Clinical trial NCT03504917
Conditions: Autism Spectrum Disorder
Sponsor: Hoffmann-La Roche
Start date: 2018-08-08; Completion date: 2020-07-01
Enrollment: 322 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg of oral administration balovaptan once a day (QD) compared with matching placebo in adults (18 years and older) with autism spectrum disorder (ASD).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Balovaptan intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 10 mg of oral administration balovaptan once a day (QD). intervention 2: Participants will receive matching placebo.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Efficacy, 
and Safety Study of Balovaptan in Adults With Autism Spectrum 
Disorder With a 2-Year Open-Label Extension 
NCT Number: NCT03504917 
Document Date: Protocol Version 3: 01-February-2019 
 
 








Balovaptan—F. Hoffmann-La Roche Ltd
4/Protocol WN39434, Version 3

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

Language has been revised to clarify that data posting will not be limited to two 
clinical trial registries and to clarify that redacted CSRs are provided only if 
requirements of Roche's global policy on data sharing have been met (Section 9.5).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Balovaptan—F. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Autism Spectrum Disorder............................ 29
1.2
Background on Balovaptan.................................................... 31
1.2.2
Clinical Studies...................................................................... 33
1.2.2.1
Safety and Tolerability ........................................................... 33
1.2.2.2
Pharmacokinetics .................................................................. 35
2.
OBJECTIVES AND ENDPOINTS ............................................................... 37
3.
STUDY DESIGN......................................................................................... 41
3.1
Description of the Study......................................................... 41
3.1.1
Overview of Study Design ..................................................... 42
3.1.1.1
Screening Period................................................................... 42
3.1.1.2
Re-Screening......................................................................... 43
3.1.1.3
Double-Blind Treatment Period ............................................. 43
3.1.1.4
Open-Label Extension Period................................................ 45
3.1.1.5
Follow-Up Period................................................................... 46
3.1.1.6
Independent Data Monitoring Committee .............................. 46
3.2
End of Study and Length of Study......................................... 46
3.3
Rationale for Study Design.................................................... 47
3.3.1
Rationale for Balovaptan Dose and Schedule ....................... 47
3.3.2
Rationale for Use of Vineland-II Adaptive 
Behavior Scales 2DC Score as the 
Primary Efficacy Endpoint...................................................... 48
3.3.3
Rationale for Use of Responder Definition............................. 49
3.3.4
Rationale for Subject Population ........................................... 49
3.3.5
Rationale for Use of Placebo................................................. 50
3.3.6
Rationale for Study Duration.................................................. 50
3.3.7
Rationale for Biomarker Assessments................................... 51


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4.
MATERIALS AND METHODS .................................................................... 51
4.1
Subjects................................................................................. 51
4.1.1
Inclusion Criteria.................................................................... 51
4.1.2
Exclusion Criteria................................................................... 53
4.1.2.1
General Exclusion Criteria..................................................... 53
4.1.2.2
Neurologic and Psychiatric Exclusion Criteria ....................... 53
4.1.2.3
Exclusions Related to Cardiovascular Disorders................... 53
4.1.2.4
Exclusions Related to Other Organ Systems......................... 54
4.1.2.5
Additional Exclusion Criteria.................................................. 54
4.1.3
Prohibited Medications and Food Products ........................... 54
4.2
Method of Treatment Assignment and Blinding..................... 55
4.3
Study Treatment and Other Treatments 
Relevant to the Study Design ................................................ 56
4.3.2
Study Treatment Dosage, Administration, 
and Compliance..................................................................... 57
4.3.3
Investigational Medicinal Product Accountability ................... 58
4.3.4
Continued Access to Balovaptan........................................... 59
4.4
Concomitant Therapy ............................................................ 59
4.4.1
Permitted Therapy................................................................. 59
4.4.2
Non-Pharmacological Interventions....................................... 60
4.4.3
Prohibited Therapy ................................................................ 60
4.5
Study Assessments ............................................................... 61
4.5.1
Informed Consent Forms and Screening Log........................ 61
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 62
4.5.3
Physical and Neurologic Examinations.................................. 62
4.5.4
Vital Signs.............................................................................. 62
4.5.5
Temperature Measurements ................................................. 63
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 63


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4.5.6.2
Clinical Genotyping Samples................................................. 65
4.5.7
Electrocardiograms................................................................ 65
4.5.8
Clinical Outcome Assessments ............................................. 66
4.5.8.1
Vineland-II Adaptive Behavior Scales, Second 
Edition.................................................................................... 67
4.5.8.2
Wechsler Abbreviated Scale of Intelligence®, 
Second Edition ...................................................................... 67
4.5.8.3
Autism Diagnostic Observation Schedule, 
Second Edition ...................................................................... 67
4.5.8.4
Social Responsiveness Scale, Second Edition, 
Adult (Relative/Other Report) ................................................ 68
4.5.8.5
Clinical Global ImpressionImprovement .............................. 68
4.5.8.6
Clinical Global ImpressionSeverity ...................................... 69
4.5.8.7
Caregiver Global ImpressionChange................................... 69
4.5.8.8
Caregiver Global ImpressionSeverity .................................. 69
4.5.8.9
Repetitive Behavior Scale–Revised....................................... 69
4.5.8.10
Pediatric Quality of Life Inventory Family Impact 
Module................................................................................... 70
4.5.8.11
Hamilton Anxiety Rating Scale .............................................. 70
4.5.8.12
EuroQol Five-Dimensions Questionnaire, Five-
Levels Version....................................................................... 70
4.5.8.15
Pediatric Quality of Life Inventory Generic 
Core Scales........................................................................... 71
4.5.8.16
Pediatric Quality of Life Cognitive Functioning 
Module................................................................................... 72
4.5.8.17
Pittsburg Sleep Quality Index ................................................ 72
4.5.8.18
Patient Global ImpressionChange ....................................... 72
4.5.8.19
Patient Global ImpressionSeverity....................................... 73
4.5.8.20
Columbia-Suicide Severity Rating Scale ............................... 73
4.5.9
Optional Samples for Research Biosample 
Repository ............................................................................. 73
4.5.9.1
Overview of the Research Biosample Repository.................. 73
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74


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4.5.9.3
Sample Collection.................................................................. 74
4.5.9.4
Confidentiality........................................................................ 74
4.5.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 75
4.5.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 75
4.5.9.7
Monitoring and Oversight....................................................... 76
4.5.10
Optional Exploratory Substudies ........................................... 76
4.6
Treatment, Subject, Study, and Site 
Discontinuation...................................................................... 77
4.6.1
Study Treatment Discontinuation........................................... 77
4.6.2
Subject Discontinuation from Study....................................... 78
4.6.3
Study Discontinuation............................................................ 79
4.6.4
Site Discontinuation............................................................... 79
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Plan ............................................................................ 79
5.1.2
Management of Subjects Who Experience 
Adverse Events ..................................................................... 81
5.1.2.1
Dose Modifications ................................................................ 81
5.1.2.2
Treatment Interruption ........................................................... 82
5.2
Safety Parameters and Definitions ........................................ 87
5.2.1
Adverse Events ..................................................................... 87


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5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 88
5.2.3
Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 88
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 89
5.3.1
Adverse Event Reporting Period ........................................... 89
5.3.2
Eliciting Adverse Event Information....................................... 90
5.3.3
Assessment of Severity of Adverse Events ........................... 90
5.3.4
Assessment of Causality of Adverse Events ......................... 90
5.3.5
Procedures for Recording Adverse Events............................ 91
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 91
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 91
5.3.5.3
Persistent or Recurrent Adverse Events................................ 91
5.3.5.4
Abnormal Laboratory Values ................................................. 92
5.3.5.5
Abnormal Vital Sign Values ................................................... 93
5.3.5.6
Abnormal Liver Function Tests.............................................. 93
5.3.5.7
Deaths ................................................................................... 94
5.3.5.8
Preexisting Medical Conditions.............................................. 94
5.3.5.9
Lack of Efficacy or Worsening of Autism 
Spectrum Disorder................................................................. 94
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 95
5.3.5.11
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 95
5.3.5.12
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 97
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 97
5.4.1
Emergency Medical Contacts................................................ 98
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 98
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 98
5.4.2.2
Events That Occur after Study Drug Initiation........................ 98
5.4.3
Reporting Requirements for Pregnancies.............................. 99
5.4.3.1
Pregnancies in Female Subjects ........................................... 99


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5.4.3.2
Abortions ............................................................................... 99
5.4.3.3
Congenital Anomalies/Birth Defects .................................... 100
5.5
Follow-Up of Subjects after Adverse Events........................ 100
5.5.1
Investigator Follow-Up......................................................... 100
5.5.2
Sponsor Follow-Up .............................................................. 100
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ......................................... 100
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 101
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 101
6.1
Analysis Populations ........................................................... 102
6.1.1
Safety Population ................................................................ 102
6.1.2
Intent-to-Treat Population.................................................... 102
6.2
Determination of Sample Size ............................................. 102
6.3
Summaries of Conduct of Study.......................................... 102
6.4
Summaries of Treatment Group Comparability ................... 102
6.5
Efficacy Analyses ................................................................ 103
6.5.1
Primary Efficacy Endpoint.................................................... 103
6.5.2
Secondary Efficacy Endpoints............................................. 103
6.5.3
Exploratory Efficacy Endpoints............................................ 103
6.5.4
Estimands............................................................................ 103
6.5.5
Primary Efficacy Analysis .................................................... 104
6.5.6
Secondary Efficacy Analyses .............................................. 104
6.5.7
Subgroup Analyses ............................................................. 104
6.5.8
Exploratory Analyses........................................................... 105
6.5.9
Futility Analyses................................................................... 105
6.6
Safety Data Analysis ........................................................... 106
6.7
Pharmacokinetic and Pharmacodynamic 
Analyses.............................................................................. 106
7.
DATA COLLECTION AND MANAGEMENT ............................................. 107
7.1
Data Quality Assurance....................................................... 107
7.2
Electronic Case Report Forms............................................. 107
7.3
Electronic Clinical Outcome Data ........................................ 107


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7.4
Source Data Documentation................................................ 108
7.5
Use of Computerized Systems ............................................ 109
7.6
Retention of Records........................................................... 109
8.
ETHICAL CONSIDERATIONS.................................................................. 109
8.1
Compliance with Laws and Regulations .............................. 109
8.2
Informed Consent................................................................ 109
8.3
Institutional Review Board or Ethics Committee.................. 111
8.4
Confidentiality...................................................................... 111
8.5
Financial Disclosure ............................................................ 112
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 112
9.1
Study Documentation .......................................................... 112
9.2
Protocol Deviations.............................................................. 112
9.3
Site Inspections ................................................................... 113
9.4
Administrative Structure....................................................... 113
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 113
9.6
Protocol Amendments ......................................................... 114
10. REFERENCES ......................................................................................... 115
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 37
Table 2
Proposed Biomarkers for Exploratory Research......................... 40
Table 3
Sequence of Scale Administration .............................................. 44
Table 3
Management Guidelines for Cardiac Events............................... 86
Table 4
Adverse Event Severity Grading Scale ....................................... 90
Table 5
NT-proBNP ULN and Diagnostic Cutoff Values .......................... 93
LIST OF FIGURES
Figure 1
Study BP28420:  Overview of Study Design............................... 33
Figure 2
Study Schema............................................................................. 42


Balovaptan—F. Hoffmann-La Roche Ltd
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LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24.......... 120
Appendix 2
Unscheduled Visit and Follow-Up Assessments:  
Double-Blind and OLE Periods ................................................. 127
Appendix 3
Schedule of Activities:  Open-Label Extension Period, 
Week 28 and Onward ............................................................... 130


Balovaptan—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, EFFICACY, AND 
SAFETY STUDY OF BALOVAPTAN IN ADULTS 
WITH AUTISM SPECTRUM DISORDER WITH A 
2-YEAR OPEN-LABEL EXTENSION
PROTOCOL NUMBER:
WN39434
VERSION NUMBER:
3
EUDRACT NUMBER:
2017-004378-32
IND NUMBER:
116,483
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return a copy of this signed form as instructed by your local study monitor and 
retain a signed copy for your study files.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, EFFICACY, AND SAFETY STUDY OF 
BALOVAPTAN IN ADULTS WITH AUTISM SPECTRUM 
DISORDER WITH A 2-YEAR OPEN-LABEL EXTENSION
PROTOCOL NUMBER:
WN39434
VERSION NUMBER:
3
EUDRACT NUMBER:
2017-004378-32
IND NUMBER:
116,483
TEST PRODUCT:
Balovaptan (RO5285119)
PHASE:
Phase III 
INDICATION:
Autism spectrum disorders
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg of oral 
administration balovaptan once a day (QD) compared with matching placebo in adults (18 years 
and older) with autism spectrum disorder (ASD).  Specific objectives and corresponding 
endpoints for the study are outlined in the following table.








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Study Design
Description of Study
Study WN39434 is a Phase III, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, 24-week, efficacy, and safety study of 10 mg of oral balovaptan QD in adults 
(18 years old or older) with ASD, followed by a 2-year open-label extension period for subjects
completing the double-blind treatment period.
Subjects providing informed consent will undergo screening within 4 weeks prior to the first 
double-blind study drug (balovaptan or placebo) administration. Eligible subjects will be 
randomized in a 1:1 ratio in a blinded fashion to either 10 mg of balovaptan or matching oral
placebo QD for 24 weeks. The primary efficacy endpoint is the change from baseline at 
Week 24 on the VinelandAdaptive Behavior Scales Vineland-IItwo-domain composite 
(2DC) score.
Thus, for subjects remaining in the full study, the approximate length of the study will be 
144 weeks or 34 months (screening [approximately 4 weeks], double-blind treatment 
[24 weeks], and an open-label extension period [104 weeks] with a follow-up period of 12 weeks 
after completion of the treatment phase). 
Subjects will be recruited from international sites, including sites in North America and limited 
rest of the world (ROW) countries. Subjects who prematurely discontinue from study treatment 
or from the study will not be replaced.  However, all subjects should be followed and their data 
(specifically, vital sign measurements, adverse events, concomitant treatment, Vineland-II, 
CGI-S, CGI-I, PedsQL 4.0 Core) collected up to and including the Week 24 visit, regardless of 
their adherence to treatment.
Randomization will be stratified by baseline Vineland-II two domain composite (2DC) (the 
average of Communication and Socialization domains) (60 vs. 60), sex (male vs. female), 
geographical region (North America vs. ROW), and age (25 years vs. 25 years).  The main 
analysis of the primary and secondary efficacy endpoints will occur once the final data from all 
visits, up to and including Week 24, have been collected and cleaned and the database has 
been locked.  An interim futility analysis will be performed by an independent Data Monitoring 
Committee (iDMC) when approximately 50% of subjects complete the Week 24 visit. 
The iDMC will meet regularly to oversee safety throughout the trial and its activities will be 
described in a separate iDMC charter.
Secondary and exploratory endpoints will examine core autism symptoms (social interaction, 
social communication, and functional deficits), associated symptoms, impact on health-related 
quality of life, and broader impacts on study partners and family.  Safety will be examined via 
adverse events, clinical laboratory values, electrocardiograms (ECGs), physical and neurologic 
examinations, and safety outcome assessments such as suicidality.
Screening Period
Subjects who are willing and who have given their consent to participate in the study will 
undergo a screening procedure within 4 weeks before the first study drug administration 
(Day 1).  Subjects must meet all of the eligibility criteria in order to qualify for the study (see the 
inclusion and exclusion criteria).
The screening period can be extended to a total period of 6 weeks in cases when a laboratory 
blood test needs to be repeated for confirmation during the screening interval or for other 
relevant clinical, administrative, or operational reasons.  Subjects must fulfill all the entry 
criteria for participation in the study.
Double-Blind Treatment Period
All subjects will undergo 24 weeks of double-blind treatment.  The study will be unblinded 
following the primary database lock when the last enrolled subject has completed the 
double-blind treatment period and all the data have been collected and cleaned. 
Randomization (Day 1) will occur only after a subject has met all eligibility criteria.  At the 
baseline visit (Day 1), subjects will undergo a series of assessments outlined in the schedule of 
activities.  Breaks should be allowed between tests when necessary.  If necessary, the baseline 
visit can be split into 2 consecutive days, and the second day will be considered the baseline 
visit date (Day 1).  If either the Week 12 or Week 24 visit is split over 2 days, study drug 
(balovaptan or placebo) must be administered QD after the completion of all assessments.


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After the predose assessments have been completed, each subject will receive an oral dose of 
balovaptan or placebo according to randomization.  After completion of the postdose 
evaluations and following a medical check-up by a physician, the subject will be discharged 
from the study center. 
Although study visits will be conducted on site, checks for signs and symptoms of infection will 
be conducted every 2 weeks either at a site visit or by telephone call conducted by site staff.  
As a general rule, the test sequence for all assessments should remain the same for a given
subject as established at screening and baseline.  At all visits, patient-reported outcome (PRO) 
assessments should be completed prior to any other assessments.  All assessments must be
performed before administration of study drug.
For informant-based assessments, the following order of assessments will be followed:

The Vineland-II will be the first informant-based assessment with a subject's study partner.

For all other informant-based assessments:  It is strongly recommended that the sequence 
provided in Section 3.1.3.1, Table 3, is followed.  It will be possible for assessments (e.g., 
the Vineland-II interview and subject assessments) to be conducted in parallel if the site has 
sufficient qualified raters available.  Importantly, the sequence established at screening and 
baseline should remain the same for a given subject; however, subject assessments should 
be prioritized.
At visits when blood samples are obtained, the order of assessments should be as follows:

12-Lead ECGs

Vital signs

Physical and neurologic examinations

Blood samples
Note:  ECGs and vital sign assessments should be completed before other invasive 
assessments such as blood samples and should occur following a short period when the study 
participant is able to rest (typically, at least 5 minutes),
Open-Label Extension Period
All subjects who complete the 24-week double-blind treatment period are eligible for 
participation in the open-label extension period of the study.  Subjects who are not willing to 
participate in the open-label extension period of the study will complete the safety follow-up 
visits.  Subject treatment allocation during the double-blind treatment period will not be 
unblinded regardless of a subject's participation in the open-label extension period.  
The 2-year (104-week) duration of the open-label extension period serves to evaluate the
long-term safety, tolerability, and efficacy of balovaptan treatment in subjects with ASD.  
All subjects will receive 10 mg of oral balovaptan QD.  
After the predose assessments have been completed, each subject will receive an oral dose of 
balovaptan.  After completion of the postdose evaluations and following a medical check-up by 
a physician, the subject will be discharged from the study center. If the visit is split over 2 days, 
study drug (balovaptan) must be administered QD after the completion of all assessments.  
Checks for signs and symptoms of infection will be conducted according to the schedule of 
activities.  
As a general rule, the test sequence for all assessments should remain the same for a given
subject as previously established at screening and baseline.  At all visits, PRO assessments 
should be completed prior to any other assessments.  All assessments must be performed
before administration of study drug.
For informant-based assessments, the following order of assessments will be followed:

The Vineland-II will be the first informant-based assessment with a subject's study partner.


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
For all other informant-based assessments, there is no restriction in the order, a sequence
established at screening and baseline should remain the same for a given subject; however, 
subject assessments should be prioritized.  The suggested sequence is provided in 
Section 3.1.3.1, Table 3.  It will be possible for assessments (e.g., the Vineland-II interview 
and subject assessments) to be conducted in parallel if the site has sufficient qualified 
raters available.
At visits when blood samples are obtained, the order of assessments should be as follows:

12-Lead ECGs

Vital signs

Physical and neurologic examinations

Blood samples
Note: ECGs and vital sign assessments should be completed before other invasive 
assessments such as blood samples and should occur following a short period when the study 
participant is able to rest (typically, at least 5 minutes),
Follow-Up Period
In order to evaluate the long-term effects of balovaptan, subjects will enter a follow-up period, 
consisting of a telephone call at Week 1 and site visits at Weeks 2 and 12.  The final follow-up 
visit for safety and limited efficacy will be conducted 12 weeks after the Week 24 visit for 
subjects who do not enter the open-label extension period or at the end of the open-label 
extension period for all other subjects.  For subjects who discontinue treatment prematurely 
and will not return for the Week 24 visit, the final follow-up visit should occur 12 weeks after 
the final dose.  
Independent Data Monitoring Committee
All available safety data will be assessed on a regular basis by an iDMC.  It is anticipated that 
these assessments will occur approximately every 6 months.
The iDMC will also undertake evaluation of any efficacy interim analyses.
Details about the iDMC will be provided in the iDMC Charter.
Number of Subjects
Approximately 350 subjects will be enrolled in the study. 
Target Population
Inclusion Criteria
Subjects must meet the following criteria for study entry:

Signed Informed Consent Form

Males or females, age 18 years or older at time of signing Informed Consent Form

Subject meets the Diagnostic and Statistical Manual of Mental Disorders, Version 5 
(DSM-5) criteria for ASD for an autism diagnosis and is confirmed using Autism Diagnostic 
Observation Schedule, Second Edition (ADOS-2) criteria
If the ADOS-2 assessment has been performed by a certified rater and documented 
within 12 months of the screening visit, there is no requirement to repeat it. 

Social Responsiveness Scale, Second Edition (SRS-2), proxy version, total t-score 
66 at screening

A full scale IQ score 70 on the Wechsler Abbreviated Scale of Intelligence®, Second 
Edition (WASI®-II)
The score should be confirmed by assessment during screening.  Previous test results 
on the WASI or equivalent scales such as Wechsler Adult Intelligence Scale, Fourth 
Edition (WAIS-IV) (including all subdomain scores) are accepted if the test has been 
performed within 12 months prior to screening by an appropriately qualified rater.

Ability and willingness to fully comply with study visit schedule and regular assessments
and fluency in the language of the site 


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
Subject’s participation in the study or discontinuation of prohibited medication will not pose 
undue risks to the subject, in the investigator’s opinion

Subject has an appropriate study partner, in the opinion of the investigator
The study partner is someone who has regular and sufficient periods of contact 
(including regular conversations and face-to-face interactions) with the subject to be
able to report on the subject’s status on relevant study assessments. 
The study partner should have sufficient capacity to evaluate social and communication 
changes in the subject and should be available throughout the entire duration of the 
study.  
The study partner will not be eligible to be a study participant in this study.
Only at visits that do not require a study partner’s input on assessments can a subject 
be accompanied by someone other than the study partner if the study partner is not 
available. 
Every effort should be made to have the same study partner participate throughout the 
subject's participation in the study. 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 28 days after the last dose of study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.
Women must agree to use an effective form of contraception during all phases of 
the study.
No specific contraception methods for males are required.
Note:  The Sponsor does not require the use of male contraception because of the 
minimal seminal dose transmitted via sexual intercourse.

Treatment with permitted medications (at a stable dose for 12 weeks before screening) and 
behavioral therapy regimens (regimens stable for 6 weeks before screening), with the intent 
that such treatments remain stable throughout the study and with no expected changes 
before the Week 24 visit
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
General Exclusion Criteria
Subjects who meet the following general exclusion criterion will be excluded from study entry:

Pregnancy or breastfeeding, or intention to become pregnant during the study
Females of childbearing potential must have a negative urine pregnancy test result 
immediately prior to initiation of study drug.
Neurologic and Psychiatric Exclusion Criteria
Subjects who meet any of the following neurologic and psychiatric exclusion criteria will be 
excluded from study entry:

Previous initiation of new or major change in psychosocial intervention (including 
investigational) within 6 weeks prior to screening




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
Allowed medications have not been stable for 12 weeks prior to screening

Previous treatment with prohibited medications or herbal remedies within 2 weeks prior to 
randomization or 5 half-lives (whichever is longer)

Blood donation or loss of blood 500 mL within 3 months prior to randomization

Previous participation in an investigational drug or device study within 60 days prior to 
randomization or previous enrollment in investigational trials of balovaptan
Prohibited Medications and Food Products
Prior use of certain therapies is permitted if the individual has undergone a washout period of 
2 weeks prior to randomization or 5the half-life (whichever is longer). 
The following therapies are prohibited throughout the study and include:

Moderate and strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, 
erythromycin, ciprofloxacin, diltiazem, and grapefruit juice)
Moderate inhibitors of CYP3A4 (e.g., erythromycin, ciprofloxacin, diltiazem) may be 
allowed for a treatment duration of no more than approximately 10 days (e.g., in the 
context of an adverse event) after discussion with the Medical Monitor or designee.  
The reason for and approval of such treatment is to be documented.

Moderate and strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, St. John’s 
Wort), with the following exceptions:
Weak inducers are permitted.

Concomitant oral medication that are P-gp substrates: 

Quinidine should not be given with balovaptan. 

Risperidone and cetirizine are allowed.  

All other clinically relevant substrates of P-gp:  An interaction cannot be ruled out and 
caution is advised in particular for those medications that have a narrow therapeutic 
window (e.g., loperamide).  However, when balovaptan is administered 5 or more hours 
prior to such a P-gp substrate, the risk of pharmacokinetic (PK) interaction is predicted 
to be small. 

Chronic adrenocorticoid or glucocorticoid use, with the following exceptions:  Inhaled 
and topical formulations are permitted.

Oxytocin

Desmopression (DDAVP®)

Bumetanide 

Agents inhibiting vasopressin receptors (e.g., tolvaptan, conivaptan)

Agents that have been associated with significant and/or irreversible hematological toxicity
and therefore require frequent hematologic monitoring (e.g., clozapine)

Use of any concomitant medication known to potentially cause peripheral neuropathy per
the Warnings and Precautions section of the U.S. label or the corresponding section of the 
local label

Agents that have been associated with significant and/or irreversible hematologic toxicity 
and therefore require frequent monitoring (e.g., clozapine)

Use of tetrahydrocannabinol due its psychoactive effects (e.g., marijuana)
End of Study
The end of the double-blind treatment period of the study is defined as the time when subjects
have either transitioned to the open-label extension period or, for subjects not entering the 
open-label extension period, when the follow-up period has been completed.
The end of study is defined as the date when the last subject, last visit occurs in the open-label 
extension period or the follow-up period.


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Length of Study
It is anticipated that it may take from 18 to 28 months to recruit all subjects for the study.  
Hence, the total length of the study is estimated to be approximately 45 years.
Investigational Medicinal Products
The investigational medicinal products for this study are balovaptan and matching placebo.
Test Product (Investigational Drug)
One tablet of study drug (balovaptan or placebo) should be taken orally QD in the morning, with 
or without food. The tablet should be swallowed whole with something to drink.
The first dose of the study drug will be administered on Day 1 after all predose baseline 
assessments have been conducted.  At subsequent visits, study drug should not be taken until 
all protocol-mandated study assessments are completed, unless otherwise specified in the 
protocol.
Statistical Methods
Database lock to enable the analysis of the 24-week, placebo-controlled phase of the study will 
occur once all subjects have either completed the 24-week assessment or withdrawn from the 
study early, and all data required for analysis have been cleaned and verified.  After database 
lock, treatment assignments will be unblinded to the Sponsor.
The final analysis of the 24-week placebo-controlled period will be performed after database 
lock.  The final analysis of all data collected in the study, including the open-label extension, will 
occur after all subjects have completed the study.
Details of the planned statistical analyses mentioned below in this section will be fully specified 
in the Statistical Analysis Plan, which will be finalized prior to the locking the study database 
and unblinding the study.
Primary Analysis
The primary efficacy analysis for this trial will compare balovaptan with placebo at Week 24.  
The following null (H0) and alternative (Ha) hypotheses will be tested at a two-sided 0.05 
level:

H0:  MEANbalovaptan = MEANplacebo versus

Ha:  MEANbalovaptan ≠ MEANplacebo
for which the MEANRO and MEANplacebo refer to the mean change from baseline for balovaptan
and placebo, respectively.
The analysis of the primary endpoint, the change from baseline at Week 24 on the Vineland-II 
2DC score, will be performed by means of analysis of covariance.  The model will include the 
corresponding endpoint baseline score as covariate and treatment, age group, sex, and 
geographical region as fixed effects.  Based on this analysis, least square means, standard 
errors, treatment difference, and corresponding 95% confidence intervals will be reported. 
The effects on continuous secondary endpoints, as well as the short-term effect at 12 weeks will 
be similarly analyzed.
As a supplementary analysis, a mixed-model repeated measurement (MMRM) analysis, will be 
performed.  The MMRM model will include the corresponding endpoint baseline score as a 
covariate, with visit, treatment, age group, sex, and geographical region as fixed effects, and 
treatment by visit interaction; visit will be fitted as a repeated effect with unstructured correlation 
across visits within each subject. 
Determination of Sample Size
The sample size of 350 randomized subjects (175 subjects per arm) provides 85% power to 
detect a difference in means between treatments in the change from baseline at Week 24 on 
the Vineland-II 2DC score of at least 4.0 points, assuming a two-sided 5% significance level and 
a standard deviation of about 12.5 points. A blinded interim analysis of the change in Vineland-
II 2DC score from baseline may be performed by the Sponsor to allow an increase in the 
sample size if necessary to achieve appropriate study power.


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Futility Analyses
One or more interim futility analyses will be performed during the study.  The analysis will be 
performed by the external independent Data Coordinating Center that generates the unblinded 
results reviewed by the iDMC on a regular basis.  
The iDMC will review the unblinded results for the primary efficacy endpoint (change from 
baseline at Week 24 in the Vineland-II 2DC score) and for the Adaptive Behavior Composite 
and the three individual Vineland-II domains standard scores. The iDMC will be given clear 
criteria, detailed in the Statistical Analysis Plan, regarding what would constitute futility, 
and it is expected to recommend stopping the trial if the futility analysis results meet those 
criteria. If the analysis of the primary endpoint results at the time of this interim analysis 
indicates that the conditional probability of success for the trial is less than a prespecified 
threshold, then the committee may recommend that the trial be terminated for futility.  The iDMC 
will communicate to the Roche Data Review Board (DRB) only this recommendation (whether 
or not to stop the study for futility); detailed results of the futility analysis will not be shared with 
the Sponsor unless specifically requested by the DRB. Roche DRB Chair (or designate) will 
make the final decision regarding stopping the trial.
No adjustment for multiple comparisons will be made to the α-level for this analysis, as the 
decision rules for the futility analysis will not allow for the opportunity to stop the study early for 
overwhelming efficacy. 
The specifics of the interim futility analysis will be documented prior to its conduct in 
the Statistical Analysis Plan. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
2DC
two-domain composite (score)
ADAMS
Anxiety, Depression, and Mood Scale
ADOS-2
Autism Diagnostic Observation Schedule, 
Second Edition
ASD
autism spectrum disorder
AUC
area under the concentrationtime curve
AVP
arginine vasopressin
AVPR1A
arginine vasopressin receptor 1A (gene)
CaGI-C
Caregiver Global ImpressionChange
CaGI-S
Caregiver Global ImpressionSeverity
CDC
Centers for Disease Control and Prevention
CGI-I
Clinical Global ImpressionImprovement
CGI-S
Clinical Global ImpressionSeverity
CK-MB
cardiac preferred isoform of CPK
CNTNAP2
contactin-associated proteinlike 2 (gene)
CPK 
creatinine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
cTnI
cardiac troponin I
DRB
Data Review Board
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 
Version 5
EC
Ethics Committee
eCOA
electronic clinical outcome assessment
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
EuroQoL Five Dimensions QuestionnaireFive Levels
FDA
Food and Drug Administration
GI
gastrointestinal
GIFT
granulocyte immunofluorescence test
GLP
Good Laboratory Practice
HAM-A
Hamilton Anxiety Rating Scale
HBcAb
hepatitis B core antibody 
HbsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life


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Abbreviation
Definition
hs cTnT
high sensitivity cardiac troponin T
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IQ
intelligence quotient
ITT
intent to treat
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system 
LLN
lower limit of normal
MMRM
mixed-model repeated measurement
NOAEL
no-observed-adverse-effect level 
NT-proBNP
N-terminal pro btype natriuretic peptide 
ObsRO
observer-reported outcome 
PedsQL
Pediatric Quality of Life Inventory
PedsQL™4.0 Core
Pediatric Quality of Life Inventory™ Generic Core 
Scales, Version 4.0
PGI-C
Patient Global ImpressionChange
PGI-S
Patient Global ImpressionSeverity
PK
pharmacokinetic
PRO
patient-reported outcome
PSQI
Pittsburgh Sleep Quality Index 
QD
once a day
QTcF
QT interval corrected through use of
Fridericia’s formula
RBR
Research Biosample Repository
RBS-R
Repetitive Behavior ScaleRevised
ROW
rest of the world
SAP
Statistical Analysis Plan
SRS-2
Social Responsiveness Scale, Second Edition 
ULN
upper limit of normal
V1a
vasopressin 1a
V1b
vasopressin 1b
V2
vasopressin 2
Vineland-II
VinelandAdaptive Behavior Scales, Second Edition
VPA
valproic acid


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Abbreviation
Definition
WAIS®-IV
Wechsler Adult Intelligence Scale®, Fourth Edition
WASI®-II 
Wechsler Abbreviated Scale of Intelligence®, 
Second Edition 
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON AUTISM SPECTRUM DISORDER
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by 
persistent deficits in social communication and social interaction and repetitive patterns of
behaviors, interests, or activities.  The prevalence of ASD is between 1 in 50 and 
1 in 88 children (Levy et al. 2009; Centers for Disease Control and Prevention [CDC] 2012)
and is approximately 1 in 42 boys and 1 in 189 girls (CDC 2016).  Core symptoms of
ASD are usually observed by 3 years of age, although typical language development
might delay identification of symptoms.  It is estimated that approximately 1.2% of the 
overall population in the United States lives with ASD (Buescher et al. 2014), and it has 
been reported to be similar in the population in the United Kingdom (Brugha et al. 2011). 
Diagnosis rates in the United Kingdom for ASD in children are currently estimated to be 
1.1% of the total population, thus suggesting that the prevalence rates between adults 
and children do not differ.  ASD is a disorder diagnosed in children that continues to 
have a life-long burden that follows the patient from childhood throughout adulthood.
Although initial symptoms may be identified between 12 and 24 months, typically ASD
does not manifest as a formal diagnosis, and even if a diagnosis is made, this may not be
stable (Kleinman et al. 2008; Chawarska et al. 2009).  Deficits in social interaction
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. Females 
with impairments in social and communication function are typically more intellectually 
impaired (Fombonne et al. 2011; Stacy et al. 2014).  Stereotyped and repetitive behavior
manifests as a preoccupation with stereotyped or restricted interests, adherence to
routines, rigidity, perseverative, motor mannerisms, and preoccupation or fascination
with parts of items, and unusual visual exploration.
In addition to these core deficits, individuals with ASD suffer from a range of co-morbid 
conditions, including irritability, depression or anxiety, attention deficits, 
obsessive-compulsive symptoms, seizures, and sleep disruption.  Furthermore, adults 
with ASD are at increased risk of suicide compared with the general population. 
Individuals with ASD die on average 18 years before the general population 
(Hirvikoski et al. 2016).  In addition, autistic adults without a learning disability were 
9 times more likely to die by suicide.  This could be a reflection of the isolation and 
depression many people with ASD experience as data show that approximately 35% of 
young adults (ages 1923 years) with ASD are unemployed or do not complete 
postgraduate education after leaving high school (Shattuck et al. 2012). 


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The etiology of ASD is highly genetic, although environmental factors also contribute.  
Heritability estimates from family and twin studies suggest that about 90% of variance
can be attributed to genetic factors (Levy et al. 2009).
At present, no pharmacological treatment exists for the core deficits of ASD, and
currently available treatments address only associated behavioral problems (Wink et al. 
2010). Non-pharmacological treatments have been developed to address the core
symptoms; however, efficacy has not been proven in large clinical trials (Warren et al. 
2011).
The hypothalamic neuropeptides vasopressin (also known as anti-diuretic hormone) and 
oxytocin, in addition to their well-defined roles in the control of osmotic balance and in 
reproduction, appear to have prominent roles in the regulation of higher brain functions, 
such as learning and memory, emotional control, and social behaviors.  Vasopressin 
mediates its effect via vasopressin receptors (vasopressin 1a [V1a], vasopressin 1b 
[V1b], and vasopressin 2 [V2]), which are all members of the G proteincoupled receptor
family.  V1a and V1b lead to intracellular increases in calcium through the
phosphatidyl-inositol pathway, whereas V2 is coupled to adenylyl-cyclase and cyclic
adenosine monophosphate production.  V1a receptors are the primary subtype found in
the CNS, expressed in several areas of the limbic system (hypothalamus, septum,
hippocampus, and amygdala) but are also present in several tissues (vascular smooth
muscle, liver, kidney, platelets, and spleen) (Loup et al. 1991; Ostrowski et al. 1994; 
Ostrowski 1998).  V1b receptors are also present in several brain regions but appear to
be the most important for the increase in corticotropin-releasing hormoneinduced 
adrenocorticotropic hormone secretion.  V2 receptors are present in the renal collecting
duct and mediate the antidiuretic effects of vasopressin.
Studies in animals and humans have implicated the vasopressin system in the
modulation of behaviors related to both core and associated symptoms of ASD.  In
non-human mammals, V1a receptors are distributed in brain regions associated with
control of stress and anxiety and social and affiliative behaviors, including parental care,
pair-bonding, social memory, and social aggression. Vasopressin levels have been
shown to be elevated during stress, as induced by the forced swim test in rats
(Ebner et al. 2002).  Central administration of a V1 peptide antagonist has shown
anxiolytic effects in an elevated plus-maze test, a standard animal model of anxiety
(Liebsch et al. 1996), and antidepressant-like effects in the forced swim test, a model of
depressive behavior.  Similarly, V1a receptor knockout mice also show reduced anxiety in
open-field, light-dark box, and elevated plus-maze tests (Bielsky et al. 2004; Egashira 
et al. 2007).  In addition, central injection of arginine vasopressin (AVP) in rodents (voles
and hamsters) has been shown to induce offensive aggressive behavior (Winslow et al. 
1993; Delville et al. 1996), which can be prevented by a V1a receptor antagonist
(Ferris et al. 2006).  Scratching and grooming, reminiscent of obsessive-compulsive
behavior, can also be observed in mice after central injection of vasopressin
(Meisenberg 1988).


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In humans, support for a role of the vasopressin system in ASD is provided by studies on 
the arginine vasopressin receptor 1A (AVPR1A) gene that encodes the V1a receptor and 
is located on chromosome 12q.  Multiple studies have shown genetic associations of the 
AVPR1A gene with ASD, mainly with genetic markers in the promoter region of the gene, 
which includes microsatellites.  However, it is unclear which microsatellite alleles show 
association with ASD or specific clinical phenotypes (Kantojärvi et al. 2015).  Consistent
with behavioral studies in animals (see above), these risk alleles have been found to
modulate activation of the amygdala during emotional face processing
(Meyer-Lindenberg et al. 2009) and to be associated with specific personality traits in
healthy volunteers (Ebstein et al. 2012).  Similarly, intranasal administration of 
vasopressin was shown to modulate the activity of a network involved in the processing
of emotional information with specific effects in the subgenual cingulate regions
(Zink et al. 2010).
Additional evidence for a role of vasopressin in modulating behaviors of relevance to
ASD is provided by studies showing increased cerebrospinal levels of vasopressin in 
obsessive-compulsive disorder and aggressive behavior (Zink et al. 2010).  
Also, increased levels of AVP in plasma of subjects with ASD have been reported
(Boso et al. 2007), although other researchers have been unable to replicate this
observation.
In summary, there is a high unmet medical need for pharmacological treatments of 
these core symptoms of the disorder.
1.2
BACKGROUND ON BALOVAPTAN
Balovaptan is a potent and highly selective human V1a receptor antagonist that blocks
the activation of the V1a G proteincoupled receptor.


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1.2.2 
Clinical Studies 
1.2.2.1 
Safety and Tolerability 
To date, balovaptan has been investigated in five completed Phase I studies in healthy 
volunteers (Studies BP25694, BP28318, BP28977, BP29279, and WP40038), and one 
completed proof-of-mechanism study (BP29412).  Clinical pharmacology studies 
investigating the effect of CYP3A modulators on the pharmacokinetics of multiple 
balovaptan doses (WP40608 and WP40609) are clinically complete.  Please refer to the 
Balovaptan Investigator's Brochure for detailed information.  
A Phase II study (BP28420, "Vanilla") in adult subjects with ASD has been completed 
and the recruitment for a Phase II study (BP30153, "aV1ation") in 5- to 17-year-old 
subjects with ASD was started in November 2016 and is ongoing. 
Study BP28420 was a proof-of-concept, randomized, double-blind, parallel-group study 
that evaluated the efficacy, and safety of 1.5, 4, and 10 mg/day of balovaptan compared 
with placebo in male adults (aged 18−45 years) with ASD.  The scheduled duration of 
treatment was 12 weeks.  Key inclusion criteria included a Social Responsiveness 
Scale, Second Edition (SRS-2) total t-score ≥66, a Clinical Global 
Impression−Severity (CGI-S) Scale score ≥4 (moderately ill), and an intelligence quotient 
(IQ) score ≥70 generated on the Wechsler Abbreviated Scale of Intelligence®, Second 
Edition (WASI®-II).  
The study was conducted in a staged fashion as outlined in Figure 1. 
Figure 1 Study BP28420:  Overview of Study Design 
 
Note:  RO5285119 is the former name for balovaptan. 
 
The primary endpoint was the change from baseline in social communication deficits in 
adult individuals with ASD, as measured by the SRS-2.  In addition, a number of 
secondary efficacy endpoints were also evaluated, including the change from baseline in 
adaptive functioning and skills, as measured by the Vineland Adaptive Behavior 
Scales, Second Edition (Vineland-II), change from baseline in behavior and symptoms 


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as measured by the Aberrant Behavior Checklist (ABC), the Repetitive Behavior 
ScaleRevised (RBS-R), the Anxiety, Depression, and Mood Scale (ADAMS), and the 
Clinical Global ImpressionsImprovement (CGI-I). 
In all, 223 subjects were enrolled in the study and 186 subjects completed the study.  
Of the 186 subjects who completed the study, 67 subjects received placebo, 26 received 
1.5 mg once a day (QD), 69 subjects received 4 mg QD, and 30 subjects received 
10 mg QD.  Two hundred thirteen subjects were included in the intent-to-treat (ITT) 
analysis dataset.
The primary efficacy endpoint was the change from baseline in social communication 
deficits, as measured by the SRS-2 total t-score after 12 weeks of treatment.  The data 
analysis showed no significant treatment effects on the SRS-2 total t-score.  The 
estimated effects for placebo in the three analysis datasets were 13.1, 11.4, and 8.3, 
which are in agreement with the placebo effect observed in recent trials
(Berry-Kravis et al. 2016).  An effect size of 0.3 favoring balovaptan was observed 
between 10 mg and placebo.
Several assessments were analyzed as secondary outcome measures of core 
symptoms, including the following:  the Vineland-II Adaptive Behavior Standard 
Composite score (hereafter referred to as Vineland-II composite score), the ABC, CGI-I, 
RBS-R, and ADAMS.
The outcome of the assessment of the Vineland-II Composite score demonstrated a
dose-dependent improvement in the composite score.  The three individual domains of 
the Vineland-II Composite were also analyzed.  Results show meaningful treatment 
effects, especially with the 10-mg dose, for the Socialization and Communication 
domains. 
Balovaptan appeared to be safe and well tolerated in adult male subjects with ASD.  
No treatment-emergent safety concerns were identified.  
 
 
 
A total of eight serious adverse events were reported for 4 subjects in Study BP28420.  
The serious adverse events included sinus node dysfunction (at the 1.5-mg dose), 
syncope (4-mg dose), and suicidal ideation (placebo).  One subject (in the 1.5-mg arm) 
experienced four serious adverse events:  two episodes of rhabdomyolysis, acute 
psychosis, and agitation.  No serious adverse events were reported in the 10-mg/day 
balovaptan treatment group.  One death due to suspected heart failure was reported 
16 weeks after treatment was withdrawn in the individual with the reported serious 
adverse event of syncope.  Except for the case of rhabdomyolysis, all other serious 
adverse events, including the syncopal event and death due to suspected heart failure,
were assessed by the respective investigators as not related to study treatment.


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Additional information is provided in Section 5.1 of the Balovaptan Investigator's 
Brochure.
1.2.2.2
Pharmacokinetics
In a single-ascending dose study, exposure to balovaptan increased in a greater than
dose-proportional manner following doses of 0.576 mg, whereas an approximately
linear increase in exposure was observed after repeated dosing with 1252 mg/day for
14 days. Balovaptan was rapidly absorbed with a median time to maximum 
concentration between 1 and 4.5 hours after administration of single doses and between
3 and 4 hours after multiple doses.  Steady state was achieved after approximately
7 days of daily dosing.  Food had no effect on the pharmacokinetics of balovaptan.
Renal excretion is the major pathway of elimination (approximately 53% of the drug 
material recovered), with most of the drug-related material in urine being composed of 
metabolites.  An additional 30% of the administered dose was recovered in feces.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study WN39434 is a Phase III, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter, 24-week, efficacy, and safety study of 10 mg of oral 
balovaptan QD in adults (18 years old or older) with ASD, followed by a 2-year 
open-label extension period for subjects completing the double-blind treatment period.
Subjects providing informed consent will undergo screening within 4 weeks prior to the 
first double-blind study drug (balovaptan or placebo) administration. Eligible subjects will 
be randomized in a 1:1 ratio in a blinded fashion to either 10 mg of balovaptan or 
matching oral placebo QD for 24 weeks. The primary efficacy endpoint is the change 
from baseline at Week 24 on the Vineland-II two-domain composite (2DC) score.
Thus, for subjects remaining in the full study, the approximate length of the study will be 
144 weeks or 34 months (screening [approximately 4 weeks], double-blind treatment 
[24 weeks], and open-label extension period [104 weeks] with a safety follow-up period 
of 12 weeks after completion of double-blind treatment period or open-label extension
period). 
Subjects will be recruited from international sites, including sites in North America and
limited rest of the world (ROW) countries. Subjects who prematurely discontinue from 
study treatment or from the study will not be replaced. However, all subjects should be 
followed and their data (specifically, vital sign measurements, adverse events, 
concomitant treatment, Vineland-II, CGI-S, CGI-I, PedsQL 4.0 Core) collected up to and 
including the Week 24 visit, regardless of their adherence to treatment.
Randomization will be stratified by baseline 2DC score of the Vineland-II score (60 vs. 
≥60), sex (male vs. female), geographical region (North America vs. ROW), and age
(25 years vs. 25 years). The main analysis of the primary and secondary efficacy 
endpoints will occur once the final data from all visits, up to and including Week 24, have 
been collected and cleaned, and the database has been locked. An interim futility 
analysis will be performed by an independent Data Monitoring Committee (iDMC) when 
approximately 50% of subjects complete the Week 24 visit. 
The iDMC will meet regularly to oversee safety throughout the trial and its activities will 
be described in a separate iDMC charter (see Section 3.1.1.5 for further details).
Secondary and exploratory endpoints will examine core autism symptoms (social 
interaction, social communication, and functional deficits), associated symptoms, impact 
on health-related quality of life (HRQoL), and broader impacts on study partners and 
family. Safety will be examined via adverse events, clinical laboratory values, 
electrocardiograms (ECGs), physical and neurologic examinations, and safety outcome 
assessments such as suicidality.


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Any substudies associated with Study WN39434 will be detailed in separate protocols, 
with the exception of the Granulocyte Immunofluorescence Test (GIFT) substudy, which 
is presented in Appendix 6.
3.1.1
Overview of Study Design
This study will enroll approximately 350 adult subjects (18 years or older) to either 
placebo or active treatment in a 1:1 ratio. All subjects completing 24 weeks of 
double-blind treatment will be eligible to enter the open-label treatment period with 
10 mg of balovaptan QD (see Figure 2).
Figure 2
Study Schema
QDonce a day.
A schedule of activities for the double-blind and open-label extension treatment periods 
are provided in Appendix 1 and Appendix 3, respectively.  The schedule of activities for 
the follow-up period is provided in Appendix 2.
The total duration of the study (from screening through to study completion) for each 
subject will be approximately 144 weeks as described in the following sections.
3.1.1.1
Screening Period
Subjects who are willing and who have given their consent to participate in the study will 
undergo a screening procedure within 4 weeks before the first study drug administration 
(Day 1). Subjects must meet all of the eligibility criteria in order to qualify for the study
(see Sections 4.1.1 and 4.1.2).
The screening period can be extended to a total period of 6 weeks in cases when a 
laboratory blood test needs to be repeated for confirmation during the screening interval 


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or for other relevant clinical, administrative, or operational reasons. Subjects must 
fulfill all the entry criteria for participation in the study.
3.1.1.2
Re-Screening 
In exceptional cases, subjects not meeting the eligibility criteria can be re-screened once 
and uncertainties should be discussed with the Medical Monitor or designee.  Re-
screening will not be allowed if a subject previously does not meet the disease-specific 
inclusion criteria (e.g., Autism Diagnostic Observation Schedule, Second Edition 
[ADOS-2] score, SRS, WASI-II). In cases where re-screening occurs, these 
assessments should not be repeated.
3.1.1.3
Double-Blind Treatment Period
All subjects will undergo 24 weeks of double-blind treatment.  The study will be 
unblinded following the primary database lock when the last enrolled subject has 
completed the double-blind treatment period and all the data have been collected and 
cleaned. 
Randomization (Day 1) will occur only after a subject has met all eligibility criteria.  At the 
baseline visit (Day 1), subjects will undergo a series of assessments outlined in the 
schedule of activities (see Appendix 1). Breaks should be allowed between tests when 
necessary.  If necessary, the baseline visit can be split into 2 consecutive days, and the 
second day will be considered the baseline visit date (Day 1).  If either the Week 12 or 
Week 24 visit is split over 2 days, study drug (balovaptan or placebo) must be 
administered QD after the completion of all assessments.
After the predose assessments have been completed, each subject will receive an oral 
dose of balovaptan or placebo according to randomization.  After completion of the 
postdose evaluations and following a medical check-up by a physician, the subject will 
be discharged from the study center. 
Although study visits will be conducted on site, checks for signs and symptoms of 
infection will be conducted every 2 weeks either at a site visit or by telephone call 
conducted by site staff.  
As a general rule, the test sequence for all assessments should remain the same for a
given subject as established at screening and baseline. At all visits, patient-reported 
outcome (PRO) assessments should be completed prior to any other assessments.  All 
assessments must be performed before administration of study drug.
For informant-based assessments, the following order of assessments will be followed:

The Vineland-II will be the first informant-based assessment with a subject's 
study partner.

For all other informant-based assessments:  It is strongly recommended that the 
sequence provided in Table 3 is followed.  It will be possible for assessments 


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(e.g., the Vineland-II interview and subject assessments) to be conducted in parallel 
if the site has sufficient qualified raters available.  Importantly, the sequence 
established at screening and baseline should remain the same for a given subject; 
however, subject assessments should be prioritized.  
Table 3
Sequence of Scale Administration
Order
Scale
Respondent(s)
1
Vineland-II
Study partner
Qualified rater
2
PedsQL 4.0 Core
Subject
3
PedsQL Cognitive 
Functioning
Subject
4
PSQI
Subject
5
EQ-5D-5L
Subject
6
PGI-S
Subject
7
PGI-C
Subject
8
HAM-A
Subject
Qualified rater
9
C-SSRS
Subject
Qualified rater
10
PedsQL Family Impact
Study partner
11
RBS-R
Study partner
12
EQ-5D-5L
Study partner
13
CaGI-S
Study partner
14
CaGI-C
Study partner
15
CGI-S
Qualified rater
16
CGI-I
Qualified rater
CaGI-CCaregiver Global ImpressionChange; CaGI-SCaregiver Global 
ImpressionSeverity; CGI-IClinical Global ImpressionImprovement; CGI-SClinical Global 
ImpressionSeverity; C-SSRSColumbia-Suicide Severity Rating Scale; EQ-5D-5LEuroQoL 
Five Dimensions QuestionnaireFive Levels; HAM-AHamilton Anxiety Rating Scale;
PedsQLPediatric Quality of Life Inventory; PedsQL 4.0 CorePediatric Quality of Life 
Inventory Generic Core Scales, Version 4.0; PGI-CPatient Global ImpressionChange; PGI-
SPatient Global ImpressionSeverity; PSQIPittsburgh Sleep Quality Index; 
RBS-RRepetitive Behavior ScaleRevised; Vineland-IIVineland Adaptive Behavior Scales, 
Second Edition.
The last assessments to be completed are the Clinical Global Impression scales. 
At visits when blood samples are obtained, the order of assessments should be
as follows:

12-Lead ECGs

Vital signs

Physical and neurologic examinations

Blood samples


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Note: ECGs and vital signs assessments should be completed before other invasive 
assessments such as blood samples and should occur following a short period when the 
study participant is able to rest (typically, at least 5 minutes).
3.1.1.4
Open-Label Extension Period
All subjects who complete the 24-week double-blind treatment period are eligible for 
participation in the open-label extension period of the study.  Subjects who are not 
willing to participate in the open-label extension period of the study will complete the 
safety follow-up visits.  Subject treatment allocation during the double-blind treatment 
period will not be unblinded regardless of a subject's participation in the open-label 
extension period.  
The 2-year (104-week) duration of the open-label extension period serves to evaluate
the long-term safety, tolerability, and efficacy of balovaptan treatment in subjects with 
ASD.  All subjects will receive 10 mg of oral balovaptan QD.  For the schedule of 
activities to be performed during the open-label extension, see Appendix 3.
After the predose assessments have been completed, each subject will receive an oral 
dose of balovaptan.  After completion of the postdose evaluations and following a 
medical check-up by a physician, the subject will be discharged from the study center. 
If the visit is split over 2 days, study drug (balovaptan) must be administered QD after 
the completion of all assessments.  
Checks for signs and symptoms of infection will be conducted according to the schedule 
of activities.  
As a general rule, the test sequence for all assessments should remain the same for a
given subject as previously established at screening and baseline. At all visits, PRO 
assessments should be completed prior to any other assessments.  All assessments
must be performed before administration of study drug.
For informant-based assessments, the following order of assessments will be followed:

The Vineland-II will be the first informant-based assessment with a subject's 
study partner.

For all other informant-based assessments, there is no restriction in the order, a
sequence established at screening and baseline should remain the same for a given
subject; however, subject assessments should be prioritized.  The suggested 
sequence is provided in Table 3.  It will be possible for assessments (e.g., the 
Vineland-II interview and subject assessments) to be conducted in parallel if the site 
has sufficient qualified raters available.
The last assessments to be completed are the Clinical Global Impression scales. 


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At visits when blood samples are obtained, the order of assessments should be as 
follows:

12-Lead ECGs

Vital signs

Physical and neurologic examinations

Blood samples
Note:  ECGs and vital signs assessments should be completed before other invasive 
assessments such as blood samples and should occur following a short period when the 
study participant is able to rest (typically, at least 5 minutes).
3.1.1.5
Follow-Up Period
In order to evaluate the long-term effects of balovaptan, subjects will enter a follow-up 
period, consisting of a telephone call at Week 1 and site visits at Weeks 2 and 12.  The
final follow-up visit for safety and limited efficacy will be conducted 12 weeks after the 
Week 24 visit for subjects who do not enter the open-label extension period or at the 
end of the open-label extension period for all other subjects. For subjects who 
discontinue treatment prematurely and will not return for the Week 24 visit, the final 
follow-up visit should occur 12 weeks after the final dose. For the list of assessments,
see Appendix 2.
3.1.1.6
Independent Data Monitoring Committee
The incidence and nature of adverse events, serious adverse events, adverse events of 
special interest, abnormalities from ECG recordings, vital sign assessments, laboratory 
parameters, as well as the results of neurologic examinations will be assessed on a 
regular basis by an iDMC.  It is anticipated that these assessments will occur 
approximately every 6 months or at the discretion of the iDMC.
The iDMC will also undertake evaluation of any efficacy interim analyses (see 
Section 6.5.9).
Details about the iDMC will be provided in the iDMC Charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the double-blind treatment period of the study is defined as the time when 
subjects have either transitioned to the open-label extension period or, for subjects not 
entering the open-label extension period, when the follow-up period has been 
completed.
The end of study is defined as the date when the last subject, last visit occurs in the 
open-label extension period or the follow-up period.


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It is anticipated that it may take from 18 to 28 months to recruit all subjects for the study.  
Hence, the total length of the study is estimated to be approximately 45 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Balovaptan Dose and Schedule
The double-blind treatment period of this study will allow the evaluation of the safety and 
efficacy of 10 mg of oral balovaptan tablets QD compared with placebo.
Results from Study BP28420 suggest that 10 mg of balovaptan QD is the only dose level 
of the dose levels tested to have shown consistent efficacy across multiple domains of 
the Vineland-II and on other instruments explored. The safety profile of balovaptan 
across dose cohorts was similar.
The 10-mg balovaptan QD dose was associated with the largest improvement on the 
2DC score of the Vineland-II, as well as individually on the Vineland-II Composite and on 
the Socialization and Communication domains of the Vineland-II scales in 
Study BP28420. The 10-mg dose was also associated with greater concordance across 
the domains of the Vineland-II compared with other doses.
Furthermore, a graphical evaluation of patient-level responses in Study BP28420 shows 
that the 10-mg balovaptan QD dose was associated with a greater proportion of positive 
response outcomes on the Vineland-II Composite score compared with either of the 
other two doses tested. Although the 4-mg balovaptan QD dose group had more 
subjects and resulted in a meaningful effect on the Vineland-II Composite score, the 
outcomes were overall less consistent than those observed with the 10-mg QD dose of
balovaptan.
Additional support for the use of a single-dose arm of 10 mg of balovaptan QD comes 
from the PedsQL 4.0 Core results in Study BP28420.  The PedsQL 4.0 Core is a generic 
assessment of HRQoL for children, adolescents, and adults (Varni et al. 1999, 2001) 
and provides subject insights into perceived treatment benefit (self-reported 
assessment), whereas the Vineland-II Composite offers the external perspective 
provided by a study partner during the structured interview and completion of the survey 
form.  The PedsQL 4.0 Core was an exploratory measure in Study BP28420.  Clinically 
meaningful improvements, as measured by the PedsQL 4.0 Core, were seen only with 
the 10-mg QD dose, which produced a clinically relevant change above the minimal 
clinically important difference threshold of 4.4 points on self-report at Week 12 (Day 84) 
(Varni et al. 2003).


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Furthermore, the Sponsor’s internal study data suggest that occupancy of the V1a
receptor reaches near maximal saturation with the 10-mg dose of balovaptan.
3.3.2
Rationale for Use of Vineland-II Adaptive Behavior Scales 2DC 
Score as the Primary Efficacy Endpoint
The Vineland-II has been used extensively in ASD research and includes
standardization and validation in diverse populations, including in individuals with autism, 
Asperger syndrome, or pervasive developmental disorder (Sparrow et al. 2005; Dawson 
et al. 2010; Virues-Ortega et al. 2013; Aman et al. 2015).  A recent Autism 
Speakssponsored Working Group panel recommended the Vineland-II scales as 
suitable (adequate reliability and validity and responsiveness to intervention) to quantify 
social communication deficits in clinical trials of subjects with ASD (Anagnostou et al. 
2015).  The Vineland-II is organized into five domains measuring adaptive behavior of 
individuals from birth to 90 years old, including assessment of the performance of daily 
activities required for personal and social sufficiency (Sparrow et al. 2005).  To support 
reliability in interview conduct and structure, the Vineland-II Survey Interview, which is a 
semi-structured interview of the study partner administered by a trained interviewer and 
takes approximately 4560 minutes to complete, will be used.  The Vineland-II will be 
administered and scored according to the manual (Sparrow et al. 2005).
In this study, a novel composite score, the Vineland-II 2DC score, has been selected as 
the primary endpoint, defined as the arithmetic mean of the Communication domain 
standard score and the Socialization domain standard score. Concepts measured in the 
Communication and Socialization domains of the Vineland-II map closely to the 
respective communication and socialization deficits in the subject-centered conceptual 
model of ASD generated through interviews conducted with people with ASD and their 
parents (Willgoss et al. 2017).  As such, the Vineland-II 2DC score enables a 
comprehensive assessment of social communication deficits in people with ASD.  
Vineland-II Socialization and Communication domain standard scores are reliable and 
valid (Sparrow et al. 2005) and have been used independently as endpoints in clinical 
trials of ASD (Scahill et al. 2016).  To explore the measurement properties of the new 
Vineland-II 2DC score, which combines these two independently validated scales into a 
single score, the Sponsor has conducted a psychometric analysis of the score using 
data from Study BP28420 (Roche internal data). The data show that the Vineland-II 
2DC score is reliable, valid, and sensitive to change and supports the Sponsor’s 


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proposal to combine the two domains into a single endpoint.  Furthermore, the data were 
discussed with the U.S. Food and Drug Administration (FDA) and European Medicines 
Agency who have provisionally approved the use of the Vineland-II 2DC score as the 
primary endpoint for Phase III trials.
3.3.3
Rationale for Use of Responder Definition
A clinically meaningful response is defined as a 6-point improvement on the Vineland-II 
2DC score at Week 24. This responder threshold was determined through anchor- and 
distribution-based analyses conducted on data from Study BP28420. Estimates 
anchored to global clinical impressions of verbal communication, non-verbal 
communication, social skills, and overall ASD severity ranged from 6.0 to 7.2 points. 
Distribution-based estimates included 0.2 SD and 0.5 SD at baseline and 1the 
standard error of the mean and ranged from 3.16 to 7.90 points. A threshold of 
6 points was selected following discussions with a panel of global ASD experts who 
agreed that individual change of this magnitude over a 24-week period would be 
indicative of a clinically relevant response to treatment.
3.3.4
Rationale for Subject Population
Study WN39434 will include both males and females.  The prevalence of ASD has been 
reported to be approximately 1 in 42 boys and 1 in 189 girls (CDC 2016).  Furthermore, 
females with impairments in social and communication function are typically more 
intellectually impaired and are less likely to meet the eligibility criteria stipulating an IQ
score 70; only 1 in 8 to 9 ASD subjects with IQ score 70 is reported to be female 
(Fombonne et al. 2011; Stacy et al. 2014).  Therefore, the proportion of females who 
would be recruited is expected to be approximately 12% of the total study population.  
To ensure that the subject population is representative of ASD epidemiology the 
proportion of female subjects will be limited to a maximum of 20% of the entire study 
population.  Randomization of subjects will be stratified by sex.
Study WN39434 is designed as an international study that will recruit subjects from 
regions, including North America and the ROW.  The proportion of subjects from the 
ROW is expected to be approximately 20% of the total study population.  Randomization 
of subjects will be stratified by region (North America vs. ROW) to increase the reliability 
of subgroup analyses within each region.
To limit the impact of diagnostic heterogeneity, eligible male and female subjects ages 
18 must meet Diagnostic and Statistical Manual of Mental Disorders, Version 5 
(DSM-5) criteria for ASD, which will be confirmed using the ADOS-2.  The ADOS-2 is a 
semi-structured, standardized assessment of communication, social interaction, 
play/imaginative use of materials, and restricted and repetitive behaviors in ASD and is 
referred to as the "gold standard" observational assessment for diagnosing ASD 
(Ozonoff et al. 2005; Kanne et al. 2008).


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Subjects with confirmed ASD who are exhibiting impairments in social communication 
will be studied.  For this study, the SRS-2 will be performed during screening; only 
subjects with a study partnercompleted (proxy) SRS-2 total t-score 66, consistent with 
moderate or severe symptoms, will be randomized.  These assessments ensure that 
subjects demonstrate relevant deficits in social communication and social interactions 
and that, collectively, these symptoms result in a moderate-to-severe phenotype.
Another dimension along which subjects are commonly categorized is the degree to 
which intellectual disability is co-morbid with their ASD symptoms.  From an assessment 
framework, there is no consensus on which cognitive measures are the most useful for 
subject categorization.  In this study, the WASI®-II will be employed to ensure 
randomized subjects score above a "cognitive floor" (i.e., IQ score 70) and do not have 
intellectual disability, consistent with the ASD literature (Siegel et al. 1996).  Full scale IQ 
and subscale scores will be collected.
3.3.5
Rationale for Use of Placebo 
To date, no pharmacological therapies have shown effectiveness treating the core 
symptoms of ASD and none is registered for its treatment in any global region.  Pursuant 
to the Helsinki Declaration, when standard treatment of a disease exists, placebo should 
generally not be used in clinical trials (ICH 2000).  However, Paragraph 33 of the 
Declaration supports the stance that placebo can be acceptable in the setting where no 
proven standard therapy exists.
Given that no standard therapy exists for the treatment of ASD, a placebo-controlled trial 
is acceptable, provided that appropriate subject consent and safeguards are instituted to 
minimize the risk of serious or irreversible harm resulting from exposure to placebo.
3.3.6
Rationale for Study Duration
There are no published studies showing significant pharmacological effects on 
communication and social behaviors in ASD as measured by the Vineland-II.  
Nevertheless, behavioral interventions have shown benefits.  For example, 
Virues-Ortega and colleagues reported a systematic review and meta-analysis of the 
effect of the TEACCH program (Virues-Ortega et al. 2013).  Some of the included 
studies used the Vineland-II, and the duration of those studies ranged from 
10 to 36 weeks, suggesting that the minimum length of a study to detect gains in 
adaptive behaviors in subjects with ASD, as measured by the Vineland-II, is in between 
these numbers.
It is thought that a treatment duration of 24 weeks would allow sufficient exposure to 
adequately and efficiently assess clinically meaningful responses in both social cognition 
and functional social outcomes as well as characterize the safety and tolerability profile 
of balovaptan.


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3.3.7
Rationale for Biomarker Assessments
ASD is a heterogeneous but highly heritable disease, with heritability estimates ranging 
from 64% to 91% in twin studies and ranging from 31% to 71% in whole genome 
genotyping studies (Autism Spectrum Disorders Working Group of the Psychiatric 
Genomics Consortium 2017).  Given that variants in the V1A receptor gene are among 
those previously associated with ASD risk (Tansey et al. 2011), not all subjects may be 
equally likely to benefit from treatment with a V1A antagonist like balovaptan.  
Additionally, V1A antagonism is associated with rescue of social impairments and 
repetitive behavior in the CNTNAP2 knockout model of autism.  This gene has also been 
strongly linked to ASD (Peñagarikano and Geschwind 2012).  Therefore, biomarker 
samples that may be predictive of efficacy will be collected for genotyping the V1A
receptor gene as well as the CNTNAP2 gene, prior to dosing, and will be assessed in an 
effort to identify those subjects who are most likely to benefit from balovaptan.  
Beyond the defined biomarkers above, available assessments from the optional 
Research Biosample Repository (RBR) (see Section 4.5.9) will be utilized to evaluate 
the potential of novel biomarkers unrelated to the proposed mechanisms.
4.
MATERIALS AND METHODS
4.1
SUBJECTS
Approximately 350 adult ASD subjects will be enrolled in this study.
4.1.1
Inclusion Criteria
Subjects must meet the following criteria for study entry:

Signed Informed Consent Form

Males or females, age 18 years or older at time of signing Informed Consent Form

Subject meets the DSM-5 criteria for ASD for an autism diagnosis and is confirmed 
using ADOS-2 criteria
If the ADOS-2 assessment has been performed by a certified rater and 
documented within 12 months of the screening visit, there is no requirement to 
repeat it. 

SRS-2, proxy version, total t-score 66 at screening

A full scale IQ score 70 on the WASI®-II 
The score should be confirmed by assessment during screening.  Previous test 
results on the WASI or equivalent scales such as Wechsler Adult Intelligence 
Scale®, Fourth Edition (WAIS®-IV) (including all subdomain scores) are accepted 
if the test has been performed within 12 months prior to screening by an 
appropriately qualified rater.

Ability and willingness to fully comply with study visit schedule and regular 
assessments and fluency in the language of the site 


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
Subject’s participation in the study or discontinuation of prohibited medication will 
not pose undue risks to the subject, in the investigator’s opinion

Subject has an appropriate study partner, in the opinion of the investigator
The study partner is someone who has regular and sufficient periods of contact 
(including regular conversations and face-to-face interactions) with the subject to 
be able to report on the subject’s status on relevant study assessments. 
The study partner should have sufficient capacity to evaluate social and 
communication changes in the subject and should be available throughout the 
entire duration of the study.  
The study partner will not be eligible to be a study participant in this study. 
Only at visits that do not require a study partner’s input on assessments can a 
subject be accompanied by others if the study partner is not available. 
Every effort should be made to have same study partner participate throughout 
the subject's participation in the study. 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% 
per year during the treatment period and for at least 28 days after the last dose of 
study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Women must agree to use an effective form of contraception during all phases 
of the study.
No specific contraception methods for males are required.
Note: The Sponsor does not require male contraception because of the 
minimal seminal dose transmitted via sexual intercourse (Banholzer et al. 2012)
(see Section 1.2.1).

Treatment with permitted medications (at a stable dose for 12 weeks before 
screening) and behavioral therapy regimens (regimens stable for 6 weeks before 
screening), with the intent that such treatments remain stable throughout the study 
and with no expected changes before the Week 24 visit


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4.1.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
4.1.2.1
General Exclusion Criteria
Subjects who meet the following general exclusion criterion will be excluded from 
study entry:

Pregnancy or breastfeeding, or intention to become pregnant during the study
Females of childbearing potential must have a negative urine pregnancy test 
result immediately prior to initiation of study drug.
4.1.2.2
Neurologic and Psychiatric Exclusion Criteria
Subjects who meet any of the following neurologic and psychiatric exclusion criteria will 
be excluded from study entry:

Previous initiation of new or major change in psychosocial intervention (including 
investigational) within 6 weeks prior to screening 
Minor changes in ongoing treatment (e.g., missed therapy sessions because of
holiday or vacation, planned break in therapy due to school holidays, or changes 
in college or school programs) are not considered significant.

Unstable or uncontrolled clinically significant affective or psychotic disorders and/or
neurologic disorder that may interfere with the assessment of safety or efficacy 
endpoints

Substance use disorders (including alcohol or substance abuse or dependence 
disorder) during the last 12 months, as defined by the DSM-5 criteria

Significant risk for suicidal behavior, in the opinion of the investigator

Epilepsy or seizure disorder considered not well controlled within the past 6 months 
or changes in anticonvulsive therapy within the last 6 months

Clinical diagnosis of peripheral neuropathy
4.1.2.3
Exclusions Related to Cardiovascular Disorders
Subjects who meet any of the following exclusion criteria related to cardiovascular 
disorders will be excluded from study entry:

Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, or New York Heart Association Class II 
or higher cardiac failure)

Uncontrolled hypertension (e.g., blood pressure repeatedly 160 mmHg systolic or 
95 mmHg diastolic)

Unexplained syncopal episode within the last 12 months

Confirmed elevation above upper limit of normal (ULN) of CK-MB (electrophoretic 
measurement), high sensitivity cardiac troponin T (hs cTnT), cardiac troponin I 
(cTnI), and/or N-terminal pro B-type natriuretic peptide (NT-proBNP)




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The following therapies are prohibited throughout the study and include:

Moderate and strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, 
erythromycin, ciprofloxacin, diltiazem, and grapefruit juice) 
Moderate inhibitors of CYP3A4 (e.g., erythromycin, ciprofloxacin, diltiazem) may 
be allowed for a treatment duration of no more than approximately 10 days 
(e.g., in context of an adverse event) after discussion with the Medical Monitor or 
designee.  The reason for and approval of such treatment is to be documented.

Moderate and strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, 
St. John’s Wort), with the following exceptions:
Weak inducers are permitted.

Concomitant oral medication that are P-gp substrates: 
–
Quinidine should not be given with balovaptan. 
–
Risperidone and cetirizine are allowed.  
–
All other clinically relevant substrates of P-gp:  An interaction cannot be ruled 
out and caution is advised in particular for those medications that have a 
narrow therapeutic window (e.g., loperamide).  However, when balovaptan is 
administered 5 or more hours prior to such a P-gp substrate, the risk of 
pharmacokinetic (PK) interaction is predicted to be small. 
–
Chronic adrenocorticoid or glucocorticoid use, with the following exceptions:  
Inhaled and topical formulations are permitted.

Oxytocin

Desmopression (DDAVP®)

Bumetanide 

Agents inhibiting vasopressin receptors (e.g., tolvaptan, conivaptan)

Use of any concomitant medication known to potentially cause peripheral 
neuropathy per the Warnings and Precautions section of the U.S. label or 
corresponding section of the local label

Agents that have been associated with significant and/or irreversible hematologic
toxicity and therefore require frequent monitoring (e.g., clozapine)

Use of tetrahydrocannabinol due its psychoactive effects (e.g., marijuana)
Please refer to Section 4.4 for additional details. 
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Approximately 350 subjects will be randomized to receive either placebo or 10 mg of oral 
balovaptan QD in a 1:1 ratio.  An independent interactive voice or web-based response 
system (IxRS) provider will conduct randomization and hold the treatment assignment 
code.  Randomization will be stratified by a subject’s baseline Vineland-II 2DC score 
(<60 vs. 60), sex (male vs. female), region (North America vs. ROW), and age 
(25 years vs. 25 years).


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There will be no replacement of subjects should a subject’s treatment be discontinued 
for any reason.
Study site personnel and subjects will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to subject treatment assignments to fulfill 
their job roles during a clinical trial.   
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which subject management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.  If unblinding occurs, subjects should not continue 
receiving study drug and should proceed to the end-of-treatment visit and subsequently 
safety follow-up. 
If the investigator wants to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  The investigator will be able to break the treatment code by contacting the 
IxRS.
Whenever disclosure of the identity of the study drug is necessary, adequate procedures
will be put in place to ensure integrity of the data.  Any unblinding at the investigational
site will be documented in the study report with the date, the reason for identifying the
drug, and the name of all person(s) who were unblinded. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The subject may continue to receive treatment, and the investigator, 
subject, and Sponsor personnel, with the exception of the Drug Safety representative 
and personnel who must have access to subject treatment assignments to fulfill their 
roles (as defined above) will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS
RELEVANT TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are balovaptan and 
matching placebo.


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4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1. 
One tablet of study drug (balovaptan or placebo) should be taken orally QD in the 
morning, with or without food. The tablet should be swallowed whole with something to 
drink.
The first dose of the study drug will be administered on Day 1 after all predose baseline 
assessments have been conducted. At subsequent visits, study drug should not be 
taken until all protocol-mandated study assessments are completed, unless otherwise 
specified on the Schedule of Activities (see Appendix 1).
Compliance regarding administration of study drug at home will be monitored by the 
maintenance of adequate drug dispensing logs and return records.  A study diary or 
application may also be provided to subjects and/or study partners.
Any overdose or incorrect administration of balovaptan or placebo should be noted on 
the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF (see Section 5.3.5.11).


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Guidelines for treatment interruption or discontinuation for subjects who experience 
adverse events are provided in Sections 5.1.2.1 and 5.1.2.2, respectively.
4.3.3
Investigational Medicinal Product Accountability
All IMPs (balovaptan and placebo) required for completion of this study will be provided
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
The investigator is responsible for the control of drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The date(s) and quantity of study drug dispensed to the subject

The date(s) and quantity of study drug returned by the subject
All records and drug supplies must be available for inspection by the Roche monitor (at
every monitoring visit).
Written documentation of destruction must contain the following:

Identity (batch numbers or study subject numbers) of investigational products 
destroyed

Quantity of investigational products destroyed

Date of destruction

Method of destruction

Name and signature of responsible person (or company) who destroyed the 
investigational product
Unused study drug from the site that has not been stored properly should not be 
destroyed until the final report has been approved. If there are any issues with the drug,
it should be returned to the appropriate Roche clinical trial supplies department for
long-term storage and not destroyed.


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4.3.4
Continued Access to Balovaptan
Currently, the Sponsor does not have any plans to provide the Roche IMP (balovaptan)
or any other study treatments or interventions to subjects who have completed the study.  
The Sponsor may evaluate whether to continue providing balovaptan in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product,
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Subjects are eligible to receive balovaptan as part of the open-label extension period, 
provided they have completed 24 weeks of treatment, as described in Section 3.1.1.4.
4.4
CONCOMITANT THERAPY
The addition of a new medication or a change in the dose of a medication after signing
the Informed Consent Form should only occur for the treatment of an adverse event.
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, approved dietary and herbal supplements, nutritional supplements, and any
non-medicinal interventions, such as individual psychotherapy, cognitive behavioral
therapy, smoking cessation therapy, and rehabilitative therapy) used by a subject
24 weeks prior to screening until the follow-up visit.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF.  All therapy and/or medications administered to manage
adverse events should be recorded on the Adverse Event eCRF.
4.4.1
Permitted Therapy
It is expected that subjects enrolled in the trial will be taking a variety of psychiatric 
medications upon entering the trial.  Such standard-of-care or "background" medications 
may include a variety of classes acting through different mechanisms to treat psychiatric 
symptoms commonly associated with ASD.  It is also common for individuals with ASD 
to be engaged in a large variety of non-medicinal therapies, including individual, group, 
and behavioral-based psychotherapies.  All psychotherapies and medications to treat 
coexisting psychiatric symptoms and medical conditions should be documented on the 
eCRF and continued at a stable frequency and dosage from screening through the 
completion of the trial; any changes should be reported on the appropriate eCRF.
Examples of allowed medications include the following:

Selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake 
inhibitor antidepressants, including fluoxetine

Atypical antipsychotics (e.g., aripiprazole, risperidone)

Melatonin

Benzodiazepines, only on an as-needed basis 


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
Attention-deficit/hyperactivity disorder medications, including psychostimulants such 
as methylphenidate

Hypnotics for insomnia and falling asleep problems (only on an as-needed basis) 

Anti-epileptic drugs used for treatment of epilepsy, including VPA and
oxcarbazepine, may be used, provided they have been given at stable dosage for at
least 6 months prior to screening and were well tolerated

Concomitant oral medications that are P-gp substrates, with the exception of 
quinidine: 
Risperidone and cetirizine are allowed. 
All other clinically relevant substrates of P-gp:  An interaction cannot be ruled out 
and caution is advised in particular for those medications that have a narrow 
therapeutic window (e.g., loperamide).  However, when balovaptan is 
administered 5 or more hours prior to such a P-gp substrate, the risk of PK 
interaction is predicted to be small. 
4.4.2
Non-Pharmacological Interventions
Non-pharmacological interventions must be stable for 6 weeks prior to screening and 
must remain stable throughout the study (e.g., psychotherapy, cognitive behavioral
therapy, and rehabilitative therapy). Minor changes in ongoing treatment (e.g., missed
therapy sessions due to holiday or vacation, planned break in therapy because of school
holidays, and changes in college or school programs) are not considered significant and 
do not need to be discussed with the Medical Monitor or designee.
4.4.3
Prohibited Therapy
The following therapies are not allowed during the study and must be stopped 2 weeks
prior to screening to ensure washout of medication.  Examples of prohibited medications 
include the following:

Inhibitors and inducers of CYP3A4

Quinidine (a Pgp substrate)

Chronic adrenocorticoid or glucocorticoid use (use of inhaled or topical formulations
are allowed)

Oxytocin

Demopressin acetate

Bumetanide 

Agents inhibiting vasopressin receptors (e.g., tolvaptan, conivaptan)

Hematotoxic drugs requiring frequent hematologic monitoring of WBCs
(e.g., clozapine)

Herbal therapies and dietary supplements (unless allowed by the Medical Monitor
or designee)


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
Use of any concomitant medication known to potentially cause peripheral neuropathy 
per the Warnings and Precautions section of the U.S. label or the corresponding 
section of the local label

Use of marijuana for recreational or medical purposes
Must meet eligibility criteria of no substance abuse or dependency. A washout 
period of 3 months is required.
Medications Prohibited due to Effects Related to Cytochrome P450 
Enzymes
In vitro data suggest that balovaptan is metabolized through CYP3A4 and there is a 
potential for drugdrug interaction with any medication that is metabolized by or strongly 
inhibits or induces this enzyme.  Therefore, the following medications are prohibited:

Strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, grapefruit juice)

Moderate inhibitors of CYP3A4 (e.g., erythromycin, ciprofloxacin, diltiazem)
For treatment duration of no more than approximately 10 days in length
(e.g., in the context of an adverse event), moderate inhibitors of CYP3A4 may be
used after discussion with and approval by the Medical Monitor or designee.  
The reasons for and approval of such use must be documented.

Strong and moderate inducers of CYP3A4 (e.g., carbamazepine, phenytoin,
St. John’s wort, and modafinil)
The above lists of medications are not necessarily comprehensive.  The investigator 
should consult the prescribing information when determining whether a concomitant 
medication can be safely administered with study drug.  
The investigator should consult with the Medical Monitor if questions arise regarding 
medications not listed above.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 3.  The schedule of activities for unscheduled visits and the safety 
follow-up period are presented in Appendix 2.  All activities must be performed and 
documented for each subject.  
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled subjects and for subjects who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that subjects meet
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 


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record details regarding all subjects screened and to confirm eligibility or record reasons 
for screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, for the previous 5 years, including clinically significant diseases, 
surgeries, reproductive status, smoking history, use of alcohol and drugs of abuse, will 
be recorded at baseline.  The date of diagnosis of ASD will be collected.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the subject within 24 weeks
prior to the screening visit as well as details of psychosocial/non-pharmacological 
interventions used during the previous 52 weeks are to be documented.  
Demographic data will include age, sex, and self-reported race/ethnicity.  Subjects and 
study partners will also be asked about the subject’s residential setting, school or
employment status, level of education, participation in educational or day programs, and
any non-medical hospitalizations.
4.5.3
Physical and Neurologic Examinations
A complete physical examination, performed at the baseline visit should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, GI, and neurologic systems.  Complete
physical examinations will not include pelvic, rectal, or breast examinations.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in subject notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
Sites will contact subjects and study partner by telephone to evaluate the presence or 
absence of signs and symptoms with regard to infections, as detailed in the schedule of 
activities (see Appendix 1 and Appendix 2).
Neurologic examinations will be performed according to schedule of activities (see 
Appendix 1, Appendix 2, and Appendix 3).  The neurologic evaluation will be completed 
at all indicated visits (see Appendix 4). 
4.5.4
Vital Signs
Vital signs will include measurement of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the subject is in a seated position, and body temperature.


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4.5.5
Temperature Measurements
Temperature will be measured at site visits as part of the vital signs assessment (see 
Section 4.5.4 and Appendix 1, Appendix 2, and Appendix 3).
Temperature measurements taken at home should be performed using a tympanic 
thermometer in an indoor environment at room temperature and recorded in a subject 
diary or device. Temperature measurements may be performed by the subject or the 
subject's study partner who will be asked to help ensure compliance and/or notify the 
site in case of non-compliance.  Site personnel should train the subject and/or study 
partner on the correct use of the thermometer and the importance of compliance with the 
procedure.
Body temperature should be measured every 2 weeks for the double-blind period and 
continue into open-label extension period up until Week 52 of trial participation.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Laboratory safety tests will be collected at the timepoints specified in the schedule of
activities (see Appendix 1, Appendix 2, and Appendix 3).
Additional blood or urine samples may be obtained 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 subject safety.  When the clinical significance of abnormal 
laboratory results is considered uncertain, screening laboratory tests may be repeated
before randomization to confirm eligibility. If there is an alternative explanation for a
positive urine or blood test for drugs of abuse (e.g., previous occasional intake of food or 
a medication containing, such as, codeine, benzodiazepines, or opiates), the test may be 
repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the tests
should be repeated immediately and sent to the central laboratory for testing.  Abnormal 
results should be followed until they have returned to the normal range and/or an
adequate explanation of the abnormality is found. 
 
Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the central laboratory, if applicable.
If clinically indicated, laboratory and PK samples may be obtained at an unscheduled 
visit (see Appendix 2).
Samples for the following laboratory tests will be sent to the relevant central laboratory 
for analysis, unless noted otherwise:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)


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
Serum chemistry panel:  sodium, potassium, chloride, bicarbonate, glucose, BUN or 
urea, creatinine, CPK, total protein, albumin, phosphorus, calcium, total and direct 
bilirubin, ALP, ALT, AST, uric acid, and LDH

 

Coagulation:  INR, aPTT, and PT

Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides

Quantitative immunoglobulins:  IgA, IgG, IgM, and IgE

Viral serology:  HIV, HBsAg, total hepatitis B core antibody (HBcAb), and HCV 
antibody
All subjects must have a negative HBsAg result and negative hepatitis C 
antibody screening tests prior to enrollment.  If total HBcAb is positive at 
screening, hepatitis B virus DNA measured by polymerase chain reaction must 
be negative to be eligible.

Urinalysis, including dipstick:  pH, specific gravity, glucose, protein, ketones, and 
blood will be performed at the study site 
If there is a clinically significant positive blood or protein result, the urine sample 
will be sent to the central laboratory for microscopy and culture.

Urine drug screen and alcohol test:  Urine samples will be analyzed for the presence 
of the following drugs:  alcohol, cannabinoids, opiates, methadone, cocaine, 
barbiturates, and phencyclidine (PCP)
The drug screen and alcohol test will be mandatory for all subjects at screening 
and may be performed for any subject at any visit at the discretion of the 
investigator.

Plasma samples for PK analysis

Pregnancy test:  All females with menarche (including those who have had a tubal 
ligation) will have a urine pregnancy test at screening and specified subsequent 
visits.  A positive urine pregnancy test should be confirmed with a serum test 
through the central laboratory prior to any additional dosing with study drug.  Study 
drug will be withheld until pregnancy test is negative.

Unscheduled visit laboratory assessments: In the event that additional laboratory 
parameters are required to interpret any adverse events or abnormal hematologic or 
chemistry finding, the following assessments may be included (however, additional 
tests may be performed at the investigator’s discretion):
Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
and other cells)
Complete serum chemistry panel: sodium, potassium, chloride, bicarbonate, 
glucose, urea, creatinine, phosphate, calcium, total and direct bilirubin, ALP, 
ALT, AST, protein, albumin, LDH, CPK, total cholesterol, LDL cholesterol


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4.5.6.2
Clinical Genotyping Samples
A mandatory predose whole blood sample will be obtained for DNA extraction from every 
participant on Day 1.  The DNA will be used to evaluate whether genetic variants of the 
AVPR1A or CNTNAP2 genes affect the efficacy, safety, and/or pharmacokinetics of
balovaptan. Clinical genotyping samples and derived analytical materials will be
destroyed no later than 2 years after the date of the final Clinical Study Report.
When a subject withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the subject specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
4.5.7
Electrocardiograms
At baseline, 12-lead ECGs will be recorded in triplicate.  Single 12-lead ECG recordings 
will be obtained at the other timepoints as outlined in the schedule of activities (see 
Appendix 1, Appendix 2, and Appendix 3). 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  


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Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the subject has been resting in a supine position for at least 5 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at the same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided during 
the pre-ECG resting period and during the ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the subject's permanent 
study file at the site.  Digital recordings will be stored at a central ECG laboratory.  The 
following parameters will be provided as non-eCRF data:  heart rate, RR interval, QRS 
interval, PR duration, uncorrected QT interval, and QT interval corrected through use of
Fridericia’s formula (QTcF) based on the machine readings of the individual ECG tracings
or, if considered appropriate by the Sponsor, ECGs may be analyzed at a central 
laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
60 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Section 4.6.1.  The investigator 
should also evaluate the subject for potential concurrent pro-arrhythmic risk factors 
(e.g., electrolyte abnormalities, concomitant medications known to prolong the QT 
interval, severe bradycardia).
4.5.8
Clinical Outcome Assessments
Subjects, study partners, and clinicians will use an electronic device to complete 
electronic clinical outcome assessments (eCOAs) with the exception of the ADOS-2 and 
WASI®-II (IQ) scales.  All item-level, domain-level, and relevant total score data will be 
transmitted electronically to a centralized database at the eCOA vendor.  The ADOS-2 
and WASI®-II data will be transferred to the electronic device by site staff and then 
transmitted as described for all other scales.  The data can be accessed by appropriate 
study personnel securely via the worldwide web.  Entries should be reviewed for 
completeness by the site staff during the visit.  Sites should only use paper forms for the 
scales specified.  A backup device will be provided to each site in the event of device 
issues.
Rater qualification for specific outcomes assessments, including, but not limited to, the 
Vineland-II, ADOS-2, and Hamilton Anxiety Rating Scale (HAM-A) scales will be 
reviewed per the criteria established by the eCOA vendor.  Only raters confirmed by the 
vendor to be qualified on those assessments should rate in this study.


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If the same qualified rater is not available within the visit window, delaying the visit is 
preferred to changing the rater.  The same rater or clinician will perform the Vineland-II 
together with the same study partner throughout the study as established at the 
baseline visit. Also, the same clinician should complete the Clinical Global Impression 
scales for a specific subject for the duration of the study.
Demonstrating good reliability and validity, the Vineland-II is recognized as an 
appropriate outcome measure in clinical ASD trials and will be used as the primary 
outcome measure in future ASD trials conducted by Roche.  The Vineland-II assessment 
will be administered by qualified raters as a semi-structured interview performed with a 
reliable study partner. The Rater Academy will provide raters the opportunity to improve 
their skills in interviewing participants so that they can qualify as eligible raters for the 
this study (refer to Appendix 7 for more details). 
4.5.8.1
Vineland-II Adaptive Behavior Scales, Second Edition
The Vineland-II is an instrument that measures communication, daily living skills, 
socialization, maladaptive behavior (not assessed in this study), and motor skills (not 
administered in adults and will not be assessed in this study) (Sparrow et al. 2005). The 
Survey Interview Form (i.e., a semi-structured interview) will be administered to a 
subject’s reliable study partner in this study, during which the rater will ask the study 
partner open-ended questions relating to the subject’s activities and behavior. 
Standardized domain scores will be obtained for the individual domains of Socialization,
Communication, and Daily Living Skills.  Standardized scores on the domains and 
composite score range from 20 to 160, with higher scores indicating better functioning.
For the purpose of this study, the Vineland-II 2DC score will be derived as the primary 
efficacy outcome measure. 
The interview will take approximately 4560 minutes to complete and will be audio 
recorded. At a clinic visit, the Vineland-II should be performed first prior to all
informant-based assessments with the study partner (see Section 3.1.1.3).  The 
Vineland-II should not be administered by telephone interview.
4.5.8.2
Wechsler Abbreviated Scale of Intelligence®, Second Edition 
The WASI®-II is a tool used to evaluate an individual’s cognitive functioning and generate 
IQ scores (Wechsler 2011) and will be administered by a certified rater at screening only. 
Scores range from 40 to 160, with higher scores indicating higher IQ.
The assessment will take approximately 30 minutes to complete.
4.5.8.3
Autism Diagnostic Observation Schedule, Second Edition
The ADOS-2 is a diagnostic tool used to document the presence of ASD (Lord et al. 
2000; Gotham et al. 2007).  During a semi-structured evaluation, the individual is 


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observed in a naturalistic social situation and assessed across areas of social 
communication, imagination, and restricted and/or repetitive behaviors. 
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 to subjects by a certified rater at screening.  Scores range 
from 1 to 10 once the algorithm is applied, with higher scores indicating greater severity 
of ASD symptoms.
The assessment will take approximately 3045 minutes to complete.
4.5.8.4
Social Responsiveness Scale, Second Edition, Adult 
(Relative/Other Report)
The SRS-2 is a 65-item, informant-based rating scale designed to measure an
individual’s ability to engage in emotionally appropriate reciprocal social behavior in a
naturalistic social setting (Constantino and Gruber 2005).
Each item on the scale assesses 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; scores range from 
35 to 90, with higher scores indicative of more severe deficits.  A total proxy (study 
partnerrated) t-score of 66 indicates moderate severity of symptoms and is the 
threshold for inclusion in this study.
The assessment will take approximately 1520 minutes to complete.
4.5.8.5
Clinical Global ImpressionImprovement
The CGI-I is a single-item, clinician-rated measure, assessing the clinician’s impression 
about changes in the subject’s condition, in this case, ASD (not other conditions or 
co-morbidities), compared with baseline.  
The CGI-I utilizes a 7-point response scale, ranging from "very much improved" (1) to 
"very much worse" (7).
Clinicians should make a judgment on any changes from baseline based on the totality 
of information available to them (e.g., insights from subject and/or study partner, 
information captured during the completion of other trial assessments).
The assessment will take up to 5 minutes to complete.


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4.5.8.6
Clinical Global ImpressionSeverity
The CGI-S is a single-item, clinician-rated measure, assessing the clinician’s impression 
of the severity of a subject’s condition, in this case, ASD (not other 
conditions/co-morbidities).  
The CGI-S utilizes a 7-point response scale, ranging from "normal, not at all ill" (1) to 
"among the most extremely ill subjects" (7).
Clinicians should make a judgment on a subject’s severity based on the totality of their 
experience of the population.
The assessment will take up to 5 minutes to complete.
4.5.8.7
Caregiver Global ImpressionChange
The Caregiver Global ImpressionChange (CaGI-C) is a 4-item, informant-based
measure assessing the study partner's impression about changes in subject’s
communication skills, social skills, daily living skills, and overall ASD compared with 
baseline.
The CaGI-C items utilize a 7-point response scale, ranging from "very much improved"
(1) to "very much worse" (7). Each item is scored independently. 
The assessment will take up to 5 minutes to complete.
4.5.8.8
Caregiver Global ImpressionSeverity
The Caregiver Global ImpressionSeverity (CaGI-S) is a 4-item, informant-based 
measure, assessing the study partner’s impression about the severity of impairment of 
the subject’s communication skills, social skills, daily living skills, and overall ASD during 
the preceding 7 days. 
The CaGI-S items utilize a 5-point response scale, ranging from "no difficulty" (1) to 
"extreme difficulty" (5).  Each item is scored independently.
The assessment will take up to 5 minutes to complete.  
4.5.8.9
Repetitive Behavior Scale–Revised 
The RBS-R is a 44-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 


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provide a rating for how much of a problem these repetitive behaviors are overall, on a 
scale from 1 to 100:  "not a problem at all" (1) to "as bad as you can imagine" (100).
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 restricted and repetitive behaviors.
The assessment will take approximately 2030 minutes to complete.
4.5.8.10
Pediatric Quality of Life Inventory Family Impact Module
The PedsQL Family Impact Module, Version 2 (Varni et al. 2004) is a 36-item,
informant-based measure that will be completed by the study partner.  The instrument
was developed to measure parent and family functioning. It encompasses six scales 
covering Physical Functioning (6 items), Emotional Functioning (5 items), Social 
Functioning (4 items), Cognitive Functioning (5 items), Communication (3 items), and 
Worry (5 items) and two scales measuring parent-reported family functioning, Daily 
Activities (3 items) and Family Relationships (5 items). The acute form, using a recall 
period of 7 days, will be employed in this trial.
Each item 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100 scale (0100, 175, 250, 325, 40), such that higher scores indicate 
better functioning (less negative impact).
In addition to the eight scale scores, a total score, a parent HRQoL summary score, and 
a family summary score can also be computed by averaging across the relevant
domains.
The assessment will take approximately 1520 minutes to complete.
4.5.8.11
Hamilton Anxiety Rating Scale 
The HAM-A is a 14-item, clinician-administered interview, assessing the severity of 
anxiety symptoms during the past 7 days (Hamilton 1959).  Seven items assess psychic 
anxiety and the remaining seven items assess somatic anxiety.
Each item utilizes a 5-point symptom severity response scale, ranging from "none" (0) to 
"very severe" (4).  A total score is calculated that ranges from 0 to 56; higher scores are 
indicative of more severe anxiety.
The assessment will take approximately 1015 minutes to complete.
4.5.8.12
EuroQol Five-Dimensions Questionnaire, Five-Levels Version
The EuroQoL Five Dimensions QuestionnaireFive Levels (EQ-5D-5L) is a validated, 
self-reported health status questionnaire that is used to calculate a health status utility 
score for use in health economic analyses (EuroQol Group 1990; Brooks 1996; 


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Herdman et al. 2011; Janssen et al. 2013).  There are two components to the EQ-5D-5L:  
a 5-item health state profile that assesses mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, as well as a visual analog scale that measures 
health state. Published weighting systems allow for creation of a single composite score 
of a subject's health status. 
Subjects and study partners will complete the measure (reporting on their own health 
status) to generate health status data to support pharmacoeconomic evaluations.
The assessment will take approximately 5 minutes to complete.
4.5.8.15
Pediatric Quality of Life Inventory Generic Core Scales
The PedsQL 4.0 Core is a 23-item, self-reported assessment encompassing four core 
scale domains (Varni et al. 2004):  Physical Functioning (8 items), Emotional Functioning 
(5 items), Social Functioning (5 items), and School Functioning (5 items).
The acute form, using a recall period of 7 days, will be employed in this study.  Different 
age-appropriate versions will be utilized:  the Young Adult version (subjects, ages 1825 
years) and the Adult version (subjects, ages 26 years).
Each item 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 


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to a 0100 scale (0100, 175, 250, 325, 40), such that higher scores indicate 
better HRQoL.
In addition to the four scale scores (Physical Functioning, Emotional Functioning, Social
Functioning, School/Work Functioning), 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 assessment will take approximately 1520 minutes to complete.
4.5.8.16
Pediatric Quality of Life Cognitive Functioning Module
The PedsQL Cognitive Functioning Module is a 6-item, self-reported assessment of 
cognitive functioning (Varni et al. 2004).
The acute form, with a recall period of 7 days, will be employed in this study.  Different 
age-appropriate versions will be utilized:  the Young Adult version (subjects, ages 1825 
years) and the Adult version (subjects, ages 26 years).
Each item 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 0–100 scale (0100, 175, 250, 325, 40) and summed to generate a total score.
Higher scores indicate better functioning.
The assessment will take approximately 5 minutes to complete.
4.5.8.17
Pittsburg Sleep Quality Index 
The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality during the previous 
month (Buysse et al. 1989).  It consists of 19 self-rated questions.  A wide variety of 
factors relating to sleep quality are assessed, including estimates of sleep duration, 
latency, and the frequency and severity of specific sleep-related problems.  The 19 items 
are grouped into seven component scores, each weighted equally on a 03 scale.  The 
global PSQI score has a range from 0 to 21, with higher scores indicating worse sleep 
quality. 
The entire index will take approximately 510 minutes to complete.
4.5.8.18
Patient Global ImpressionChange 
The Patient Global ImpressionChange (PGI-C) is a 4-item, self-reported measure
assessing a subject's impression about changes in his or her communication skills, social
skills, daily living skills, and overall autism compared with baseline.
The PGI-C items utilize a 7-point response scale, ranging from "very much improved" (1) 
to "very much worse" (7). Each item is scored independently. 
The assessment will take up to 5 minutes to complete.


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4.5.8.19
Patient Global ImpressionSeverity
The Patient Global ImpressionSeverity (PGI-S) is a 4-item, self-reported measure, 
assessing the subject’s impression about the severity of impairment of his or her 
communication skills, social skills, daily living skills, and overall autism during the 
preceding 7 days. 
The PGI-S items utilize a 5-point response scale, ranging from "no difficulty" (1) to 
"extreme difficulty" (5).  Each item is scored independently.
The assessment will take up to 5 minutes to complete.  
4.5.8.20
Columbia-Suicide Severity Rating Scale
The assessment for suicidality in clinical trials is a requirement for CNS-active molecules 
requested by health authorities.
The Columbia-Suicide Severity Rating Scale (C-SSRS; http://www.cssrs.columbia.edu) 
is a clinician-rated tool recommended by health authorities, including the U.S. FDA, to
assess previous suicidality of a subject (C-SSRS Baseline version) as well as any new
instances of suicidality during this study (C-SSRS Since Last Visit version to be used at
subsequent visits).  The C-SSRS incorporates a structured interview to prompt
recollection of suicidal ideation, including the intensity of the ideation, behavior, and
attempts with actual/potential lethality.
If the investigator concludes there is a risk of suicidality for a subject, the investigator
must further evaluate the risk, which may involve local experts in the field of suicidality.
4.5.9
Optional Samples for Research Biosample Repository
4.5.9.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
subjects in the future.
Specimens for the RBR will be collected from subjects who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition


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
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (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 (Section 4.5.9) will not be 
applicable at that site.
4.5.9.3
Sample Collection
One optional sample for DNA extraction will be collected per the schedule of activities in
Appendix 1; however, if it is not collected during the scheduled visit, it may be collected at
any time (after subject randomization) during the conduct of the clinical study.
The sample collected for DNA extraction may be sent to one or more laboratories for 
analysis of germline or somatic mutations via whole genome sequencing (WGS) or other 
genomic analysis methods.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and exome,
respectively, 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.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique subject identification 
number.
Subject medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
subject, unless permitted or required by law.


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Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each subject the 
objectives, methods, and potential hazards of participation in the RBR.  Subjects will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a subject's agreement to provide optional RBR specimens.  
Subjects who decline to participate will not provide a separate signature.
The investigator should document whether or not the subject has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Subjects who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the subject.  However, if RBR 
specimens have been tested prior to withdrawal of consent, results from those tests will 
remain as part of the overall research data.  If a subject wishes to withdraw consent to 
the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the subject's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com


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A subject's withdrawal from Study WN39434 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a subject's withdrawal from the RBR does not 
constitute withdrawal from Study WN39434.
4.5.9.7
Monitoring and Oversight
RBR specimens 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 specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to subject participation in the 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 RBR samples.
4.5.10
Optional Exploratory Substudies
Subjects who are randomized into the main study WN39434 may have the option to 
participate in exploratory substudies provided in separate protocols and upon consent 
and fulfillment of additional exploratory protocol criteria.  
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4.6
TREATMENT, SUBJECT, STUDY, AND SITE
DISCONTINUATION
An excessive rate of withdrawals (either because of subjects discontinuing study drug or 
withdrawal from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of subjects should be avoided and all efforts should be taken to 
motivate subjects to comply with all the study specific procedures and to be followed 
until the end of the 24-week placebo controlled treatment period.
Every attempt should be made to keep subjects on study drug throughout the duration of 
the trial.
Before permanently discontinuing study drug (either initiated by the subject or the
investigator), an interruption should be considered. Subjects, who temporarily
discontinue study drug for any reason, should restart as soon as medically justified in the 
opinion of the investigator.
The investigator should show due diligence and explore all possible options to reach a 
subject who fails to return to a visit. The site must document all attempts to try to 
contact the subject in the subject's medical records and source documents. 
In order to avoid loss-to-follow-up, the investigator should ask the subject at the study 
start for the contact details of a relative or friend who can be contacted in case the 
subject cannot be reached. 
Subjects should not be withdrawn from follow-up unless a subject explicitly withdraws 
consent to be contacted. All efforts should therefore be made to minimize the number of 
subjects who withdraw consent. 
If premature withdrawal from the study occurs for any reason, the investigator must 
determine the primary reason for a subject's premature withdrawal from the study and 
record this information in the subject's medical records and on the eCRF. 
4.6.1
Study Treatment Discontinuation
Subjects must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the subject’s safety if he or she continues to receive study treatment


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
Investigator or Sponsor determines it is in the best interest of the subject

Pregnancy




Subject unable to continue to comply with study requirements
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Subjects who discontinue study treatment prematurely will not be
replaced.
All subjects who withdraw or discontinue from the study treatment early will be asked to 
return as soon as possible (and within 1 week after the last dose of study drug) for an 
early termination visit, when the primary and secondary efficacy assessments will be 
performed.  Subjects will also be asked to return for assessments of the primary and 
secondary efficacy outcomes at the end of the 24-week planned visit, regardless of their 
adherence to treatment.  If the time between the early termination visit and the 24-week 
planned visit is fewer than 6 weeks, then subjects are exempted from the 24-week 
planned visit.  If the time between the early termination visit and the previous visit is 
fewer than 6 weeks, then subjects are exempted from completing again all the primary 
and secondary assessments at the early termination visit.
4.6.2
Subject Discontinuation from Study
Subjects 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 subject from the study at any 
time.  Reasons for withdrawal from the study may include, but are not limited to, the 
following:

Subject withdrawal of consent

Study termination or site closure

Any medical condition that may jeopardize the subject’s safety if he or she continues
in the study as determined by the investigator or Sponsor

In the best interest of the subject as determined by the investigator or Sponsor

Subject non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on subjects who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the
appropriate eCRF.  If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Subjects 
who withdraw from the study will not be replaced.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects

Subject enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all subjects have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Balovaptan is in clinical development and not approved or marketed in any country. The 
safety plan for subjects in this study is based on clinical experience with balovaptan in 
completed and ongoing studies.  The potential important safety risks for balovaptan are 
outlined below.  Please refer to the Balovaptan Investigator's Brochure for a complete 
summary of safety information.
Several measures will be taken to ensure the safety of subjects participating in this 
study.  Eligibility criteria have been designed to exclude subjects at potential higher risk 
for toxicities.  Subjects will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for treatment interruption or 
discontinuation, are provided in the following sections.


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5.1.2
Management of Subjects Who Experience Adverse Events
5.1.2.1
Dose Modifications
No dose modifications will be allowed in this study.


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5.1.2.2
Treatment Interruption
Balovaptan treatment may be temporarily or permanently suspended in subjects who 
experience toxicity considered to be related to study drug.  Balovaptan treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures) with Medical 
Monitor approval.  The investigator and the Medical Monitor will determine the 
acceptable length of treatment interruption.
Temporary interruptions of study drug may occur and should be considered before
deciding to permanently stop study drug. Reinstatement of study medication should be
considered as soon as medically justified. In general, temporary study drug interruptions
should be kept as short as possible. In the event of a subject experiencing intolerable
adverse events considered by the investigator to be related to study drug the subjects 
should permanently discontinue study drug.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, ECGs, and conducting other protocol-specified tests that are deemed critical to 
the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)


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5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
subject at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.9)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the subject’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to Adverse 
Events Severity Grading Scale; see Section 5.3.3); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 


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considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.




5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each subject contact.  All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).  Any other 
adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of the relationship to study 
drug, will be reported until 6 weeks after the last dose of study drug.


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After a period of 6 weeks from the last dose of study drug, investigators should only 
report any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all subject evaluation timepoints.  Examples of 
non-directive questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
Table 4 provides guidance for assessing adverse event severity.
Table 4
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
For subjects receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are 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.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
subject evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 


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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF. If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between subject evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is 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

Is 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., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) 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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
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For NT-proBNP, ULN and diagnostic cutoffs with regard to heart failure in adults
from published analyses are defined for the study as provided in Table 5.
Table 5
NT-proBNP ULN and Diagnostic Cutoff Values
ULN a
Diagnostic Cutoff b
Age
pg/mL
Age
pg/mL
18
125
18
300
ULN upper limit of normal.
a
Nir et al. 2009.
b
Lin et al. 2014.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is 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

Is 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 only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by 
Hy's Law).  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


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
Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  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").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Autism Spectrum Disorder
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 symptoms related to ASD on 
the Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors.


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5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), 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 subject has not experienced an adverse event
5.3.5.11
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 subject, drug misuse 
could involve the drug being administered to someone other than the subject.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with balovaptan regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.


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
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.

Drug administered to someone other than the subject:  Enter the drug name and 
"subject supplied drug to third party" as the event term.  Check the "Drug 
misuse" box.
Each adverse event associated with a special situation should be recorded separately on 
the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  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.

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.
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.
5.3.5.12
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived from PRO or observer-reported outcome 
(ObsRO) data by the Sponsor, and safety analyses will not be performed using PRO or 
ObsRO data.  Sites are not expected to review the PRO or ObsRO data for adverse 
events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery


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
Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites 
Medical Monitor:
, M.D. (Primary)
Mobile Telephone No.:
Medical Monitor:
, O.T.
Mobile Telephone No.:
To ensure the safety of study subjects, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible contact information, will be distributed to all 
investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 6 weeks after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 


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the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur beyond 6 weeks after the last
dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Subjects
Female subjects of childbearing potential should use the contraception method defined 
by the protocol for the duration of the trial and for 28 days after receiving their last dose 
of balovaptan and should take all appropriate precautions to avoid becoming pregnant.  
Regular pregnancy tests will be performed during the study.
Female subjects of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the subject, discussing the risks of the pregnancy 
and the possible effects on the fetus. 
In the event of pregnancy, the investigator must counsel the subject as to the risks of 
continuing with the pregnancy and the possible effects on the fetus. Given there are 
insufficient, well-controlled data from studies testing the use of balovaptan in pregnant or 
breastfeeding women, all dosing of balovaptan must be suspended until the end of 
pregnancy and breastfeeding. 
Monitoring of the subject should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  


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If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female subject or a female 
partner of a male subject exposed to study drug should be classified as a serious 
adverse event, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the subject is lost to 
follow-up, or the subject withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the subject’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome
and reported according to the instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
The investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as 6 weeks after the last dose of 
study drug). However, the Sponsor should be notified if the investigator becomes aware 


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of any serious adverse event that occurs after the end of the adverse event reporting 
period if the event is believed to be related to prior study drug treatment.  
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
Independent from the causality assessment, the following serious adverse events and 
non-serious adverse events of special interest will be reported to the FDA on an 
expedited basis: death, arrhythmia, syncope, dyspnea, palpitations, and chest pain.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events to balovaptan using the following reference 
document:

Balovaptan 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.  An iDMC will 
monitor the incidence of these events during the study.  An aggregate report of any 
clinically relevant imbalances that do not favor the test product will be submitted to 
health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Database lock to enable the analysis of the 24-week, placebo-controlled phase of the 
study will occur once all subjects have either completed the 24-week assessment or 
withdrawn from the study early, and all data required for analysis have been cleaned and 
verified.  After database lock, treatment assignments will be unblinded to the Sponsor.
The final analysis of the 24-week placebo-controlled period will be performed after 
database lock.  The final analysis of all data collected in the study, including the 
open-label extension, will occur after all subjects have completed the study.


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Details of the planned statistical analyses mentioned below in this section will be fully 
specified in the Statistical Analysis Plan, which will be finalized prior to the locking the 
study database and unblinding the study.
6.1
ANALYSIS POPULATIONS
6.1.1
Safety Population
The safety population will consist of all subjects who receive any study treatment. 
Randomized subjects who receive incorrect therapy from that intended will be 
summarized in the group according to their planned randomized treatment.
The safety population will be the primary population for all analyses of safety data.
6.1.2
Intent-to-Treat Population
The ITT population will consist of all subjects who receive any study treatment.  
Randomized subjects who receive incorrect therapy from that intended will be 
summarized in the group according to their planned randomized treatment.  
The ITT population will be the primary population for all analyses of primary and 
secondary efficacy variables.
6.2
DETERMINATION OF SAMPLE SIZE
The sample size of 350 randomized subjects (175 subjects per arm) provides 85% 
power to detect a difference in means between treatments in the change from baseline 
at Week 24 on the Vineland-II 2DC score of at least 4.0 points, assuming a two-sided 
5% significance level and a standard deviation of about 12.5 points. A blinded interim 
analysis of the change in Vineland-II 2DC score from baseline may be performed by the 
Sponsor to allow an increase in the sample size if necessary to achieve appropriate 
study power.
6.3
SUMMARIES OF CONDUCT OF STUDY
The number of subjects who enroll, discontinue, or complete the study will be 
summarized by treatment group.  Reasons for premature study withdrawal will be listed 
and summarized.  
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including age, sex, WASI®-II IQ score, SRS-2 
total t-score) will be summarized by treatment group using means, standard deviations, 
medians and ranges for continuous variables, and proportions for categorical variables, 
as appropriate.  Summaries will be presented overall and by treatment.


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6.5
EFFICACY ANALYSES
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline at Week 24 on the Vineland-II
2DC score, defined as the mean of the Communication domain standard score and the 
Socialization domain standard score.
6.5.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are identified in Section 2, Table 1.
6.5.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are identified in Section 2, Table 1.
6.5.4
Estimands
The primary efficacy study estimand is the difference in means between balovaptan and 
placebo in the change from baseline at Week 24 in Vineland-II 2DC score in the targeted 
ASD adult population, as identified by the study inclusion and exclusion criteria.
Intercurrent events that occur after treatment initiation and either preclude observation of 
the variable or affect its interpretation might occur.  The appropriate strategy to treat 
intercurrent events will be described in the Statistical Analysis Plan.  As a general 
principle, if treatment discontinuation is due to:

Study drugrelated reasons (e.g., treatment-related adverse event, or lack of 
efficacy) then the actual “off-treatment” values will be used in the analysis

Not study drugrelated reasons (e.g., lost to follow-up), then “imputed hypothetical” 
values, as if subjects had continued receiving study drug, will be used in the 
analysis
The primary statistical analysis will be performed according to a combination of
"treatment-policy strategy" and "hypothetical strategy" in order to account for the 
different types of intercurrent events.  
The Sponsor will put mechanisms in place to ensure that, as much as possible, all 
subjects are followed and their data are collected, up to and including the Week 24 visit,
regardless of their adherence to treatment ("retrieved dropout" strategy).  In case 
missing data are still present, imputation techniques may be considered separately for 
each treatment arm by using values while the subject was "on-treatment."  The primary 
estimator will be derived by the statistical model described in Section 6.5.5 on the 
dataset completed after multiple imputation.  Details of each imputation statistical 
approach (e.g., the number of imputed datasets created, imputation methodology) will be 
described in the Statistical Analysis Plan.  


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6.5.5
Primary Efficacy Analysis
The primary efficacy analysis for this trial will compare balovaptan with placebo at 
Week 24.  The following null (H0) and alternative (Ha) hypotheses will be tested at a 
two-sided 0.05 level:

H0:  MEANbalovaptan = MEANplacebo versus

Ha:  MEANbalovaptan ≠ MEANplacebo
for which the MEANRO and MEANplacebo refer to the mean change from baseline for 
balovaptan and placebo, respectively.
The analysis of the primary endpoint, the change from baseline at Week 24 on the 
Vineland-II 2DC score, will be performed by means of analysis of covariance.  The 
model will include the corresponding endpoint baseline score as covariate and
treatment, age group, sex, and geographical region as fixed effects.  Based on this 
analysis, least square means, standard errors, treatment difference, and corresponding 
95% confidence intervals will be reported. 
The effects on continuous secondary endpoints, as well as the short-term effect at 
12 weeks will be similarly analyzed.
As a supplementary analysis, a mixed-model repeated measurement (MMRM) analysis,
will be performed.  The MMRM model will include the corresponding endpoint baseline 
score as a covariate, with visit, treatment, age group, sex, and geographical region as 
fixed effects, and treatment by visit interaction; visit will be fitted as a repeated effect with 
unstructured correlation across visits within each subject. 
6.5.6
Secondary Efficacy Analyses
Similar hypotheses will also be tested for the secondary continuous efficacy parameters.  
Methods for controlling the type I error in the testing of secondary endpoints as well as 
their hierarchical order will be described in the Statistical Analysis Plan.
Categorical endpoints, such as the CGI-I and change from baseline of CGI-S, will be 
analyzed by means of logistic regression after dichotomizing the results into two 
categories (improved and not improved), considering the CGI-S baseline value as a 
covariate, and treatment, age group, sex and geographical region as factors.  Logistic 
regression will be performed also for the responder endpoint, considering the Vineland-II 
2DC score at baseline as a covariate, and treatment, age group, sex, and geographical 
region as factors.
6.5.7
Subgroup Analyses
The results of selected efficacy variables will be summarized within subgroups using 
descriptive statistics.  The following variables will be used to define the subgroups:

Baseline 2DC score of the Vineland-II (60 vs. 60)


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
Sex (male vs. female)

Geographical region (North America vs. ROW)

Age (25 years vs. 25 years)
Additional exploratory analyses of efficacy results may be performed using an MMRM 
model, with subgroup, treatment-by-subgroup interaction, and subgroup-by-time 
interaction terms included along the independent effects described above. Such 
exploratory analyses will be performed if the descriptive statistics results indicate 
substantial differences between the subgroups.
6.5.8
Exploratory Analyses
The exploratory endpoints will be summarized using tables, listings, and graphs 
as appropriate. 
6.5.9
Futility Analyses
One or more interim futility analyses will be performed during the study.  The analysis 
will be performed by the external independent Data Coordinating Center that generates 
the unblinded results reviewed by the iDMC on a regular basis, as described in 
Section 3.1.1.6.  
The iDMC will review the unblinded results for the primary efficacy endpoint (change 
from baseline at Week 24 in the Vineland-II 2DC score) and for the Adaptive Behavior 
Composite and the three individual Vineland-II domains standard scores.  The iDMC 
will be given clear criteria, detailed in the Statistical Analysis Plan, regarding what 
would constitute futility, and it is expected to recommend stopping the trial if the 
futility analysis results meet those criteria. If the analysis of the primary endpoint 
results at the time of this interim analysis indicates that the conditional probability of 
success for the trial is less than a prespecified threshold, then the committee may 
recommend that the trial be terminated for futility.  The iDMC will communicate to the 
Roche Data Review Board (DRB) only this recommendation (whether or not to stop the 
study for futility); detailed results of the futility analysis will not be shared with the 
Sponsor unless specifically requested by the DRB. Roche DRB Chair (or designate) 
will make the final decision regarding stopping the trial.
No adjustment for multiple comparisons will be made to the -level for this analysis, as 
the decision rules for the futility analysis will not allow for the opportunity to stop the 
study early for overwhelming efficacy. 
The specifics of the interim futility analysis will be documented prior to its conduct in 
the Statistical Analysis Plan. 


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6.6
SAFETY DATA ANALYSIS
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to Table 4.  All safety data will be 
reported in individual listings and summarized by treatment for each assessment time 
using descriptive statistics.  Data collected during the follow-up period (i.e., after 
discontinuation of study treatment) will be summarized separately from the data 
collected during the treatment period. 
The incidence of adverse events will be summarized on the basis of body systems and 
dictionary preferred terms.  The incidence of adverse events by severity and relationship 
to study drug and incidence of marked abnormal laboratory test results will be provided.  
Laboratory tests, ECG, and vital signs data will be summarized by descriptive statistics 
both as original value as well as the change from baseline. 
The iDMC will review safety data throughout the study.  Analyses required for the iDMC 
data review will be performed as described in the iDMC Charter. 
6.7
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
A population-PK analysis will be performed to describe the pharmacokinetics of 
balovaptan in subjects with ASD and to assess the influence of covariates of interest on 
the PK parameters.  Non-linear mixed effects modeling (using the software, NONMEM) 
will be used to analyze the concentrationtime data of balovaptan.  The starting model 
will be a model developed based on data from previous Phase I/II studies (Roche Report 
No. 1081347).  The data collected in this study may be pooled with data collected in 
previous studies as appropriate to inform the population-PK model. Population and 
individual primary PK parameters (e.g., clearances and volumes) will be estimated.
Secondary PK parameters such as AUC and maximum plasma concentration will be 
derived from the individual post-hoc predictions.  In addition, measured plasma 
concentrations of M2 (as applicable) and M3 metabolites will be summarized by 
timepoint and the relationship of parent and metabolite, as well as the influence of 
covariates of interest may be explored graphically. Plasma concentrations of 
balovaptan, its metabolites M2 (RO7045402) as applicable, and M3 (RO5273004) will be 
measured using a specific and validated liquid chromatography tandem mass 
spectrometry method.
Graphical exploration of the relationship between balovaptan exposure and the 
Vineland-II 2DC score and other selected clinical efficacy and safety endpoints will be 
performed. If indicated by such exploration, more formal analyses of the 
exposureresponse relationship will be performed using pharmacometric modeling 
methods.


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Details of the PK and pharmacodynamic analyses will be described in a Modeling and 
Simulation Analysis Plan. The results will be reported in a document separate from the 
Clinical Study Report.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. Discrepancies in vendor data (e.g., central 
laboratory and eCOA) will be managed outside of the EDC system.
The Sponsor will produce an EDC Study Specification document (Data Quality Review 
Plan and Data Management Plan) that describes the quality checking to be performed 
on the data.  Central laboratory data and eCOA data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
eCOA data will be collected through the use of an electronic device provided by a 
vendor (see Section 7.3 for details).
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC CLINICAL OUTCOME DATA
Subjects, study partners, and clinicians will use an electronic device to capture eCOA 
data.  The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. FDA regulations for electronic records (21 CFR, 


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Part 11).  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.
The electronic data will be available for view access only, via a secure vendor web 
portal.  Only identified and trained users may view the data, and their actions will 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive subject data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered on the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which subject data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, subject files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered on the eCRFs must not be obliterated or destroyed and must be retained per the 
policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.




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Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each subject the 
objectives, methods, and potential risks associated with each optional procedure.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a subject's agreement to participate in optional procedures.  Subjects who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each subject shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the subject or the subject’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include subject
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the 
site utilizes a separate Authorization Form for subject 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.


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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any subject recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number.  This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
subject, unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors,
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the investigator will receive 
the subject data, including an audit trail containing a complete record of all changes 
to data.
The Sponsor shall also submit as a periodic safety report once a year, a Development 
Safety Update Report, to the independent EC and regulatory authorities according to 
local regulatory requirements and timelines of each country participating in the study.
It is the understanding of the Sponsor that this protocol (and any modifications), as well
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an IRB.  This board must operate in accordance with the current federal regulations. 
The Sponsor will be sent a letter or certificate of approval prior to initiation of the study 
and whenever subsequent amendments modifications are made to the protocol. 
A Clinical Study Report will be written and submitted to relevant IRBs/ECs and 
regulatory authorities in accordance with local requirements.  To fulfill the requirements
for the E.U. Directive No. 75/318/EEC, the Clinical Study Report will be signed by a 
coordinating investigator who will be designated at a later stage.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on subject safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.


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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 50 sites globally will participate to enroll approximately 350 subjects.  
Enrollment will be managed through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker, and PK analyses), as specified in 
Section 4.5.5. Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An iDMC will be employed to monitor and evaluate subject safety throughout the study.  
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials
Data at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in subjects involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.


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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  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.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  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.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24
Week(s)
Screening
Treatment
4 to 1
BL
1
2
4
8
12
16
20
24 or 
ET a, b
Day(s) (3 days)
–28 to –1
1 c
8 
15
29
57
85c
113
141
169 c
Informed consent
x
Medical history, demographics, and 
baseline conditions d
x
Weight and height (height to be 
measured at screening only)
x
x
x
Vital signs e, f
x
x
x
x
x
x
x
x
x
PK blood sample g
x
x
x
x
x
Clinical genotyping sample
x
RBR blood sample (optional) h
x
Complete physical examination i
x
Limited physical examination i
x
x
Neurologic evaluation j
x
x
x
x
x
x
x
Clinical signs and symptoms of 
infection check k
x
Every 2 weeks 
12-Lead ECG l
x
x
x
x
x
Pregnancy test m
x
x
x
x
x
Serology (HIV, hepatitis B, and 
hepatitis C) n
x


Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
121/Protocol WN39434, Version 3
Week(s)
Screening
Treatment
4 to 1
BL
1
2
4
8
12
16
20
24 or 
ET a, b
Day(s) (3 days)
–28 to –1
1 c
8 
15
29
57
85 c
113
141
169 c
Hematology o
x
x
x
x
x
x
x
x
Coagulation p
x
x
Chemistry q
x
x
(x)
x
x
Quantitative immunoglobulins
x
x
Urinalysis r
x
x
x
Urine analysis for substance use s
x
x
ADOS-2 (if not completed within 
12 months by a certified rater)
x
SRS-2 (study partner)
x
IQ test (if not completed within 
12 months by a certified rater) t
x
Vineland-II (clinician and
study partner)
x
x
x
PedsQL4.0 Core (subject)
x
x
x
PedsQLCognitive Functioning 
(subject)
x
x
x
PSQI (subject)
x
x
x
EQ-5D-5L (subject)
x
x
x
PGI-S (subject)
x
x
x
PGI-C (subject)
x
x


Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
122/Protocol WN39434, Version 3
Week(s)
Screening
Treatment
4 to 1
BL
1
2
4
8
12
16
20
24 or 
ET a, b
Day(s) (3 days)
–28 to –1
1 c
8 
15
29
57
85 c
113
141
169 c
HAM-A (clinician and subject)
x
x
x
C-SSRS BL/SLV u
x
x
x
x
x
PedsQL Family Impact (study partner)
x
x
x
RBS-R (study partner)
x
x
x
EQ-5D-5L (study partner)
x
x
x
CaGI-S (study partner)
x
x
x
CaGI-C (study partner)
x
x
CGI-S (clinician)
x
x
x
x
x
x
CGI-I (clinician)
x
x
x
x
Previous and concomitant medications w
x
x
x
x
x
x
x
x
x
x
Adverse events x
x
x
x
x
x
x
x
x
x
x
Study drug dispensation y
x
x
x
x
x
x
(OLE)


Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
123/Protocol WN39434, Version 3
ADOS-2Autism Diagnostic Observation Schedule, Second Edition; BLbaseline; CaGI-CCaregiver Global 
ImpressionChange; CaGI-SCaregiver Global ImpressionSeverity; CGI-IClinical Global ImpressionImprovement; 
CGI-SClinical Global ImpressionSeverity; C-SSRS Colombia-Suicide Severity Rating Scale; cTnItroponin I; eCRF
electronic Case Report Form; EQ-5D-5LEuroQoL Five Dimensions QuestionnaireFive Levels; ETearly termination; 
HAM-AHamilton Anxiety Rating Scale; HBcAb hepatitis B core antibody; HBsAghepatitis B surface antigen; 
HCVhepatitis C virus;
 IQintelligence quotient; OLEopen-label extension; 
PedsQLPediatric Quality of Life Inventory; PedsQL4.0 CorePediatric Quality of Life Inventory™ Generic Core Scales, 
Version 4.0; PGI-CPatient Global ImpressionChange; PGI-SPatient Global ImpressionSeverity; PKpharmacokinetic; 
PSQIPittsburgh Sleep Quality Index; RBRResearch Biosample Repository; RBS-RRepetitive Behavior ScaleRevised; 
SLVsince last visit; SRS-2Social Responsiveness Scale, Second Edition; ULNupper limit of normal; 
Vineland-IIVinelandAdaptive Behavior Scales, Second Edition; WAIS®-IVWechsler Adult Intelligence Scale®, Fourth 
Edition; WASI®-IIWechsler Abbreviated Scale of Intelligence®, Second Edition.
Notes:  The visit window is 3 days, and all assessments should be completed within the visit window.  Subjects should 
return to the initial planned schedule per randomization for subsequent visits.  For subjects who terminate early, assessments 
listed under the ET visit should be completed.  For the schedule of activities to be performed at unscheduled visits and during 
the safety follow-up period, see Appendix 2.
a To be conducted if a subject discontinues from the study or study drug treatment prematurely.
b If a subject continues into the OLE period, the follow-up visit will be conducted 1 week, 2 weeks, and 12 weeks after the 
last dose of study drug in OLE period. If the subject does not enter the OLE period, the follow-up visit will be conducted 
1 week, 2 weeks, and 12 weeks after completion of the double-blind phase (see Appendix 2).
c The visit may be split over 2 days, as long as the visit remains within visit window.  If the baseline visit is split over 2 days, 
then dosing should occur on the second day. If the Week 12 or 24 visit is split over 2 days, then dosing should occur at the 
end of the each visit, i.e., no dosing should be skipped.
d Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the subject within 24 weeks prior to the screening visit as well as details of 
psychosocial or non-pharmacological interventions used during the previous 52 weeks.  Demographic data will include 
age, sex, and self-reported race/ethnicity.  Subjects and study partners will also be asked about the subject’s residential
setting, school, or employment status, level of education, participation in educational or day programs, and any non-medical
hospitalizations.  Demographics of the subject's study partner will also be recorded, including age, relationship to subject, 
education level attained, and employment status.


Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
124/Protocol WN39434, Version 3
e Vital signs include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressure while the subject 
is in a seated position, and body temperature (measured using a tympanic thermometer).  Vital sign assessments should 
be performed just prior to study drug administration.  All vital signs should be recorded on the eCRF.
f
Temperature will be recorded (measured using a tympanic thermometer) every 2 weeks for the double-blind period and 
continue into OLE period up until Week 52 of trial participation by the subject or study partner and recorded in a subject
diary or device.  
g For Weeks 2, 12, and 24, PK samples should be obtained just prior to study drug administration, if possible.  For Weeks 8 
and 20, the subject should take the study drug approximately 2 hours prior to the study visit. The PK sample should be 
obtained at least 3 hours after study drug administration.  Accurate recording of the time of study drug administration and 
sample collection is critical.
h Not applicable for a site that has not been granted approval for RBR sampling.  Perform only for subjects at participating 
sites who have provided written informed consent to participate.
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, and neurologic systems.  Complete physical examinations will not include pelvic, rectal, or
breast examinations.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  
Limited, symptom-directed physical examinations should be performed at Weeks 12 and 24, and as clinically indicated.  
Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
j
Neurologic evaluations will be completed at the baseline and at the Week 4, 8, 12, 16, 20, and 24 visits (see Appendix 4).  
k Site personnel will contact the subject and/or study partner every 2 weeks to ask about signs and symptoms of infections 
(see Appendix 5 for details).  In the event of such reports, the investigator should use clinical judgement as to whether to 
call a subject in for further evaluations.
l
Twelve-lead ECGs are to be performed after the subject has been in a supine position for 5 minutes.  ECGs for each 
subject should be obtained from the same machine whenever possible and performed prior to any blood draws.  At 
Week 4, perform predose and 4 hours postdose.  ECGs obtained at baseline will be in triplicate.  All others will be single 
recordings.  In the event of prolongation of the QTc interval, an unscheduled PK sample should be obtained.
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test 
performed at the site prior to each dose administration at the specified visits.  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source 
documents.




Appendix 1
Schedule of Activities:  Double-Blind Period to Week 24 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
126/Protocol WN39434, Version 3
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  The investigator is not required to actively monitor subjects for 
adverse events after the end of the adverse event reporting period (defined as 6 weeks after the last dose of study drug).  
However, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that occurs after 
the end of the adverse event reporting period if the event is believed to be related to prior study drug treatment.  Every 
effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
y Study drug administration should occur only after all assessments and rating scales for the subject are completed.  
Subjects should be instructed to take their medication at the same time each day, with the exception of study visits when 
they should take only their study drug once all assessments are completed.  Study drug dispensation can take place at any 
time during the visit. For the Week 8 and 20 study visits, the subject should take his or her medication approximately 
2 hours prior to the study visit.


Balovaptan—F. Hoffmann-La Roche Ltd
127/Protocol WN39434, Version 3
Appendix 2
Unscheduled Visit and Follow-Up Assessments: 
Double-Blind and OLE Periods
Week
Unscheduled 
Visit a
Follow-Up Period b
(3 days)
NA
1
2
12
Day
NA
176
183
253
Study site visit
NA

x
x c
Vital signs d
x
x
x
PK blood sample e
x
Physical examination
x
Neurologic evaluation f
x
x
Temperature g
x
Clinical signs and symptoms of infection check h
x
x
12-Lead ECG i
x
x
Pregnancy test j
x
Hematology k
x
x
x
Chemistry l
x
x
x
Coagulation m
x
Urinalysis n
x
x
Urine analysis for substance use o
x
Vineland-II (clinician and study partner)
x
PedsQL4.0 Core (subject)
x
PedsQLCognitive Functioning (subject)
x
PSQI (subject)
x
EQ-5D-5L (subject)
x
PGI-S (subject)
x
PGI-C (subject)
x
HAM-A (clinician and subject)
x
C-SSRS BL/SLV
x
x
PedsQL Family Impact (study partner)
x
RBS-R (study partner)
x
EQ-5D-5L (study partner)
x
CaGI-S (study partner)
x
CaGI-C (study partner)
x


Balovaptan—F. Hoffmann-La Roche Ltd
128/Protocol WN39434, Version 3
Appendix 2
Unscheduled Visit and Follow-Up Assessments:
Double-Blind and OLE Periods (cont.)
Week
Unscheduled 
Visit a
Follow-Up Period b
(3 days)
NA
1
2
12
Day
NA
176
183
253
Study site visit
NA

x
x c
CGI-S (clinician)
x
x
CGI-I (clinician)
x
x
Previous and concomitant medications p
x
x
x
x
Adverse events q
x
x
x
x
BLbaseline; CaGI-CCaregiver Global ImpressionChange; CaGI-SCaregiver Global 
ImpressionSeverity; CGI-IClinical Global ImpressionImprovement; CGI-SClinical 
Global ImpressionSeverity; C-SSRS Colombia-Suicide Severity Rating Scale; 
eCRFelectronic Case Report Form; EQ-5D-5LEuroQoL Five Dimensions 
QuestionnaireFive Levels; HAM-AHamilton Anxiety Rating Scale; HBcAbhepatitis B 
core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; NAnot 
applicable; OLEopen-label extension; PedsQLPediatric Quality of Life Inventory; 
PedsQL4.0 CorePediatric Quality of Life InventoryGeneric Core Scales, Version 4.0; 
PGI-CPatient Global ImpressionChange; PGI-SPatient Global ImpressionSeverity; 
PKpharmacokinetic; PSQIPittsburgh Sleep Quality Index; RBS-RRepetitive Behavior 
ScaleRevised; SLVsince last visit; Vineland-IIVinelandAdaptive Behavior Scales, 
Second Edition.
a Assessments performed at unscheduled visits will depend on the clinical needs of the 
subject.  This applies to both the double-blind period and the OLE period.
b If a subject continues into the OLE period, the follow-up visit will be conducted 1 week, 
2 weeks, and 12 weeks after the last dose of study drug in OLE period.  If the subject 
does not enter the OLE period, the follow-up visit will be conducted 1 week, 2 weeks, and 
12 weeks after completion of the double-blind phase.
c Visit may be split over 2 days as long as visit remains within the visit window.  All 
assessments for that particular day should be completed prior to dosing.
d Vital signs include measurements of respiratory rate, pulse rate, and systolic and diastolic 
blood pressure while the subject is in a seated position, and body temperature (measured 
using an oral or tympanic thermometer).  Vital sign assessments should be performed 
just prior to study drug administration.  All vital signs should be recorded on the eCRF. 
e Accurate recording of the time of sample collection is critical.
f
Neurologic evaluation as presented in Appendix 4 should be used. 
g Temperature will be recorded (measured using a tympanic thermometer) every 2 weeks 
by the subject or study partner and values recorded on a patient diary or device that will 
be provided to them for the first 52 week of a subject's study participation.
h Site personnel will contact the subject and/or study partner during the first 52 weeks of 
the study to ask about signs and symptoms of infections (see Appendix 5 for details).  
In the event of such reports, the site should use clinical judgement as to whether to call 
subject in for further evaluations.


Balovaptan—F. Hoffmann-La Roche Ltd
129/Protocol WN39434, Version 3
Appendix 2
Unscheduled Visit and Follow-Up Assessments:
Double-Blind and OLE Periods (cont.)
i
Twelve-lead ECGs are to be performed after the subject has been in a supine position for 
5 minutes.  ECGs for each subject should be obtained from the same machine whenever 
possible and performed prior to any blood draws.  In the event of prolongation of the
QTc interval, an unscheduled PK sample should be obtained.
j
Females of childbearing potential (including those who have had a tubal ligation) must 
have a urine pregnancy test performed at the site prior to each dose administration.  If a 
urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the 
central laboratory.  Results are to be recorded only in the source documents.
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells).
l
Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or 
urea, creatinine, CPK, total protein, albumin, phosphorus, calcium, total and direct 
bilirubin, ALP, ALT, AST, uric acid, LDH, cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides,
 
m Coagulation assessments include INR, aPTT, and PT.
n Urinalysis will be performed at the site by dipstick for blood, protein, glucose, ketones, 
specific gravity, and pH.  Microscopic examination performed at the central laboratory if 
blood and/or protein results are positive or strongly positive. 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.  Results do not need to be recorded on the eCRF.
o Urine samples will be analyzed for the presence of the following drugs:  cannabinoids, 
opiates, cocaine, barbiturates, methadone, and phencyclidine (PCP).  Results will be 
used to verify subject eligibility pertaining to drugs of abuse.  Inconclusive results may be 
repeated once during the screening period.  Investigators should use their best clinical 
judgment in cases where results may be erroneous (e.g., permitted use of opiates or 
ingestion of food or food supplements).
p Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, approved dietary and herbal supplements, nutritional supplements and any
non-medicinal interventions, such as individual psychotherapy, cognitive behavioral
therapy, smoking cessation therapy, and rehabilitative therapy) used by a subject since 
the last visit until the follow-up visit.
q The investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as 6 weeks after the last dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that occurs after the end of the adverse event reporting period if 
the event is believed to be related to prior study drug treatment.  Every effort should be 
made to follow all serious adverse events considered to be related to study drug or 
trial-related procedures until a final outcome can be reported.


Balovaptan—F. Hoffmann-La Roche Ltd
130/Protocol WN39434, Version 3
Appendix 3
Schedule of Activities: Open-Label Extension Period, Week 28 and Onward
Week
Open-Label Treatment
ET a, b
28
32
36
40
44
48
52
64
76
88
104
116
128
Day
197
225
253 a
281
309
337
365 a
449
533 a
617
729 a
813
897 a
Vital signs c
x
x
x
x
x
x
x
x
x
x
x
x
x 
x 
Weight
x
x
x
x
PK blood sample d
x
x
x
x
x
Complete physical examination e
x
Limited physical examination e
x
x
x
x
x
Neurologic evaluation f
x
x
x
x
x
x
x
x
x
x
x
x
Temperature g
x
x
x
x
x
x
x
x
12-Lead ECG h
x
x
x
x
x
x
Pregnancy test i
x
x
x
x
x
x
x
x
x
Hematology j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry k
x
x
x
x
x
x
x
x
x
Urinalysis l
x
x
x
x
x
Urine analysis for substance use m
x
x
x
x
x
Vineland-II (clinician and
study partner)
x
x
x
x
x
x
PedsQL4.0 Core (subject)
x
x
x
x
x
x


Appendix 3
Schedule of Activities:  Open-Label Extension Period, Week 28 and Onward (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
131/Protocol WN39434, Version 3
Week
Open-Label Treatment
ET a, b
28
32
36
40
44
48
52
64
76
88
104
116
128
Day
197
225
253 a
281
309
337
365 a
449
533 a
617
729 a
813
897 a
PedsQLCognitive Functioning 
(subject)
x
x
x
x
x
x
PSQI (subject)
x
x
x
x
x
x
EQ-5D-5L (subject)
x
x
x
x
x
x
PGI-S (subject)
x
x
x
x
x
x
PGI-C (subject)
x
x
x
x
x
x
HAM-A (clinician and subject)
x
x
x
x
x
x
C-SSRS BL/SLV
x
x
x
x
x
x
x
x
x
x
x
x
PedsQL Family Impact (study 
partner)
x
x
x
x
x
x
RBS-R (study partner)
x
x
x
x
x
x
EQ-5D-5L (study partner)
x
x
x
x
x
x
CaGI-S (study partner)
x
x
x
x
x
x
CaGI-C (study partner)
x
x
x
x
x
x
CGI-S (clinician)
x
x
x
x
x
x
x
x
x
CGI-I (clinician)
x
x
x
x
x
x
x
x
x
Study drug dispensation n
x
x
x
x
x
x
x
x
x
x
x
x
Previous and concomitant 
medications o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events p
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 3
Schedule of Activities:  Open-Label Extension Period, Week 28 and Onward (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
132/Protocol WN39434, Version 3
BLbaseline; CaGI-CCaregiver Global ImpressionChange; CaGI-SCaregiver Global ImpressionSeverity; CGI-IClinical Global 
ImpressionImprovement; CGI-SClinical Global ImpressionSeverity; C-SSRS Colombia-Suicide Severity Rating Scale; 
eCRFelectronic Case Report Form; EQ-5D-5EuroQoL Five Dimensions QuestionnaireFive Levels; ET early termination; 
HAM-AHamilton Anxiety Rating Scale; PedsQLPediatric Quality of Life Inventory; PedsQL4.0 CorePediatric Quality of Life 
InventoryGeneric Core Scales, Version 4.0; PGI-CPatient Global ImpressionChange; PGI-SPatient Global 
ImpressionSeverity; PKpharmacokinetic; PSQIPittsburgh Sleep Quality Index; RBS-RRepetitive Behavior ScaleRevised; 
SLV since last visit; Vineland-IIVinelandAdaptive Behavior Scales, Second Edition.
Notes:  The visit window is 3 days and all assessments should be completed within the visit window.  Subjects should return to 
initial planned schedule per randomization for subsequent visits.  For subjects who terminate early, assessments listed under the 
ET visit should be completed.  For the schedule of activities to be performed at unscheduled visits and during the safety follow-up 
period, see Appendix 2.
a The Week 36, 52, 76, 104, 128, and ET visits may be split over 2 days, as long as the visit remains within the visit window.  
All assessments for that particular day should be completed prior to dosing.
b To be conducted if a subject discontinues prematurely for any reason.
c Vital signs include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressure while the subject is in a 
seated position, and body temperature (measured using an oral or tympanic thermometer).  Vital sign assessments should be 
performed just prior to study drug administration.  All vitals should be recorded on the eCRF.  
d All scheduled PK samples should be obtained just prior to study drug administration, if possible.  Accurate recording of the time 
of study drug administration and sample collection is critical.
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems.  Complete physical examinations will not include pelvic, rectal, or breast examinations.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits,
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Limited, symptom-directed physical 
examinations should be performed at Weeks 36, 52, 76, 104, and 128, and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF.
f
The neurologic evaluation will be completed at the Week 36, 48, 52, 64, 76, 104, and 128 visits. 


Appendix 3
Schedule of Activities:  Open-Label Extension Period, Week 28 and Onward (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
133/Protocol WN39434, Version 3
g Temperature will be recorded (measured using a tympanic thermometer) every 2 weeks by the subject or study partner, and the 
values should be recorded in a subject diary or device that will be provided.  Site personnel will contact the subject and/or study 
partner every 2 weeks up until Week 52 to ask about signs and symptoms of infections (see Appendix 5 for details).  In the event 
of such reports, the site should use clinical judgement as to whether to call the subject in for further evaluations.
h Twelve-lead ECGs are to be performed after the subject has been in a supine position for 5 minutes.  ECGs for each subject 
should be obtained from the same machine whenever possible and performed prior to any blood draws.  In the event of
prolongation of the QTc interval, an unscheduled PK sample should be obtained.
i
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at 
the site prior to each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at 
the central laboratory.  Results are to be recorded only in the source documents.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, and other cells).
k Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, CPK, total protein, 
albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, LDH, cholesterol, LDL cholesterol, HDL 
cholesterol, and triglycerides,
l
Urinalysis will be performed at the site by dipstick for blood, protein, glucose, ketones, specific gravity, and pH.  Microscopic 
examination performed at the central laboratory if blood and/or protein results are positive or strongly positive.  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.  Results do not need to be recorded on the eCRF.
m Urine samples will be analyzed for the presence of the following drugs:  cannabinoids, opiates, cocaine, barbiturates, methadone, 
and phencyclidine (PCP).  Results will be used to verify subject eligibility pertaining to drugs of abuse.  Inconclusive results may 
be repeated once during the screening period.  Investigators should use their best clinical judgment in cases where results may 
be erroneous (e.g., permitted use of opiates or ingestion of food or food supplements).
n Study drug administration should occur only after all assessments and rating scales for the subject are completed.  Subjects 
should be instructed to take their medication at the same time each day, with the exception of study visits at which they should 
take only their study drug once all assessments are completed.  Study drug dispensation can take place at any time during the
visit.


Appendix 3
Schedule of Activities:  Open-Label Extension Period, Week 28 and Onward (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
134/Protocol WN39434, Version 3
o Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter drugs, approved dietary and herbal
supplements, nutritional supplements and any non-medicinal interventions (e.g., individual psychotherapy, cognitive behavioral
therapy, smoking cessation therapy, and rehabilitative therapy) used by a subject since the last visit until the follow-up visit.
p The investigator is not required to actively monitor subjects for adverse events after the end of the adverse event reporting period 
(defined as 6 weeks after the last dose of study drug).  However, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that occurs after the end of the adverse event reporting period if the event is believed to be 
related to prior study drug treatment.  Every effort should be made to follow all serious adverse events considered to be related to 
study drug or trial-related procedures until a final outcome can be reported.


Balovaptan—F. Hoffmann-La Roche Ltd
135/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
136/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
137/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
138/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
139/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
140/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
141/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
142/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
143/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
144/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
145/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
146/Protocol WN39434, Version 3


Balovaptan—F. Hoffmann-La Roche Ltd
147/Protocol WN39434, Version 3