Events and Serious Adverse Events.......................... 99 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 99 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events .................................................................................... 100 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .. 100 
8.3.3.1 
Investigator Follow-Up ........................................................... 100 
8.3.3.2 
Sponsor Follow-Up ................................................................ 100 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events .................................................................................... 100 
8.3.4.1 
Emergency Medical Contacts ................................................ 101 
8.3.5 
Pregnancy.............................................................................. 101 
8.3.6 
Non-Serious Adverse Events of Special Interest ................... 101 
8.3.7 
Management of Specific Adverse Events .............................. 102 
8.3.7.1 
Potential Risks Associated with RO7017773 ......................... 103 
8.3.7.2 
Guidelines for Managing Specific Events .............................. 105 
8.4 
Treatment of Overdose .......................................................... 109 






RO7017773—F. Hoffmann-La Roche Ltd 
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Appendix 7 
Alcohol Unit Calculation - Examples ......................................... 166 
Appendix 8 
List of Marketed Drugs Known to Prolong the QT Interval ........ 168 
Appendix 9 
Grading for Adverse Events of Special Interest with Regard 
to Somnolence and Sleep ......................................................... 171 
Appendix 10 
Preferred Term Examples for Gastrointestinal Adverse 
Events of Special Interest ......................................................... 172 
Appendix 11 
Supplementary Information for Digital Biomarkers .................... 173 


RO7017773—F. Hoffmann-La Roche Ltd 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADOS-2 
Autism Diagnostic Observation Schedule, Second 
Edition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time 
ASD 
Autism spectrum disorder 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-inf 
Area under the concentration–time curve from time 0 to 
infinity 
AUCτ 
Area under the concentration-time curve for a dosing 
interval 
BA 
Bioavailability 
BAI 
Beck Anxiety Inventory 
BID 
Twice a day 
BMI 
Body mass index 
BP 
Blood pressure 
BRCP 
Breast cancer resistance protein 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
COA 
Clinical outcome assessments 
CPAL 
Continuous Paired Associate Learning Test 
CRRI 
Caregiver-Reported Routines Inventory 
CSF 
Cerebrospinal fluid 
CSR 
Clinical Study Report 
C-SSRS
Columbia-Suicide-Severity Rating Scale 
CT
Clinical team 
CTCAE
Common Terminology Criteria for Adverse Events 
CY-BOCS-ASD
Children’s Yale-Brown Obsessive Compulsive Scale 
modified for Autism Spectrum Disorder 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DDAVP 
1-deamino-8-D-arginine vasopressin




 
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15/Protocol BP41316, Version 5 
Abbreviation 
Definition 
HRQoL 
Health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Intellectual disability 
IDN 
Identification Test 
IEC 
Independent Ethics Committee 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IQ 
Intelligence quotient 
ISL 
International Shopping List Test 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
IxRS 
IVRS or IWRS (Interactive voice response system or 
Interactive web response system) 
KSS 
Karolinska Sleepiness Scale 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LF 
Low functioning participant 
LFA 
Low-functioning adult 
LPLV 
Last participant, last visit 
MAD 
Multiple-ascending dose 
NDD 
Neurodevelopmental disorder 
NGS 
Next generation sequencing 
NIMP 
Non-investigational medicinal product 
NSAESI 
Non-serious adverse event of special interest 
OCL 
One Card Learning Test 
ONB 
One Back Test 
OTC 
Over-the-counter 
PAM 
Positive allosteric modulator 
PD 
Pharmacodynamic 
PedsQL 
Pediatric Quality of Life InventoryTM 
PET 
Positron emission tomography 
P-gp 
P-glycoprotein 
phMRI 
Pharmacological magnetic resonance imaging 




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Abbreviation 
Definition 
ULN 
Upper limit of normal 
Vineland II 
VinelandTM Adaptive Behavior Scales, Second Edition 
Vineland-3 
VinelandTM Adaptive Behavior Scales, Third Edition 
Vss 
Volume of distribution under steady-state conditions 
WAIS 
Wechsler Adult Intelligence Scale 
WASI-II 
Wechsler Abbreviated Scale of Intelligence, Second 
Edition 
WBC 
White blood cell 
WES 
Whole exome sequencing 
WGS 
Whole genome sequencing 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of non-childbearing potential 
Y-BOCS
Yale-Brown Obsessive Compulsive Scale 


RO7017773—F. Hoffmann-La Roche Ltd 
18/Protocol BP41316, Version 5 
1.
PROTOCOL SUMMARY
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
12-WEEK TREATMENT, 3-ARM, PARALLEL-GROUP,
PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE
EFFICACY, SAFETY, AND TOLERABILITY OF RO7017773 IN
PARTICPANTS AGED 15 TO 45 YEARS WITH AUTISM
SPECTRUM DISORDER (ASD)
SHORT TITLE 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 2 STUDY TO INVESTIGATE THE EFFICACY AND SAFETY 
OF RO7017773 IN PARTICPANTS AGED 15 TO 45 YEARS WITH 
AUTISM SPECTRUM DISORDER (ASD)  
PROTOCOL NUMBER: 
BP41316 
VERSION: 
5 
TEST PRODUCT: 
RO7017773 
PHASE: 
II 
RATIONALE 
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized 
by two core domains: impairments in social interaction and communication as well as presence of 
repetitive or restricted behaviors, interests, or activities. Core symptoms of ASD affecting 
domains of socialization, communication, and repetitive behavior are usually observed by 3 years 
of age, although typical language development might delay identification of symptoms. Deficits in 
socialization manifest themselves as impaired use of non-verbal communication, delayed and 
reduced interactions with peers, absent sharing of enjoyable experiences and interest with peers, 
and lack of social judgment. Abnormalities in communication include a delay in verbal language 
development, impaired expressive language, deficient language pragmatics, as well as 
stereotyped, repetitive, or idiosyncratic use of language. Stereotyped and repetitive behavior 
manifests as a preoccupation with stereotyped or restricted interests, adherence to routines, 
rigidity, perseverative and stereotyped behavior, motor mannerisms, preoccupation, or fascination 
with parts of items, and unusual visual exploration. In addition to these core deficits, patients with 
ASD suffer from a range of comorbid conditions, including irritability, depression or anxiety, 
attention deficits, obsessive compulsive symptoms, seizures, and sleep disruption. RO7017773 is 
a selective gamma-aminobutyric acid type A, alpha 5 (GABAA-α5) subunit-containing receptor 
positive allosteric modulator (PAM). RO7017773 is being developed for the treatment of the two 
core domains of ASD: social communication deficits and restricted and repetitive behaviors 
(RRBs). RO7017773 has the potential to normalize gamma-aminobutyric acid (GABA)-ergic 
signaling in key brain regions implicated in ASD without the side effects of non-specific GABA 
modulators (e.g., benzodiazepines). 


RO7017773—F. Hoffmann-La Roche Ltd 
19/Protocol BP41316, Version 5 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 

To evaluate the efficacy of 12-week
treatment with RO7017773 compared
with placebo in treating social
communication deficits in participants
with ASD

Change from baseline to Week 12 in
the Adaptive Behavior Composite score
of the Vineland Adaptive Behavior
Scales, Third Edition (Vineland-3)
Secondary 

To evaluate the safety and tolerability of
a 12-week treatment with RO7017773
in 15- to 45-year-old participants with
ASD.

Incidence and severity of adverse
events (AEs) and serious adverse
events (SAEs)

Incidence of treatment discontinuations
due to AEs

Change from baseline over time and
incidence of clinically relevant
abnormalities in vital signs including
orthostatic changes, electrocardiogram
(ECG) parameters and safety laboratory
values including the incidence of
marked laboratory abnormalities

Change from baseline over time in
suicide risk (using the Columbia-
Suicide-Severity Rating Scale
[C-SSRS])

Incidence of daytime sleepiness
assessed with the Karolinska
Sleepiness Scale (KSS), the Epworth
Sleepiness Scale (ESS) or the ESS for
children and adolescents (ESS-CHAD),
and the Sudden Onset of Sleep
Questionnaire

To evaluate the efficacy of a 12-week
treatment with RO7017773 compared
with placebo on restricted and repetitive
behaviors (RRBs)

Change from baseline to Week 12 in
behavior/symptoms as measured by all
domains of the Repetitive Behavior
Scale-Revised (RBS-R) scale

To evaluate the efficacy of a 12-week
treatment with RO7017773 compared
with placebo on social behaviors

Change from baseline to Week 12 on
the Vineland-3 Socialization domain

To evaluate the efficacy of a 12-week
treatment with RO7017773 compared
with placebo on communication skills

Change from baseline to Week 12 on
the Vineland-3 Communication domains
OVERALL DESIGN 
This is a multicenter, randomized, double-blind, parallel-group, 3-arm, placebo-controlled, 
12-week treatment Phase II study to investigate the efficacy, safety and tolerability, and
pharmacokinetics of RO7017773 in participants aged 15 to 45 years with a diagnosis of ASD
and Wechsler Abbreviated Scale of Intelligence (WASI-II) score ≥50.
STUDY DESIGN 
Approximately 105 participants with ASD (in order to have approximately 84 evaluable 
participants at study end) aged 15 to 45 years will be enrolled into the study. Participants will be 




 
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Access to treatment assignment information will follow the Sponsor’s standard procedures.  
PARTICIPANT POPULATION 
Male and female participants aged 15 to 45 years with ASD according to the Diagnostic and 
Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) criteria who fulfill all the inclusion 
criteria listed below and for whom none of the exclusion criteria listed below apply will be 
included into the study. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. Study participants or legal representatives should be able and willing to provide written 
informed consent or assent, as applicable and as per local requirements according to 
International Council for Harmonisation (ICH) and local regulations. Alternatively, a legally 
authorized representative must be able to consent for the participant according to ICH and 
local regulations and assent must be given whenever possible. The ability to provide 
informed consent for each participant will be based on the Principal investigator’s clinical 
judgment. 
2. Availability of a parent or other reliable support person who is fluent in local language and 
has frequent and sufficient contact with the participant. The same person must agree to 
accompany the participant to all clinic visits and provide information about the participant’s 
behavior and symptoms and must agree to oversee the participant’s adherence with 
protocol-specified procedures and study medication dosing. 
• 
For support persons of high-functioning adult participants, no on-site visits are 
necessary after the screening visit if all eCOA assessments, interview, and forms are 
performed remotely. 
 
Age 
3. Age 15 to 45 years, at the time of signing the informed consent or assent form 
Type of Participants and Disease Characteristics 
4. Male and female participants with Autism Spectrum Disorder (ASD) according to the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. 
• 
For transgender participants, the Investigator should consult with the Medical Monitor or 
delegate to assess potential safety concerns or interference with safety and efficacy 
testing. Transgender participants will be enrolled by their biological sex. 
Note: It is important that a high-confidence autism diagnosis has been established by an 
autism expert prior to screening and is supported by medical records. 
5. Social Responsiveness Scale, Second Edition (SRS-2) (T-score) ≥ 66. 
6. Wechsler Abbreviated Scale Intelligence second edition (WASI-II) or equivalent assessment 
≥ 50 at screening or within the last 12 months prior to screening (for adults within the last 5 
years prior to screening if the assessment was done at age 18 or older). The proportion of 
low-functioning participants (IQ ≥ 50 to 69) will be limited to 25% overall. 
• 
If a previous assessment is used, the Investigator should assess whether it has been 
performed by an appropriately qualified rater. 
7. ASD or autism diagnosis confirmed by Autism Diagnostic Observation Schedule (ADOS-2), 
done by a certified rater at screening, or within the last 6 months prior to screening. 
8. Presence of at least moderate to severe repetitive behaviors as per Children’s Yale-Brown 
Obsessive Compulsive Scale modified for ASD (CY-BOCS-ASD) total score of at least 8 at 
screening. 
Weight 
9. Body mass index (BMI) within the range of 18.5 to 40 kg/m2 (inclusive). 


 
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Sex 
10. Male and female participants with contraception requirements.  
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 
preventing drug exposure. 
a) Female Participants 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Women of non-childbearing potential (WONCBP) as defined in Appendix 5 
• 
Women of childbearing potential (WOCBP), who: 
- 
Agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
methods (hormonal or non-hormonal) that result in a failure rate of <1% per year during the 
treatment period and for at least 28 days after the last dose of study drug. Examples of 
contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, 
male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices (see Appendix 5).  
Hormonal contraceptive methods must be supplemented by a barrier method (as defined in 
Appendix 5, preferably a condom with a spermicide) if participants are receiving any drug 
known to reduce the effect of hormonal contraception (including anti-epileptic drugs inducing 
drug metabolism). In such a situation, the risk assessment should be discussed with the 
Medical Monitor.  
Note: Females who reach menarche after enrollment in the study must agree from this time 
forward to regular blood or urine pregnancy testing as defined in the Schedule of Activities 
(SoA) and must agree to either remain completely sexually abstinent or comply with the same 
contraceptive requirements as outlined above for WOCBP from first menses until 28 days after 
the last dose of study treatment (see Appendix 5).  
b) Male Participants 
Male contraception is not required in this study because of the minimal seminal dose transmitted 
through sexual intercourse (Banholzer et al 2016, Appendix 5).  
 
Additional Inclusion Criteria: 
11. Language, hearing, and vision compatible with the study measurements as judged by the 
Investigator. Non-verbal individuals will be excluded from study participation. 
12. Allowed existing treatment regimens should be stable for 8 weeks prior to screening except: 
• 
6 weeks for non-pharmacological interventions 
• 
12 weeks in the case of antipsychotic therapies 
• 
6 months for antiepileptic treatments 
Investigator expects stability of these treatments and behavioral interventions for the 
duration of the study. 
13. In the Investigator’s opinion, able to participate and deemed appropriate for participation in 
the study, capable of following the study SoA and able to comply with the study restrictions. 
14. In the Investigator’s opinion, participation in the study or discontinuation of prohibited 
medication will not pose undue risks. 
 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 


 
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Medical Conditions 
Neurologic/psychiatric conditions 
1. Presence of chromosome 15q11.2 q13.1 duplication syndrome (Dup15q syndrome), known 
“syndromic” forms of ASD (confirmed per genetic results available at screening): fragile X 
syndrome, Prader Willi syndrome, Rett’s syndrome, tuberous sclerosis, and Angelman 
syndrome, as well as genetic alterations strongly associated with ASD per genetic results 
available at screening affecting the following genes: CHD8, ANDP, SHANK3. 
• 
Clinical suspicion of the presence of Dup15q syndrome should lead to study 
exclusion. Please contact the Medical Monitor for any questions related to a clinical 
suspicion of Dup15q syndrome. 
• 
Other genetic information available at screening should be taken into 
consideration for assessment of participant eligibility. The Principal Investigators 
are encouraged to consult with the Sponsor (Medical Monitor or designee) for 
advice. 
2. Medical history of alcohol and/or substance abuse/dependence in the last 12 months or 
positive test for drugs of abuse at screening (unless the finding is related to the intake of 
concomitant medications allowed by the protocol). 
3. Initiation of a major change in psychosocial intervention (including investigational) within 
6 weeks prior to screening. Minor changes in ongoing treatment (e.g., missed therapy 
sessions due to holiday/vacation; planned break in therapy due to holidays; changes in 
college/university programs) are not considered major changes. 
4. Clinically significant psychiatric and/or neurological disorder that may interfere with the 
safety or efficacy endpoints. 
• 
Participants with a psychiatric diagnosis other than ASD, including but not limited to, 
bipolar disorder, psychosis, schizophrenia, post-traumatic stress disorder or major 
depressive disorder will be excluded if the psychiatric comorbidity has the potential 
to confound results or impact safety. 
• 
Participants with non-suicidal self-injurious behaviors (e.g., cutting, head banging) 
that interferes with safety and efficacy testing will be excluded. 
5. Risk of suicidal behavior in the opinion of a certified clinician or as evidenced by a "yes" to 
questions 4 and/or 5 of Columbia-Suicide-Severity Rating Scale (C-SSRS) taken at 
screening with respect to the last 12 months or any suicide attempt in the past 5 years. 
6. Unstable epilepsy/seizure disorder within the past 6 months. 
 
Cardiovascular conditions 
7. Concurrent cardiovascular disease considered not well controlled by drug treatment, 
including participants with clinically significant hypertension, bradycardia and arrhythmias, 
myocardial infarction within 12 months of screening or uncompensated heart failure. 
8. Confirmed clinically significant abnormality on 12-lead electrocardiogram (ECG), including a 
QTc of ≥450 ms (based on the average of 3 consecutive measurements). Central ECG 
readings should be used to determine if this criterion is met. 
9. Congenital heart diseases not treated and congenital QTc prolongation or family history of 
Long QT Syndrome.  
 


 
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Other conditions 
10. Medical history of malignancy if not considered cured or if occurred within the last 3 years 
with the exception of fully excised non-melanoma skin cancers or in-situ carcinoma of the 
cervix that has been successfully treated. 
11. Concomitant disease, condition, or treatment which would either interfere with the conduct 
of the study or pose an unacceptable risk to the participant in the opinion of the Investigator.  
12. Known active or uncontrolled bacterial, viral, or other infection (excluding fungal infections 
of nail beds) or any major episode of infection or hospitalization (relating to the completion 
of the course of antibiotics) within 6 weeks prior to the start of drug administration. 
 
Prior/Concomitant Therapy 
13. Use of prohibited medications or herbal remedies (with the exception of herbal remedies 
approved by the Medical Monitor or designee) within 6 weeks or 5 half-lives (t1/2) prior to 
randomization, (whichever is longer). 
 
Prior/Concurrent Clinical Study Experience 
14. Donation or loss of blood over 500 mL in adults and 250 mL in adolescents within 3 months 
prior to randomization. 
15. Participation in an investigational drug study within 1 month or 5 times the t1/2 of the 
investigational molecule (whichever is longer) prior to randomization or participation in a 
study testing an investigational medical device within 1 month prior to randomization or if 
the device is still active.  
16. 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. 
 
Diagnostic Assessments 
17. Confirmed clinically significant abnormality in hematological, chemistry or coagulation 
laboratory parameters.  
18. Positive test result at screening for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV, untreated), or human immunodeficiency virus (HIV)-1/2. HCV participants who have 
been successfully treated and who test negative for HCV RNA may be considered eligible 
for entry into the study. 
 
Other Exclusions 
19. Uncorrected hypokalemia or hypomagnesaemia. 
 
NUMBER OF PARTICIPANTS 
Approximately 105 participants with ASD randomized in a 1:1:1 ratio between two active dosing 
regimens and placebo need to be recruited in order to obtain evaluable data from at least 
84 participants after 12 weeks of treatment. 
CONCOMITANT THERAPY 
Permitted Therapy 
Participants must be on a stable prescribed medication regimen for 8 weeks before screening, 
with the exception of antipsychotic therapies and antiepileptic treatments (where participants 
need to be on a stable regimen for at least 12 weeks and 6 months before screening, 
respectively; see inclusion criterion 12). Any stable prescribed medication at screening should 
remain stable throughout the study. All changes in prescribed medication need to be discussed 
with the Sponsor (Medical Monitor or designee). 
Examples of allowed medications: 
Use of the following therapies is permitted, as specified below: 
• 
Selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors 
(SSRI/SNRI) antidepressants including fluoxetine (see also inclusion criteria) 


 
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• 
Melatonin 
• 
Trazodone (at low doses) for insomnia  
• 
Aripiprazole 
• 
Risperidone 
• 
Psychostimulants (e.g., methylphenidate) 
• 
Clonidine 
• 
Occasional use of paracetamol/acetaminophen  
• 
Antiepileptic medication (carbamazepine and phenytoin are prohibited because of 
cytochrome P450 [CYP] 3A4 induction) must be stable for 6 months 
• 
Benzodiazepines with a short t1/2 (e.g., lorazepam, alprazolam, or oxazepam) are allowed if 
- 
taken only on an as needed (PRN) basis,  
- 
limited to 3 times per week,  
- 
prescribed for short-term or intermittent medical conditions and,  
- 
not taken immediately before the assessments visits (i.e., not within 2 days or within 
5 times the elimination t1/2, whichever is longer before a scheduled visit). 
Note: for benzodiazepines with a long t1/2 (except for benzodiazepines to treat emerging 
symptoms of rebound and/or withdrawal effects) see below (Prohibited Therapy). 
• 
Drugs known to prolong the QTc interval will be allowed if stable at screening provided the 
screening QTc does not meets exclusion QTc criterion (see list of drugs known to prolong 
QT in Appendix 8 of the protocol). 
• 
Any medication for medical illnesses other than ASD not listed under prohibited medications 
• 
Vaccines, including those against COVID-19 
 
Any other medications require the approval from the Investigator and the Sponsor’s Medical 
Monitor (or designee). 
Participants who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
PROHIBITED THERAPY 
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy listed above unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor. 
Use of the following therapies (e.g., prescription drugs, over-the-counter (OTC) drugs, herbal 
remedies, nutritional supplements) is prohibited during the study and for at least 6 weeks prior 
to randomization (or within 5 times the elimination t1/2, whichever is longer) to ensure washout of 
medication and until follow-up, unless otherwise specified below.  
Examples of prohibited medications: 
• 
Strong inhibitors of CYP3A4/5 (e.g., ketoconazole, clarithromycin, grapefruit juice)  
• 
Strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, 
St. John’s Wort)  
• 
Under no circumstances should a strong CYP3A4 inhibitor be given in combination because 
of the potential increase in exposure. If the use of a strong inhibitor is indicated, the 
Investigator should contact the Sponsor to discuss alternative options (e.g., replacement of 
clarithromycin by azithromycin, which is not a CYP3A4 inhibitor). For certain cases, the 
Sponsor may advise pausing the treatment with RO7017773 and restarting when the 
CYP3A4 inhibitor has been discontinued and 5 times the elimination t1/2 of the CYP3A4 
inhibitor have elapsed.  
• 
Chronic adrenocorticoid or glucocorticoid use (use of inhaled and topical formulations are 
allowed) 












 
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Table 1 
Schedule of Activities - 12-Week, Double-Blind, Placebo-Controlled Period and Follow-Up (cont.) 
 
11 
Day 1: 2 hours (+/- 0.5 hours), 4 hours (+/- 0.5 hours), and 6 hours (+0.5 hours) postdose, all on the same day; the last sample can be done on site or at 
home. All Day 1 samples are mandatory for adolescents until the 2nd Internal Monitoring Committee (IMC) + Scientific Oversight Committee (SOC) 
review. Day 1: only 2 hours (+/- 0.5 hours) postdose is mandatory for high- and low-functioning adult participants.  
Day 14: Predose and at 2 hours (+/- 0.5 hours), 4 hours (end of visit but at least 4 hours postdose), and 6 hours (6-8 hours) postdose; the last sample can be 
done on site or at home, either on the same day or at a later day within the same timeframe. Day 14: 6 hours (6-8 hours) postdose sample is optional for 
low-functioning adult participants. 
PK and safety samples will preferably be taken at the site; however, home nursing services will be available to allow for flexibility in the schedule of visits and 
to shorten site visits when the visit length depends on blood sampling. 
12 
PD biomarker assessments at time of the day +/- 1 hour of the tmax (i.e., approximately 3 to 4 hours postdose [time window: 2.5 to 4.5 hours postdose]) at 
Pre-Baseline, Day 1, Week 2 and Week 12 visits (for resting state qEEG) and at Pre-baseline, Day 1, and Week 2 visits for saccadic peak velocity [SPV], 
measured by means of electrooculography [EOG] (SPV is not to be assessed at Week 12).  
At pre-baseline visit (no dosing), these assessments should be conducted at about the same time of the day (+/- 1 hour) corresponding to tmax, (i.e., 
approximately 3 to 4 hours postdose at dosing days); The duration is approximately ~15 min assessment time + 30 minutes of EEG preparation time. 
13 
Eye-tracking and EEG tasks to take place at the time of the day +/-1h of the tmax (i.e., approximately 3 to 4 hours postdose [time window: 2.5 to 4.5 hours 
postdose]) at Week 12. At pre-baseline visit (no dosing), these assessments should be conducted at about the same time of the day (+/- 1h) corresponding to 
tmax, (i.e., approximately 3 to 4 hours postdose at dosing days). The duration is approximately 50 min assessment time. The tasks will be performed 
immediately after the PD Biomarker assessments (see footnote 12) using the same equipment and therefore no extra EEG preparation time is needed. 
14 
Additional pretreatment PD biomarker assessment on Day 1 (schedule as described in footnote 12). It is not necessary to remove the EEG electrodes after 
the pretreatment assessment and therefore the EEG preparation time for the 2nd assessment around tmax, (i.e., approximately 3-4 hours postdose; see 
Footnote 12) will be considerably shorter.  
15 
See Table 3 for details on the digital biomarker SoA. 
16 
Clinical genotyping sample to be drawn once from every participant at any convenient time between Day 1 and the last visit. Leftover from mandatory 
genotyping samples will be used for RBR if participant consents to RBR.  
17 
Leftover from mandatory PK plasma samples will be used for RBR if participant consents to RBR. 
19 
Whole blood sample will be taken if participant consents to RBR on Day 1 predose and at Week 12 or Early Termination visit. 
20 
Telephone interview to assess for any clinically significant symptoms and/or new medication. 
21 
The serum safety sample can be collected any time for specific assay (e.g., GLDH in case of Liver enzymes) if deemed appropriate by the Investigator for the 
safety evaluation. 
22 
Refer to Table 9 for further details on the applicable versions of scales to be used according to the age cohort. 




 
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Table 2 
Visit Scheduling Details 
Week 
Screening 
Pre-Baseline 
Baseline 
Week 1 
Week 1 
Week 2 
Week 6 
Week 12 
Follow-up 
(2 Weeks) 
Follow-up 
(6 Weeks) 
Early 
Termination 
Day 
D-42 to  
D-15 
Day -14 
Days -3 to -1 
Day 1 
Day 7 
Day 14 
Day 42 
Day 84 
Week 12 
visit + 14 
days 
Week 12 
visit + 
42 days 
 
Visit 
Window 
 
+/- 3 days 
 
 
+/- 3 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
8-day 
window 
On-site 
assessments 
May be split 
up into two 
visits within 
a 7-day 
window (but 
up to a 15-day 
window in 
case of 
unexpected 
delays due to 
logistical or 
technical 
reasons). 
 
May be split 
into two 
visits within 
visit time 
window. 
May be split 
into two 
visits within 
visit time 
window. 
Visit cannot 
be split. 
N/A 
Visit cannot 
be split. 
May be split 
into two 
visits within 
visit time 
window. 
May be split 
into two 
consecutive 
days. 
May be split 
into two 
visits within 
visit time 
window. 
May be split 
into two 
visits within 
visit time 
window. 
May be split 
into two 
visits within 
visit time 
window. 
Remote 
eCOA 
assessments 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
May be done on 
any day prior to 
the last on-site 
assessment 
within the visit 
window 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
May be done 
at any day 
within visit 
time window. 
 
 
 


 
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Table 3 
Digital Biomarker Schedule of Activities 
  
Screening 
Pre- 
baseline 
Baseline 
Week 1 
Week 1 
Week 2 
Week 6 
Week 12 
Follow Up 
(2 Weeks) 
Follow Up 
(6 Weeks) 
Early 
Terminationa 
Day 
D-42  
to D-15 
D-14 
D-3 
to D-1 
Day 1 
Day 7 
Day 14 
Day 42 
Day 84 
Week 12 visit 
+ 14 days 
Week 12 visit 
+ 42 days 
  
Visit window 
 
+/- 3 days 
 
 
+/- 3 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
 
Assessments 
Site Visit 
Site Visit 
Site Visit 
Site Visit 
Phone 
Call 
Site Visit 
Site Visit 
Site Visit 
Site Visit 
Site Visit 
Site Visit 
Identification of 
targeted behaviors 
for app 
 
X 
 
 
 
 
 
 
 
 
 
Hand over 
technology and 
training 
 
X 
 
 
 
 
 
 
 
 
 
Completion of In-
Clinic 
Assessments 
 
X 
Xd 
 
X 
X 
X 
 
 
 
Completion of At-
Home 
Assessmentse 
 
X 
 
 
 
Review of 
complianceb 
 
 
 
X 
X 
X 
X 
 
 
 
 
Return of 
technology and 
completion of 
satisfaction 
surveyc 
 
 
 
 
 
 
 
X 
 
 
X 
a. 
If participant discontinues or withdraws from the study treatment prematurely all efforts should be done to perform and complete the Early Termination visit. 
b. 
Participants with inadequate compliance will be re-encouraged to use the digital biomarker technology. If technical problems are identified devices may be 
exchanged or guidance will be given how to correctly use the technology. 
c. 
Final satisfaction surveys on the participant’s experience about collection of digital biomarker data will be completed by participants and by support persons on 
the tablet computers used for the electronic clinical outcome (eCOA) assessments. 
d. 
Completion of in-clinic assessments can be done either at baseline or on Day 1. 
e. 
At-home active tests will be done once a week. 
 


 
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Table 4 
Schedule of Use of Technology for Digital Biomarkers 
Activity type 
Activity description 
Duration 
Frequency 
 
EQ-5D-5L 
2 minutes Monthly 
Smartphone data collected through user interaction (Active 
Tasks)a 
 
Three tasks that capture data relevant to core and 
associated symptoms of ASD 
5 minutes 
Weekly 
 
Recording of a conversation between the support 
person and study participant 
5 minutes 
Weekly 
Data collected without user interaction (Passive Monitoring) 
Body movement, location, sleep and physiological 
recording 
Continuous Daily 
a Three Active Tasks should be completed each week by the study participant. In addition, the support person should record a conversation with the study 
participant at least once per week and complete a numerical response scale to evaluate conversation quality. Active Tasks can be performed at days and times 
which the study participant and/or support person deem convenient. Study participants are strongly encouraged to choose a regular day each week to complete 
all tasks, adhere to this schedule and collect as much data as they are able to. If participants find the schedule too burdensome, they may choose to reduce the 
assessment frequency without violating the protocol. 
 
 


 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The objectives of this Phase 2 proof-of-concept study (BP41316) are to investigate the 
efficacy, safety, and tolerability of RO7017773 in adolescents and adults (15 to 45 years 
of age) with autism spectrum disorder (ASD), with a target on the core symptoms of ASD 
of social communication deficits, and restricted and repetitive behaviors (RRBs) and 
interests. In addition, a set of biomarkers linked to the mechanism of action of the study 
drug or to ASD-related alterations will be investigated in a representative patient 
population to pilot the idenfitication of responder subgroups (see Section 8.7.1.3 and 
Section 8.7.1.4). To date, very few studies have investigated the effect of 
pharmacological treatments on the core symptoms of ASD and no pharmacological 
agents are approved. 
A key challenge in the development of new therapies to treat the core social symptoms 
in ASD is the change of symptoms across different stages of development in longitudinal 
studies (Sarrett and Rommelfanger 2015) in both social deficits as well as in RRB. The 
presentation of RRB is known to be associated with age and level of intellectual 
functioning (Lam and Aman 2007, Esbensen et al 2009, Richler et al 2010, Kim and Lord 
2010). Thus, interventional treatment may have different effects, depending on age and 
intelligence quotient (IQ), in individuals with ASD. Hence, treatment effects in older 
adolescents and adults may not be extrapolated to effects in the pediatric population, 
given the potential difference in manifestations of both social skills and RRB with age. 
Adolescents and adults aged 15 to 45 years with ASD will be enrolled in this study to 
allow for the generation of data on the safety and tolerability and the potential efficacy in 
these age groups.  
The rationale for the study design is provided in Section 4.2. 
2.2 
BACKGROUND 
2.2.1 
Background on Disease  
Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental 
disorders (NDDs) characterized by two core domains: impairments in social interaction 
and communication as well as presence of restrictive and repetitive behaviors, interests, 
or activities (American Psychiatric Association, 2013). Recently the prevalence of 
diagnosis of ASD in the U.S. has been reported to be 1.68% (1 in 59) in children of 8 
years of age (Baio et al 2018) or 2.79% in children from 3 to 7 years of age (Xu et al 
2019). In Europe, the prevalence of ASD is within the same range with 1 in 100 people 
(Elsabbagh et al 2012). 
Core symptoms of ASD affecting domains of socialization, communication, and repetitive 
behavior are usually observed by 3 years of age, although typical language development 
might delay identification of symptoms. Deficits in socialization manifest themselves as 






























 
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3. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 6. 
Table 6 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of 12-week 
treatment with RO7017773 compared 
with placebo in treating social 
communication deficits in participants with 
Autism Spectrum Disorder (ASD)  
• 
Change from baseline to Week 12 in the 
Adaptive Behavior Composite score of 
the Vineland Adaptive Behavior Scales, 
Third Edition (Vineland-3)  
Secondary 
 
• 
To evaluate the safety and tolerability of a 
12-week treatment with RO7017773 in 
15- to 45-year-old participants with ASD.  
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events 
(SAEs). 
• 
Incidence of treatment discontinuations 
due to AEs 
• 
Change from baseline over time and 
incidence of clinically relevant 
abnormalities in vital signs including 
orthostatic changes, ECG parameters and 
safety laboratory values including the 
incidence of marked laboratory 
abnormalities  
• 
Change from baseline over time in suicide 
risk (using the Columbia-Suicide-Severity 
Rating Scale [C-SSRS])  
• 
Incidence of daytime sleepiness assessed 
with the Karolinska Sleepiness Scale 
(KSS), the Epworth Sleepiness Scale 
(ESS) or the ESS for children and 
adolescents (ESS-CHAD), and the 
Sudden Onset of Sleep Questionnaire 
• 
To evaluate the efficacy of a 12-week 
treatment with RO7017773 compared 
with placebo on restricted and repetitive 
behaviors (RRBs) 
• 
Change from baseline to Week 12 in 
behavior/symptoms as measured by all 
domains of the Repetitive Behavior Scale-
Revised (RBS-R) scale 
• 
To evaluate the efficacy of a 12-week 
treatment with RO7017773 compared 
with placebo on social behaviors 
• 
Change from baseline to Week 12 on the 
Vineland-3 Socialization domain 
• 
To evaluate the efficacy of a 12-week 
treatment with RO7017773 compared 
with placebo on communication skills 
• 
Change from baseline to Week 12 on the 
Vineland-3 Communication domains 


 
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Table 6 
Objectives and Endpoints (cont.) 
 
Objectives 
Endpoints 
Exploratory 
 
• 
To investigate the pharmacokinetics (PK) 
in 15- to 45-year-old participants with 
ASD and exposure-response 
relationships of RO7017773 
• 
Plasma concentration per timepoints 
specified in the SoA (Section 1.3) 
• 
Other PK parameters as appropriate 
• 
To evaluate the efficacy of a 12-week 
treatment with RO7017773 compared 
with placebo on RRBs 
• 
Change from baseline to Week 12 
on the Caregiver-Reported Routines 
Inventory (CRRI) scale 
• 
To explore the effects of a 12-week 
treatment with RO7017773 compared 
with placebo on global clinical severity 
and symptoms of ASD 
 
• 
Change from baseline to Week 12 
o 
on the Clinical Global Impression 
Scale – Improvement (CGI-I) and 
Clinical Global Impression Scale – 
Severity (CGI-S)  
o 
on the Beck Anxiety Inventory (BAI) 
o 
on the Parent Rated Anxiety Scale-
ASD (PRAS-ASD) 
o 
on the Adolescent/Adult Sensory 
Profile questionnaire 
o 
on the Short Sensory Profile (SSP-2) 
– (mandatory for adolescents and 
optional for low-functioning adults) 
o 
on the Patient-Reported Outcomes 
Measurements Information System 
(PROMIS) Sleep Disturbance short 
form 8 items  
o 
on the PROMIS Sleep-Related 
Impairment short form 8 items 
• 
To explore the acute (Day 1), subchronic 
(2-week) and chronic (12-week) effects of 
RO7017773 compared with placebo on 
PD biomarkers 
• 
Change from baseline to Weeks 2 and 12 
and change on Day 1 from pre- to 
post-dosing in resting state EEG power in 
the beta band (12-30 Hz), and change 
from baseline to Weeks 2 and change on 
Day 1 from pre- to post-dosing in 
saccadic peak velocity (SPV).  
• 
To explore the effects of a 12-week 
treatment with RO7017773 compared 
with placebo on neuronal responses to 
face viewing 
• 
Change from baseline to Week 12 in EEG 
response to faces (including the N170 of 
the Event Related Potential to faces)  


 
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Table 6 
Objectives and Endpoints (cont.) 
 
Objectives 
Endpoints 
Exploratory (cont.) 
 
• 
To explore the effects of a 12-week 
treatment with RO7017773 compared 
with placebo on eye-tracking biomarkers 
related to ASD 
• 
Change from baseline to Week 12 in 
Gaze pattern related to social preference 
in visual scenes 
• 
To explore the effects of a 12-week 
treatment with RO7017773 compared 
with placebo on metabolic and molecular 
dynamics 
• 
Change from baseline to Week 12 in the 
hair exposome 
• 
To explore the overall genetic risk for 
ASD and treatment response with 
RO7017773  
• 
ASD polygenic risk score and genetic 
GABAA score derived from genetic 
sample to predict treatment response 
• 
To assess health-related quality of life in 
individuals with ASD as reported by 
parent/support person over a 12-week 
treatment period 
• 
Change from baseline to Week 12 in 
PedsQLTM Quality of Live Inventory 
Generic Core Scale  
• 
To assess effects on cognition over a 
12-week treatment period  
• 
Change from baseline to Week 12 in 
Cogstate neurocognitive battery with a 
focus on attention/reaction time, verbal 
learning and working memory) 
• 
Change from baseline to Week 12 in 
PedsQLTM Cognitive Functioning Scale 
• 
To explore the effects of a 12-week 
treatment with RO7017773 compared 
with placebo in core and associated 
symptoms of ASD as measured by digital 
biomarkers and to evaluate the feasibility 
of implementation of digital biomarkers in 
a clinical study setting 
• 
Change from baseline to Week 12 in core 
and associated symptoms of ASD 
(including sociability, communication 
deficits, restricted and repetitive 
behaviors, spatial working memory, 
anxiety and sleep) as measured remotely 
with digital health technology 
• 
Adherence to the digital biomarker 
schedule of assessments between 
baseline and Week 12 
 
Feedback from support persons or parents will be collected with entry and exit questions 
at baseline and at the end of the study, respectively. 
4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
An overview of the study design is provided in Figure 1. 




 
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4.1.1 
Length of the Study 
The total duration of the study for each participant will be up to 24 weeks (approximately 
5.6 months), divided as follows: 
• 
Screening period of at least 2 weeks and up to 4 weeks  
• 
Study pre-baseline and baseline period (2 weeks) 
• 
Study treatment period with fixed dose (12 weeks) 
• 
Safety and efficacy follow-up period (6 weeks). 
 
4.1.2 
Individual Stopping Criteria  
Dosing will be stopped at any time during the study in a given individual participant if 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: 
• 
QTc: A confirmed QTcF (average of triplicate values) above 480 ms or a change 
from baseline by more than 60 ms (when confirmed in repeat measurement within 
30 minutes), will result in drug interruption. For the assessment of the QTcF stopping 
rule, central ECG readings should be used to determine whether the criteria have 
been met. An expedited review by the central vendor should be requested by the 
Investigator to ensure that the results are available before the next administration of 
the study drug. If the central readings are not available at the time of next dosing, 
this stopping criterion will apply. Study drug may be resumed with the joint 
agreement of the Investigator and the Sponsor’s Medical Monitor when follow-up test 
results show that the participant no longer meets the dose interruption criteria.  
• 
Liver safety: Any participant with the occurrence of either of the following liver 
values will be discontinued: 
– 
ALT or AST >3 x ULN and bilirubin >2 x ULN 
– 
ALT or AST >3 x ULN associated with symptoms (new or worsening) believed 
to be related to liver injury or hypersensitivity 
• 
Other findings which, at the joint discretion of the Sponsor’s Medical Monitor, the 
Sponsor Safety Science Leader and the Investigator, indicate that dosing in this 
individual should be stopped (e.g., severe sedation/somnolence, cognitive 
impairment) (see also Table 10).  
 
Ultimately and in case of disagreement, the Investigator remains responsible for the 
decision to stop dosing. 
4.1.3 
Administrative Structure 
4.1.3.1 
Internal Monitoring Committee (IMC) and Scientific Oversight 
Committee (SOC) 
An IMC consisting of a selected subset of Roche representative(s) as identified in the 
“IMC Agreement” will be responsible to perform interim analyses of accumulated safety, 
tolerability, PK, and efficacy (as required) data. The IMC members, the clinical 










 
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4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he/she has completed the last 
scheduled procedure shown in the SoA (Section 1.3). 
The end of the study will be considered to be the date of the last visit (including the last 
follow-up visit) of the last participant in the study (last participant last visit [LPLV]). 
5. 
STUDY POPULATION 
The study population rationale is provided in Section 4.2.1. 
Male and female participants aged 15 to 45 years with ASD according to DSM-5 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 will be included in the study.  
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted. 
The final decision on whether a participant will enter the randomized, double-blind 
treatment period will be made by the Principal Investigator in accordance with the 
protocol. An Eligibility Assessment Form (EAF, see Section 8.11.1) will be completed as 
part of the screening process and forwarded to an external vendor and Medical Monitor 
in order to help ensure all relevant information has been taken into account. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Informed Consent 
1. Study participants or legal representatives should be able and willing to provide 
written informed consent or assent, as applicable and as per local requirements 
according to International Council for Harmonisation (ICH) and local regulations. 
Alternatively, a legally authorized representative must be able to consent for the 
participant according to ICH and local regulations and assent must be given 
whenever possible. The ability to provide informed consent for each participant will 
be based on the Principal investigator’s clinical judgment. 
2. Availability of a parent or other reliable support person who is fluent in local language 
and has frequent and sufficient contact with the participant. The same person must 
agree to accompany the participant to all clinic visits and provide information about 
the participant’s behavior and symptoms and must agree to oversee the participant’s 
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• 
For support persons of high-functioning adult participants, no on-site visits 
are necessary after the screening visit if all eCOA assessments, interview, 
and forms are performed remotely (see Section 4.1 and Appendix 1 
Section 2.1.2.2). 
Age 
3. Age 15 to 45 years, at the time of signing the informed consent or assent form. 
Type of Participants and Disease Characteristics 
4. Males and female participants with Autism Spectrum Disorder according to 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 
• 
For transgender participants, the Investigator should consult with the Medical 
Monitor or delegate to assess potential safety concerns or interference with 
safety and efficacy testing. Transgender participants will be enrolled by their 
biological sex. 
Note: It is important that a high-confidence autism diagnosis has been established 
by an autism expert prior to screening and is supported by medical records. 
5. Social Responsiveness Scale, Second Edition (SRS-2) (T-score) ≥ 66. 
6. Wechsler Abbreviated Scale of Intelligence (WASI-II) or equivalent assessment  ≥ 50 
at screening or within the last 12 months prior to screening (for adults within the 
last 5 years prior to screening if the assessment was done at age 18 or older). The 
proportion of low-functioning participants (IQ ≥  50 to 69) will be limited to 25% 
overall. 
• 
If a previous assessment is used, the Investigator should assess whether it has 
been performed by an appropriately qualified rater. 
7. ASD or Autism diagnosis confirmed by Autism Diagnostic Observation Schedule 
(ADOS-2), done by a certified rater at screening, or within the last 6 months prior to 
screening. 
8. Presence of at least moderate to severe repetitive behaviors as per Children’s 
Yale-Brown Obsessive Compulsive Scale modified for ASD (CY-BOCS-ASD) total 
score of at least 8 at screening. 
 
Weight 
9. Body mass index (BMI) within the range of 18.5 to 40 kg/m2 (inclusive). 
 


 
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Sex 
10. Male and female participants with contraception requirements.  
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 preventing drug exposure. 
a) Female Participants 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Women of non-childbearing potential (WONCBP), as defined in Appendix 5. 
• 
Women of childbearing potential (WOCBP), who: 
– 
Agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods (hormonal or non-hormonal) that result in a failure rate of 
<1% per year during the treatment period and for at least 28 days after the last 
dose of study drug. Examples of contraceptive methods with a failure rate of 
<1% per year include bilateral tubal ligation, male sterilization, established 
proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices (see Appendix 5). 
Hormonal contraceptive methods must be supplemented by a barrier method (as 
defined in Appendix 5; preferably condom with a spermicide) if participants are 
receiving any drug known to reduce the effect of hormonal contraception (including 
anti-epileptic drugs inducing drug metabolism). In such a situation, the risk 
assessment should be discussed with the Medical Monitor. 
Note: Females who reach menarche after enrollment in the study must agree from 
this time forward to regular blood or urine pregnancy testing as defined in the SoA 
and must agree to either remain completely sexually abstinent or comply with the 
same contraceptive requirements as outlined above for WOCBP from first menses 
until 28 days after the last dose of study treatment (see Appendix 5). 
b) Male Participants 
Male contraception is not required in this study because of the minimal seminal 
dose transmitted through sexual intercourse (Banholzer et al 2016, Appendix 5). 
 


 
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Additional Inclusion Criteria: 
11. Language, hearing, and vision compatible with the study measurements as judged 
by the Investigator. Non-verbal individuals will be excluded from study participation. 
12. Allowed existing treatment regimens should be stable for 8 weeks prior to screening 
except: 
• 
6 weeks for non-pharmacological interventions 
• 
12 weeks in the case of antipsychotic therapies 
• 
6 months for antiepileptic treatments 
Investigator expects stability of these treatments and behavioral interventions for the 
duration of the study. 
13. In the Investigator’s opinion, able to participate and deemed appropriate for 
participation in the study, capable of following the study SoA and able to comply with 
the study restrictions 
14. In the Investigator’s opinion, participation in the study or discontinuation of prohibited 
medication will not pose undue risks. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
Neurologic/psychiatric conditions 
1. Presence of chromosome 15q11.2 q13.1 duplication syndrome (Dup15q syndrome), 
known “syndromic” forms of ASD (confirmed per genetic results available at 
screening): fragile X syndrome, Prader Willi syndrome, Rett’s syndrome, tuberous 
sclerosis, and Angelman syndrome, as well as genetic alterations strongly 
associated with ASD per genetic results available at screening affecting the 
following genes: CHD8, ANDP, SHANK3. 
• 
Clinical suspicion of the presence of Dup15q syndrome should lead to study 
exclusion. Please contact the Medical Monitor for any questions related to a 
clinical suspicion of Dup15q syndrome. 
• 
Other genetic information available at screening should be taken into 
consideration for assessment of participant eligibility. The Principal 
Investigators are encouraged to consult with the Sponsor (Medical Monitor or 
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2. Medical history of alcohol and/or substance abuse/dependence in the last 12 months 
or positive test for drugs of abuse at screening (unless the finding is related to the 
intake of concomitant medications allowed by the protocol). 
3. Initiation of a major change in psychosocial intervention (including investigational) 
within 6 weeks prior to screening. Minor changes in ongoing treatment (e.g., missed 
therapy sessions due to holiday/vacation; planned break in therapy due to holidays; 
changes in college/university programs) are not considered major changes. 
4. Clinically significant psychiatric and/or neurological disorder that may interfere with 
the safety or efficacy endpoints. 
• 
Participants with a psychiatric diagnosis other than ASD, including but not 
limited to, bipolar disorder, psychosis, schizophrenia, post-traumatic stress 
disorder or major depressive disorder will be excluded if the psychiatric 
comorbidity has the potential to confound results or impact safety. 
• 
Participants with non-suicidal self-injurious behaviors (e.g., cutting, head 
banging) that interferes with safety and efficacy testing will be excluded. 
5. Risk of suicidal behavior in the opinion of a certified clinician or as evidenced by a 
"yes" to questions 4 and/or 5 of Columbia-Suicide-Severity Rating Scale (C-SSRS) 
taken at screening and baseline with respect to the last 12 months or period since 
the screening visit, respectively, or any suicide attempt in the past 5 years.  
6. Unstable epilepsy/seizure disorder within the past 6 months. 
 
Cardiovascular conditions 
7. Concurrent cardiovascular disease considered not well controlled by drug treatment, 
including participants with clinically significant bradycardia and arrhythmias, 
myocardial infarction within 12 months of screening or uncompensated heart failure. 
8. Confirmed clinically significant abnormality on 12-lead electrocardiogram (ECG), 
including a QTcF of ≥450 ms (based on the average of 3 consecutive 
measurements). Central ECG readings should be used to determine if this criterion is 
met. 
9. Congenital heart diseases not treated and congenital QTc prolongation or family 
history of Long QT Syndrome.  
 
Other conditions 
10. Medical history of malignancy if not considered cured or if occurred within the last 
3 years with the exception of fully excised non-melanoma skin cancers or in-situ 
carcinoma of the cervix that has been successfully treated. 
11. Concomitant disease, condition or treatment which would either interfere with the 
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The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations. 
The study site should follow all instructions included with each shipment of IMP. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit for all IMPs received and that any discrepancies have been reported and resolved 
before use of the IMPs. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
The study site (i.e., Investigator or other authorized personnel [e.g., pharmacist or 
nurse]) is responsible for maintaining records of IMP delivery to the site, IMP inventory at 
the site, IMP use by each participant, and disposition or return of unused IMP, thus 
enabling reconciliation of all IMP received, and for ensuring that participants are 
provided with doses specified by the protocol. 
Upon arrival of the IMPs at the site, site personnel will complete the following: 
• 
Check the IMPs for damage. 
• 
Verify proper identity, quantity, integrity of seals and temperature conditions. 
• 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The qualified individual responsible for dispensing the study treatment will dispense the 
pack(s) according to the numbers issued by the interactive (voice/web) response system 
(IxRS).  
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 is responsible for study treatment accountability, reconciliation, and 
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The randomization list will be computer generated centrally by a third party and made 
available only to those individuals responsible for PK sample bioanalysis and to 
statisticians or programmers at the Sponsor directly involved in the production of outputs 
to support IMC and SOC meetings. The data will be analyzed in a secure area which is 
not accessible to any blinded personnel.  
6.3.2 
Blinding 
The IxRS will be programmed with blind-breaking instructions. The blind may be broken 
if, in the opinion of the Investigator, it is in the participant’s best interest to know the 
study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which 
the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition (e.g., antidote available). In this case, the 
Sponsor must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and Clinical 
Study Report (CSR), as applicable. 
Unblinding should not result in the withdrawal of the participants from the study. Every 
effort should be made to retain unblinded participants. 
If unblinding is necessary for participant management (in the case of an SAE), the 
Investigator will be able to break the treatment code by contacting the IxRS. Treatment 
codes should not be broken except in emergency situations. If the Investigator wishes to 
know the identity of the study treatment for any other reason, he/she should contact the 
Medical Monitor directly. The Investigator should document and provide an explanation 
for any premature unblinding (e.g., accidental unblinding, unblinding due to an SAE). 
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs (see Section 8.3.4) that are considered by the Investigator 
to be related to study treatment. 
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data.  
6.4 
TREATMENT COMPLIANCE 
The qualified individual responsible for dispensing the study treatment will prepare the 
study medication according to the randomization schedule. This individual will write the 
date, number of bottles dispensed and participant number on the study treatment bottle, 
label and Drug Accountability Record. This individual will also record the number of 
tablets received by each participant during the study. 
Compliance regarding administration of study medication at home will be monitored by 
the completion of a medication diary by the participants (or the support persons as 
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6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including approved over-the-counter [OTC] or prescription 
medicines, as well as approved dietary, herbal, and nutritional supplements) used by a 
participant from 12 weeks prior to screening until the follow-up visit must be recorded on 
the Concomitant Medications electronic Case Report Form (eCRF) along with reason for 
use, dates of administration (including start and end dates) and dosage information 
(including dose and frequency). 
Any non-pharmacological interventions (as defined in Section 6.5.2) must be recorded 
on the appropriate eCRF. 
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1 
Permitted Therapy 
Participants must be on a stable prescribed medication regimen for 8 weeks before 
screening, with the exception of antipsychotic therapies and antiepileptic treatments 
(where participants need to be on a stable regimen for at least 12 weeks and 6 months 
before screening, respectively; see inclusion criterion 12 in Section 5.1). Any stable 
prescribed medication at screening should remain stable throughout the study. All 
changes in prescribed medication need to be discussed with the Sponsor (Medical 
Monitor or designee). 
Examples of Allowed Medications: 
• 
Selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor 
(SSRI/SNRI) antidepressants including fluoxetine (see also inclusion criterion in 
Section 5.1) 
• 
Melatonin  
• 
Trazodone (at low doses) for insomnia 
• 
Aripiprazole 
• 
Risperidone 
• 
Psychostimulants (e.g., methylphenidate) 
• 
Clonidine 
• 
Occasional use of paracetamol/acetaminophen  
• 
Antiepileptic medication (except carbamazepine and phenytoin, which are prohibited 
because of CYP3A induction) must be stable for 6 months (see also inclusion 
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• 
Benzodiazepines with a short t1/2 (e.g., lorazepam, alprazolam, or oxazepam) are 
allowed if 
- taken only on an as needed (PRN) basis,  
- limited to 3 times per week,  
- prescribed for short-term or intermittent medical conditions and,  
- not taken immediately before the assessments visits (i.e., not within 2 days or 
within 5 times the elimination t1/2, whichever is longer before a scheduled visit). 
Note: for benzodiazepines with a long t1/2 (except for benzodiazepines to treat 
emerging symptoms of rebound and/or withdrawal effects) see Section 6.5.3. 
• 
Drugs known to prolong QTc interval will be allowed if stable at screening provided 
the screening QTc does not meets exclusion QTc criterion (see list of drugs known to 
prolong QTc in Appendix 8).  
• 
Any medication for medical illnesses other than ASD not listed under prohibited 
medications 
• 
Vaccines, including those against COVID-19 
 
Any other medications require the approval from the Investigator and the Sponsor’s 
Medical Monitor (or designee). 
Participants who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  
6.5.2 
Non-Pharmacological Interventions 
Non-pharmacological interventions (e.g., participant psychotherapy, cognitive behavioral 
therapy, applied behavioral analysis, speech therapy, occupational therapy, rehabilitative 
therapy, and social skills training) must be stable for 6 weeks prior to screening and 
must remain stable throughout the ongoing study in terms of type of intervention and 
intensity. Minor changes in ongoing treatment (e.g., missed therapy sessions due to 
holiday/vacation; planned break in therapy due to school holidays; changes in 
college/school programs) are not considered significant and need not to be discussed 
with the Sponsor (Medical Monitor or designee). 
A complete history of non-pharmacological interventions for the treatment of ASD 
including all previously completed therapies will be reported on eCRF and will include 
start and end date, name of therapy and number of hours per week. 
6.5.3 
Prohibited Therapy 
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy (as listed in Section 6.5.1) unless the rationale for exception is 
discussed and clearly documented between the Investigator and the Sponsor. 


 
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Use of the therapies listed below (e.g., prescription drugs, OTC drugs, herbal remedies, 
nutritional supplements) is prohibited during the study and for at least 6 weeks prior to 
randomization (or within 5 times the elimination t1/2, whichever is longer) to ensure 
washout of medication and until follow-up, unless otherwise specified below.  
Examples of prohibited medications (see also Appendix 6): 
• 
Strong inhibitors of CYP3A4/5 (e.g., ketoconazole, clarithromycin, grapefruit juice)  
• 
Strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, 
phenobarbital, St. John’s Wort)  
• 
Under no circumstances should a strong CYP3A4 inhibitor be given in combination 
because of the potential increase in exposure. If the use of a strong inhibitor is 
indicated, the Investigator should contact the Sponsor to discuss alternative options 
(e.g., replacement of clarithromycin by azithromycin, which is not a CYP3A4 
inhibitor). For certain cases, the Sponsor may advise pausing the treatment with 
RO7017773 and restarting when the CYP3A4 inhibitor has been discontinued and 5 
times the elimination t1/2 of the CYP3A4 inhibitor have elapsed.  
• 
Chronic adrenocorticoid or glucocorticoid use (use of inhaled and topical 
formulations are allowed) 
• 
Regarding the use of anxiolytics, sedatives, and hypnotics: benzodiazepines with a 
long t1/2 or benzodiazepine-like drugs pharmacologically similar to benzodiazepine 
(e.g., zolpidem, zopiclone, eszopiclone, and zaleplon) will not be allowed during 
screening and treatment periods (for benzodiazepines with a short t1/2 that are 
allowed see Section 6.5.1. 
In case of emerging symptoms of rebound and/or withdrawal effects of the study 
drug during the follow-up period after end of treatment at Week 12, treatment with 
benzodiazepines is allowed (see Section 8.3.7) and must be reported on the 
appropriate section of the eCRF. 
• 
Barbiturates and opioids 
• 
Alcohol consumption – more than 1 drink per week (see Section 5.3) 
• 
Other GABA agonists (direct/indirect): tiagabine, vigabatrin, baclofen, phenelzine, 
topiramate, felbamate, zonisamide, pregabalin 
• 
Valproic acid and its salts 
• 
Oxytocin 
• 
Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) 
• 
All other psychotropic medications or medications used for a psychotropic effect 
(unless allowed by the Medical Monitor or designee)  
• 
Tetrahydrocannabinol due to its psychoactive effects (e.g., marijuana) 
• 
Herbal and dietary supplements including cannabidiol (unless allowed by the Medical 
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motivate participants to comply with all the study-specific procedures as outlined in this 
protocol.  
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed, see the SoA (Section 1.3). 
Reasons for discontinuation of study treatment (or withdrawal from the study) may 
include but are not limited to the following: 
• 
Participant unable to continue to comply with the study treatment and study 
requirements  
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study  
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
• 
Pregnancy 
• 
Any event that meets the stopping criteria defined in Section 4.1.2 
• 
Specific adverse events if discontinuation of treatment is required to manage the 
event 
 
Every effort should be made to obtain information on participants who withdraw from the 
study treatment but have not withdrawn consent. Participants who discontinue study 
treatment prematurely will be asked to return to the clinic for a study completion/early 
termination visit and may undergo follow‑up assessments (see Section 8.11.3), unless 
the participant withdrew consent. The primary reason for premature study treatment 
discontinuation should be documented on the appropriate eCRF. Participants who 
discontinue study treatment prematurely will not be replaced. 
7.1.1 
Temporary Interruption 
If study treatment administration is delayed by more than 3 days relative to the scheduled 
administration date, this will be considered a treatment interruption. Administration may 
resume at the next planned dosing date. A missed dose of study treatment will not be 
made up. 
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator or Sponsor), an interruption should be considered.  
Temporary study drug interruption is an acceptable method to manage AEs related to any 
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should be considered for restarting as soon as medically justified in the opinion of the 
Investigator. 
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 be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR). 
Participants who withdraw from the study will not be replaced.  
For data to be collected at the time of study discontinuation and at safety and follow-up 
visits and for any further evaluations that need to be completed, see SoA (Section 1.3). 
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. 


 
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• 
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 timepoints are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine whether 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 ICF may be utilized for screening 
or baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time-frame defined in the SoA. 
8.1 
EFFICACY ASSESSMENTS 
The primary objective of this study is to evaluate the efficacy of a 12-week treatment with 
RO7017773 compared with that of placebo in socialization and communication in adults 
aged 18 to 45 years and adolescents aged 15 to 17 years with ASD, as measured by the 
change from baseline on the composite of the Vineland-3. 
Secondary efficacy objectives are the evaluation of a 12-week treatment with 
RO7017773 compared with placebo on restricted and repetitive behaviors, social 
behaviors, and communication skills.  
All assessments (see Table 9) will take place at the timepoints specified in Section 1.3. 


 
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Table 9 
Overview Clinical Scales/Clinical Outcome Assessments 
Scale group 
Specific scale 
High-functioning 
Low-functioning 
Administration 
Respondent 
Time [min] 
Adolescents 
Adults 
Adolescents 
Adults 
Assessments During Screening (Section 8.1.4) 
WASI-II 
 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 30 
ADOS-2 
 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 35 – 40 
SRS-2 
 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 15 – 20 
CY-BOCS-ASD 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Central rater 
Support person 
and participant 
~ 20 
Clinical Outcome Assessments (Section 8.1.5) 
Vineland-3 
 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Central rater 
Support person 
45 – 80 
Repetitive 
Behavior 
RBS-R 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 15 
CRRI 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 17 
CGI-S interview 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Support person 
and participant 
~ 30 
CGI-S / CGI-I  
(after initial pre-baseline interview) 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Support person 
and participant 
~ 15 
(combined) 
Anxiety 
BAI 
Mandatory 
Mandatory 
NA 
NA 
eCOA 
Participant 1 
~ 5 
PRAS-ASD 
Mandatory 
NA 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 10 
Sensory 
Sensitivities 
AASP 
Mandatory 
Mandatory 
NA 
NA 
eCOA 
Participant 1 
10 – 15 
SSP-2 
Mandatory 
NA 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 7 
PedsQL 
Generic Core and 
Cognitive 
Functioning Scales 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Participant for HF 
adults and HF 
adolescents 
Support person for 
all LF. 
~ 10 


 
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Table 9 
Overview Clinical Scales/Clinical Outcome Assessments (cont.) 
Scale group 
Specific scale 
High-functioning 
Low-functioning 
Administration 
Respondent 
Time [min] 
Adolescents 
Adults 
Adolescents 
Adults 
Neurocognitive 
Battery 
DET 
Mandatory 
Mandatory 
Mandatory3 
Mandatory3 
Clinician 
Participant 
~ 3 
IDN 
Mandatory 
Mandatory 
Mandatory3 
Mandatory3 
Clinician 
Participant 
~ 3 
OCL 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 6 
ONB 
Mandatory 
Mandatory 
Mandatory3 
Mandatory3 
Clinician 
Participant 
~ 4 
TWOB 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 4 
ISL 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 15 (total 
for 3 parts) 
CPAL 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 7 
GMLT 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant 
~ 7 
Somnolence 
and Sudden 
Onset of Sleep 
KSS 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Participant for HF 
adults 
Support person for 
all others 2 
~ 5 
ESS  
NA 
Mandatory 
NA 
NA 
eCOA 
Participant 
~ 5 
ESS-CHAD 
Mandatory 
NA 
Mandatory 
Mandatory 
eCOA 
Support person 
~ 5 
Sudden Onset of 
Sleep Questionnaire 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
Clinician 
Participant for HF 
adults 
Support person for 
all others 2 
~ 5 


 
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Table 9 
Overview Clinical Scales/Clinical Outcome Assessments (cont.) 
Scale group 
Specific scale 
High-functioning 
Low-functioning 
Administration 
Respondent 
Time [min] 
Adolescents 
Adults 
Adolescents 
Adults 
Sleep 
 
PROMIS Sleep 
Disturbance 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Participant for HF 
adults and HF 
adolescents 1 
Support person for 
all adolescents and 
all LF 
~ 5 
PROMIS Sleep-
Related Impairment 
Mandatory 
Mandatory 
Mandatory 
Mandatory 
eCOA 
Participant for HF 
adults and HF 
adolescents 1 
Support person for 
all adolescents and 
all LF 
~ 5 
Entry and Exit Questions 
NA 
NA 
NA 
NA 
eCOA 
Support person 
~ 5 
 
AASP = Adolescent/Adult Sensory Profile; ADOS-2 = Autism Diagnostic Observation Schedule, Second Edition; BAI = Beck Anxiety Inventory; CGI-I = Clinical 
Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; CPAL = Continuous Paired Associate Learning Test; CRRI = Caregiver-
Reported Routines Inventory; CY-BOCS-ASD = Children’s Yale-Brown Obsessive Compulsive Scale Modified for ASD; DET = Detection Test; eCOA = electronic 
clinical outcome assessment; ESS = Epworth Sleepiness Scale; ESS- CHAD = Epworth Sleepiness Scale for Children and Adolescents; GMLT = Groton Maze 
Learning Test; HF = high-functioning participant; IDN = Identification Test; ISL = International Shopping List Test; KSS = Karolinska Sleepiness Scale; LF = low-
functioning participant; NA = not applicable; OCL = One Card Learning Test; ONB = One Back Test; PedsQL = Pediatric Quality of Live Inventory; PRAS-ASD = 
Parent-rated Anxiety Scale for ASD; PROMIS = Patient-Reported Outcomes Measurements Information System; RBS-R = Repetitive Behavior Scale-Revised; 
SRS-2 = Social Responsiveness Scale, Second Edition; SSP-2 = Short Sensory Profile 2; TWOB = Two Back Test; Vineland-3 = Vineland Adaptive Behavior 
Scales, Third Edition; WASI-II = Wechsler Abbreviated Scale of Intelligence, Second Edition. 
1 If the participant is not able to complete the self-reported scale, the support person-reported form/scale will be used, i.e., PRAS-ASD instead of BAI; SSP-2 
instead of AASP; PROMIS proxy-forms instead of PROMIS self-reported forms. 
2 If the KSS or Sudden Onset of Sleep Questionnaire is reported by the support person this has to be done together with the study participant. Sudden Onset of 
Sleep Questionnaire is administered as an interview. 
3 For LF participants, the selection of attention tasks (detection, identification, and one back tests) should be prioritized and performed first. All effort should 
be made to also collect the remainder of the tasks if the study participant is able to comply. 
 


 
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An external company(ies) and external consultants will provide training to all raters on 
the various scales and will provide all sites with the relevant record forms, instruction 
manuals, and kits as appropriate. Training and requirements on rater qualifications are 
described separately in the external company(ies)’ documentation. 
For some electronic clinical outcome assessments (eCOAs) audio recordings may be 
captured. These audio recordings will be reviewed by central raters to verify whether 
these scales were administered according to the rating standards. If necessary, raters 
will be contacted for remediation and additional training.  
Remote centralized ratings for the Vineland-3 scale (see Section 8.1.5.1) and the 
CY-BOCS-ASD (see Section 8.1.4.4) will be carried out via live secure videoconference. 
The interview for the Vineland-3 scale will be audio-recorded for quality purposes.  
The centralized rater may be observed by another clinician for quality control purposes. 
If a remote administration session cannot occur for an unforeseen reason, it will be 
rescheduled. 
It is not planned to extract any information about the participant and support person from 
these video or audio recordings.  
8.1.1 
Requirements for Support Persons 
Each participant will need a reliable caregiver, parent, or support person (moving 
forward they will be deemed the “support person”). The same support person will provide 
feedback on all informant- based assessments throughout the study and the same 
person must attend all on-site visits. If a support person visit cannot be completed as 
arranged (e.g., the support person is delayed in transit) visits should be rescheduled as 
soon as possible after the original appointment within the specified time window, or 
incomplete or missing eCOA assessment may be completed remotely (see Appendix 1, 
Section 2.1.2.2). For support persons of high-functioning adult participants, no on-site 
visits are necessary after the screening visit if all eCOA assessments, interview, and 
forms are performed remotely (see Appendix 1, Section 2.1.2.2). 
In the Investigator’s opinion, the support person should be deemed appropriate to 
participate in the study and able of following the applicable study procedures, including 
participation in video calls with the central rater for the Vineland-3 and CY-BOCS-ASD 
assessments.  
The support person must live with the participant or have substantial and sufficient 
periods of contact with the participant (see below) and is willing and able to attend the 
on-site visits when required. The support person must oversee the participant’s 


 
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adherence with protocol-specified procedures, and report on the participant’s status via 
completion of study assessments. 
If the support person does not live with the participant, the Investigator has to be 
satisfied that the participant can contact the support person readily during the times 
when the support person is not with the participant. If in doubt about whether a 
participant’s care arrangements are suitable for inclusion, the Investigator should 
discuss this with Sponsor (Medical Monitor or designee). A non-cohabitating support 
person must spend sufficient time with the participant so that, in the opinion of the 
Investigator, the support person can reliably assess the participant’s mental status, 
activities and behavior, and report on the participant’s adherence and health. This would 
normally be possible when the support person spends a few hours with the participant 
every day. 
The support person arrangements for participants living in a residential home need to be 
assessed carefully on a case by case basis:  
• 
A staff member of the residential home can be the support person if this person 
spends sufficient time with the participant. In the opinion of the Investigator, the 
support person must be able to reliably assess the participant’s mental status, 
activities, and behavior, and report on the participant’s adherence and health. This 
would normally be possible when the support person spends a few hours with the 
participant every day. 
• 
A family member living at the participant’s home can be the support person if the 
participant returns home every night. When the participant only returns home over 
the weekend, a family member can be the support person only if they have intensive 
interaction with the participant during the week e.g., via phone calls, calls via Skype, 
SMS messages, etc. The quality of these interactions between support person and 
participant needs to be assessed for each participant to determine whether the level 
of interaction is sufficient. 
• 
A family member cannot be the support person when the participant lives full time in 
the residential home, unless the family member spends a few hours in the residential 
home with the participant every day. 
 
If in doubt about whether a participant’s care arrangements are suitable for inclusion, the 
Investigator should discuss this with the Sponsor (Medical Monitor or designee). 
8.1.2 
Instructions for Support Person 
Because of the important role of the support persons as the respondents in several key 
assessments, they will be provided with instructions on their role in the study as well as 
background information on ASD symptoms and behaviors at screening (see SoA in 
Section 1.3) by the Investigator. This aims to help them report accurately on the 


 
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participant’s health and behaviors and mitigate the risk of overt placebo response. 
Instructions will also be provided at the baseline and Week 12 visits prior to the 
administration of clinical scales. 
The instructions will take approximately 5 to 10 minutes. 
8.1.3 
Administration of Participant-Reported Scales to Illiterate 
Participants 
For participants who are illiterate or have reading deficits the following procedure for the 
mandatory participant-reported scales should be used: 
• 
The scale administrator will read out the questions and answers and show the 
answers on the Rater station. 
• 
The participant will choose one of the possible answers on the Rater station. 
 
If the participant is still unable to complete the scale even with the described assistance, 
the scale will be skipped.  
8.1.4 
Screening Assessments 
The following assessments will be performed at screening to check the participant’s 
eligibility for this study. 
8.1.4.1 
Wechsler Abbreviated Scale of Intelligence, Second Edition 
(WASI-II) 
The WASI-II is a tool used to evaluate an individual’s cognitive functioning and generate 
IQ scores (Wechsler 1999, Wechsler 2011) and will be administered by a qualified rater 
at screening. If the WASI-II or an equivalent assessment (e.g., the Wechsler Adult 
Intelligence Scale [WAIS]) has been performed by an appropriately qualified rater and 
documented within 12 months of the screening visit (within 5 years prior to screening 
for adults if the assessment was done at the age of 18 years or older), there will be no 
requirement to repeat it.  
The assessment will take approximately 30 minutes to complete. 
8.1.4.2 
Autism Diagnostic Observation Schedule, Second Edition 
(ADOS-2) 
The ADOS-2 is a diagnostic tool used to document the presence of ASD (Gotham et al 
2007, Lord et al 2000). During a semi-structured evaluation, the individual is observed in 
a naturalistic social situation and assessed across areas of social communication, 
imagination, and restricted and/or repetitive behaviors. Only qualified ADOS-2 raters are 
allowed to perform the ADOS-2 to confirm eligibility of participants. 


 
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The ADOS-2 includes four modules for use with different age groups and language 
levels; modules 2, 3, and 4 will be used in this study. The appropriate module of the 
ADOS-2 will be administered by a certified rater at screening. 
The assessment will take approximately 35 to 40 minutes to complete. 
8.1.4.3 
Social Responsiveness Scale, Second Edition (SRS-2) 
The SRS-2 is a 65-item informant-based rating scale designed specifically for use in 
ASD to quantitatively measure an individual’s ability to engage in emotionally 
appropriate reciprocal social behavior in a naturalistic social setting (Constantino 2005). 
Each item on the scale enquires about an observed aspect of reciprocal social behavior 
that is rated on a scale from 1 (not true) to 4 (almost always true). Social skill levels are 
assessed over five domains: Social Awareness, Social Cognition, Social 
Communication, Social Motivation, and Autistic Mannerisms. The total score generated 
serves as an index of severity of social deficits in the autism spectrum. The SRS-2 total 
score is expressed in raw and T-scores. Raw scores are converted to T-scores for 
gender and respondent. T-scores of 66 through 75 are interpreted as indicating 
moderate deficiencies in reciprocal social behavior that are clinically significant and lead 
to substantial interference in everyday social interactions. A total T-score of 76 or higher 
is considered to indicate severe deficiencies and strongly associated with clinical 
diagnosis of autistic disorder (Wilkinson 2017).  
The support person will complete the rating scale at screening. A clinician will be 
available to assist the support person during completion of the questionnaire. 
This assessment will take approximately 15 to 20 minutes to complete. 
8.1.4.4 
Children’s Yale-Brown Obsessive Compulsive Scale Modified 
for ASD (CY-BOCS-ASD) 
 
The CY-BOCS-ASD is a modified version of the Yale-Brown Obsessive Compulsive 
Scale (Y-BOCS), for children and adolescents with ASD. The interviewer asks the 
support person about past and present repetitive behaviors, guided by the revised 
repetitive behavior checklist (Scahill 2014). It contains a list of 25 behaviors, classified 
into the following categories: hoarding/ritualistic behavior, sensory-motor and arranging, 
insistence on routines, self-injurious behaviors, stereotypy, and restricted interests. This 
checklist was expanded from the original version to include repetitive behaviors 
commonly seen in children with ASD. A target symptom list comprising the four most 
troublesome behaviors is established by the interviewer. The severity (0 to 4) of each 
target behavior is rated for the following five items: time spent, interference, distress, 
resistance, and degree of control to generate a total score (0-20). Two additional items 


 
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(repetitive behavior-free interval and peculiarity) are also rated but are not included in 
the total score. 
The ratings evaluate the symptom severity over the past week and are based on the 
information collected from the participant and support person during the interview. The 
final rating is based on the clinical judgment of the central rater. 
The interview should take approximately 20 minutes to complete.  
8.1.5 
Clinical Outcome Assessments  
All assessments will take place at the timepoints specified in the SoA in Section 1.3. 
Support persons, clinicians and participants will use an electronic device to capture 
clinical outcome assessments (COAs) specified in the sections below (see also 
Appendix 1, Section 2.1.2.1). The specific sequence of assessments will be predefined 
on the electronic device for each participant and should be followed throughout the 
study.  
Any entries on COA should be reviewed for completeness by site staff during the visit 
and support person and participants should be requested to complete any blank items. If 
a scale cannot be completed during the visit or for a scale, the total score (e.g., the 
composite scores for Vineland-3) cannot be calculated with the available data, it 
should be attempted to repeat the scale during an unscheduled visit as soon as possible 
(within the next 7 days). 
 
8.1.5.1 
Vineland Adaptive Behavior Scale, Third Edition (VinelandTM-3) 
The Vineland is an instrument that measures communication, daily living skills, 
socialization, motor skills (only used in children up to 9 years of age) and maladaptive 
(not assessed in this study) behaviors of individuals with developmental disabilities 
(Sparrow et al 2005). The Comprehensive Interview will be administered to a 
participant’s support person in this study, during which the rater or clinician will ask to 
the support person open-ended questions relating to the participant’s activities and 
behavior. Domain scores will be obtained for the individual domains of Socialization, 
Communication, and Daily Living Skills and used to calculate the Vineland Adaptive 
Behavior Composite score. Standardized scores on the Adaptive Behavior Composite 
score range from 20 to 160, with higher scores indicating better adaptive functioning.  
VinelandTM-3 will be administered at different visits (see SoA in Section 1.3) by central 
raters via live, secure telemedicine platform. For any individual participant, the same 
rater should administer the VinelandTM.  


 
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This interview will take approximately 45 to 60 minutes. The rater will interview the 
support person to complete the VinelandTM. 
8.1.5.2 
Repetitive Behavior Scale-Revised (RBS-R) 
The RBS-R is a 43-item informant-based questionnaire, assessing the variety of 
restricted and repetitive behaviors observed in individuals with ASD (Bodfish et al 2000). 
The scale is grouped into six subscales: Stereotyped, Self-Injurious, Compulsive, 
Ritualistic, Sameness, and Restricted Behaviors. Each item utilizes a 4-point response 
scale assessing the presence and severity of a restricted or repetitive behavior. 
Response options range from "Behavior does not occur" (0) to "Behavior occurs and is a 
severe problem" (3). On the last question, participants are asked to “lump together” all of 
the behaviors described in the questionnaire and provide a rating for how much of a 
problem these repetitive behaviors are overall, on a scale from 1 to 100: where “1” 
represents “not a problem at all” and “100” represents “as bad as you can imagine”. 
A total score is generated for each subscale and an overall total score encompasses all 
the subscales. The overall total score ranges from 0 to 129; higher scores are indicative 
of more severe RRBs.  
It will take the support person approximately 15 minutes to complete the RBS-R. 
8.1.5.3 
Caregiver-Reported Routines Inventory (CRRI) 
The CRRI is a caregiver-reported RRB scale for older adolescents and adults based on 
the Children Routine Inventory-Revised (Evans et al 2017). It has been developed by the 
author of the Children Routine Inventory-Revised in collaboration with the Sponsor in 
order to extend the age-range for caregiver-reported Routine Inventory scales to older 
adults and adolescents. The CRRI questionnaire captures a wide range of RRBs, 
including stereotypies, tics, compulsions, habits, sensory sensitivities, and focused 
interests, in the context of typical and atypical development in adults and adolescents 
(Evans et al 2017). All items will be answered on a five-point Likert scale from “not at 
all/never,” “a little/rarely,” “somewhat/sometimes,” “quite a lot/often,” and “very much 
/always.” Forms with appropriate recall periods will be used at the timepoints indicated in 
the SoA (Section 1.3).  
The CRRI scale includes 62 items. It will take the support person approximately 
17 minutes to complete the CRRI. 
8.1.5.4 
Clinical Global Impression-Severity (CGI-S) and Improvement 
(CGI-I) Scales 
The CGI rating scales are tools used to evaluate both the severity of illness and change 
from Baseline (Guy et al 1976). The CGI-S reflects the rater’s impression of the 
participant’s current autism severity on a 7-point scale ranging from no symptoms (1) to 




 
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Seeking”, “Sensory Sensitivity”, and “Sensation Avoiding”. The adolescent/adult form is 
a unique sensory measure in that it is a self-reported questionnaire. 
The questionnaire takes 10 to 15 minutes for the participant to complete. 
8.1.5.8 
Short Sensory Profile 2 (SSP-2) 
The Short Sensory Profile Version 2 (SSP-2; Dunn 2014) is a 34-item parent or support 
person-reported questionnaire that probes for the effect of sensory processing 
anomalies on a person’s ability to function in daily life. Item responses occur on a five-
point Likert-rating scale from 1 (almost never) to 5 (almost always). The SSP-2 was 
based on the Sensory Processing Framework (Dunn 1999) and provides scores in four 
quadrants based on the child’s neurological threshold to sensory input and their method 
of self-regulation. The four quadrants are Seeking (“the degree to which a child obtains 
sensory input”), Avoiding (“the degree to which a child is bothered by sensory input”), 
Sensitivity (“the degree to which a child detects sensory input.”), and Registration (“the 
degree to which a child misses sensory input.”). 
The SSP-2 will be performed by support persons of adolescents and low-functioning 
adults. It will take the support person approximately 7 minutes to complete the SSP-2. 
8.1.5.9 
Pediatric Quality of Life Inventory (PedsQL) Version 4.0 
Generic Core Scale and Cognitive Functioning Scale 
The Pediatric Quality of Life Inventory (PedsQL™) Version 4.0 Generic Core Scale 
assessment consists of a 23-item questionnaire encompassing four core scale domains: 
Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning 
(5 items) and School Functioning (5 items). In addition to the four scale scores a 
Psychosocial Health Summary score, a Physical Health Summary score, and a total 
score can also be computed by averaging across the relevant domains. 
The PedsQL Cognitive Functioning Scale, which contains six items, will also be 
completed. Each item in the PedsQL Generic Core and Cognitive Functioning scales 
utilizes a 5-point response scale ranging from "never (a problem)" (0) to "almost always 
(a problem)" (4). Items are then reverse-scored and linearly transformed to a 0- to 100-
point scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0), i.e., higher scores indicate better 
quality of life or cognitive function.  
The following standard forms with a recall period of one month will be employed in this 
study (Varni et al 2004): adult self-report (ages 18+, high-functioning), pediatric self-
report (adolescents aged 15 to -17 years, high-functioning). In addition, support 
person-reported forms will be used for all low-functioning participants.  


 
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It will take approximately 10 minutes to complete the PedsQL Generic Core and 
Cognitive Functioning scales. 
The cognitive tests will be applied as part of the safety assessments (see Section 8.2.7). 
8.1.5.10 
Neurocognitive Battery 
The cognitive tests will be applied as part of the safety assessments (see Section 8.2.7). 
The total battery takes approximately 45 minutes to perform, the selection of attention 
tasks (detection, identification, and one back tests) takes approximately 10 minutes to 
perform.  
For low-functioning participants, the selection of attention tasks (detection, 
identification, and one back tests) should be prioritized and performed first. All effort 
should be made to also collect the remainder of the tasks if the study participant is able 
to comply. If not all tasks can be completed, an explanation should be recorded on the 
“Additional Observations” eCRF. 
Two test sessions of shorter duration will be carried out at the pre-baseline visit for 
habituation to the test environment.  
Detection Test (Psychomotor Function) 
The Detection Test (DET) is a measure of psychomotor function and uses a well-
validated simple reaction time paradigm with playing card stimuli. In this test, the playing 
cards all depict the same joker. The participant is asked to press the “Yes” key as soon 
as the card in the center of the screen turns face up. The software measures the speed 
and accuracy of each response.  
This assessment takes approximately 3 minutes to perform. 
Identification Test (Attention) 
The Identification Test (IDN) is a measure of visual attention and uses a well-validated 
choice reaction time paradigm with playing card stimuli. In this test, the playing cards are 
all either red or black jokers. The participant is asked whether the card displayed in the 
center of the screen is red. The participant responds by pressing the “Yes” key when the 
joker card is red and No when it is black. The software measures the speed and 
accuracy of each response. 
This assessment takes approximately 3 minutes to perform. 


 
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One Card Learning Test (Visual Learning) 
The One Card Learning Test (OCL) is a measure of visual learning and uses a well-
validated pattern separation paradigm with playing card stimuli. In this test, the playing 
cards are identical to those found in a standard deck of 52 playing cards (without the 
joker cards). The participant is asked whether the card displayed in the center of the 
screen was seen previously in this test. The participant responds by pressing the “Yes” 
or “No” key. The software measures the speed and accuracy of each response. 
This assessment takes approximately 6 minutes to perform. 
One Back Test (Working Memory) 
The One Back Test (ONB) is a measure of working memory and uses a well-validated n-
back paradigm with playing card stimuli. In this test, the playing cards are identical to 
those found in a standard deck of 52 playing cards (without the joker cards). The 
participant is asked whether the card displayed in the center of the screen is the same 
as the card presented immediately previously. The participant responds by pressing the 
“Yes” or “No” key. Because no card has been presented yet on the first trial, a correct 
first response is always “No”. The software measures the speed and accuracy of each 
response. 
This assessment takes approximately 4 minutes to perform. 
Two Back Test (Working Memory) 
The Two Back Test (TWOB) is a measure of working memory and uses a well-validated 
n-back paradigm with playing card stimuli. In this test, the playing cards are identical to 
those found in a standard deck of 52 playing cards (without the joker cards). The 
participant is asked whether the card displayed in the center of the screen is the same 
as the one presented two cards previously. The participant responds by pressing the 
“Yes” or “No” key. Because no card has been presented two-back on the first and 
second trials, a correct response on these trials is always “No”. The software measures 
the speed and accuracy of each response. 
This assessment takes approximately 4 minutes to perform.  
The International Shopping List Test (Verbal Learning) 
The International Shopping Test (ISL) is a measure of verbal learning and uses a well-
validated list-learning paradigm. The test is administered using a computer. High 
frequencies, high imagery, concrete nouns (items from a shopping list) are read to the 


 
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participant by the test supervisor at the rate of one word every two seconds. Once 
all 12 words have been read, the participant is asked to recall as many of the words as 
he/she can as quickly as possible. The test supervisor uses a mouse or stylus to mark 
the words recalled by the participant on the computer screen. When the subject can 
recall no more words, the same list is read a second time. The test supervisor records 
the words recalled by the participant on this trial. This is then repeated a third time. 
30 minutes later: without having the list read again, the participant is asked to recall the 
words from the list (delayed recall condition). The recall test is followed by a recognition 
condition test where the test supervisor reads a shopping list item that may or may not 
have been on the original list and the participant has to respond either affirmatively (if 
the item was on the original list) or negatively (if it was not). The recall and recognition 
test is repeated the next day about 24 hours after the list learning. If the clinic visit is split 
into two days (which is possible for Week 6, Week 12, and 6-week follow-up visits, see 
SoA in Section 1.3) the repeats are performed at the clinic. If the participant returned 
home after the first day the repeats are performed over the phone as close in time to the 
24h timepoint as possible. In addition, questions about the sleep quantity and quality will 
be asked. The software registers the number of correct responses as recorded by the 
test supervisor. 
This assessment takes approximately 15 minutes to perform (5 minutes for each of the 
three parts).  
Continuous Paired Associate Learning Test (Paired Associate Learning) 
The Continuous Paired Associate Learning Test (CPAL) is a measure of visual associate 
memory and uses a well-validated paired associate learning paradigm in which the 
subject must learn the locations of a number of amoeba-like shapes on the computer 
screen. This test consists of a single amoeboid shape displayed in the center of the 
screen surrounded by a number of blue- filled circles. Beneath all but two of the blue 
spheres are amoeboid shapes, one of which matches the central display; the two 
remaining circles are distractors. In the exposure phase of the test all of the to-be-
remembered pattern-location associations are presented on the computer screen 
simultaneously. After a five second delay, a pattern is shown in the central location and 
this signals that the subject should touch the location in the periphery that contains the 
same pattern. This process continues until the participant has acknowledged all of the 
pattern-location associations. The learning phase begins with the same test display 
presented during the exposure phase except that now all of the peripheral locations are 
shown as blue spheres. One of the patterns presented in the exposure phase is 
presented in the center location. With the presentation of this pattern, the participant is 
required to select the peripheral location where an identical pattern is hidden beneath 
the blue sphere. This process continues until the correct location of each pattern is 


 
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found. Finding the correct location for all patterns in the set is defined as a learning trial. 
There are six learning trials (a single trial delayed recall condition will be done after a 30-
minute delay). The software records each move as an error or as a correct move. 
This assessment takes approximately 7 minutes to perform.  
Groton Maze Learning Test (Executive Function) 
The Groton Maze Learning Test (GMLT) measures executive function using a maze 
learning paradigm. A 10 x 10 grid of tiles is presented to the participant on the screen. A 
28-step pathway is hidden among these tiles. A blue tile indicates the start and a tile with 
red circles indicates the finish. The participant must move one step at a time from the 
start toward the end by touching a tile next to their current location. If the correct move is 
made a green checkmark appears and if the move is incorrect a red cross is revealed. 
Once completed, they are returned to the start location to repeat the test and must try to 
remember the pathway they have just completed. The software records the total number 
of errors made in attempting to learn the same hidden pathway on 5 consecutive trials 
during a single session. 
This assessment takes approximately 7 minutes to perform. 
8.1.5.11 
Karolinska Sleepiness Scale (KSS) 
The Karolinska Sleepiness Scale (KSS; Akersted and Gillberg 1990, Baulk et al 2001) 
will be completed as part of the safety assessments (see Section 8.2.7). The KSS 
measures the subjective level of sleepiness at a particular time during the day. On this 
scale, participants (or support persons for adolescents aged 15 to 17 years and for low-
functioning participants) indicate which level best reflects the psycho-physical state 
experienced in the last 5 minutes. The KSS is a 9-point scale (1 = extremely alert, 9 = 
very sleepy, great effort to keep awake, fighting sleep).  
This assessment takes approximately 5 minutes to perform.  
8.1.5.12 
Epworth Sleepiness Scale (ESS) 
The Epworth Sleepiness Scale (ESS; Johns 1991, Johns 1992) will be completed as 
part of the safety assessments (see Section 8.2.7). The ESS is a brief, self-administered 
eight-item questionnaire that measures daytime sleepiness in adults. Participant will be 
asked to rate on a scale of 0-3 the chances that, “over the past month” and “since last 
visit”, he/she would have dozed in eight specific situations that are commonly met in 
daily life (0 = would never doze; 3 = high chance of dozing). Thus, the participant is 
asked to characterize, retrospectively, part of his usual behavior in a variety of situations 
that are more or less soporific. The ESS score is the sum of eight item-scores and can 
range from 0 to 24.  


 
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This assessment takes approximately 5 minutes to perform.  
8.1.5.13 
ESS for Children and Adolescents (ESS-CHAD) 
The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD; Johns 2015) 
will be completed as part of the safety assessments (see Section 8.2.7). The ESS-CHAD 
is a brief, support person-administered eight-item questionnaire that measures daytime 
sleepiness in children and adolescents. Support persons of adolescents and participants 
with an IQ score <70 will be asked to rate on a scale of 0-3 the chances that, "Over the 
past month," and “since last visit”, “your child” would have dozed in eight specific 
situations that are commonly met in daily life (0 = would never doze; 3 = high chance of 
dozing). Thus, the support person is asked to characterize, retrospectively, part of his 
usual behavior in a variety of situations that are more or less soporific. The ESS score is 
the sum of eight item-scores and can range from 0 to 24.  
This assessment takes approximately 5 minutes to perform.  
8.1.5.14 
Sudden Onset of Sleep Questionnaire  
The Sudden Onset of Sleep Questionnaire has been developed by the Sponsor for this 
study and will be completed as part of the safety assessments (see Section 8.2.7). Each 
participant (or support person for adolescents aged 15 to 17 years and for 
low-functioning participants) will be asked to answer a series of up to 8 questions to 
assess the occurrence of daytime somnolence, its suddenness (level of awareness), 
frequency and circumstances in which the episode(s) took place, impact on work/daily 
activities/ social life, if worried by episode and ease of waking up (see Appendix 2 for 
reporting of AEs). This questionnaire will be administered as an interview. 
This assessment takes approximately 5 minutes to perform. 
8.1.5.15 
Patient-Reported Outcomes Measurements Information System 
(PROMIS) Sleep Disturbance Questionnaire Short Form  
The Patient-Reported Outcomes Measurements Information System (PROMIS) Sleep 
Disturbance Short Form (Yu Lan et al 2011, Buysse et al 2010) assesses self-reported 
perceptions of sleep quality, sleep depth, and restoration associated with sleep. This 
includes perceived difficulties and concerns with getting to sleep or staying asleep, as 
well as perceptions of the adequacy of and satisfaction with sleep. This questionnaire 
assesses sleep disturbance over the past seven days.  
The following versions of the Sleep Disturbance short form (8 items) will be implemented 
in this study: adult self-report (ages 18+, high-functioning), pediatric self-report 
(adolescents aged 15 to -17 years, high-functioning). In addition, proxy forms completed 
by the support person will be used for all adolescents, as well as low-functioning adults. 


 
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This assessment takes approximately 5 minutes to perform.  
8.1.5.16 
Patient-Reported Outcomes Measurements Information System 
(PROMIS) Sleep-Related Impairment Questionnaire Short Form 
The PROMIS Sleep-Related Impairment Short Form (Buysse et al 2010) focuses on 
self-reported perceptions of waking alertness, sleepiness, and function within the context 
of overall sleep-wake function. This questionnaire assesses sleep-related impairment 
over the past seven days. 
The following versions of the PROMIS Sleep-Related Impairment Short Form (8 items) 
will be implemented in this study: adult self-report (ages 18+, high-functioning), pediatric 
self-report (ages 15 to 17, high-functioning). In addition, proxy forms completed by the 
support person will be used for all adolescents, as well as low-functioning adults. 
This assessment takes approximately 5 minutes to perform.  
8.1.5.17 
Entry and Exit Questions 
Support persons will be asked a set of entry questions at baseline about their 
expectations regarding the study drug and about the skills or behaviors of the study 
participant they would like most to see improve. 
As a follow-up, at the Week 12 visit or Early Termination visit, support persons will be 
asked to report if they observed any changes in the skills or behaviors of the study 
participant during the study, as well as some feedback on the study drug. 
Both entry and exit questions will be answered on an electronic device. 
The entry and exit questions will take about 5 minutes to complete. 
8.1.6 
Other Assessments 
For PD biomarker assessments see Section 8.7.1. 
8.2 
SAFETY ASSESSMENTS 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious adverse events of special interest (NSAESI); measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs, ECGs; and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 




 
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8.2.3 
Vital Signs 
Vital signs will include temperature (tympanic), SBP and DBP, and pulse rate. They will 
be taken before blood collection and measured in a supine position after at least 
5 minutes of rest. At some timepoints, BP will also be measured in two positions (once 
supine and once, 3 minutes later, standing) for orthostatic changes. At visits with dosing, 
vital signs and orthostatic changes will be measured pre-dose and postdose (for 
frequency see SoA (Section 1.3).  
Blood pressure and pulse measurements will be assessed obtained in a quiet room at a 
comfortable temperature, with the participant's arm unconstrained by clothing or other 
material and using a completely automated device with a digital readout throughout the 
study. 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. 
8.2.4 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the HR and measures QRS complex, PR, 
QT, and QTc intervals.  
The 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. 
To minimize variability, it is important that participants be in a resting position for at least 
10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in HR. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to meals and 
any scheduled vital sign measurements and blood draws. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  
If any values at or beyond the protocol-defined parameters are detected from the 
machine reading, an expedited review by the central vendor should be requested to 
confirm the reading. 
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. 


 
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The recordings will be electronically transferred to a central ECG analysis vendor. The 
following parameters will be obtained from the digital recordings: heart rate, QRS 
duration, PQ (PR), RR and QT intervals (QTcB (Bazett’s correction) and QTcF 
(Fridericia’s correction) as well as information on T-wave and U-wave. Changes in 
T-wave and U-wave morphology and overall ECG interpretation will be documented on 
the eCRF or may be sent electronically. If considered appropriate by Roche, ECGs may 
be analyzed retrospectively at a central laboratory. 
ECG characteristics, including HR, QRS duration, and PR, and QT intervals, will be 
recorded on the eCRF or loaded electronically. QTcF, QTcB and RR interval will be 
calculated automatically and recorded on the eCRF or loaded automatically. T-wave 
information will be captured as normal or abnormal and U-wave information will be 
captured in two categories: absent/normal or abnormal. 
8.2.5 
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 eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
• 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. 
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
• 
If laboratory values from non-protocol specified laboratory assessments performed at 
the local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (e.g., SAE or AE or dose-modification) then, 
the results must be recorded in the eCRF. 
 
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. 




 
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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 NSAESI and disease-
related events and/or disease-related outcomes not qualifying as AEs or SAEs are 
discussed in Section 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. Any other 
AEs should not be reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the last follow-up visit (approximately 42 days after the 
last dosing; see SoA in Section 1.3). 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period after the last follow-up visit 
(approximately 42 days after the last dosing; see SoA in Section 1.3).  
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 


 
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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 
adverse event 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 up each AE until the event has resolved to baseline grade 
or better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported. If a 
participant discontinues from the study early (as described in Section 4.1.2 and 
Section 7), all AEs should be followed up until they are resolved as long as the 
participant has not withdrawn consent.. 
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 up until pregnancy 
outcome and reported according to the instructions provided in Section 8.3.5. 
8.3.3.2 
Sponsor Follow-Up 
For SAEs, NSAESI, 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 
event. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification (i.e., no more than 24 hours after learning of the event; see 
Appendix 2 for reporting instructions) by the Investigator to the Sponsor of an 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. 


 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators.  
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 an 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. Details will be available separately. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 28 days after the final 
dose of study treatment.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Non-Serious Adverse Events of Special Interest 
Non-serious adverse events of special interest (NSAESI) are required to be reported by 
the Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Appendix 2 for reporting instructions). 


 
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NSAESIs for this study include the following: 
• 
Hypersomnia, somnolence, depressed level of consciousness or lethargy of intensity 
other than mild (i.e., > Grade 1 according to the Common Terminology Criteria for 
Adverse Events [CTCAE]; see Appendix 9) 
• 
Sudden onset of sleep (see Appendix 9 for determining if an event should be 
classified as sudden onset sleep versus somnolence or both and its severity) 
• 
Paradoxical effects (see Section 8.3.7) 
• 
Rebound and/or withdrawal symptoms after drug discontinuation (e.g., insomnia, 
anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitches, 
indigestion, diarrhea, and photophobia) 
• 
Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Appendix 3, Section 6 
• 
Confirmed QTcF (average of triplicate values) >480 msec based on central ECG 
reading 
• 
Confirmed QTcF (average of triplicate values) change from baseline >60 msec 
based on central ECG reading 
• 
Gastrointestinal events other than mild (see Appendix 2, Section 3.1); preferred term 
examples for gastrointestinal events are provided in Appendix 10) 
• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
participant 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. 
Several measures are taken to ensure the safety of participants participating in this 
study. Eligibility criteria have been designed to exclude participants at potentially higher 
risk for toxicities. Participants will undergo safety monitoring during the study. In addition, 
guidelines for managing AEs, including criteria for treatment interruption or 
discontinuation, are provided in the following sections. 
Participants should not engage in hazardous activities while taking study medication 
(see Section 5.3). 








 
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(e.g., consider switching the time of study drug administration from morning to evening, 
pause dosing and consider restarting after resolution of symptoms). If a participant 
discontinues from the study early (as described in Section 4.1.2 and Section 7), all 
specific events should be followed up until they are resolved as long as consent has not 
been withdrawn. 


 
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Table 10 Guidelines for Managing Specific Events 
Type of Risk  
Risk Mitigation 
CNS effects  
• 
Daytime somnolence, sudden 
onset of sleep, dizziness 
 
• If daytime somnolence or sudden onset of sleep 
occurs during a site visit within 1 hour postdose, or 
anytime thereafter, the Investigator will monitor vital 
signs and orthostatic changes hourly for 3 hours and 
more frequently if clinically warranted, perform ECG 
in triplicate, and record the number of minutes 
asleep for each event of falling asleep. 
• Investigators will instruct the participants and their 
support persons to contact the site immediately if 
daytime somnolence (other than mild) or sudden 
onset of sleep occurs outside of the specific site 
visits and to take the appropriate safety precautions 
with ambulation and driving (if applicable). In case of 
mild episodes of somnolence or daytime 
somnolence, switching dosing from morning to 
evening administration should be considered after 
discussion with the Sponsor’s Medical Monitor. 
• In case of recurrent, sustained, or medically relevant 
episodes of hypersomnia, daytime somnolence, 
lethargy, sudden onset of sleep, decreased level of 
alertness, or dizziness, discontinuation of dosing and 
withdrawal of the participant should be considered. 
 
Psychiatric effects 
• 
Mood disorders, major 
depression disorders 
• Severe, pause dosing  
• 
Agitation, irritability emotional 
release, excitement, and 
excessive movement 
 
• Assess if signs and symptoms evoke paradoxical 
reactions, stop dosing, consider symptomatic 
treatment 
Suicidal risk 
• In case of treatment-emergent suicidal risks, 
complete the C-SSRS and consider further 
evaluation and clinical management (e.g., immediate 
referral to mental health services and patient safety 
precautions)  
 


 
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Table 10 Guidelines for Managing Specific Events (cont.) 
 
Type of Risk  
Risk Mitigation 
Withdrawal/rebound effects  
• Depending on the severity, consider surveillance and 
symptomatic treatment (e.g., midazolam, diazepam, 
melatonin, and trazodone) 
• In case of emerging symptoms of rebound and/or 
withdrawal effects of the study drug during the follow-
up period after end of treatment at Week 12, 
treatment with benzodiazepines is allowed (if possible 
after discussion with the Sponsor).  
• Seizures; Handling of seizures should follow the 
recommendation by the International League against 
Epilepsy 
(https://journals.sagepub.com/doi/10.5698/1535-
7597-16.1.48):  
- 
In case of participants with a first seizure, the local 
emergency doctor should be called; the diagnostic 
workup as well as the treatment will depend on the 
type and duration of the seizure. 
- 
In case of participants with known seizures, the 
emergency medication (typically, intramuscular 
midazolam, intravenous (IV) lorazepam, or IV 
diazepam) should be given after 3 to 5 minutes (as 
per local recommendation). 
Paradoxical reactions  
• Depending upon severity, consider symptomatic 
treatment; if necessary take the advice of an 
emergency physician (treatment option: e.g., blood 
pressure management, physostigmine, flumazenil, 
and haloperidol)  
• If a participant experiences a paradoxical reaction, 
anxiety, or mood agitation, treatment must be paused 
and can be restarted only after discussion with the 
Sponsor.  
Overdose with exacerbated 
CNS effects 
• In cases of exacerbated symptoms of sedation, coma, 
or respiratory depression, consult an emergency 
physician and apply symptomatic treatment (e.g., 
blood pressure and airway management, flumazenil).  
QTc Prolongation 
• QTcF (average of triplicate values) >480 msec or a 
change from baseline of >60 ms (when confirmed in 
repeat measurement within 30 minutes and based on 
central reading): stop dosing (see also stopping rules 
in Section 4.1.2) 
• If the QTcF does not normalize after interruption of 
the study drug and a washout period of 1 week, the 
participant should receive appropriate emergent 
treatment and be referred to a cardiologist for 
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3. Obtain, if possible, a blood sample for PK analysis within 24 hours from the date 
of the final dose of study treatment, if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose, as well as the duration of the 
overdose, in the eCRF. 
5. In case of overdose with exacerbated CNS effects, refer to guidelines for man 
gauging overdose with exacerbated CNS effects in Table 10. 
Previous PK samples collected at the time of the incorrect administration of study 
treatment may be used to further evaluate overdose. 
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. Note: On visits Day 1 and Day 14, 
the study drug should be taken with breakfast or some food such that tmax is reached 
after approximately 2 hours). Following review of the second interim analysis, sampling 
on Day 1 may be reduced for adolescents to be similar to that for high- and low-
functioning adults. This will be confirmed as part of the IMC + SOC review of PK data 
from adolescents. Plasma RO7017773 concentrations will be measured by a specific and 
validated LC-MS/MS method. Topical application of local anesthetic is permitted if 
necessary for blood sampling. Home nursing services may be provided, if feasible to 
collect blood samples at the participant’s household.  
If required, remaining PK samples may also be used for assay development/validation 
(e.g., for metabolites and measurement of exploratory biomarkers). 
The PK samples will be destroyed within 2 years after the date of final CSR. Details on 
sampling procedures, sample storage and shipment are given in the Sample Handling 
Manual.  
For participants who consent to RBR, leftover samples will be transferred to RBR (see 
Section 8.9). 
Drug concentration information that would unblind the study, will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of timepoints for any planned study assessments 
must be documented and approved by the relevant study team member and archived in 
the Sponsor and site study files. This will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF. 


 
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8.6 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity will not be evaluated in this study.  
8.7 
BIOMARKER ANALYSES 
The rationale for using these specific tests is provided in Section 4.2.3. 
8.7.1 
Biomarkers 
8.7.1.1 
Digital Biomarkers 
At the pre-baseline visit, the support person and the participant will be provided with a 
study smartphone and smartwatch, a “sleep mat”, detailed instructions and training on 
how to use the technology, and, optionally, small Bluetooth transmitters (“beacons”). 
The number of “room beacons” should be based on the number of rooms within the 
participant’s home and their sociability level as reported by the support person and 
participant, and at least one “more social” and one “less social” room beacon must be 
dispensed. The support person and participant will be instructed to place one “room 
beacon” in each separate room of the participant’s home (as appropriate) based on their 
sociability level (“more social” or “less social”). Regarding the “people beacons”, at least 
one will be dispensed to the support person, or a number to match the number of people 
living with the participant and that are eligible to carry a beacon. The support person and 
participant will be instructed to distribute the “people beacons” to each member of the 
household, where appropriate. The people beacons should be worn by the household 
members whenever they are at home. Any complementary information related to the 
dispensing of beacons can be reported in the “Dispense” eCRF’s form in the “comments” 
field. The beacons transmit a regular Bluetooth signal that is recorded by the watch, 
allowing for an estimation of the proximity of the beacon. The study phone and watch will 
have applications pre-installed, that include a collection of digital biomarker 
assessments, comprising surveys and active tasks, for the support person and 
participant to complete. The applications will collect: 
1) Smartphone data through user interaction (Active Tasks) 
Participants will be assessed with three active tasks within the smartphone app. In 
total the active tasks will last on average 5 minutes. The tasks will assess spatial 
working memory, emotion recognition as well as social and communication deficits. 
Once a week, support persons will be asked to record a conversation with the 
participant that is at least 5 minutes long to assess communication deficits. When not 
in use, the phone should be left in the participant’s living room on charge whenever 
possible. Throughout the day the phone will measure the volume of noise in the 
environment and the time that people spend speaking. The raw audio recordings 
(and so actual words spoken) will not be uploaded from the phone and will be 
automatically deleted from the phone. For more details on the audio recordings 
please see Appendix 11. 


 
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2) Smartphone and smartwatch data without user interaction (Passive Monitoring) 
The participant will be asked to wear a smartwatch each day for the continuous 
capture of behavioral and physiological data related to core and associated 
symptoms of ASD (‘passive monitoring’), including (a) body movement to 
characterize repetitive body movements, (b) heart-rate parameters as biomarkers of 
anxiety and stress, (c) dereferenced geolocation and time information to characterize 
social behavior when outdoors, and (d) level and quality of background sound to 
characterize social interactions (recorded on smartphone). 
The people beacons also include a button that should be pressed by the support 
person when they observe the participant performing a repetitive movement. This 
“tagging” of repetitive movements can also be performed in the smartphone app. To 
avoid over-burden, tagging needs not be done for every observed repetitive 
movement. However, for a successful assessment a substantial number of events 
(e.g., a few each day) need to be tagged. Furthermore, the support person should 
tag all repetitive movements for a certain period of time (at least 2 hours) on a day of 
their own choice, i.e. to do “dense” tagging. 
3) Participant and Study-Partner Reported Outcomes on smartphone (Surveys) 
Once per month questions on HRQoL (EuroQol 5-Dimension, 5-Level Questionnaire 
[EQ-5D-5L]) will be asked. 
In addition, a sleep mat that will be placed by the support person under the participant’s 
mattress and contains a sensor to detect body movement, breathing and heart-rate 
signals that will be used to collect data on sleep behavior. 
The ability of the participant to complete the active tasks will be assessed by the clinician 
at the pre-baseline visit and if any of the active tasks are not suitable for the participant, 
they will be deactivated on the study smartphone. Participants and support persons will 
have the opportunity to ask any questions they may have. During the study, at 
scheduled phone contact and site visits, site personnel will follow-up on the participant’s 
progress. Adherence and technical status of the technology will be checked throughout 
the study, and the participant and support person will receive daily reminders to 
complete the active tasks and surveys, which may include calls from the site. The 
technology must be returned to the clinic at the end of the study and upon early 
termination. At those times, both the participant and the support person will be asked to 
complete satisfaction surveys on their experience using the technology during the study. 
Full details on the type of data captured and the methods used to ensure participant 
privacy are provided in Appendix 11. 


 
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8.7.1.2 
Hair Biomarkers 
The exposome assay will provide 4- to 6-hour molecular measurements of physiological 
metabolites, environmental chemicals, and essential elements such as zinc and copper. 
The metabolic and biochemical dynamics of the participants, i.e., temporal changes in 
the levels of the different factors that are assessed, will be mapped from before the start 
of study drug administration throughout the treatment and follow-up periods to identify 
which molecular pathways show a sustained response to the study drug (see SoA, 
Section 1.3). In addition to monitoring the temporal exposome of the participants at the 
molecular level, the hair assay may also assess the levels of RO7017773 and its 
metabolites to provide further information on the relationship of potential changes in the 
exposome with RO7017773 administration. Lastly, the data generated by the hair assay 
will be used to undertake molecular phenotyping to identify participant subgroups who 
respond differently to the study treatment. Optional hair samples from support persons 
who provide consent will serve as a control. 
8.7.1.3 
Pharmacodynamic Biomarkers: Assessments of 
Neurophysiological Effects  
The PD biomarker assessments comprise resting state EEG and SPV (measured by 
means of EOG recorded during an oculomotor task). These assessments will be 
performed at the timepoints specified in the SoA (Section 1.3). Resting state EEG will be 
acquired in alternating 1 min blocks of eyes open and eyes closed while participants sit 
relaxed, following the recommendations of the International Pharmaco-EEG Society 
(Jobert et al 2012). Resting state data will be processed off-line to derive the beta power 
(12 to 30 Hz). During the oculomotor task, participants will be instructed to look at and 
follow a target stimulus on the screen, which switches horizontally from the screen 
center to either side at fixed amplitudes. Participants’ head movements will be reduced 
by means of a chin rest. The system will be initially calibrated to establish the conversion 
between EOG signals and eye movement amplitude. EOG data will be analyzed off-line 
to derive saccadic peak velocities.  
8.7.1.4 
Response Biomarkers: Eye-Tracking and Task EEG 
Biomarkers 
Eye-tracking and task EEG biomarkers will be acquired twice: before dosing and at the 
end of treatment (see SoA in Section 1.3).  
In the eye-tracking assessments, participants will be presented several static and 
dynamic visual stimuli while the eye-tracking system estimates their gaze position and 
pupil size. The visual stimuli include social (faces, people, activities, biological motion, 
etc.) and non-social elements (toys, objects, background furniture, etc.). Derived 
parameters will include time spent looking at specific stimuli type and image and video 
scanning patterns. Additionally, participants’ pupil constriction during pupillary light reflex 
will be measured.  


 
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During the task EEG assessments, participants will perform tasks with visual stimulation. 
This will consist of a “Face ERP” task, where they look at images of upright faces, 
inverted faces, and houses. Derived parameters for analyses will include event related 
potential component amplitudes and latencies.  
The response biomarker assessments will be performed after the PD biomarker 
assessments (see Section 8.7.1.3) and are ordered by priority on the recording setup. In 
case low-functioning participants are not able to complete the full set of response 
biomarkers (e.g., because of agitation or inability to wear the EEG cap for the duration 
of the entire task battery), the remaining tasks may be skipped. 
8.7.2 
Genetic and Genomic Analyses  
8.7.2.1 
Clinical Genotyping  
In this study, genetic analyses will be performed to possibly identify subgroups of 
individuals who benefit from RO7017773. 
A mandatory whole blood sample will be taken from every participant for DNA extraction 
(see SoA in Section 1.3 and Section 8.8.1). The DNA may be used for, but analysis is 
not limited to:  
• 
Genetic variants of pathways related to ASD, including but not limited to genes 
related to disease status, drug target, and treatment response. 
• 
Genetic variants of CYPs, transporters or receptors which might affect the 
metabolism, PK, PD, or safety of RO7017773. 
Data arising from all biosamples will be subject to the same confidentiality as the rest of 
the study (see Appendix 1).  
8.7.2.2 
Whole Genome/Exome/Targeted DNA Analysis 
The sample collected for DNA extraction (see Section 8.8.1) includes, but is not limited 
to, genomic analysis and may be sent to one or more laboratories for analysis of 
germline or somatic mutations via whole genome sequencing (WGS), whole exome 
sequencing (WES), next-generation sequencing (NGS), or other genomic analysis 
methods. 
Genomics is increasingly informing researchers' understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents. 


 
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Given the complexity and exploratory nature of these analyses, genomic data and 
analyses will not be shared with Investigators or study participants unless required by 
law. Participants will not be identified by name or any other personally identifying 
information. Data arising from all biosamples including samples for analyses of inherited 
DNA will be subject to the confidentiality standards described in the sample 
documentation.  
8.7.3 
Overview of the Research Biosample Repository 
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional RBR. Collected RBR samples will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, AEs, or progressive disease. 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation. 
• 
To increase knowledge and understanding of disease biology and drug safety. 
• 
To study treatment response, including drug effects and the processes of drug 
absorption and disposition.  
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
8.8 
BIOMARKER SAMPLES 
8.8.1 
Mandatory Samples 
The following samples are required and will be collected from all participants in this 
study: 
• 
Whole blood sample for DNA extraction (see Section 8.7.2) 
• 
Hair samples for exposome analysis (see Section 8.7.1.2) 
o Note: No hair samples will be collected from study participants with no or 
insufficient hair. 
 
A mandatory whole blood sample will be taken for DNA extraction to support clinical 
genotyping from every participant at any convenient time between Day 1 and follow-up 


 
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visit. In addition, hair samples for exposome analysis will be collected at the timepoints 
specified in the SoA (see Section 1.3). 
Clinical genotyping samples and derived analytical material will be destroyed within 
5 years following completion of the CSR. Hair samples for exposome analysis will be 
destroyed within 2 years following completion of the CSR. For sampling procedures, 
storage conditions, and shipment instructions, see the separate laboratory manual and 
instructions. 
For participants who consent to RBR, leftover blood and hair samples will be transferred 
to RBR (see Section 8.9).  
8.8.2 
Optional Samples 
Optional hair samples will be collected from support persons who provide consent on the 
applicable ICF at the timepoints specified in the SoA (see Section 1.3). These optional 
samples will serve as a control to assess the potential contribution of shared 
environmental factors in the exposome analysis (see Section 8.8.1). 
8.9 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY 
8.9.1 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ASD and related 
disorders and drug safety: 
• 
Leftover PK samples (see Section 8.5) 
• 
Leftover genetic sample (see Section 8.8.1) 
• 
Additional whole blood sample for RBR on Day 1 predose and at Week 12 or Early 
Termination visit (see SoA in Section 1.3) 
• 
Leftover hair samples of the study participants (see Section 8.8.1) 
 
The sample collected for DNA extraction include, but is not limited to, genomic analysis 
and may be sent to one or more laboratories for analysis of germline or somatic 
mutations via whole genome sequencing (WGS), whole exome sequencing (WES), next-
generation sequencing (NGS), or other genomic analysis methods. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents. 


 
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The hair samples may likewise be sent to other laboratories and analyzed with 
exposomic methods. Biochemical assays of the hair samples will allow molecular 
phenotyping, which is not possible with blood analysis alone. These data will interface 
with other datasets, including genomics data, to support the identification of potential 
new targets and pathways. 
Participants will not be identified by name or any other personally identifying information. 
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies. The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.  
For all samples, dates of consent and sample collection should be recorded on the 
associated RBR page of the eCRF. Details on processes for collection and shipment of 
these samples can be found in separate sample documentation. 
RBR samples will be stored and used until no longer needed. The RBR storage period 
will be in accordance with the IRB/EC‑approved ICF and applicable laws (e.g., Health 
Authority requirements). 
The repository samples will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1). 
 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
8.11 
TIMING OF STUDY ASSESSMENTS 
8.11.1 
Screening and Pre-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 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site. 
All screening assessments (related to entry criteria), must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure. 


 
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Screening and pretreatment assessments (i.e., assessments at the pre-baseline and 
baseline visits) will be performed at the timepoints indicated in the SoA (see 
Section 1.3); however, in case of unexpected delays due to logistical or technical 
reasons (e.g., sickness of support persons or raters), the screening or pre-treatment 
period (see Figure 1) may be extended to up to 2 additional weeks. Beyond these 2 
weeks, the participant is considered a screen failure, but can be re-screened (see 
Section 5.4). 
Once all inclusion and exclusion criteria are met, the EAF (see Sections 1.3 and 8.2.1) is 
sent to the external vendor as part of the screening process, ideally before the 
pre-baseline visit. The Principal Investigator will decide whether a participant will be 
enrolled and may consult with the Sponsor (Medical Monitor or designee) for advice or 
clarification of any eligibility criteria. 
The Principal Investigators are highly encouraged to use the voluntary eligibility 
consultation offered by the external vendor to ensure meeting all eligibility criteria and 
avoid protocol deviations related to participant eligibility. 
For a participant to enter the randomized, double-blind treatment period the following 
criteria must be fulfilled: 
• 
No significant new or worsening psychiatric or medical illness since screening that in 
the opinion of the Investigator would interfere with the participant’s ability to 
participate in the study. 
• 
No change in medications since screening. 
 
8.11.2 
Assessments during Treatment 
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified be permitted to be allocated a new randomization number and re-
enroll in the study. 
All assessments must be performed as per SoA (see Section 1.3). The recommended 
order of assessments to be performed at the clinic will be defined in a separate 
document. The order of assessments may be adapted to allow efficient administration of 
all assessments at the site with the exception of assessments that have to be done at a 
specific time before or after taking the study drug as per SoA (see Section 1.3). The 
order of assessments that have to be taken at home is predefined on the electronic 
device for each participant (see Section 8.7.1.1). The site will contact the participant or 
support person over the phone to assess for any clinically significant symptoms and/or 
new medication, to ensure compliance to the study drug and digital biomarker 
assessments as well as to administer questionnaires/scales/tests when appropriate as 
per SoA (see Section 1.3). 


 
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8.11.3 
Assessments at Follow Up /Early Termination Visit 
Participants who complete the 12-week study treatment period will be asked to return to 
the clinic approximately 2 weeks and 6 weeks after the last dose of study treatment for 
safety follow-up visits (see Section 1.3).  
Assessments at the follow-up/early termination visits will be performed as indicated in 
the SoA (see Section 1.3). After the study completion/early termination visit, AEs should 
be followed as outlined in Sections 8.3.1 and 8.3.3. 
If participants discontinue from the study early (as described in Section 4.1.2 and 
Section 7), all efforts should be made to ask participants to return to the clinic for an 
early termination visit. All AEs should be followed up until they are resolved and 
additional unscheduled safety assessments should be performed at Investigator’s 
discretion after discussion with the Medical Monitor if required. 
8.11.4 
Assessments at Unscheduled Visits  
Unscheduled visits will be performed for safety reasons (e.g., for repetition of safety 
laboratory sampling). If due to a safety-related event a participant is unable to physically 
go to the site for an unscheduled visit, blood and urine samples may be collected by the 
home nurse services.  
The unscheduled visit should be used to collect all assessments that are missing at that 
time.  
If a COA (see Section 8.1.5) cannot be completed during the visit or for a scale, the total 
score (e.g., the composite scores for Vineland-3) cannot be calculated with the 
available data, the scale should be repeated via the phone within the corresponding visit 
window or at an unscheduled visit as soon as possible (within the next 7 days). 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
Because the nature of this Phase II study is purely hypothesis generating, no formal 
testing of a predefined null hypothesis is performed. 
9.2 
SAMPLE SIZE DETERMINATION 
Approximately 105 participants with ASD randomized in a 1:1:1 ratio between two active 
dosing regimens and placebo need to be recruited in order to obtain evaluable data from 
approximately 84 participants after 12 weeks of treatment. Evaluable data from 84 ASD 
participants provides at least 80% power to detect a mean difference between baseline 
and 12-week follow-up of 4.5 points on a Vineland-3 composite between any active 
treatment arm and the placebo arm with α = 0.10 error control (1-sided). The minimally 






 
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Table 13 Safety Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Adverse events 
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor. 
Adverse events will be summarized by mapped term and appropriate 
thesaurus level. 
Clinical laboratory 
tests 
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
tabular summaries and 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 of raw values and change from baseline will be used, as 
appropriate. 
ECG  
ECG data will be presented by individual listings. In addition, tabular 
summaries of raw values and change from baseline will be used, as 
appropriate. 
Concomitant 
medications 
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level. 
Concomitant medications will be presented in summary tables and listings. 
 
C-SSRS, 
PedsQL 
Cognitive 
Functioning Scale, 
and cognitive 
assessments, 
KSS, ESS or ESS-
CHAD, and 
Sudden Onset of 
Sleep 
Questionnaire 
Data will be presented in summary tables and listings 
  
9.4.4 
Pharmacokinetic Analyses  
For all participants, plasma concentrations of RO7017773 will be presented descriptively 
by dose.  
Nonlinear mixed effects modeling may be used to analyze the sparse sampling dose 
versus concentration versus time data collected for RO7017773. The PK data collected 
in this study may be pooled with data from other clinical studies conducted with 
RO7017773. Population and individual PK parameters such as clearance and volume of 
distribution may be estimated, and the influence of various covariates such as age, 
gender, and body weight, on these parameters may be investigated. Secondary PK 


 
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parameters may be derived from the model as appropriate. The results of the analysis 
may be reported separately from the CSR. 
The participant’s exposure to RO7017773 may be assessed and correlated with 
selected efficacy, PD, biomarkers and safety parameters as appropriate. 
9.4.5 
Analysis of Clinical Outcome Assessments, and Exploratory 
Pharmacodynamic and Response Biomarker Analyses  
All parameters will be presented by listings and descriptive summary statistics 
separately by group or cohorts. 
9.4.6 
Genotyping Analysis 
The genotyping data may e.g., be used to derive ASD and GABA-related genetic scores 
for responder analyses.  
9.5 
INTERIM ANALYSES  
Two interim safety analyses are planned for this study.  
The first interim analysis of accumulated safety, tolerability and PK will be performed 
once approximately 18 high-functioning adults have completed 6 weeks of treatment. 
The aim of this analysis is to evaluate the safety, tolerability and PK in high-functioning 
adults before allowing the recruitment of the adolescents and low-functioning adult 
participants.  
A second interim analysis of PK and accumulated safety and tolerability will be 
conducted once approximately 12 adolescents have completed 2 weeks of treatment. 
The aim of this analysis is to enable internal decisions to inform the design and dose 
selection for the adolescent participants and additional studies in the program.  
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses. The decision to conduct such optional 
interim efficacy analyses and the timing of these analyses will be documented in the 
Sponsor’s trial master file prior to the conduct of each interim analysis. The CSR will also 
document all interim analyses that occurred. All interim analyses will be performed and 
interpreted by members of the IMC, external experts (SOC), and appropriate senior 
management personnel. IMC and SOC members will be unblinded at the individual 
participant level, Sponsor senior management will be unblinded at the treatment group 
level. Access to treatment assignment information will follow the Sponsor’s standard 
procedures. 
The “IMC Agreement” will describe the planned interim analyses in detail. 


 
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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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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
The following section includes Appendix 1 (for regulatory, ethical and study oversight 
considerations), Appendix 2 (for AE definitions, reporting) and Appendix 3 (Procedures 
of recording), Appendix 4 (Clinical laboratory tests), Appendix 5 (Contraceptive guidance 
and collection of pregnancy information), Appendix 6 (Examples of prohibited 
concomitant medications), Appendix 7 (Alcohol unit calculation – examples), Appendix 8 
(List of Marketed Drugs Known to Prolong the QT Interval), Appendix 9 (Grading for 
Adverse Events of Special Interest with Regard to Somnolence, and Sleep), 
Appendix 10 (Preferred Term Examples for Gastrointestinal Adverse Events of Special 
Interest), and Appendix 11 (Supplementary Information for Digital Biomarkers).  
 
 


 
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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. In addition, any participant recruitment materials must be 
approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix 1). 
The Investigator should follow the requirements for reporting all AEs to the Sponsor. 
Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 
1.3. 
INFORMED CONSENT 
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Support person'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 
or their legally authorized representative will be required to sign a statement of informed 


 
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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 or the participant’s legally authorized representative. 
In this study, support person specific information will be collected to evaluate support 
person burden requiring that a separate written informed consent be obtained from the 
support person. A separate, specific signature will be required to document a support 
person’s agreement to provide optional hair samples. Support persons who decline to 
participate will not provide a separate signature. 
The ICFs 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 ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant to 
take part. The final revised IRB/EC-approved ICFs must be provided to the Sponsor for 
Health Authority submission purposes if required as per local regulations. 
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant or a legally authorized representative may be 
re-consented by signing the most current version of the ICFs or the addendum, in 
accordance with applicable laws and IRB/EC policy). For any updated or revised ICFs, 
the case history or clinical records for each participant shall document the informed 
consent process and that written informed consent was obtained using the 
updated/revised ICFs for continued participation in the study. The study team will 
provide guidance for which participants need to re-consent in the event of an update to 
the Consent form. 
A copy of each signed ICFs must be provided to the participant or the participant’s 
legally authorized representative. All signed and dated ICFs must remain in each 
participant’s study file or in the site file and must be available for verification by study 
monitors at any time. 


 
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A participant who is re-screened is not required to sign another ICF if the re-screening 
occurs within 60 days from the previous ICF signature date. 
Consent to Participate in the Research Biosample Repository 
The ICF will contain a separate section that addresses participation in the RBR. The 
Investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of participation in the RBR. Participants will be told that 
they are free to refuse to participate and may withdraw their samples at any time and for 
any reason during the storage period. A separate, specific signature will be required to 
document a participant’s agreement to provide optional RBR samples. Participants who 
decline to participate will not provide a separate signature. 
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF. 
In the event of death or loss of competence of a participant who is participating in the 
Research, the participant's samples and data will continue to be used as part of the 
RBR. 
For sites in the United States, each ICF may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for participant authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, and 
other processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
Approval by the Institutional Review Board or Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site's 
IRB/EC and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
BP41316 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 


 
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participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP41316. Data already generated before time of withdrawal of consent to RBR will still 
be used. 
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. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request. 
Confidentiality for Research Biosample Repository 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant, unless 
permitted or required by law. 


 
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Data derived from RBR sample analysis on individual participants will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
Monitoring and Oversight Research Biosample Repository 
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the ICF. 
The Sponsor’s monitors and auditors will have direct access to appropriate parts of 
records relating to participant participation in RBR for the purposes of verifying the data 
provided to the Sponsor. The site will permit monitoring, audits, IRB/EC review, and 
Health Authority inspections by providing direct access to source data and documents 
related to the samples. 
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., LPLV). 
2. 
DATA HANDLING AND RECORD 
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 


 
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The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
2.1.2. 
Clinical Outcome Assessment Data 
2.1.2.1 
Electronic Clinical Outcome Assessment Data  
An electronic clinical outcome assessment (eCOA) device will be used to capture COA 
data. The data will be transmitted electronically to a centralized database at the eCOA 
vendor. Entries should be reviewed for completeness during the clinic visit. 
eCOA data will be collected using an electronic device provided by an eCOA vendor. 
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11). System backups for data stored by the Sponsor 
and records retention for the study data will be consistent with the Sponsor’s standard 
procedures. 
2.1.2.2 Remote Administration of Electronic Clinical Outcome Assessments  
All caregiver- and patient-reported scales, forms, and interviews including the 
Vineland-3, CY-BOCS-ASD, and CGI assessments may be administered remotely at the 
participants’ home if all requirements (see below) are fulfilled. This will reduce the 
duration of site visits and burden on participants and increase flexibility for both sites and 
study participants. 
Detailed guidance will be provided to the study sites for remote administration of eCOA 
assessments by the eCOA vendor. Remote assessments should be scheduled within 
the corresponding visit window and can only be done if the participants have access to a 
location where privacy can be assured and distractions kept to a minimum. In addition, 
the participants need access to suitable hardware, software, and internet connections. 


 
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Remote caregiver- and patient-reported scales and forms will be performed using a 
secure screen-share connection with the site rater connecting to the regular electronic 
device provided by the eCOA vendor (see Section 2.1.2.1 above) and the participants 
connecting remotely from their home or other suitable location. In case of unforeseen 
technical issues, the assessments may be done via live videoconference or phone call 
with the site rater. Alternatively, devices for eCOA administration may be provided by the 
Sponsor for the duration of the study participation such that assessments can be 
performed directly on the device by the study participants and support persons. If the 
Vineland-3 or CY-BOCS-ASD assessments are administered remotely at the 
participants’ home, a live videoconference with the Central Rater will be used. Only in 
case of unforeseen technical issues the interview may be completed over the phone. 
For a given participant and/or support person, both on-site and remote assessments 
may be performed at individual study visits and for individual scales (i.e., they may 
choose the mode of administration freely). The mode of administration will be recorded 
on the eCOA device. 
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, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical study. 
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
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 study‑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. 
2.1.5. 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study. In addition, safety biomarker data will not inform decisions on participant 
management. 
2.2. 
RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities. 
If Audio recordings have been used, they will be maintained on a secure server 
throughout the duration of the study and will be destroyed one retained for at least 15 
years after study completion on approval by the Sponsor. No records may be destroyed 
during the retention period without the written approval of the Sponsor. 
For countries where Ethics Committees or the Ministry of Health will not approve audio 
recording of participant interviews, review of the scale worksheets, submitted as part of 
the assessment source information, will be performed to verify accuracy of scoring and 
adherence to study conventions. 


 
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2.3. 
STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study. 
2.3.1. 
Protocol Amendments 
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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2.3.3. 
Dissemination of Clinical Study Data 
A clinical study report containing the results of this study will be made available to 
anyone who requests a copy. A description of this clinical study and a summary of its 
results will be available at http://www.ClinicalTrials.gov. 
2.3.4. 
Management of Study Quality 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity. 
Prior to the first participant’s entry into the study, the Sponsor will identify and evaluate 
potential risks associated with critical trial processes and data and will implement 
controls for the communication, review, and reporting of these risks. Details regarding 
the applied approach for the study will be provided in the integrated Risk Based Quality 
Management Plan.  
Risk control includes the selection of risk-based parameters and establishing associated 
quality tolerance limits. Detection of deviations from defined quality tolerance limits will 
trigger an evaluation to determine if action is needed. Details on the management and 
review of quality tolerance limits will be provided in a separate Quality Tolerance Limit 
Plan. 
2.3.5. 
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 study is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for 
the study management, data management, statistical analysis and medical writing for 
the clinical study report.  
This study uses an Internal Monitoring Committee (IMC) plus Scientific Oversight 
Committee (SOC). Details are provided in Section 4.1.3.  
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 AEs in this or other studies indicates a potential health 
hazard to participants. 


 
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• 
Participant enrollment is unsatisfactory. 
 
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of participants by the Investigator. 
• 
Discontinuation of further study treatment development. 
 
 


 
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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 participant 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
 
Events Meeting the AE Definition: 
• 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a 
change in study treatment or concomitant treatment or discontinuation from study 
treatment (see Appendix 3, Section 4). 
• 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
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). 
 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting, such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
  
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. 


 
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• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
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. 


 
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This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect. 
• 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the 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. 


 
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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 guidance 
for assessing adverse event severity). Further guidance on grading non-serious adverse 
events of special interest with regard to somnolence and sleep is provided in 
Appendix 9. 
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 the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE V5.0] 
criteria); the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event). 
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. 
• 
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. 


 
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• 
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 Medical 
Monitor or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology when available 
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 study. 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) (see Section 8.3.6) 
• 
Pregnancies (see Section 8.3.5) 
 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis. 
• 
Significant new diagnostic test results. 


 
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• 
Change in causality based on new information. 
• 
Change in the event’s outcome, including recovery. 
• 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC. 
5.1 
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
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 immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to Investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event). 
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
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 


 
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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 OVERDOSE, 
MEDICATION ERROR, DRUG ABUSE, OR DRUG MISUSE 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse} 
(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 
• 
Intentional overdose: intentional 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. 
• 
Drug abuse: intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm} 
• 
Drug misuse: intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the 
participant. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events. 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). For RO7017773 and placebo, 
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. 
• 
Intentional overdose: Enter the adverse event term. Check the "Intentional overdose" 
box. If drug abuse is suspected, check the "Drug abuse" box. If drug abuse is not 
suspected, check the "Drug misuse" box. 
• 
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.  


 
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• 
Drug abuse that does not qualify as an overdose: Enter the adverse event term. 
Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose: Enter the adverse event term. Check the 
"Intentional overdose" and "Drug abuse" boxes.} 
• 
Drug misuse that does not qualify as an overdose: Enter the adverse event term. 
Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose: Enter the adverse event term. Check the 
"Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with RO7017773 and placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and should be recorded as described below: 
• 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
• 
Intentional overdose: Enter the drug name and "intentional overdose" as the event 
term. Check the "Intentional overdose" box. If drug abuse is suspected, check the 
"Drug abuse" box. If drug abuse is not suspected, check the "Drug misuse" box. 
• 
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. 
• 
Drug abuse that does not qualify as an overdose: Enter the drug name and "drug 
abuse" as the event term. Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug abuse" 
boxes. 
• 
Drug misuse that does not qualify as an overdose: Enter the drug name and "drug 
misuse" as the event term. Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug misuse" 
boxes. 


 
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• 
Drug administered to someone other than the participant: Enter the drug name and 
"patient supplied drug to third party" as the event term. Check the "Drug misuse" 
box. 
 
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 
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 through use of the reference safety 
information in the document listed below: 
Drug 
Document 
RO7017773 
RO7017773 Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


 
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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 
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 timepoints. 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 timepoints 
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. 
 
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) and 


 
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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 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor. This includes 
death attributed to worsening of comorbidities related to ASD. 
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. 
LACK OF EFFICACY OR WORSENING OF ASD  
Medical occurrences or symptoms of deterioration that are anticipated as part of ASD 
should be recorded as an adverse event if judged by the Investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study. When recording an unanticipated worsening of ASD symptoms on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., ”worsening of repetitive behaviors”). 


 
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10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in 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 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
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. 
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. 
 
11. 
PATIENT-REPORTED OUTCOME DATA (COA DATA 
REPORTED DIRECTLY BY PARTICIPANTS) 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data. Roche/Genentech study team will determine whether any PRO data 
elements may be indicative of a medically significant adverse event (e.g., suicidal 
ideation, worsening of depression, worsening of hemoptysis) and could necessitate real 
time review by the site or Sponsor.  


 
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Appendix 4  
Clinical Laboratory Tests 
The tests detailed in Table 1 will be performed by the central laboratory. If the local 
laboratory results are used, the results must be captured in source documentation and 
entered into the eCRF. 
Local laboratory results are only required for the serum and urine pregnancy test and in 
the event that the central laboratory results are not available in time for either study 
treatment administration and/or response evaluation. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time. Additionally, 
if the local laboratory results are used to make either a study treatment decision or 
response evaluation, the results must be captured in source documentation and entered 
as a comment into the eCRF}. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of the serum and urine pregnancy tests, as well as the dipstick test for 
urinalysis. Instruction manuals and supply kits will be provided for all central laboratory 
assessments. Laboratory test variables measured will include: 
Laboratory Assessments 
Parameters 
Hematology 
• 
Leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (absolute) (neutrophils, eosinophils, basophils, 
monocytes and lymphocytes)  
Clinical Chemistry 
• 
Sodium, potassium, chloride, bicarbonate, glucose (non-fasting) 
urea (BUN), creatinine, creatine phosphokinase (CPK), total 
protein, albumin, phosphate, calcium, magnesium, total bilirubin, 
alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (γ-GT), 
lactate dehydrogenase (LDH), HbA1c and GLDH (this last 
parameter will be optional; to be tested if the participant has 
elevated liver enzyme levels). 
Coagulation 
• 
Prothrombin time (INR), activated partial thromboplastin time 
(aPTT).  


 
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Laboratory Assessments 
Parameters 
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 
• 
Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides. 
Thyroid Hormones 
• 
Thyroxine (Free T4), thyroid stimulating-hormone (TSH) 
Hormone 
• 
Estradiol, follicle-stimulating hormone (FSH) 
Pregnancy Test 
• 
All women of childbearing potential (including those who have had 
a tubal occlusion/ligation) will have a blood pregnancy test at 
screening. At specified subsequent visits, urine sample will be 
used; tests results will be evaluated by the site’s local laboratory. In 
case of a positive result on urine test, a confirmation with blood test 
has to be obtained.  
• 
Serum human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential). 
Urinalysis 
• 
Dipstick: pH, glucose, protein, blood, will be performed at the study 
center (or directly at the participant’s home in case of an 
unscheduled home visit, see Section 8.11.4).  
• 
If there is a clinically significant positive result, urine will be sent to 
the central laboratory for repeat urinalysis and reflex microscopy 
and culture, as needed. As per operator judgement, a second 
dipstick testing can be conducted beforehand for confirmation of 
the positive result. If there is an explanation for the positive dipstick 
results (e.g., menses), it should be recorded and there is no need 
to perform microscopy and culture. 
• 
Microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria), if blood or protein is abnormal. 
Other Tests 
• 
Urine alcohol and drug screen (to include the following: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines). 
• 
SARS-CoV-2 could be tested through serology and/or respiratory 
swab at the discretion of the Investigator and Sponsor at screening 
and/or at any time during the study. 
 


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


 
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Appendix 5  
Contraceptive Guidance and Collection of Pregnancy 
Information 
1. 
DEFINITIONS 
• 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
• 
Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP) 
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. 
 


 
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2. 
CONTRACEPTION GUIDANCE 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use highly effective method of contraception consistently and correctly as described in 
Table 1 below. 
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly as described in Table 1 below. 
Table 1 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependent a 
(Failure rate of < 1% per year when used consistently and correctly) 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Injectable  
Highly Effective Methods That Are User-Independent 
(Failure rate of < 1% per year) 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion/ligation 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
 
 


 
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Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective 
(Failure rate of > 1% per year when used consistently and correctly) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• 
Male or female condom with or without spermicide b 
• 
Cap, diaphragm or sponge with spermicide b 
 
a) Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.  
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
b) A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control 
methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely. 
 
Male Participants 
Male contraception is not required in this study because of the minimal seminal dose 
transmitted through sexual intercourse. Indeed, the exposure margins with a vaginal 
dose of RO7017773 after sexual intercourse (assuming 6 mL volume of semen) are 
approximately 49000 fold (rabbit/human) and 124000-fold (rat/human) based on 
embryo fetal development NOAEL in relevant species (Banholzer et al 2016). 
 
3. 
PREGNANCY TESTING 
For WOCBP enrolled in the study, blood and urine pregnancy tests will be performed 
according to Schedule of Activity tables (see Section 1.3). 
In addition, pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected and according to local practice. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
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. 


 
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While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Appendix 2. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment and will 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 or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form. 
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female participant 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).  
 


 
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Appendix 6  
Examples of Prohibited Concomitant Medications 
Please note that this is not an exhaustive list of prohibited medications. 
Barbiturates 
Allobarbital, amobarbital, aprobarbital, barbexaclone, barbital, butabarbital, cyclobarbital, 
ethallobarbital, heptabarbital, hexobarbital, hexobarbital, metharbital, methohexital, 
methohexital, methylphenobarbital, pentobarbital, phenobarbital, primidone, proxibarbal, 
reposal, secobarbital, talbutal, thiopental, thiopental, vinbarbital, vinylbital 
Benzodiazepines and benzodiazepine-related drugs 
Adinazolam, bromazepam, brotizolam, camazepam, chlordiazepoxide, cinolazepam, 
clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, doxefazepam, estazolam, 
eszopiclone, ethyl loflazepate, etizolam, fludiazepam, flunitrazepam, flurazepam, 
halazepam, haloxazolam, ketazolam, loprazolam, lormetazepam, medazepam, 
midazolam, nimetazepam, nitrazepam, nordazepam, oxazolam, pinazepam, potassium 
clorazepate, prazepam, quazepam, temazepam, tetrazepam, tofisopam, triazolam, 
zaleplon, zolpidem, zopiclone 
Other anxiolytics, hypnotics and sedatives (if used longer than 1 week in 
duration) 
Acetyl glycinamide chloral hydrate, bromides, chloral hydrate, chloralodol, clomethiazole, 
dichloralphenazone, emylcamate, ethchlorvynol, mebutamate, meprobamate, 
methaqualone, paraldehyde 
Anti-epileptic drugs 
Phenelzine, tiagabine, vigabatrin, valproic acid, topiramate, felbamate, zonisamide, 
pregabalin 
Note: see also CYP3A4 inducers for additional anti-epileptic drugs that are prohibited. 
 
CYP3A inducers 
Barbiturates, carbamazepine, efavirenz, systemic glucocorticoids, modafinil, nevirapine, 
phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort (hyperforin) 
mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, enzalutamide, lumacaftor. 
CYP3A inhibitors 
Aprepitant, clarithromycin, fluconazole, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, verapamil, tipranavir, 
cobicistat (GS-9350), troleandomycin, telaprevir, danoprevir, elvitegravir lopinavir, 
voriconazole, mifepristone, mibefradil, posaconazole, ceritinib, conivaptan, nefazodone, 
ribociclib, idelalisib, and grapefruit juice.  






 
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Appendix 8  
List of Marketed Drugs Known to Prolong the QT Interval 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Aclarubicin 
(non-U.S. market only) 
Aclacin, Aclacinomycin, 
Aclacinon, Aclaplastin, 
Jaclacin 
Anti-cancer 
Amiodarone 
Cordarone, Pacerone, 
Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Antipsychotic / Antiemetic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Cocaine 
Cocaine 
Local anesthetic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Domperidone 
(non-U.S. market only) 
Motilium, Motillium, Motinorm 
Costi, Nomit 
Antiemetic 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 
Droperidol 
Inapsine, Droleptan, Dridol, 
Xomolix 
Antipsychotic / Antiemetic 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, 
Erythrocot, E-Base, 
Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, 
Abboticin-ES, Erycin, PCE 
Dispertab, Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Escitalopram 
Cipralex, Lexapro, Nexito, 
Anxiset-E (India), Exodus 
(Brazil), Esto (Israel), 
Seroplex, Elicea, Lexamil, 
Lexam, Entact (Greece), 
Losita (Bangladesh), Reposil 
(Chile), Animaxen 
(Colombia), Esitalo 
(Australia), Lexamil (South 
Africa) 
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, 
Apocard, Ecrinal, Flécaine 
Antiarrhythmic 
Fluconazole 
Diflucan, Trican 
Antifungal 
Halofantrine 
(non-U.S. market only) 
Halfan 
Antimalarial 
Haloperidol 
Haldol (U.S. & UK), 
Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol 
(Germany), Einalon S, 
Eukystol, Halosten, Keselan, 
Linton, Peluces, Serenace, 
Serenase, Sigaperidol 
Antipsychotic 
Hydroquinidine 
(Dihydroquinidine) 
(non-U.S. market only) 
Serecor 
Antiarrhythmic 
Ibogaine 
(non-U.S. market only) 
None 
Psychedelic 
Ibutilide 
Corvert 
Antiarrhythmic 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Levomepromazine 
(Methotrimeprazine) 
(non-U.S. market only) 
Nosinan, Nozinan, 
Levoprome 
Antipsychotic 
Levosulpiride 
(non-U.S. market only) 
Lesuride, Levazeo, Enliva 
(with rabeprazole) 
Antipsychotic 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Ondansetron 
Zofran, Anset, Ondemet, 
Zuplenz, Emetron, Ondavell, 
Emeset, Ondisolv, Setronax 
Antiemetic 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Papaverine HCl (Intra-
coronary) 
none 
Vasodilator, Coronary 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, 
Quinact, Quinidex, Cin-Quin, 
Quinora 
Antiarrhythmic 
Roxithromycin 
(non-U.S. market only) 
Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, Biaxsig, 
Roxar, Roximycin, 
Roxomycin, Rulide, Tirabicin, 
Coroxin 
Antibiotic 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Sulpiride 
(non-U.S. market only) 
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor 
Antipsychotic, atypical 
Sultopride 
(non-U.S. market only) 
Barnetil, Barnotil, Topral 
Antipsychotic, atypical 
Terlipressin 
(non-U.S. market only) 
Teripress, Glypressin, 
Terlipin, Remestyp, Tresil, 
Teriss and others 
Vasoconstrictor 
Terodiline 
(non-U.S. market only) 
Micturin, Mictrol (not 
bethanechol) 
Muscle relaxant 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anti-cancer 
 
Source https://crediblemeds.org/new-drug-list/ - Last revision date: September 15, 2019


 
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Appendix 9  
Grading for Adverse Events of Special Interest with Regard to Somnolence and Sleep 
Term 
Grade 1 -Mild 
Grade 2 – Moderate 
Grade 3 -Severe 
Definition 
Source 
Hypersomnia 
Mild increased need for 
sleep 
Moderate increased 
need for sleep 
Severe increased need for sleep 
Excessive sleepiness 
during the daytime. 
CTCAE 
V5.0 
Somnolence 
Mild but more than usual 
drowsiness or 
sleepiness 
Moderate sedation; 
limiting instrumental ADL 
Obtundation or stupor 
Excessive sleepiness and 
drowsiness. 
CTCAE 
V5.0 
Depressed Level 
of Consciousness 
Decreased level of 
alertness 
Sedation; slow response 
to stimuli; limiting 
instrumental ADL 
Difficult to arouse 
A disorder characterized 
by a decrease in ability to 
perceive and respond 
CTCAE 
V5.0 
Lethargy 
Mild symptoms; reduced 
alertness and 
awareness 
Moderate symptoms; 
limiting instrumental ADL 
No CTCAE V5.0 grade 3 
A disorder characterized 
by a decrease in 
consciousness 
characterized by mental 
and physical inertness. 
CTCAE 
V5.0 
Sudden Onset 
Sleep  
 
no or mild disruption or 
work/activities/ social life  
moderate disruption or 
work/activities/ social life  
important disruption or work/activities/ 
social life 
A sensation of sudden, 
irresistible, daytime 
sleepiness without 
awareness of falling 
asleep 
Roche 
internal  
ADL = activities of daily living 
 


 
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Appendix 10  
Preferred Term Examples for Gastrointestinal Adverse Events of 
Special Interest 
Source: MedDRA Version 22.1 Standardised MedDRA Queries (SMQ) 
Gastrointestinal non-specific symptoms and therapeutic procedures (SMQ-narrow) 
Abdominal discomfort 
Abdominal distension 
Abdominal pain 
Abdominal pain lower 
Abdominal pain upper 
Abdominal symptom 
Abdominal tenderness 
Abnormal faeces 
Aerophagia 
Anorectal discomfort 
Bowel movement irregularity 
Change of bowel habit 
Constipation 
Defaecation urgency 
Diarrhoea 
Epigastric discomfort 
Eructation 
Faecal volume decreased 
Faecal volume increased 
Faeces hard 
Faeces soft 
Flatulence 
Frequent bowel movements 
Gastrointestinal pain 
Gastrointestinal sounds abnormal 
Gastrointestinal toxicity 
Infrequent bowel movements 
Nausea 
Non-cardiac chest pain 
Oesophageal discomfort 
Oesophageal pain 
Premenstrual cramps 
Vomiting 
 


 
RO7017773—F. Hoffmann-La Roche Ltd 
173/Protocol BP41316, Version 5 
Appendix 11  
Supplementary Information for Digital Biomarkers 
PARTICIPATION: BENEFITS, TRAINING, AND COMPLIANCE 
WHAT IS THE BENEFIT OF COLLECTING THESE DATA? 
The traditional approaches to measuring the signs and symptoms of a condition, through 
the report of a participant, observer, or clinician, have a variety of drawbacks. Reports 
can be unreliable due to the dependence on subjective ratings. They require the 
participant to visit a clinical site and this may require travelling a long distance and the 
time taken to administer the assessments can be great, creating a high burden for the 
participant. The frequency of measurement is low; therefore, changes in symptom 
severity in-between site visits is not captured. If symptom severity is much higher on the 
day of the visit, this will give a misleading impression of their status. Digital Health 
Technology has the potential to address these drawbacks by measuring the signs of a 
condition objectively, remotely and frequently using sensor technology that can be used 
independently by participants in their daily life. This study will explore the feasibility of 
using this technology in this cohort. 
IS A PARTICIPANT OBLIGED TO COMPLETE A TASK IF THEY FIND THE 
DIGITAL BIOMARKER SCHEDULE OF ASSESSMENTS TOO DEMANDING? 
We encourage participants to complete the tasks at home as per the digital biomarker 
schedule of assessments, but if a participant does not complete a task on one or more 
days this will not count as a protocol deviation. 
IS A PARTICIPANT OBLIGED TO COMPLETE A TASK IF THEY ARE 
UNABLE TO UNDERSTAND THE INSTRUCTIONS? 
The tasks are designed to be simple to understand and full instructions are provided in 
the application. Participants are then provided with full training by site staff. Some 
participants may, however, remain unable to understand the task instructions. 
Understanding instructions may be particularly problematic for those participants with 
intellectual disability. In such cases site staff can de-activate the task for that participant. 
ARE ALL PARTICIPANTS OBLIGED TO WEAR THE SMARTWATCH? 
When the participant consents to the study, they agree to wear the smartwatch on a 
daily basis, but if a participant does not wear the smartwatch on one or more days this 
will not count as a protocol deviation. 
ARE ALL PARTICIPANTS OBLIGED TO INSTALL THE BEACONS? 
The use of the beacons is optional. If the participant agrees to install the beacons in their 
home but subsequently does not, this will not count as a protocol deviation. 




 
RO7017773—F. Hoffmann-La Roche Ltd 
175/Protocol BP41316, Version 5 
equipment in the device sheet that is included with the technology and the eCRF. The 
device sheet should then be scanned and emailed to Roche at the contact address 
provided with the training material. 
DATA SECURITY AND PRIVACY 
DO YOU CAPTURE ANY PERSONALLY-IDENTIFIABLE INFORMATION? 
The participant’s name and other identifiable text are not captured. The site is asked to 
enter the participant’s screening ID into the smartphone application and all other data 
captured with the technology is then related to the participant through the screening ID. 
Please see questions below for issues related to location and audio data. 
HOW IS DATA SECURITY MAINTAINED? 
Once the data have been collected, the data are encrypted using industry gold standard 
256-bit asymmetric encryption. This encryption method makes it impossible for anyone, 
including the study participant, to decrypt and read the data. The data can only be 
decrypted and processed by named researchers of the Sponsor. Whenever the study 
participant connects to Wi-Fi, the data are transmitted via a secure transfer protocol 
(HTTPS) to a secure cloud (Microsoft Azure). 
Data from a participant are uploaded to the Microsoft Azure server located in the 
Netherlands. The Microsoft Azure cloud servers are managed by the Sponsor. Upon 
successful data transfer, the data copy on the smartphone is deleted. Data on the 
secure cloud remain asymmetrically encrypted at all times. For data processing and 
analysis purposes, data are mirrored from the secure cloud to one of the Sponsor’s 
physical servers that are located behind the Sponsor’s firewall. Here data are decrypted 
by named researchers. The data are then processed for the computation of features 
from the sensor data. 
HOW WILL THE AUDIO RECORDINGS BE PROCESSED TO PROTECT THE 
CONFIDENTIALITY OF THE PERSON(S) BEING RECORDED? 
Audio is recorded on the smartphone (only) during the Describe the Picture task and 
Conversation task. At the end of each task participants have the option to delete the 
recording. If they agree to transfer the recording, it will be uploaded to the Sponsor via 
the secure server described above. The audio recordings may then be listened to by a 
small, limited number of researchers employed by the Sponsor. Features will be derived 
from the audio recordings for analysis. These features will not include personally-
identifiable information. There will be a delay between the audio recordings being 
recorded, transferred to the Sponsor, and analyzed by the Sponsor, potentially lasting up 
to many months; therefore, the recordings will not be used for detecting adverse events. 


 
RO7017773—F. Hoffmann-La Roche Ltd 
176/Protocol BP41316, Version 5 
Background noise is also recorded continuously by the smartphone application. 
Statistical features of these data are extracted by the smartphone application. The raw 
audio recordings are not stored on the smartphone – they are held in temporary memory 
and discarded after extraction of the statistical features. The statistical features are then 
transferred to the Sponsor via the server described above. These statistical features 
allow one to infer the volume and duration of speech in the environment, but not the 
actual words spoken. 
HOW IS LOCATION DATA PROCESSED TO PROTECT PARTICIPANT 
PRIVACY? 
GPS location data are obfuscated at data capture. From the obfuscated data it is not 
possible to determine the participant’s actual location, only the direction and distance 
that they travel. Specifically, the data points are translated into latitudinal and 
longitudinal direction and also rotated using a certain factor within their natural ranges of 
-90° : +90° for latitude, -180° : +180° for longitude and 0° : 360° for rotation. 
REMOTE ADMINISTRATION OF IN-CLINIC ASSESSMENTS FOR DIGITAL 
BIOMARKERS  
In the event that the study participant and support person are not able to access their 
clinical site to attend in-clinic visits as scheduled per Table 3, in-clinic assessment for the 
digital biomarkers might be administrated remotely in a telemedicine visit (e.g., phone 
call, virtual meeting) set up to best fit patient’s and support person’s needs as well as 
site capabilities. Remote in-clinic assessments are in any case to be performed under 
the supervision (in–remote) of study site personnel, who should provide support as 
needed to study participant and support person. Within the study phone app, a remote 
in-clinic assessment feature has been built and it is unattained password protected. This 
function is not hosted in the clinician area, but is specifically designed to be accessed 
only by study participants. Detailed guidance will be provided to the study sites for 
remote administration of the in-clinic assessment for digital biomarkers.  
Remote assessments should be scheduled within the corresponding visit window and 
can only be done if the participants have access to a location where privacy can be 
assured and distractions kept to a minimum. 
 



SAP_001.pdf: 
Official Title: 
A Phase II Multicenter, Randomized, Double-Blind, 12-Week 
Treatment, 3-Arm, Parallel-Group, Placebo-Controlled Study to 
Investigate the Efficacy, Safety and Tolerability of RO7017773 in 
Participants Aged 15 to 45 Years With Autism Spectrum Disorder 
(ASD) 
NCT Number: 
NCT04299464 
Document Date: 
Statistical Analysis Plan Version 2: 28-June-2024 


STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A PHASE II MUL TIC ENTER, RANDOMIZED, DOUBLE-BLIND, 
12-WEEK TREATMENT, 3-ARM, PARALLEL-GROUP, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF ALOGABAT IN 
PARTICIPANTS AGED 15 TO 45 YEARS WITH AUTISM 
SPECTRUM DISORDER (ASD) 
STUDY NUMBER: 
BP41316 
STUDY NAME: 
Aurora 
VERSION NUMBER: 
v.2 
ROCHE COMPOUND: 
RO7017773 
COMPOUND NAME: 
Alogabat 
EUDRACT NUMBER: 
2019-003524-20 
IND NUMBER: 
141893 
PLAN PREPARED BY: 


STATISTICAL ANALYSIS PLAN APPROVAL 
28-Jun-2024 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
DATE FINAL: 
r . ;edby: 
(J 
Signer Name: 
L
Signing Reason: I approve this document 
Signing Time: 28-Jun-2024 11 :55:28 PM GEST 
1 0EC3CF5F664481 FBAE0AD933DC0A009 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
See electronic date stamp above 
CONFIDENTIAL 
-
This is an F. Hoffmann-La Roche Ltd document that contains confidential information. Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 


STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on Roche SAP model document V 2.0. 
Based on Protocol 
SAP Version 
Approval Date 
(Version, Approval Date} 
2 
lsee electronic date stamp 
US VS, 02 JUNE 2022 
on title pagel 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
No key changes to the SAP occurred since version 1. Minor changes were made to 
detail further the derivation of endpoints, and the specification of subgroup analyses. 
Further edits were made to the list of outputs, and the entire document to improve clarity 
and consistency. 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
3 


TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 7 
1.1 
Objectives and Endpoints .......................................................... 7 
1.2 
Study Design ............................................................................. 8 
1.2.1 
Treatment Assignment and Blinding .......................................... 9 
1.2.2 
Independent Review Facility .................................................... 10 
1.2.3 
Data Monitoring ....................................................................... 10 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 10 
2.1 
Statistical Hypotheses ............................................................. 10 
2.2 
Sample Size Determination ..................................................... 11 
3. 
ANALYSIS SETS .......................................................................... 11 
4. 
STATISTICAL ANALYSES ........................................................... 12 
4.1 
General Considerations .......................................................... 12 
4.1.1 
Missing Data ............................................................................ 16 
4.1.2 
Baseline Definitions ................................................................. 16 
4.1.3 
Characteristics of Efficacy Endpoints ....................................... 16 
4.1.4 
Characteristics of Safety Endpoints ......................................... 19 
4.2 
Primary, Secondary and Exploratory Efficacy Analysis ........... 30 
4.2.1 
Definition of Primary Endpoint ................................................. 30 
4.2.2 
Main Analytical Approach for Primary, Secondary, CRRI 
and CGl-I Endpoints ............................................................... 30 
4.2.2.1 
Subgroup Analyses for Primary and Secondary Efficacy 
Endpoints ................................................................................. 31 
4.3 
Supportive Exploratory Efficacy Endpoints Analyses ............... 32 
4.4 
Safety Analyses ....................................................................... 32 
4.4.1 
Extent of Exposure .................................................................. 34 
4.5 
Other Analyses ........................................................................ 34 
4.5.1 
Summaries of Demographics and Baseline Characteristics .... 34 
4.5.2 
Pharmacokinetic Analyses ....................................................... 34 
4.5.3 
Biomarker Analyses ................................................................. 34 
4.6 
Interim Analyses ...................................................................... 35 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
4 


5. 
6. 
SUPPORTING DOCUMENTATION .............................................. 36 
REFERENCES .............................................................................. 36 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AASP Adolescent/ Adult Sensory Profile 
ADaM Analysis Data Model 
ADOS Autism Diagnostic Observation Schedule 
AE Adverse Event 
ANCOVA Analysis of Covariance 
ASD Autism Spectrum Disorder 
BAI Beck Anxiety Inventory 
BL Baseline 
CDISC Clinical Data Interchange Standard Consortium 
CGI Clinical Global Impression 
CSR Clinical Study Report 
C-SSRS Columbia-Suicide-Severity Rating Scale 
CY-BOCS-ASD Children's Yale-Brown Obsessive Compulsive Scale Modified for ASD 
ECG Electrocardiogram 
eCOA electronic Clinical Outcome Assessments 
eCRF electronic Case Report Form 
EEG Electroencephalography, Electroencephalogram 
ESS Epworth Sleepiness Scale 
ESS-CHAD Epworth Sleepiness Scale for Children and Adolescents 
GSV Growth Scale Value 
HF High Functioning 
IA Interim Analysis 
IMC Internal Monitoring Committee 
IRF Independent Review Facility 
lxRS Interactive voice/web-based Response System 
KSS Karolinska Sleepiness Scale 
LF Low Functioning 
MDD Minimally Detectable Difference 
MedDRA Medical Dictionary for Regulatory Activities 
PedsQLTM Pediatric Quality of Life Inventory TM 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
5 


PD Pharmacodynamic 
PK Pharmacokinetic 
PRAS-ASD Parent-rated Anxiety Scale for ASD 
PROMIS Patient-Reported Outcomes Measurements Information System 
RBS-R Repetitive Behavior Scale-Revised 
RRB Restricted and Repetitive Behavior 
SAE Serious Adverse Events 
SAP Statistical Analysis Plan 
SD Standard deviation 
SoA Schedule of Assessments 
soc Scientific Oversight Committee 
SSP Short Sensory Profile 
TFL Table Figure Listing 
WASI Wechsler Abbreviated Scale of Intelligence 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
6 


1. 
INTRODUCTION 
The objectives of this Phase 2 proof-of-concept study (BP41316) is to investigate the 
efficacy, safety, and tolerability of Alogabat in adolescents and adults (15 to 45 years of 
age) with autism spectrum disorder (ASD), with a target on the core symptoms of ASD of 
social communication deficits, and restricted and repetitive behaviors (RRBs) and 
interests. In addition, a set of biomarkers linked to the mechanism of action of the study 
drug or to ASD-related alterations is investigated in a representative patient population 
to pilot the identification of responder subgroups. To date, very few studies have 
investigated the effect of pharmacological treatments on the core symptoms of ASD and 
consequently no pharmacological agents are approved that offer a treatment for the core 
symptoms in this population of high unmet clinical need. 
A key challenge in the development of new therapies to treat the core symptoms in ASD 
is the change of symptoms across different stages of development in longitudinal studies 
in both social communication deficits as well as in RRBs (Simonoff et al. 2020; Richler et 
al. 2010; Pender et al. 2020). The presentation of RRBs is known to be associated with 
age and the level of intellectual functioning (Lam and Aman 2007, Esbensen et al 2009, 
Richler et al 2010, Kim and Lord 2010, Uljarevic et al 2022). Thus, interventions may 
have different effects, depending on age and intelligence quotient (IQ), on individuals 
with ASD and treatment effects in older adolescents and adults may not be extrapolated 
to effects in the pediatric population, given the potential difference in manifestations, 
both quantitatively and qualitatively, of social communication deficits and RRBs with age. 
Adolescents and adults aged 15 to 45 years with ASD are enrolled in this study to allow 
for the generation of data on the safety and tolerability, and the potential efficacy in 
these age groups. 
Analyses of the primary and secondary endpoints as described in the protocol will be 
performed as planned. 
1.1 
Table 1 
OBJECTIVES AND ENDPOINTS 
Primary and Secondary Objectives 
Primary Objective 
Endpoint 
• 
To evaluate the efficacy of 
• Change from baseline to Week 12 in the Adaptive 
12-week treatment with 
alogabat compared with 
placebo in treating social 
communication deficits in 
participants with Autism 
Spectrum Disorder (ASD) 
Secondary Objectives 
• To evaluate the safety and 
tolerability of a 12-week 
treatment with alogabat in 15-
to 45-year-old participants 
with ASD 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
Behavior Composite score of the Vineland™ 
Adaptive Behavior Scales, Third Edition 
(Vineland™-3) 
Endpoints 
• Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
7 


• Incidence of treatment discontinuations due 
toAEs 
• Change from baseline over time and 
incidence of clinically relevant abnormalities 
in vital signs including orthostatic changes, 
electrocardiogram (ECG) parameters and 
safety laboratory values including the 
incidence of marked laboratory 
abnormalities 
• Change from baseline over time in suicide 
risk (using the Columbia-Suicide-Severity 
Rating Scale [C-SSRS]) 
• Incidence of daytime sleepiness assessed 
with the Karolinska Sleepiness Scale (KSS), 
the Epworth Sleepiness Scale (ESS) or the 
ESS for children and adolescents (ESS-
CHAD), and the Sudden Onset of Sleep 
Questionnaire 
• To evaluate the efficacy of a • Change from baseline to Week 12 in 
12-week treatment with 
behavior/symptoms as measured by all domains 
alogabat compared with 
of the Repetitive Behavior Scale-Revised (RBS-
placebo on restricted and 
R) scale 
repetitive behaviors (RRBs) 
• To evaluate the efficacy of a 
• Change from baseline to Week 12 on the 
12-week treatment with 
Vineland-3 Socialization domain 
alogabat compared with 
placebo on social behaviors 
• To evaluate the efficacy of a 
12-week treatment with 
• Change from baseline to Week 12 on the 
alogabat compared with 
Vineland-3 Communication domain 
placebo on communication 
skills 
1.2 
STUDY DESIGN 
Study BP41316 is a multicenter, randomized, double-blind, parallel-group, 3-arm, 
placebo-controlled, 12-week treatment Phase II study to investigate the efficacy, safety 
tolerability, and pharmacokinetics of Alogabat in participants aged 15 to 45 years with a 
diagnosis of ASD and a Wechsler Abbreviated Scale of Intelligence, Second Edition 
(WASl-11) score of;:: 50. Approximately 105 participants with ASD (in order to have at 
least 84 evaluable participants at study end) aged 15 to 45 years are enrolled into the 
study. Participants are randomized 
in a 1:1:1 ra 10 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
8 


In addition, randomization was staggered with the enrollment of high-functioning adults 
(defined as WASl-II 
70; [HFA]) first, followed by adolescents and low-functioning adults 
defined as WASl-11 < 70; [LFA]). After approximately 18 high-functioning adults (aged 18 
to 45 years) had completed 6 weeks of treatment 
e 
oge er wI 
e 
con uc e a 
, sa e , an 
o era 1 1 review 
t Interim 
Analysis). Adequate PK, safety, and tolerability in high-functioning adults was 
established and PK-model predictions from healthy adult volunteers were confirmed to 
be comparable with the observed PK results in high-functioning adults. Low-functioning 
adults and adolescents aged 15 to 17 years (both high- and low-functioning) were 
included in the study. A 2nd Interim Analysis was performed by the IMC+ SOC to 
evaluate PK, safety, and tolerability data from all available participants once 12 
adolescents had completed 2 weeks of treatment. Hereby, adequate PK, safety, and 
tolerability was confirmed in adults and established in adolescents. 
Each participant was evaluated using several scales and tests at each visit at the clinic. 
A total of 9 clinic visits (screening period included) and 1 phone contact, to assess for 
any clinically significant symptoms and/or new medication, were planned. In addition, 
digital biomarker data was collected. Each participant needed a reliable caregiver, 
parent, or support person who oversaw the participant's adherence with protocol-
specified procedures and provided feedback on all informant-based assessments 
throughout the study. The same support person attended all on-site visits. For support 
persons of high-functioning adult participants, no on-site visits were necessary after the 
screening visit if the support persons opt to complete all electronic clinical outcome 
assessments (eCOA}, interview, and forms remotely. 
The primary analysis will be performed at database lock after Last Participant Last Visit. 
1.2.1 
Treatment Assignment and Blinding 
Randomization took place on Day 1. Randomization to the different treatment arms 
(placebo,_ 
alogabat or- alogabat-with a ratio of 1:1:1) was stratified by 
age [adolescenfs, adults] an~F. HF], andcapping rules were applied as follows: 
Table 2 
Capping Rules 
Clinical Factor 
IQ (as assessed by WASl-11) 
50 to 69 vs 
70 
Sex 
female vs male 
Capping Rule 
The proportion of low-functioning 
participants (IQ 
50 to 69) is limited 
to 25% overall. 
The proportion of female participants is 
limited to a maximum of 25%. 
All participants were centrally assigned to randomized study treatment using an lxRS. 
Before the study was initiated, the telephone number and call-in directions for the lxRS 
and/or the login information and directions for the lxRS was provided to each site. 
Alogabat-F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
9 


The randomization list was computer generated centrally by a third party and made 
available only to those individuals responsible for PK sample bioanalysis and to 
statisticians or programmers at the Sponsor directly involved in the production of outputs 
to support IMC and SOC meetings. The data was analyzed in a secure area which is not 
accessible to any blinded personnel. 
Blinding 
The lxRS was programmed with blind-breaking instructions: The blind may be broken if, 
in the opinion of the Investigator, it is in the participant's best interest to know the study 
treatment assignment. The Sponsor must be notified before the blind is broken unless 
identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management 
of the participant's condition (e.g., antidote available). In this case, the Sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and Clinical Study Report (CSR), 
as applicable. 
Unblinding should not result in the withdrawal of the participants from the study. Every 
effort should be made to retain unblinded participants. As per Health Authority reporting 
requirements, the Sponsor will break the treatment code for all unexpected SAEs that 
are considered by the Investigator to be related to study treatment. Whenever disclosure 
of the identity of the test medication is necessary, adequate procedures will be in place 
to ensure integrity of the data. 
1.2.2 
Independent Review Facility 
No Independent Review Facility (IRF) was planned for this study. 
1.2.3 
Data Monitoring 
An IMC consisting of a selected subset of Roche representatives as identified in the 
"IMC + SOC Agreement" was responsible to perform interim analyses of accumulated 
safety, tolerability, PK, and efficacy (as required) data. The IMC members, the clinical 
pharmacologist, and the pharmacometrician were unblinded to individual study treatment 
allocation. 
An SOC consisting of one external expert supported the IMC in making their 
recommendations. The SOC member was likewise unblinded to individual study 
treatment allocation. Access to treatment assignment information followed the Sponsor's 
standard procedures. Based on accumulated study data available at their review, the 
IMC and SOC could have recommended for example adjustment(s) of the dose levels, 
dosing regimen, or the timing of dosing. Further details can be found in the "IMC + SOC 
Agreement". 
2. 
2.1 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
STATISTICAL HYPOTHESES 
No formal hypothesis testing will be done. However, to quantify gating criteria it was 
useful to specify a standardized minimal effect size (MOD) in a way that if the observed 
drug effect would be above the MOD, a hypothesis test based on p-values of the 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
10 


ANCOVA models as described in section 3.3 would come out significant, assuming at 
least 28 subjects are evaluable per arm. Gating criteria will be based on p-values of the 
ANCOVA models. 
2.2 
SAMPLE SIZE DETERMINATION 
Approximately 105 participants with ASD randomized in a 1: 1: 1 ratio between two active 
dosing regimens and placebo need to be recruited in order to obtain evaluable data from 
approximately 84 participants after 12 weeks of treatment. Evaluable data from 84 ASD 
participants provides at least 80% power to detect a mean difference between baseline 
and 12-week follow-up of 4.5 points on a Vineland™ -3 composite between any active 
treatment arm and the placebo arm with a = 0.10 error control (1-sided). The minimally 
detectable difference in this cohort is 2. 7 points. It is assumed that the standard 
deviation of the differences between baseline and 12 weeks follow up is 8.0 points, that 
20% of participants will not provide evaluable data, and that the participants recruited will 
consist of at most 25% low-functioning participants, at most 25% female participants. 
Because the purpose of this study is exploratory, no adjustment for comparison of 
multiple active doses to a single placebo arm is performed. 
3. 
ANALYSIS SETS 
The analysis data sets for the purposes of analyses are presented in Table 3. 
Efficacy analyses based on the Efficacy Analysis Population will be restricted in a way 
that assessments at week 12 will be excluded from the efficacy analyses if the 
participant missed more than 7 consecutive study medications immediately preceding 
the day of the assessment (if performed), or if the overall IMP compliance, i.e. the ratio 
of administered study medication to planned study medication until the assessment, was 
<60%. 
Post treatment EEG assessments will be excluded from the PD analysis if the last dose 
of study medication was taken more than 6 hours before the EEG. Additionally, Week 2 
and Week 12 EEG assessments will be excluded from the PD analysis if the study 
participant missed more than 3 doses in the week preceding the EEG. 
Table 3 
Analysis Sets 
Population 
Safety Population 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
Description 
All participants randomized to study 
treatment and who received at least one 
dose of the study treatment, whether 
prematurely withdrawn from the study or 
not, will be included in the safety 
analysis. 
11 


Pharmacokinetic Population 
All participants providing pharmacokinetic 
data will be included in the PK 
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. 
Efficacy Analysis Population 
All participants who give informed 
consent, are randomized, and receive at 
least one dose of double-blind study 
medication. 
4. 
STATISTICAL ANALYSES 
4.1 
GENERAL CONSIDERATIONS 
Table 4 
Analysis Time Windows 
Assessments will be assigned to analysis study days according to visit windows defined 
below: 
Analysis 
Baseline 
Day 1 
Day7 
Window 
Label 
Planned 
1 (a) 
1 
-
Study Day 
ECGs 
Study Day 
s 1 (a) 
1 
-
Vital Signs, KSS 
Study Day 
s 1 (a) 
1 
-
Lab (Hematology, Chemistry, Urinalysis) 
Study Day 
s 1 (a) 
-
ESS 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
-
Day 14 
Day42 
Day63 
Day84 
(c) 
14 
42 
63 
84 
2 to 28 
-
-
.:: 71 
2 to 28 
29 to 55 -
.:: 71 
2 to 28 
29 to 55 
56 to 70 
.:: 71 
(b) 
12 


Study Day 
s 1 
-
-
2 to 28 
29 to 70 -
2: 71 
ESS-CHAD 
Study Day 
s 1 
-
-
2 to 28 
29 to 55 
56 to 70 
2: 71 
Coagulation 
Study Day 
s 1 (a) 
-
-
-
-
56 to 70 
2: 71 
Vineland-3, RBS-R, CRRI, BAI, PRAS-ASD, SSP, AASP, PedsQL, PROMIS, 
Anthropometric Measurements 
Study Day 
s 1 (a) 
-
-
-
-
-
2: 71 
CGI-S, CGl-1 (d) 
Study Day 
s 1 (a) 
-
-
2 to 28 
29 to 70 -
2: 71 
(b) 
Neurocognitive Battery 
Study Day 
s 1 (a) 
1 
-
2 to 28 
29 to 70 -
2: 71 
(b) 
Sudden Onset of Sleep 
Study Day 
s 1 
-
2 to 10 
11 to 28 
29 to 55 
56 to 70 
2: 71 
(a) Latest assessment prior to intake of first study medication. Use date and time, if 
available. 
(b) May include assessments on day 1 if after the time of first study medication. 
(c) Planned for adolescent participants only. 
(d) No baseline for CGl-1. 
If more than one assessment is in the same time window, the assessment that is closest 
to the planned study day will be selected to enter the summary tables. 
Table 5 
General Descriptive Statistics 
Continuous variables will be summarized with the following descriptive statistics and 
nomenclature: 
n 
mean 
SD 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
number of observations or participants 
arithmetic mean 
standard deviation 
13 


min 
minimum value 
q1 
first quartile value 
median 
median value 
q3 
third quartile value 
max 
maximum value 
Categorical variables will be summarized and presented with the following 
nomenclature: 
Percentage by category will be based on the number of participants exposed within a 
category. Categories of NOT REPORTED, MISSING, and/or UNKNOWN will be 
excluded from summaries if null or n/a. 
Besides descriptive summaries, listings, and plots will be provided where deemed 
necessary. Listings will also include multiple assessments within the same time window. 
Table 6 
ADaM Datasets 
The analysis datasets will be generated in accordance with Clinical Data Interchange 
Standard Consortium (CDISC) Analysis Data Model (ADaM) Version 2.1. ADaM 
compliant datasets will be created by the sponsor. 
ADaM Dataset Name Description 
ADSL 
Subject Level 
Analysis Dataset 
ADAE 
Adverse Events 
Analysis Dataset 
ADCM 
Concomitant 
Medications Analysis 
Dataset 
ADMH 
Medical History 
Analysis Dataset 
ADEX 
Exposure Analysis 
Dataset 
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Double Programmed ? 
Yes 
No 
No 
No 
No 
14 


ADVS 
Vital Signs Analysis 
Dataset 
ADEG 
ECG Analysis 
Dataset 
ADLB 
Laboratory Analysis 
Dataset 
ADDV 
Protocol Deviations 
Analysis Dataset 
ADSUB 
Subcategory Analysis 
Dataset 
ADCSSRS 
C-SSRS Analysis 
Dataset 
ADKSS 
KSS Analysis 
Dataset 
ADVABS3 
VABS-111 
Questionnaire 
Analysis Dataset 
ADRBSR 
RBS-R 
Questionnaire 
Analysis Dataset 
ADESS 
ESS Questionnaire 
Analysis Dataset 
ADSOSQ 
Sudden Onset of 
Sleep 
Questionnaire 
Analysis Dataset 
ADNEURO 
Neurocognitive 
Battery Analysis 
Dataset 
ADCRRI 
CRRI 
Questionnaire 
Analysis Dataset 
ADCGII 
CGl-1 Analysis 
Dataset 
ADCGIS 
CGI-S Analysis 
Dataset 
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Yes 
Yes 
No 
No 
Yes 
No 
No 
Yes 
Yes 
No 
No 
No 
Yes 
Yes 
No 
15 


ADBAI 
BAI Analysis 
Yes 
Dataset 
ADPRAS 
PRAS-ASD 
Yes 
Analysis Dataset 
ADSSP 
SSP Analysis 
No 
Dataset 
ADAASP 
AASP Analysis 
No 
Dataset 
ADPROMIS 
PROMIS Analysis 
No 
Dataset 
ADPEDSQL 
PedsQL Analysis 
No 
Dataset 
4.1.1 
Missing Data 
Generally, no data imputations will be made. 
4.1.2 
Baseline Definitions 
Unless otherwise stated, baseline is defined as the last observation recorded before the 
first study drug administration. The last observation can be an unscheduled/ repeated 
measurement. If a pre-treatment observation is missing, then the pre-baseline 
(preferred) or screening value may be used. 
As the age at screening was determining the choice of questionnaires, and for reasons 
of consistency, the age at screening was chosen to be the analysis age. 
ECG baseline is defined as the mean of the triplicate measurement before the first study 
drug administration on Day 1. 
4.1.3 
Characteristics of Efficacy Endpoints 
Vineland-3 
The Vineland-3 (Sparrow et al. 2016) is a semi-structured interview that measures an 
individual's adaptive behaviour across three domains of communication, socialisation 
and daily living skills. Additional domains of motor skills (only used in children up to 9 
years of age) and maladaptive behaviours were not captured in this study. Each 
adaptive behaviour domain is composed of three subdomains. Subdomain raw scores 
are used to derive two types of scores: Standard (V-scale scores; range from 1-24) and 
Growth Scale Values (GSVs). Standard scores are scores relative to a normative age 
group and can range from 20-140. A GSV is a person-ability score that is used to track 
an individual's progress. A higher score indicates better adaptive functioning. 
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Repetitive Behaviour Scale-Revised {RBS-R) 
The RBS-R (Bodfish, 1999) is a 43-item informant-based questionnaire, assessing the 
variety of restricted and repetitive behaviours observed in individuals with ASD. A total 
RBS-R score is calculated as the sum of the scores for the 43 items. The total RBS-R 
score ranges from 0 to 129, with a higher score indicating more severe repetitive and 
restrictive behaviours. The RBS-R subscale scores will also be calculated as the sum of 
the scores for each item within each subscale. 
Caregiver-Reported Routines Inventory {CRRI) 
The CRRI is a 62-item caregiver-reported restricted and repetitive behaviours scale for 
older adolescents and adults based on the Children Routine Inventory-Revised (CRI-R; 
Evans et al 2017). It has been developed by the author in collaboration with the Sponsor 
in order to extend the age-range to older adults and adolescents. The CRRI 
questionnaire captures a wide range of restrictive and repetitive behaviours, including 
stereotypies, tics, compulsions, habits, sensory sensitivities, and focused interests, in 
the context of typical and atypical development in adults and adolescents. A total score 
is calculated as the sum of the scores for the 62 items.The scores range from 62 to 310, 
with a higher score indicating more severe repetitive and restricted behaviours. The 
CRRI subscale scores will also be calculated as the sum of the scores for each item 
within each subscale. 
Clinical Global Impression-Severity {CGI-S) and Improvement {CGl-1) Scales 
The CGI rating scales are tools used to evaluate both the severity of illness and change 
from Baseline (Guy et al 1976). The CGI-S reflects the rater's impression of the 
participant's current autism severity on a 7-point scale ranging from no symptoms (1) to 
very severe symptoms (7). The CGl-I is used to assess the clinical change as compared 
with symptoms at baseline using a 7-point scale, ranging from very much improved (1) to 
very much worse (7). For this study, modified versions will be used (Busner and Targum 
2007). 
Beck Anxiety Inventory {BAI) 
The BAI is a well-validated 21-item participant-administered inventory probing for 
common symptoms of anxiety (Beck et al 1988). Each item contains four possible 
responses, which range in severity from 0=not at all (e.g., unable to relax) to 3=severely 
(e.g., it bothered me a lot). Participants are asked to provide answers based on the way 
they have been feeling over the past month, including the assessment day. A total score 
is calculated as the sum of the score for the 21 items. The scores range from 0 to 63, 
with a higher score indicating greater levels of anxiety. 
Parent-Rated Anxiety Scale-ASD {PRAS-ASD) 
The PRAS-ASD is a support person-rated scale with 25 items to assess the severity of 
anxiety symptoms in children and adolescents with ASD. Support persons of adolescent 
participants will be asked to describe their child's worries and anxiety-related behaviors 
over the past 2 weeks on a Oto 3-point scale from "NONE=not present", "MILD=present 
sometimes, not a real problem", "MODERA TE=often present and a problem", and 
"SEVERE=very frequent and a major problem". The PRAS-ASD total score is calculated 
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as the sum of the scores for the 25 items. The scores range from 0 to 75, with a higher 
score indicating greater levels of anxiety. 
Short Sensory Profile 2 (SSP-2) 
The Short Sensory Profile Version 2 (SSP-2; Dunn 2014) is a 34-item parent or support 
person-reported questionnaire that probes for the effect of sensory processing 
anomalies on a person's ability to function in daily life. Item responses occur on a five-
point Likert-rating scale from 1 (almost never) to 5 (almost always). The SSP-2 was 
based on the Sensory Processing Framework (Dunn 1999) and provides scores in four 
quadrants based on the child's neurological threshold to sensory input and their method 
of self-regulation. Raw score totals are calculated for each of the four quadrants: 
Seeking ("the degree to which a child obtains sensory input"), Avoiding ("the degree to 
which a child is bothered by sensory input"), Sensitivity ("the degree to which a child 
detects sensory input."), and Registration ("the degree to which a child misses sensory 
input."). A Sensory raw score and Behavioral raw score will also be calculated. The 
score ranges from Oto 100 (depending on the subscale), with a higher score indicating 
more frequent sensory behaviors and symptoms. 
Adolescent/Adult Sensory Profile (AASP) 
The Adolescent/Adult Sensory Profile (Brown and Dunn 2002) is a self-reported 
questionnaire consisting of 60 items rated for frequency of the behavior at home or in the 
community. Raw score totals are calculated for each of the four quadrants: "Low 
Registration", "Sensation Seeking", "Sensory Sensitivity", and "Sensation Avoiding". The 
raw scores for each quadrant range from 15 to 75, with higher scores indicating more 
frequent sensory behaviors and symptoms. 
Patient-Reported Outcomes Measurements Information System (PROMIS) 
The Patient-Reported Outcomes Measurements Information System (PROMIS) Sleep 
Disturbance Short Form (Yu Lan et al 2011, Buysse et al 2010) assesses self-reported 
perceptions of sleep quality, sleep depth, and restoration associated with sleep. This 
includes perceived difficulties and concerns with getting to sleep or staying asleep, as 
well as perceptions of the adequacy of and satisfaction with sleep. This questionnaire 
assesses sleep disturbance over the past seven days. The following versions of the 
Sleep Disturbance short form (8 items) will be implemented in this study: adult self-report 
(ages 18+, high-functioning), pediatric self-report (adolescents aged 15 to -17 years, 
high-functioning). In addition, proxy forms completed by the support person will be used 
for all adolescents, as well as low-functioning adults. 
The sleep disturbance total raw score is calculated as the sum of the scores for the 8 
items. The score will range from 8 to 40, with a higher score indicating greater sleep 
disturbance. 
The PROM IS Sleep-Related Impairment Short-Form (Buysse et al 2010) assesses self-
reported perceptions of waking alertness, sleepiness and function within the context of 
overall sleep-wake function. This questionnaire assesses sleep-related impairment over 
the past seven days. The following versions of the PROM IS Sleep-Related Impairment 
Short Form (8 items) will be implemented in this study: adult self-report (ages 18+, high-
functioning), pediatric self-report (ages 15 to 17, high-functioning) and for support 
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persons serving as proxy reporters for the participants (adolescents aged 15 to17 years 
and low-functioning adults). 
The sleep-related impairment total raw score is calculated as the sum of the scores for 
the 8 items. The score will range from 8 to 40, with a higher score indicating greater 
sleep impairment. 
4.1.4 
Characteristics of Safety Endpoints 
Suicide Severity Rating Scale (C-SSRS} 
A baseline assessment of suicidal ideation is performed and treatment-emergent suicidal 
ideation and behavior during the study is monitored using the Columbia Suicide Severity 
Rating Scale (C-SSRS) forms "At Baseline" and "Since Last Visit" at the timepoints 
indicated in the SoA. C-SSRS assessments are completed by a certified clinician. 
Karolinska Sleepiness Scale (KSS} 
The Karolinska Sleepiness Scale (KSS; Akersted and Gillberg 1990, Baulk et al 2001) 
will be completed as part of the safety assessments. The KSS measures the subjective 
level of sleepiness at a particular time during the day. On this scale, participants (or 
support persons for adolescents aged 15 to 17 years and for low-functioning 
participants) indicate which level best reflects the psycho-physical state experienced in 
the last 5 minutes. The KSS is a 9-point scale (1 = extremely alert, 9 = very sleepy, great 
effort to keep awake, fighting sleep). This assessment takes approximately 5 minutes to 
perform. 
Epworth Sleepiness Scale (ESS} 
The Epworth Sleepiness Scale (ESS; Johns 1991, Johns 1992) will be completed as 
part of the safety assessments. The ESS is a brief, self-administered eight-item 
questionnaire that measures daytime sleepiness in adults. Participant will be asked to 
rate on a scale of 0-3 the chances that, "over the past month" and "since last visit", 
he/she would have dozed in eight specific situations that are commonly met in daily life 
(0 = would never doze; 3 = high chance of dozing). Thus, the participant is asked to 
characterize, retrospectively, part of his usual behavior in a variety of situations that are 
more or less soporific. The ESS score is the sum of eight item-scores and can range 
from Oto 24. This assessment takes approximately 5 minutes to perform. 
ESS for Children and Adolescents (ESS-CHAD} 
The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD; Johns 2015) 
will be completed as part of the safety assessments. The ESS-CHAD is a brief, support 
person-administered eight-item questionnaire that measures daytime sleepiness in 
children and adolescents. Support persons of adolescents and participants with an IQ 
score <70 will be asked to rate on a scale of 0-3 the chances that, "Over the past 
month," and "since last visit", "your child" would have dozed in eight specific situations 
that are commonly met in daily life (0 = would never doze; 3 = high chance of dozing). 
Thus, the support person is asked to characterize, retrospectively, part of his usual 
behavior in a variety of situations that are more or less soporific. The ESS score is the 
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sum of eight item-scores and can range from O to 24. This assessment takes 
approximately 5 minutes to perform. 
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale 
The Pediatric Quality of Life Inventory (PedsQL ™) Version 4.0 Generic Core Scale 
assessment consists of a 23-item questionnaire encompassing four core scale domains: 
Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning 
(5 items) and School Functioning (5 items). Each item utilizes a 5-point response scale 
ranging from "never a problem" (0) to "almost always a problem" (4). 
Each item will be reversed scored and linearly transformed to a 0-100 scale as follows: 
0=100, 1 =75, 2=50, 3=25, 4=0. Scores will be calculated as the sum of all the items over 
the number of items answered within each domain. In addition, a Psychosocial Health 
Summary score, Physical health summary score and total score will be calculated. The 
scores range from O to 100, with higher scores indicating better quality of life. 
Pediatric Quality of Life Inventory (PedsQL) Cognitive Functioning Scale 
The Pediatric Quality of Life Inventory (PedsQL ™) Version 3.0 Cognitive Functioning 
Scale consists of 6-items. Each item utilizes a 5-point response scale ranging from 
"never a problem" (0) to "almost always a problem" (4). 
Each item will be reversed scored and linearly transformed to a 0-100 scale as follows: 
0=100, 1 =75, 2=50, 3=25, 4=0. PedsQL Cognitive Functioning Score will be calculated 
as the sum of all the items over the number of items answered. The score ranges from 0 
to 100, with a higher score indicating better cognitive functioning. 
Sudden Onset of Sleep Questionnaire 
The Sudden Onset of Sleep Questionnaire has been developed by the Sponsor for this 
study and will be completed as part of the safety assessments. Each participant (or 
support person for adolescents aged 15 to 17 years and for low-functioning participants) 
will be asked to answer a series of up to 8 questions to assess the occurrence of 
daytime somnolence, its suddenness (level of awareness), frequency and circumstances 
in which the episode(s) took place, impact on work/daily activities/ social life, if worried 
by episode and ease of waking up (see Appendix 2 for reporting of AEs). This 
questionnaire will be administered as an interview. This assessment takes approximately 
5 minutes to perform. 
Neurocognitive Battery 
The cognitive tests will be applied as part of the safety assessments. The total battery 
takes approximately 45 minutes to perform, the selection of attention tasks (detection, 
identification, and one back tests) takes approximately 10 minutes to perform. For low-
functioning participants, the selection of attention tasks (detection, identification, and one 
back tests) should be prioritized and performed first. All effort should be made to also 
collect the remainder of the tasks if the study participant is able to comply. If not all tasks 
can be completed, an explanation should be recorded on the "Additional Observations" 
eCRF. Two test sessions of shorter duration will be carried out at the pre-baseline visit 
for habituation to the test environment. 
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Detection Test (Psychomotor Function) 
The Detection Test (DET) is a measure of psychomotor function and uses a well-
validated simple reaction time paradigm with playing card stimuli. In this test, the playing 
cards all depict the same joker. The participant is asked to press the "Yes" key as soon 
as the card in the center of the screen turns face up. The software measures the speed 
and accuracy of each response. This assessment takes approximately 3 minutes to 
perform. 
Identification Test (Attention) 
The Identification Test (ION) is a measure of visual attention and uses a well-validated 
choice reaction time paradigm with playing card stimuli. In this test, the playing cards are 
all either red or black jokers. The participant is asked whether the card displayed in the 
center of the screen is red. The participant responds by pressing the "Yes" key when the 
joker card is red and No when it is black. The software measures the speed and 
accuracy of each response. This assessment takes approximately 3 minutes to perform. 
One Card Learning Test (Visual Learning) 
The One Card Learning Test (OCL) is a measure of visual learning and uses a well-
validated pattern separation paradigm with playing card stimuli. In this test, the playing 
cards are identical to those found in a standard deck of 52 playing cards (without the 
joker cards). The participant is asked whether the card displayed in the center of the 
screen was seen previously in this test. The participant responds by pressing the "Yes" 
or "No" key. The software measures the speed and accuracy of each response. This 
assessment takes approximately 6 minutes to perform. 
One Back Test (Working Memory) 
The One Back Test (ONB) is a measure of working memory and uses a well-validated n-
back paradigm with playing card stimuli. In this test, the playing cards are identical to 
those found in a standard deck of 52 playing cards (without the joker cards). The 
participant is asked whether the card displayed in the center of the screen is the same 
as the card presented immediately previously. The participant responds by pressing the 
"Yes" or "No" key. Because no card has been presented yet on the first trial, a correct 
first response is always "No". The software measures the speed and accuracy of each 
response. This assessment takes approximately 4 minutes to perform. 
Two Back Test (Working Memory) 
The Two Back Test (TWOB) is a measure of working memory and uses a well-validated 
n-back paradigm with playing card stimuli. In this test, the playing cards are identical to 
those found in a standard deck of 52 playing cards (without the joker cards). The 
participant is asked whether the card displayed in the center of the screen is the same 
as the one presented two cards previously. The participant responds by pressing the 
"Yes" or "No" key. Because no card has been presented two-back on the first and 
second trials, a correct response on these trials is always "No". The software measures 
the speed and accuracy of each response. This assessment takes approximately 4 
minutes to perform. 
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The International Shopping List Test (Verbal Learning) 
The International Shopping Test (ISL) is a measure of verbal learning and uses a well-
validated list-learning paradigm. The test is administered using a computer. High 
frequencies, high imagery, concrete nouns (items from a shopping list) are read to the 
participant by the test supervisor at the rate of one word every two seconds. Once all 12 
words have been read, the participant is asked to recall as many of the words as he/she 
can as quickly as possible. The test supervisor uses a mouse or stylus to mark the 
words recalled by the participant on the computer screen. When the subject can recall 
no more words, the same list is read a second time. The test supervisor records the 
words recalled by the participant on this trial. This is then repeated a third time. 30 
minutes later: without having the list read again, the participant is asked to recall the 
words from the list (delayed recall condition). The recall test is followed by a recognition 
condition test where the test supervisor reads a shopping list item that may or may not 
have been on the original list and the participant has to respond either affirmatively (if 
the item was on the original list) or negatively (if it was not). The recall and recognition 
test is repeated the next day about 24 hours after the list learning. If the clinic visit is split 
into two days (which is possible for Week 6, Week 12, and 6-week follow-up visits), the 
repeats are performed at the clinic. If the participant returned home after the first day the 
repeats are performed over the phone as close in time to the 24h timepoint as possible. 
The software registers the number of correct responses as recorded by the test 
supervisor. This assessment takes approximately 15 minutes to perform (5 minutes for 
each of the three parts). 
Continuous Paired Associate Learning Test (Paired Associate Learning) 
The Continuous Paired Associate Learning Test (CPAL) is a measure of visual associate 
memory and uses a well-validated paired associate learning paradigm in which the 
subject must learn the locations of a number of amoeba-like shapes on the computer 
screen. This test consists of a single amoeboid shape displayed in the center of the 
screen surrounded by a number of blue- filled circles. Beneath all but two of the blue 
spheres are amoeboid shapes, one of which matches the central display; the two 
remaining circles are distractors. In the exposure phase of the test all of the to-be-
remembered pattern-location associations are presented on the computer screen 
simultaneously. After a five second delay, a pattern is shown in the central location and 
this signals that the subject should touch the location in the periphery that contains the 
same pattern. This process continues until the participant has acknowledged all of the 
pattern-location associations. The learning phase begins with the same test display 
presented during the exposure phase except that now all of the peripheral locations are 
shown as blue spheres. One of the patterns presented in the exposure phase is 
presented in the center location. With the presentation of this pattern, the participant is 
required to select the peripheral location where an identical pattern is hidden beneath 
the blue sphere. This process continues until the correct location of each pattern is 
found. Finding the correct location for all patterns in the set is defined as a learning trial. 
There are six learning trials (a single trial delayed recall condition will be done after a 30-
minute delay). The software records each move as an error or as a correct move. This 
assessment takes approximately 7 minutes to perform. 
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Groton Maze Learning Test {Executive Function) 
The Groton Maze Learning Test (GML T) measures executive function using a maze 
learning paradigm. A 10 x 10 grid of tiles is presented to the participant on the screen. A 
28-step pathway is hidden among these tiles. A blue tile indicates the start and a tile with 
red circles indicates the finish. The participant must move one step at a time from the 
start toward the end by touching a tile next to their current location. If the correct move is 
made a green checkmark appears and if the move is incorrect a red cross is revealed. 
Once completed, they are returned to the start location to repeat the test and must try to 
remember the pathway they have just completed. The software records the total number 
of errors made in attempting to learn the same hidden pathway on 5 consecutive trials 
during a single session. This assessment takes approximately 7 minutes to perform. 
Table 7 
Efficacy Endpoints Details and Description 
Efficacy Endpoint 
Vineland-3 ABC Composite GSV 
Vineland-3 Socialization GSV 
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Description 
A raw score will be calculated for each 
subdomain of the Socialization (interpersonal 
relationships, play and leisure time, coping skills), 
Communication (receptive, expressive, written) 
and Daily Living Skills (personal, domestic, 
community) domain as the sum of the scores for 
each item within the subdomain. 
The raw scores for each of the 9 subdomains will 
be mapped to GSV scores. A conversion table for 
mapping raw scores to GSV scores is found in 
Appendix 3. This was based on Table B.2 in the 
Vineland-3 manual. 
The Vineland-3 ABC Composite GSV score will 
be calculated as the mean GSV score (i.e. 
summing the 9 GSV subdomain scores and 
dividing by 9). 
A raw score will be calculated for each 
subdomain of the Socialization domain 
(interpersonal relationships, play and leisure time, 
coping skills) as the sum of the scores for each 
item within the subdomain. 
The raw scores for each of the 3 subdomains will 
be mapped to GSV scores. 
The Vineland-3 Socialization GSV score will be 
calculated as the mean GSV score (i.e. summing 
the 3 GSV subdomain scores and dividing by 3). 
23 


Vineland-3 Communication GSV 
A raw score will be calculated for each 
subdomain of the Communication domain 
(receptive, expressive, written) as the sum of the 
scores for each item within the subdomain. 
The raw scores for each of the 3 subdomains will 
be mapped to GSV scores using the conversion 
table in Appendix 3. 
The Vineland-3 Communication GSV score will 
be calculated as the mean GSV score (i.e. 
summing the 3 GSV subdomain scores and 
dividing by 3). 
Vineland-3 Daily Living Skills GSV A raw score will be calculated for each 
subdomain of the Daily Living Skills domain 
(personal, domestic, community) as the sum of 
the scores for each item within the subdomain. 
Repetitive-Behaviors Scale-
Revised (RBS-R) total score 
Repetitive-Behaviors Scale-
Revised (RBS-R) subscale score 
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The raw scores for each of the 3 subdomains will 
be mapped to GSV scores. 
The Vineland-3 Daily Living Skills GSV score will 
be calculated as the mean GSV score (i.e. 
summing the 3 GSV subdomain scores and 
dividing by 3). 
The RBS-R total score will be calculated as the 
sum of the scores for each of the 43 items. 
The RBS-R subscale score will be calculated as 
the sum of the raw scores for each item within 
each of the following subscales, a 6-factor 
conceptual model; Bodfish et al. 1999: 
-
Stereotyped (items 1-6) 
-
Self-injurious (items 7-14) 
-
Compulsive (items 15-22) 
-
Ritualistic (items 23-28) 
-
Sameness (items 29-39) 
-
Restricted behavior (items 40-43) 
And a 3-factor model (Mirenda et al. 2010) 
confirmed by internal analyses: 
• 
Repetitive Sensory Motor (items 1-6, 40-
43) 
• 
Self-injurious (items 7-14) 
24 


Caregiver-Reported Routines 
Inventory (CRRI) total score 
Caregiver-Reported Routines 
Inventory (CRRI) subscale score 
Clinical Global Impressions Scale 
- Severity (CGI-S) 
Domain score 
Clinical Global Impressions Scale 
- Severity (CGI-S) 
Overall score 
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• Insistence on Sameness (items 15-39) 
The CRRI total score will be calculated as the 
sum of the scores for each of the 62 items. 
The CRRI subscale score will be calculated as 
the sum of the raw scores for each item within 
each of the following subscales. The subscale 
structure was derived from the oRBiting study 
(Crawley et al. manuscript in preparation): 
-
'Just right' behaviors 
(items 5,9, 15, 16, 18, 19,23,29,30,37,40,61) 
-
Routines and Sameness behaviors 
(items 1,2,4,6, 7,8, 10,20,42,58,59) 
-
Sensory & Motor Behaviors 
(items 11, 13, 14, 17,24,25,27,28,31,32,33, 
34,35,43,44,45,46,48,50,51) 
-
Restricted Interests I Stereotypies 
(items 26,36,38,39,47,53,54,55,56,57,62) 
-
Food Rigidities 
(items 3, 12,21,22,41,49,52,60) 
Of note, items 52 and 60 will be reverse coded. 
An impairment rating score with 7 categories (no 
symptoms to very severe symptoms) for each of 
the following domains: 
-
communication/speech 
-
activities of daily living 
-
social functioning 
-
disruptive behavior 
-
restricted and repetitive behavior 
Note: The customizable "other" symptom domain 
will not be summarized. 
A rating score with 7 categories (no symptoms to 
very severe symptoms) for the overall rating. 
25 


Clinical Global Impressions Scale 
- Improvement (CGl-I) 
Domain score 
Clinical Global Impressions Scale 
- Improvement (CGl-I) 
Overall score 
Vineland-3 ABC standard score 
A rating score with 7 categories (very much 
improved to very much worse) for each of the 
following domains: 
-
communication/speech 
-
activities of daily living 
-
social functioning 
-
disruptive behavior 
-
restricted and repetitive behavior 
Note: The customizable "other" symptom domain 
will not be summarized. 
A rating score with 7 categories (very much 
improved to very much worse) for the overall 
rating. 
A raw score will be calculated for each 
subdomain of the Socialization (interpersonal 
relationships, play and leisure time, coping skills), 
Communication (receptive, expressive, written) 
and Daily Living Skills (personal, domestic, 
community) domain as the sum of the scores for 
each item within the subdomain. 
The raw scores for each of the 9 subdomains will 
be mapped to V-scale scores relative to a 
normative age group as described in the 
Vineland-3 scoring manual (Sparrow et al. 2016). 
A standard score will be calculated for each of the 
three domains (Communication, Socialization and 
Daily Living Skills) as the sum of the V-scale 
scores within each domain. 
The Vineland-3 ABC standard score will be 
calculated as the sum of the standard scores for 
the three domains. 
Vineland-3 Socialization standard 
A raw score will be calculated for each 
score 
subdomain of the Socialization domain 
(interpersonal relationships, play and leisure time, 
coping skills) as the sum of the scores for each 
item within the subdomain. 
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The raw scores for each of the 3 subdomains will 
be mapped to standard (V-scale) scores relative 
26 


Vineland-3 Communication 
standard score 
Vineland-3 Daily Living Skills 
standard score 
Beck Anxiety Inventory (BAI) 
Parent Rated Anxiety Scale- ASD 
(PRAS-ASD) 
Adolescent/Adult Sensory Profile 
(MSP) 
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to a normative age group as described in the 
Vineland-3 scoring manual (Sparrow et al. 2016) 
The Vineland-3 Socialization standard score will 
be calculated as the sum of the V-scale scores 
within each subdomain. 
A raw score will be calculated for each 
subdomain of the Communication domain 
(receptive, expressive, written) as the sum of the 
scores for each item within the subdomain. 
The raw scores for each of the 3 subdomains will 
be mapped to standard (V-scale) scores relative 
to a normative age group as described in the 
Vineland-3 scoring manual (Sparrow et al. 2016) 
The Vineland-3 Communication standard score 
will be calculated as the sum of the V-scale 
scores within each subdomain. 
A raw score will be calculated for each 
subdomain of the Daily Living Skills domain 
(personal, domestic, community) as the sum of 
the scores for each item within the subdomain. 
The raw scores for each of the 3 subdomains will 
be mapped to standard (V-scale) scores relative 
to a normative age group as described in the 
Vineland-3 scoring manual (Sparrow et al. 2016). 
The Vineland-3 Daily Living Skills standard score 
will be calculated as the sum of the V-scale 
scores within each subdomain. 
The BAI total score will be calculated as the sum 
of the scores for each of the 21 items. 
The PRAS-ASD total score will be calculated as 
the sum of the scores for each of the 25 items. 
Quadrant raw scores will be calculated as the 
sum of the scores for items within each of the 
following quadrants: 
27 


Short Sensory Profile (SSP-2) 
Pediatric Quality of Life Inventory 
(PedsQL) Generic Core Scale 
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-
low registration 
(items 3, 6, 12, 15, 21, 23, 36, 37, 39, 41, 
44, 45, 52, 55 and 59) 
-
seeking 
(items 2, 4, 8, 10, 14, 17, 19, 28, 30, 32, 
40, 47, 50 and 58) 
-
sensitivity 
(items 7, 9, 13, 16, 20, 22, 25, 27, 31, 33, 
34, 48, 51, 54 and 60) 
-
avoiding 
(items 1, 5, 11, 18, 24, 26, 29, 35, 38, 43, 
45, 49, 53, 56 and 57) 
Reference: AdolescenUAdult Sensory Profile 
The SSP-2 sensory raw score will be calculated 
as the sum of the scores for items 1-14. 
The SSP-2 behavioral raw score will be 
calculated as the sum of the scores for items 15-
34. 
Quadrant raw scores will be calculated as the 
sum of the scores for items within each of the 
following quadrants: 
-
seeking (items 6-8, 11, 14, 31 and 32) 
-
avoiding (items 16-20 and 22-26) 
-
sensitivity (items 1-5, 21, 25, 28, 29 and 
33) 
-
registration (items 9, 10, 12, 13, 15, 27, 30 
and 34) 
Reference: Short-Sensory Profile-2 Caregiver 
Questionnaire 
The first step is to transform the scores. Each 
item will be reversed scored and linearly 
transformed to a 0-100 scale as follows: 0=100, 
1=75,2=50, 3=25,4=0. 
The second step is to calculate scores for each of 
the four dimensions: 
-
physical functioning 
-
emotional functioning 
-
social functioning 
-
school functioning 
28 


Pediatric Quality of Life Inventory 
(PedsQL) Cognitive Functioning 
Scale 
Patient-Reported Outcomes 
Measurements Information 
System (PROMIS)- Sleep-
Disturbance Short Form Scale 
Patient-Reported Outcomes 
Measurements Information 
System (PROMIS) - Sleep-
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Statistical Analysis Plan BP41316 
If more than 50% of the items in the scale are 
missing, the scale scores should not be 
computed. 
Mean scores for each dimension will be 
calculated as the sum of the items over the 
number of items answered. 
Psychosocial Health Summary Score will be 
calculated as the sum of the items over the 
number of items answered in the Emotional, 
Social, and School Functioning Scales. 
Physical Health Summary Score is the Physical 
Functioning Scale Score 
PedsQL Total Score will be calculated as the sum 
of all the items over the number of items 
answered on all the scales. 
Reference: PedsQL scoring manual 
The first step is to transform the scores. Each 
item will be reversed scored and linearly 
transformed to a 0-100 scale as follows: 0=100, 
1=75,2=50, 3=25,4=0. 
PedsQL Cognitive Functioning Score will be 
calculated as the sum of all the items over the 
number of items answered. 
Reference: PedsQL scoring manual 
A PROMIS Sleep-Disturbance raw score will be 
calculated as the sum of the scores for each of 
the 8 items. 
The raw score will be mapped to a T-score using 
the PROMIS Sleep Disturbance scoring manual. 
Reference: PROMIS Sleep Disturbance Scoring 
Manual 
A PROMIS Sleep-Related Impairment raw score 
will be calculated as the sum of the scores for 
each of the 8 items. 
29 


Related Impairment Short Form 
Scale 
The raw score will be mapped to a T-score using 
the PROMIS Sleep-Related Impairment scoring 
manual. 
Reference: PROMIS Sleep-Related Impairment 
Scoring Manual 
4.2 
PRIMARY, SECONDARY AND EXPLORATORY EFFICACY 
ANALYSIS 
The primary efficacy analysis evaluates the mean change from baseline to 12 weeks of 
treatment as measured by the Vineland-3 ABC three-domain GSV composite. The 
difference in the mean change from baseline between each of the two active doses and 
placebo will be extracted as contrasts from the ANCOVA model. 
The efficacy analyses of the secondary endpoints and of the CRRI total score evaluate 
the mean change from baseline to 12 weeks of treatment. The difference in the mean 
change from baseline of the two active doses and placebo will be extracted as contrasts 
from the ANCOVA model. 
The efficacy analysis of CGl-I evaluates the overall score at 12 weeks of treatment. The 
difference of the two active doses and placebo will be extracted as contrasts from the 
ANCOVA model. 
4.2.1 
Definition of Primary Endpoint 
The primary endpoint is Change from baseline to Week 12 in the Adaptive Behavior 
Composite score of the Vineland™ Adaptive Behavior Scales, Third Edition (Vineland™-
3), as defined in Section 1.1 of SAP (see Table 1 ). 
4.2.2 
Main Analytical Approach for Primary, Secondary, CRRI and 
CGl-I Endpoints 
The analyses of primary, secondary, CRRI and CGl-I efficacy endpoints will include all 
participants in the Efficacy Analysis Population. 
An analysis of covariance (ANCOVA) model will be used to compare treatment effects 
for the primary, secondary, CRRI and CGl-I efficacy endpoints across the overall 
Efficacy Analysis Population of adolescents and adults. The model will include treatment 
as main effect, individual age at screening, IQ, and baseline score as covariates. 
Treatment differences will be estimated together with their 80% confidence intervals as 
derived from the model and their associated p-values. 
The ANCOVA model will be applied to change from baseline data Yii of participants i, and 
treatment j E {placebo (reference), low dose, high dose} as follows: 
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where µ gives the overall endpoint mean change, followed by the fixed effect t which 
models the effect of treatment, age a, IQ, the endpoint baseline value BL, and E, which 
gives the overall error term with N(O,a/). 
Table 8 
Efficacy Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Primary 
ANCOVA 
Secondary 
CRRI, CGl-I 
4.2.2.1 
Subgroup Analyses for Primary and Secondary Efficacy 
Endpoints 
The generalizability of Vineland-3 ABC three-domain GSV composite and RBS-R total 
score results when comparing any active treatment arm to placebo will be investigated 
by estimating the treatment effect in subgroups based on geographic region (North 
America vs. Europe), rater change (yes vs. no), site type (academic vs. ASD research 
sites), age categories (adolescents vs. adults), and IQ categories (high functioning vs. 
low functioning). 
The dependence of BAI total score and RBS-R total score results on a history of clinical 
diagnosis of anxiety at baseline (yes vs. no) will be investigated. 
For RRB endpoints RBS-R total score, CRRI total score and CGII (RRB domain) 
subgroups of male vs female will be investigated. 
Summaries of these subgroup analyses will be provided in forest plots. 
Selected categories used in this section, and their characteristic values are provided in 
the following table: 
Table 9 
Selected Categories and Characteristic Values 
Category 
Characteristic Value 
Anxiety at Baseline 
Preferred Terms: 
Anxiety, Anxiety Disorder, Generalized 
Anxiety Disorder, Social Anxiety Disorder 
ASD Research Site 
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Southwest Autism Research And 
Resource Center, UNITED STATES 
Nathan Kline Institute, UNITED STATES 
APG Center for Autism & ADHD, 
31 


UNITED STATES 
Okanagan Clinical Trials, CANADA 
4.3 
SUPPORTIVE EXPLORATORY EFFICACY ENDPOINTS 
ANALYSES 
Additional exploratory analyses will be performed in a descriptive manner for continuous 
endpoints Vineland-3, RBS-R, CRRI, CGI, MSP, PRAS-ASD, BAI, SSP-2, PedsQL™, 
and PROM IS per treatment arm comprising baseline values, (up to) week 12 values and 
change from baseline to (up to) week 12 values. 
For endpoint CGI, analyses will be performed to get the proportion of subjects in each of 
the rating categories per treatment arm and per time point. 
For the assessment of differences between each Alogabat group and placebo regarding 
the CGl-I overall score at week 12, a mixed-effects MMRM analysis incorporating data 
up to 12 weeks of treatment will be used to utilize all the data collected over time with 
consideration of the variance-covariance matrix of the repeated measures. The model 
will include the CGl-I overall score as the dependent variable. The effects in the model 
will include independent variables of the fixed, categorical effects of treatment, 
assessment weeks relative to the first dose of study medication (i.e., time), and 
treatment-by-time interaction, along with covariates of the baseline value, age at 
screening and IQ at baseline. Time will be treated as the repeated variable within a 
subject. An unstructured variance-covariance structure will be applied to model the 
within-subject errors. 
For the primary, secondary, CRRI and CGl-I endpoints, the ANCOVA will be repeated to 
model change from baseline data Yii of participants i, and treatment j E {placebo 
(reference), low dose, high dose} incorporating interactions to the model as follows: 
Yij=µ+tj+ai+IQi+ttlQi•B Li+Eij 
and 
where µ gives the overall endpoint mean change, followed by the fixed effect t which 
models the effect of treatment, age a, IQ, the interactions t*IQ and t*a respectively, the 
endpoint baseline value BL, and E, which gives the overall error term with N(O,a/J. 
4.4 
SAFETY ANALYSES 
All safety analyses will be based on the safety analysis population. 
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Table 10 
Safety Statistical Analysis Methods 
Endpoint 
Adverse events 
Clinical laboratory tests 
Vital signs 
ECG 
Concomitant medications 
C-SSRS, Neurocognitive Battery, KSS, 
ESS or ESS-CHAD, and Sudden Onset of 
Sleep Questionnaire 
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Statistical Analysis Methods 
The original terms recorded on the eCRF 
by the Investigator for AEs will be coded 
by the Sponsor. Adverse events will be 
summarized by mapped term and 
appropriate thesaurus level. 
All clinical laboratory data will be stored on 
the database in the units in which they 
were reported. Laboratory test values will 
be presented by tabular summaries, plots, 
and individual listings with flagging of 
abnormal results. Hereby, by default the 
International System of Units (SI units; 
Systeme International d'Unites) will be 
applied, and values will be transformed to 
common Roche standard reference range 
(following Roche Safety Lab 
Standardisation Guidance) where 
applicable. 
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 of raw values and change from 
baseline will be used, as appropriate. 
ECG data will be presented by individual 
listings. In addition, tabular summaries of 
raw values and change from baseline will 
be used, as appropriate. 
The original terms recorded on the 
participants' eCRF by the Investigator for 
concomitant medications will be 
standardized by the Sponsor by utilizing a 
mapped term and appropriate drug 
dictionary level. Concomitant medications 
will be presented in summary tables and 
listings. 
Data will be presented in summary tables 
and listings 
33 


4.4.1 
Extent of Exposure 
A summary will be produced showing the treatment duration in days, the total cumulative 
number of doses and the total cumulative dose in mg per treatment arm. A histogram 
binned by hours will be produced showing the distribution of dosing times per treatment 
arm. 
4.5 
4.5.1 
OTHER ANALYSES 
Summaries of Demographics and Baseline Characteristics 
Demographics and baseline characteristics data such as baseline values of relevant 
scales, medical history including medications and treatments, support person status, 
educational status of participant and parents, etc. will be summarized by treatment, age 
cohort, and IQ cohort. 
Additional listings, summary tables of descriptive statistics, frequency tables, and 
corresponding graphs will be provided as appropriate. 
4.5.2 
Pharmacokinetic Analyses 
For all participants, plasma concentrations of Alogabat will be presented descriptively by 
dose and age group. 
Nonlinear mixed effects modeling will be used to analyze the sparse sampling dose 
versus concentration versus time data collected for Alogabat. The PK data collected in 
this study will be pooled with data from other clinical studies conducted with Alogabat. 
Population and individual PK parameters such as clearance and volume of distribution 
will be estimated, and the influence of various covariates such as age, gender, and body 
weight, on these parameters will be investigated, as appropriate. Secondary PK 
parameters will be derived from the model as appropriate. The results of the PopPK 
analysis will be reported separately from the CSR. 
Subjects excluded from the PK Analysis Population will be documented in a listing. 
Depending on results it will be decided post hoc after database lock whether analyses 
will be performed that investigate the participant's exposure to Alogabat, and whether 
correlations of exposure to Alogabat exist with selected efficacy, PD, biomarkers and 
safety endpoints. 
4.5.3 
Biomarker Analyses 
Resting state EEG is recorded up to five times per patient: Pre-baseline, day 1 pre-dose, 
day 1 post-dose, week 2 post-dose (optional recording) and week 12 post-dose. EEG 
beta power is defined as the total power in the 13-30 Hz range averaged over the fronto-
central channels Fz and Cz. 
To estimate pharmacodynamic effects, beta power for post-dose recordings are 
normalized with baseline beta power to estimate relative change. Baseline beta power is 
defined as the average of the pre-baseline and day 1 pre-dose values. For each post-
dose recording (day 1, week 2, week 12) and dose level, the mean change and SD of 
change will be reported. Additionally, two-tailed two sample t-tests comparing placebo to 
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each treatment arm will be performed for each post-dose recording. Hereby the null-
hypothesis of no difference in beta power with Alogabat treatment compared to placebo 
will be rejected if the p-value resulting from a two-sided t-test is < 0.1 . 
It will also be examined whether baseline beta power predicts clinical response. The 
hypothesis is that clinical efficacy increases as beta power decreases (patients with 
lower baseline beta power benefit more from alogabat than patients with higher baseline 
beta power). To this end beta power is normalized with power outside the beta range. 
The Baseline value is defined as the average of the pre-baseline and day 1 pre-dose 
values. The Pearson correlation coefficient between baseline beta power and change 
from baseline clinical efficacy scores will be computed for each active treatment arm and 
placebo. For active treatment arms the p-value will be derived from a two-sided test with 
null-hypothesis: r = 0. The null hypothesis will be rejected if the two-sided p-value is < 
0.2. The test will be performed for the clinical efficacy endpoints Vineland-3 ABC GSV 
composite, Vineland-3 Socialization GSV composite, RBS-R total, and CRRI total. 
4.6 
INTERIM ANALYSES 
Two interim safety analyses are planned for this study. The first interim analysis of 
accumulated safety, tolerability and PK will be performed once approximately 18 high-
functioning adults have completed 6 weeks of treatment. The aim of this analysis is to 
evaluate the safety, tolerability, and PK in high-functioning adults before allowing the 
recruitment of the adolescents and low-functioning adult participants. 
A second interim analysis of PK and accumulated safety and tolerability will be 
conducted once approximately 12 adolescents have completed 2 weeks of treatment. 
The aim of this analysis is to enable internal decisions to inform the design and dose 
selection for the adolescent participants and additional studies in the program. 
The CSR will document all interim analyses that occurred. All interim analyses will be 
performed and interpreted by members of the IMC, external experts (SOC), and 
appropriate senior management personnel. IMC and SOC members will be unblinded at 
the individual participant level, sponsor senior management will be unblinded at the 
treatment group level. Access to treatment assignment information will follow the 
Sponsor's standard procedures. 
The "IMC Agreement" will describe the planned interim analyses in detail. 
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5. 
SUPPORTING DOCUMENTATION 
The layout of TFLs will be according to Roche standards. Templates that deviate from 
these standards or which are tailored to meet special requirements are presented below 
in this section: 
Change from Baseline to week 12 
Placebo 
RO7017773IIII 
RO7017773IIII 
n 
Adjusted Mean 
80% Cl for Adjusted Mean 
Difference in Adjusted Means 
80% Cl for Difference in Adjusted Means 
P-value 
6. 
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Busner J, Targum S. The clinical global impressions scale: applying a research tool in 
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and 
Spearing, MK, Post RM, Leverich GS. Modification of the clinical global 
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Buysse D, Yu L, Moul DE et al. Development and Validation of Patient-Reported 
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Dunn, W. Sensory profile. San Antonio, TX: The Psychological Corporation, 1999. 
Dunn, W. Sensory profile 2: User's Manual. Bloomington, MN: Pearson, 2014. 
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Evans DW, Uljarevic M, Lusk LG, Loth E, Frazier T. Development of two dimensional 
measures of restricted and repetitive behavior in parents and children. J Amer 
Acad Child Adolesc Psychiatry. 2017;56:51-8. 
Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rev. ed. Washington 
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Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness 
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Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 
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Johns M. The assessment of sleepiness in children and adolescents. Sleep Biol Rhythm. 
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Kim SH, Lord C. Restricted and repetitive behaviors in toddlers and preschoolers with 
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(ADOS). Autism Res. 2010;3:162-73. 
Lam KS, Aman MG. The Repetitive Behavior Scale-Revised: independent validation in 
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APPENDIX 1 
LIST OF PLANNED OUTPUTS FOR EFFICACY AND SAFETY 
Provisional 
Population 
Title 
Output 
Name 
l_ae_gloss 
Safety 
Glossary of Adverse Event Preferred Terms and 
Investigator-Specified Adverse Event Terms 
l_ae 
Safety 
Listing of Adverse Events 
l_ae_postdose 
Safety 
Listing of new onset AEs after last dose of study 
medication 
l_ae_disc 
Safety 
Listing of Adverse Events Leading to Study Treatment 
Discontinuation 
l_cm_gloss 
Safety 
Glossary of Concomitant Medication Class, Preferred 
Name, and Investigator-Specified Terms 
l_cm 
Safety 
Listing of Concomitant Medication 
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l_cssrs 
Safety 
l_ds 
Safety 
l_dv 
Safety 
l_eg 
Safety 
l_ex_ti 
Safety 
l_mh_gloss 
Safety 
l_mh 
Safety 
l_vs 
Safety 
t_ae_int 
Safety 
t_ae_oview 
Safety 
t_ae 
Safety 
t_cssrs 
Safety 
t_dm 
Safety 
t_ds 
Safety 
t_eg_cfb 
Safety 
t_ess_cat 
Safety 
t_ess_cfb 
Safety 
t_ess_chad_c 
Safety 
at 
t_ess_chad_cf 
Safety 
b 
t_ex 
Safety 
t_kss_cfb 
Safety 
t_lb_abn_ls 
Safety 
t_lb_abn_nls 
Safety 
t_lb_cfb_ls 
Safety 
Columbia-Suicide Severity Rating Scale (C-SSRS} 
Listing of Patients who Discontinued from Study 
Listing of Major Protocol Deviations 
Listing of ECG Data 
Listing of Drug Administration and Dosing Time 
Glossary of Medical History Coded Terms 
Listing of Medical History 
Listing of Vital Signs 
Adverse Events by Greatest Intensity 
Safety Summary 
Adverse Events 
Columbia-Suicide Severity Rating Scale (C-SSRS} 
Demographic and Baseline Characteristics 
Patient Disposition 
ECG Parameters Change from Baseline by Visit 
Epworth Sleepiness Scale (ESS} Total Score 
Categories 
Epworth Sleepiness Scale (ESS} Change from 
Baseline by Visit 
ESS for Adolescents Sleepiness Scale (ESS-CHAD} 
Total Score Categories 
ESS for Adolescents Sleepiness Scale (ESS-CHAD} 
Change from Baseline by Visit 
Study Treatment Exposure 
Karolinska Sleepiness Scale (KSS} Change from 
Baseline by Visit 
Laboratory Abnormalities (Standardised parameters} 
Laboratory Abnormalities (Non-Standardised 
parameters} 
Laboratory Tests and Change from Baseline by Visit 
(Standardised parameters} 
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t_lb_cfb_nls 
Safety 
Laboratory Tests and Change from Baseline by Visit 
(Non-Standardised parameters) 
t_neuro_cfb 
Safety 
Neurocognitive Battery Change from Baseline by Visit 
t_sudden 
Safety 
Sudden Onset of Sleep Questionnaire 
t_vs_cfb 
Safety 
Vital Signs Change from Baseline by Visit 
l_ae_ser 
Safety 
Listing of Serious Adverse Events 
l_dm 
Safety 
Listing of Demographic and Baseline Characteristics 
l_lb_abn 
Safety 
Listing of Laboratory Abnormalities 
l_lb 
Safety 
Listing of Laboratory Data and Change from Baseline 
by Visit 
t_ae_pt 
Safety 
Adverse Events by Preferred Term 
t_ae 
Safety 
Adverse Events Related to Study Treatment 
t_cm 
Safety 
Medications Started after Baseline by Medication 
Class and Preferred Name 
t_cm 
Safety 
Medications Ongoing at Baseline by Medication Class 
and Preferred Name 
t_cm 
Safety 
Medications Completed Prior to Baseline by 
Medication Class and Preferred Name 
t_eg_abn 
Safety 
ECG Parameters outside Normal Limits Regardless of 
Abnormality at Baseline 
t_eg_abnbl 
Safety 
ECG Parameters outside Normal Limits Among 
Patients without Abnormality at Baseline 
t_eg_qtcf 
Safety 
QTcF Actual Values and Change from Baseline by 
Visit 
t_mh 
Safety 
Previous and Concurrent Medical History 
l_ae_nsaesi 
Safety 
Listing of Non-Serious Adverse Events of Special 
Interest 
t_ae_nsaesi 
Safety 
Non-Serious Adverse Events of Special Interest 
g_ex_hist 
Safety 
Histogram of Dosing Time 
g_vs_mean 
Safety 
Mean Plot from of Vital Sign Parameters Over Time 
with 95% Cl 
Safety 
Mean Change from Baseline Plot of Vital Sign 
g_ vs_mean_cfb 
Parameters Over Time with 95% Cl 
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g_lb_mean_ls 
Safety 
Roche-Standardized Laboratory Data 
g_lb_mean_nl 
Safety 
Non-Standardized Laboratory Data 
s 
g_eg_mean 
Safety 
Mean Plot of ECG Parameters Over Time with 95% Cl 
Safety 
Mean Change from Baseline Plot of ECG Parameters 
g_eg_mean_cfb 
Over Time with 95% Cl 
g_ess 
Safety 
ESS over Time 
g_ess_cfb 
Safety 
ESS Change from Baseline over Time 
g_kss 
Safety 
KSS over Time 
g_kss_cfb 
Safety 
KSS Change from Baseline over Time 
g_neuro 
Safety 
Neurocognitive Battery 
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t_ vabs3_ancov 
Efficacy 
Vineland-3 ABC GSV Score ANCOVA no interactions 
a 
t_vabs3_ancov 
Efficacy 
Vineland-3 ABC GSV Score ANCOVA age interaction 
a 
t_ vabs3_ancov 
Efficacy 
Vineland-3 ABC GSV Score ANCOVA IQ interaction 
a 
t_ vabs3_ancov 
Efficacy 
Vineland-3 SOC GSV Score ANCOVA no interactions 
a 
t_vabs3_ancov 
Efficacy 
Vineland-3 SOC GSV Score ANCOVA age interaction 
a 
t_ vabs3_ancov 
Efficacy 
Vineland-3 SOC GSV Score ANCOVA IQ interaction 
a 
t_ vabs3_ancov 
Efficacy 
Vineland-3 COM GSV Score ANCOVA no interactions 
a 
t_vabs3_ancov 
Efficacy 
Vineland-3 COM GSV Score ANCOVA age interaction 
a 
t_ vabs3_ancov 
Efficacy 
Vineland-3 COM GSV Score ANCOVA IQ interaction 
a 
t_vabs_cfb 
Efficacy 
Vineland-3 ABC GSV Score Change from Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 SOC GSV Score Change from Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 COM GSV Score Change from Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 DLS GSV Score Change from Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 ABC Standard Score Change from 
Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 SOC Standard Score Change from 
Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 COM Standard Score Change from 
Baseline 
t_vabs_cfb 
Efficacy 
Vineland-3 DLS Standard Score Change from Baseline 
t_rbsr_ancova 
Efficacy 
t_rbsr_ancova 
Efficacy 
t_rbsr _ancova 
Efficacy 
t_rbsr_cfb 
Efficacy 
t_rbsr_cfb 
Efficacy 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
RBS-R Total Score ANCOVA no interactions 
RBS-R Total Score ANCOVA age interaction 
RBS-R Total Score ANCOVA IQ interaction 
RBS-R Total Score Change from Baseline 
RBS-R Subscale Score (3FM} Change from Baseline 
42 


t_crri_ancova 
Efficacy 
CRRI Total Score ANCOVA no interactions 
t_crri_ancova 
Efficacy 
CRRI Total Score ANCOVA age interaction 
t_crri_ancova 
Efficacy 
CRRI Total Score ANCOVA IQ interaction 
t_crri_cfb 
Efficacy 
CRRI Total Score Change from Baseline 
t_crri_cfb 
Efficacy 
CRRI Subscale Score (5FM) Change from Baseline 
t_cgii_ancova 
Efficacy 
CGl-1 Overall Score ANCOVA no interactions 
t_cgii_ancova 
Efficacy 
CGl-1 Overall Score ANCOVA age interaction 
t_cgii_ancova 
Efficacy 
CGl-1 Overall Score ANCOVA IQ interaction 
t_cgii_mmrm 
Efficacy 
CGl-1 Overall Score MMRM 
t_cgii 
Efficacy 
CGl-1 Overall Score 
t_cgii_cat 
Efficacy 
CGl-1 Proportions per Rating Category 
t_cgis 
Efficacy 
CGI-S Overall Score 
t_cgis_cat 
Efficacy 
CGI-S Proportions per Rating Category 
t_bai_cfb 
Efficacy 
BAI Total Score Change from Baseline 
t_pras_cfb 
Efficacy 
PRAS-ASD Total Score Change from Baseline 
t_ssp_cfb 
Efficacy 
SSP-2 Summary Score Change from Baseline 
t_aasp_cfb 
Efficacy 
AASP Quadrant Summary Score Change from 
Baseline 
t_promis_cfb 
Efficacy 
PROMIS Sleep-Disturbance T-Score Change from 
Baseline 
t_promis_cfb 
Efficacy 
PROMIS Sleep Related Impairment T-Score Change 
from Baseline 
t_<> 
Efficacy 
Change from Baseline in EEG beta power 
t_<> 
Efficacy 
Correlation between Baseline EEG beta power and 
clinical efficacy 
t_pql_tot_cfb 
Efficacy 
PedsQL™ Total Score Change from Baseline 
t_pql_cfs_cfb 
Efficacy 
PedsQL™ Cognitive Functioning Score Change from 
Baseline 
g_cgii 
Efficacy 
CGl-1 Overall Score over Time 
g_cgis 
Efficacy 
CGI-S Overall Score over Time 
g_forest 
Efficacy 
Vineland-3 ABC GSV composite 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
43 


by Geographic Region with 80% Cl 
g_forest 
Efficacy 
Vineland-3 ABC GSV composite 
by Rater Change with 80% Cl 
g_forest 
Efficacy 
Vineland-3 ABC GSV composite 
by Site Type with 80% Cl 
g_forest 
Efficacy 
Vineland-3 ABC GSV composite 
by Age Category with 80% Cl 
g_forest 
Efficacy 
Vineland-3 ABC GSV composite 
by IQ Category with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Geographic Region with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Rater Change with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Site Type with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Age Category with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by IQ Category with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Diagnosis of Anxiety at Baseline with 80% Cl 
g_forest 
Efficacy 
RBS-R total score 
by Sex with 80% Cl 
g_forest 
Efficacy 
CRRI total score 
by Sex with 80% Cl 
g_forest 
Efficacy 
CGII (RRB domain) 
by Sex with 80% Cl 
g_forest 
Efficacy 
BAI total score 
by Diagnosis of Anxiety at Baseline with 80% Cl 
Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
44 


Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
45 


Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
46 


Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
47 


Alogabat -F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP41316 
48 


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