Clinical trial NCT02901431
Conditions: Autism Spectrum Disorder
Sponsor: Hoffmann-La Roche
Start date: 2016-11-21; Completion date: 2020-06-30
Enrollment: 339 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
For participants enrolled prior to Version 6 of the protocol: This was a Phase II multi-center, randomized, double-blind, 24-week, 3-arm, parallel group, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of balovaptan in children and adolescents aged 5-17 years with ASD who are high functioning (intelligence quotient \[IQ\] greater than or equal to \[\>=\] 70).

For participants enrolled according to Version 6 of the protocol: This was a Phase II multi-center, randomized, double-blind, 24-week, parallel group, placebo-controlled, 2-arm study with participants assigned either to a 10 milligram (mg) or equivalent dose of balovaptan, or placebo. All other study parameters remained as stated above.

There are three parts to this study: PK Part (Study part 1) included up to 8 weeks of treatment, Main Treatment Part (Study part 2) included 24 week of treatment, and the Open Label Extension Part (Study part 3) included Week 24 to Week 76 of treatment.

All participants that completed the 24-week treatment period were eligible to participate in an optional 52-week open-label extension (OLE) during which they received balovaptan treatment.

Detailed description:

Arms: arm 1: Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks. arm 2: Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks (up to 52 additional weeks for those enrolled in the OLE). arm 3: Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks. This arm is open only to those participants enrolled prior to Version 6 of the study protocol.
Interventions: intervention 1: Placebo intervention 2: RO5285119
Intervention descriptions: intervention 1: Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks. intervention 2: Participants received age-adjusted total daily oral dose approximately equivalent to the adult doses of either 4 mg/d or 10 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks (up to 52 additional weeks for those enrolled in the OLE).

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A Phase II Multi-Center, Randomized, Double-Blind, 24 Week, 
Parallel Group, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of Balovaptan (RO5285119) in Children and 
Adolescents Age 5-17 With Autism Spectrum Disorder (ASD) 
NCT Number: NCT02901431   
Document Date: Protocol Version 6: 19-December-2018 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 
and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, 
for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written authorization from 
Roche except to the extent necessary to obtain informed consent from persons to whom the drug 
may be administered.
Balovaptan—F. Hoffmann-La Roche Ltd
Protocol BP30153, Version 6
PROTOCOL
TITLE:
A PHASE II MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, 24-WEEK, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE THE EFFICACY 
AND SAFETY OF BALOVAPTAN (RO5285119) IN CHILDREN 
AND ADOLESCENTS AGE 517 WITH AUTISM SPECTRUM 
DISORDER (ASD)
PROTOCOL NUMBER:
BP30153
VERSION NUMBER:
6
EUDRACT NUMBER:
N/A
IND NUMBER:
116,483
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 23 March 2016
DATES AMENDED: 
Version 2: 02 Aug 2016
Version 3:  30 Jan 2017
Version 4:  19 May 2017
Version 5:  29 March 2018
Version 6:  See electronic time stamp below.
 
19-Dec-2018 02:26:35
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Balovaptan—F. Hoffmann-La Roche Ltd
2/Protocol BP30153, Version 6
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol BP30153, Version 6 has been amended primarily to change the study design 
(main study) to a single balovaptan dose (10 mg age equivalent) compared with placebo
study, in accordance to a randomization ratio of 1:1 of 10 mg equivalent:placebo; to 
increase the overall number of subjects; to reduce the screening window duration for all 
new subjects; to update the requirements for cardiac monitoring in response to specific 
requests received from the U.S. Food and Drug Administration (FDA) and removal of 
capillary blood draw option introduced with Version 5; to change the initial starting dose
for subjects aged 8 years and above; and to define some statistical analysis details.  
Changes to the protocol, along with a rationale for each change, are summarized below: 

The study design has been changed to a single dose (10 mg equivalent balovaptan) 
compared with placebo in accordance to a randomization ratio of 1:1 of balovaptan
10 mg equivalent:placebo (Sections 3.1, 3.3, and 4.3).
Rationale:  A recent Internal Monitoring Committee (IMC) and Scientific Oversight 
Committee (SOC) review of pharmacokinetic (PK) data determined that subjects 
aged 14 years and younger received doses providing exposures lower than 
anticipated.  Consequently, dose adjustments were implemented.  However, the 
dose equivalencies for balovaptan 4 mg and 10 mg doses were for the majority of 
subjects below the respective target concentrations observed with 4 and 10 mg 
once daily dosing in adults.  Insufficient data has been collected at the 10 mg 
equivalent dose whereas more data than expected has been generated in the lower 
concentration range.  Therefore, recruitment for the 4 mg balovaptan arm has been 
closed to ensure that sufficient subjects can be recruited to both 10 mg and placebo.

Adolescent subjects who have been discontinued because of lack of dose 
confirmation (per protocol prior to Week 8) will be replaced in the study. The total 
sample size of the study has been increased to 340 subjects (Sections 3.1.3
and 6.8).
Rationale: Because the adolescent and child subjects in the 10 mg equivalent arm 
have been under dosed, to obtain evaluable data at the correct 10 mg balovaptan
dose (exposure), the sample size has been increased.

The initial starting dose (main study) has been changed following review of available 
safety and PK data from the study.  A table has been added to outline updated 
starting doses for adolescents and children, aged 8 to 17 years (Section 4.4.2, 
Table 2).
Rationale:  Available PK and safety/tolerability results from this study were reviewed 
by the IMC and SOC and compared with the exposures measured in adults in 
Study BP28420.  Median area under the concentration–time curve of the 57, 812, 
and 1314 year old subjects were found to be considerably below the target 
exposures.  Therefore, the initial starting dose for all adolescents and children 
8 years and above has been updated and should be implemented at his or her next 
study drug dispensation visit.


Balovaptan—F. Hoffmann-La Roche Ltd
3/Protocol BP30153, Version 6

The screening window duration has been reduced for all new subjects
(Sections 3.1.1, 4.2.1, 4.6.2.1 and Appendix 1).
Rationale:  An extended screening window was considered necessary during 
recruitment to the PK cohorts to try and minimize subjects being discontinued from 
treatment in the absence of dose confirmation. As the PK cohorts are essentially 
complete, the screening window duration will be decreased from 8 weeks to 
4 weeks.

 
 
 
 
 
 
 

Capillary blood sampling (introduced in Version 5 of this protocol) has been 
removed (Sections 5.2.1 and 5.2.4).
Rationale: Capillary blood sample for hematological and CPK monitoring at certain 
timepoints was introduced in Version 5 of the protocol because neutrophil counts 
and CPK can be measured by a capillary blood sample and a capillary blood sample 
may be better tolerated than blood draws by venipuncture. However, Troponin T 
has not been shown to be reliably measured from capillary blood.  Thus, with the 
reduced CPK assessments and the increased troponin T assessments, capillary 
blood sampling has been removed.
Additional changes to the protocol, along with a rationale for each change, are 
summarized below: 

The study rationale has been updated to excluding data from a nonclinical study of 
prenatal valproic acid (VPA) in a rat model (Section 1.3).
Rationale: A recent independent in-house analysis of the data from a nonclinical 
pharmacology study, the effects of balovaptan in the prenatal VPA rat model, was 
unable to verify the original results. It is important to note that this does not have 
any effect on the safety profile of balovaptan, and data in support of the mechanism 
of action was provided from other sources, including clinical data.

It has been clarified that subjects who test positive for hepatitis B core antibodies 
(HBcAb) may still be eligible for the study if the subject has a negative hepatitis B 
surface antigen (HBsAg) and/or hepatitis B cDNA (HBcDNA), no medical history of 
hepatitis, and no indication of liver dysfunction through liver enzyme or coagulation 
results (Sections 3.2.3 and 4.6.1.7). 
Rationale:  Few subjects screened for this study have been found positive for 
HBcAb in the absence of any other evidence for hepatitis including medical history.  
False positive HBcAb testing is a known phenomenon and has been found to occur 


Balovaptan—F. Hoffmann-La Roche Ltd
4/Protocol BP30153, Version 6
up to 16% [51] of cases.  No liver toxicity alert for balovaptan administration has 
emerged in animals or in clinical trials.

Changes in the statistical section in terms of primary treatment comparison and 
efficacy analysis populations (Sections 6.1, 6.3.3, and 6.6).
Rationale: The primary efficacy analysis will compare balovaptan 10 mg equivalent 
dose with placebo, reflecting the change in the study objective and design.  The 
definition of the primary efficacy analysis population has been refined in alignment 
with the one planned for the confirmatory Phase III balovaptan trials, which are 
currently ongoing/planned.  The availability of both baseline and at least one 
postdose assessment, which was the specific of the originally planned modified 
intent-to-treat population, is not required for identifying the appropriate set of data 
according to the principle of the intention to treat.  The same rationale, that is, the 
alignment with confirmatory Phase III framework, justifies the removal of the 
originally planned additional, secondary, analysis on the per-protocol population.

Reporting of cardiovascular AESI (arrhythmia, syncope, dyspnea, palpitations, or 
chest pain) has been clarified (Section 5.1.3). Expedited reporting to investigators 
and IRBs has been removed.
Rationale: FDA requested expedited reporting of these cardiovascular terms.  This 
was updated in Version 5 of the protocol (Section 5.7); however, the update did not 
clarify that expedited reporting of these terms was only to the FDA.

Eligibility criteria related to stability of concomitant medications for subjects who 
enter the OLE through the substudy have been clarified (Appendix 11). 

The Medical Monitor has been changed from 
, M.D. to 
, Ph.D., and the secondary Medical Monitor contact has been updated 
to 
, M.D. (Section 5.4.1).
Additional minor changes have been made to correct errors, and 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
6/Protocol BP30153, Version 6
42
3.3.3
Rationale for Use of Single Dose in Subjects 
Enrolled in Accordance to Version 6...................................... 42
3.3.4
Rationale for Study Population .............................................. 43
3.3.5
Rationale for Use of Vineland™-II Adaptive
Behavior Scales 2-Domain Composite Score as 
the Primary Efficacy Endpoint................................................ 43
3.3.6
Rationale for Open-Label Extension...................................... 44
3.3.7
Rationale for Use of Responder Definition............................. 44
3.4
Outcome Measures ............................................................... 44
3.4.1
Efficacy Outcome Measures.................................................. 44
3.4.2
Exploratory Outcome Measures ............................................ 45
3.4.3
Safety Outcome Measures .................................................... 45
3.4.4
Pharmacokinetic (PK) Outcomes........................................... 45
3.4.5
Biomarker/Genotyping Sample Collection ............................. 46
3.4.5.1
Clinical Genotyping (CG) Samples........................................ 46
3.4.5.2
Research Biosample Repository ........................................... 46
4.
MATERIALS AND METHODS .................................................................... 46
4.1
Center.................................................................................... 46
4.2
Study Population ................................................................... 47
4.2.1
Recruitment Procedures........................................................ 47
4.2.2
Inclusion Criteria.................................................................... 48
4.2.3
Exclusion Criteria................................................................... 49
4.2.4
Eligibility for Open-Label Extension Phase............................ 51
4.3
Method of Treatment Assignment and Blinding..................... 51
4.4
Study Treatment.................................................................... 53
53
53
4.4.2
Dosage, Administration, and Compliance.............................. 53
4.4.2.1
Age-adjusted Doses .............................................................. 53
4.4.2.2
Administration and Compliance............................................. 55
4.4.2.3
Treatment in the Open-Label Extension, 
Including Age-Adjusted Doses............................................... 55
4.4.3
Investigational Medicinal Product Accountability ................... 56


Balovaptan—F. Hoffmann-La Roche Ltd
7/Protocol BP30153, Version 6
4.5
Concomitant Therapy ............................................................ 57
4.5.1
Permitted Therapy................................................................. 57
4.5.2
Non-Pharmacological Interventions....................................... 58
4.5.3
Prohibited Therapy ................................................................ 58
4.5.4
Caution Regarding P-gp Substrates ...................................... 59
4.6
Study Assessments ............................................................... 59
4.6.1
Description of Study Assessments ........................................ 59
4.6.1.1
Medical History and Demographic Data ................................ 59
4.6.1.2
Physical and Neurological Examinations............................... 60
4.6.1.3
Tanner Staging...................................................................... 61
4.6.1.4
Palatability Test ..................................................................... 61
4.6.1.5
Vital Signs.............................................................................. 61
4.6.1.6
Electrocardiograms................................................................ 62
4.6.1.7
Laboratory Assessments ....................................................... 62
4.6.1.8
Pharmacokinetic Assessments.............................................. 65
4.6.1.9
Clinical Genotyping Samples................................................. 66
4.6.1.10
Disease-Specific Assessments.............................................. 66
4.6.1.11
 Patient-Reported Outcomes.................................................. 71
4.6.1.12
Columbia Suicide Severity Rating Scale 
(C-SSRS)............................................................................... 72
4.6.1.13
Samples for Research Biosample Repository ....................... 72
4.6.2
Timing of Study Assessments ............................................... 76
4.6.2.1
Screening and Pretreatment Assessments............................ 76
4.6.2.2
Assessments during Treatment............................................. 77
4.6.2.3
Assessments at Study Completion/Early 
Withdrawal Visit..................................................................... 78
4.6.2.4
Follow-Up Assessments ........................................................ 78
4.7
Subject, Study, and Site Discontinuation............................... 79
4.7.1
Subject Discontinuation ......................................................... 79
4.7.1.1
Discontinuation from Study Drug........................................... 79
4.7.1.2
Withdrawal from Study........................................................... 79
4.7.2
Study and Site Discontinuation.............................................. 80
5.
ASSESSMENT OF SAFETY....................................................................... 80


Balovaptan—F. Hoffmann-La Roche Ltd
8/Protocol BP30153, Version 6
5.1
Safety Parameters and Definitions ........................................ 80
5.1.1
Adverse Events ..................................................................... 81
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 81
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 82
5.2
Safety Plan ............................................................................ 82
82
5.2.2
Blood Pressure and ECG Monitoring..................................... 84
84
85
85
5.2.6
Tanner Staging...................................................................... 87
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 87
5.3.1
Adverse Event Reporting Period ........................................... 87
5.3.2
Eliciting Adverse Event Information....................................... 87
5.3.3
Assessment of Severity of Adverse Events ........................... 88
5.3.4
Assessment of Causality of Adverse Events ......................... 88
5.3.5
Procedures for Recording Adverse Events............................ 88
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 88
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 89
5.3.5.3
Persistent or Recurrent Adverse Events................................ 89
5.3.5.4
Abnormal Laboratory Values ................................................. 89
5.3.5.5
Abnormal Vital Sign Values ................................................... 90
5.3.5.6
Abnormal Liver Function Tests.............................................. 91
5.3.5.7
Deaths ................................................................................... 91
5.3.5.8
Preexisting Medical Conditions.............................................. 91
5.3.5.9
Hospitalization or Prolonged Hospitalization.......................... 92
5.3.5.10
Patient-Reported Outcome Data ........................................... 92
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92
5.4.1
Emergency Medical Contacts................................................ 93


Balovaptan—F. Hoffmann-La Roche Ltd
9/Protocol BP30153, Version 6
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 93
5.4.3
Reporting Requirements for Pregnancies.............................. 94
5.4.3.1
Pregnancies in Female Subjects ........................................... 94
5.4.3.2
Pregnancies in Female Partners of Male 
Subjects................................................................................. 94
5.4.3.3
Abortions ............................................................................... 94
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 94
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 95
5.5
Follow-Up of subjects after Adverse Events .......................... 96
5.5.1
Investigator Follow-Up........................................................... 96
5.5.2
Sponsor Follow-Up ................................................................ 97
5.6
Post-Study Adverse Events................................................... 97
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 97
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98
6.1
Determination of Sample Size ............................................... 98
6.2
Summaries of Conduct of Study............................................ 98
6.3
Analysis Populations ............................................................. 98
6.3.1
Safety Analysis Population .................................................... 98
6.3.2
Pharmacokinetic Analysis Population.................................... 99
6.3.3
Efficacy Analysis Population.................................................. 99
6.3.3.1
For All Subjects Enrolled prior to Version 6 of the 
Protocol: ................................................................................ 99
6.3.3.2
For Subjects Enrolled in Accordance to Version 6 
of the Protocol ...................................................................... 99
6.4
Summaries of Treatment Group Comparability ................... 100
6.5
Safety Analyses................................................................... 100
6.5.1
Adverse Events ................................................................... 100
6.5.2
Clinical Laboratory Test Results.......................................... 100
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................. 101


Balovaptan—F. Hoffmann-La Roche Ltd
10/Protocol BP30153, Version 6
6.5.2.2
Definition of Laboratory Abnormalities................................. 101
6.5.3
Vital Signs and ECG............................................................ 102
6.5.4
Concomitant Medications .................................................... 102
6.6
Efficacy Analyses ................................................................ 102
6.7
Pharmacokinetic Analyses................................................... 103
6.8
Interim Analyses .................................................................. 103
7.
DATA COLLECTION AND MANAGEMENT ............................................. 104
7.1
Data Quality Assurance....................................................... 104
7.2
Electronic Case Report Forms............................................. 104
7.3
Electronic Patient-Reported Outcome Data......................... 105
7.4
Source Data Documentation................................................ 105
7.5
Use of Computerized Systems ............................................ 106
7.6
Retention of Records........................................................... 106
8.
ETHICAL CONSIDERATIONS.................................................................. 107
8.1
Compliance with Laws and Regulations .............................. 107
8.2
Informed Consent................................................................ 107
8.3
Institutional Review Board or Ethics Committee.................. 108
8.4
Confidentiality...................................................................... 108
8.5
Financial Disclosure ............................................................ 109
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 109
9.1
Study Documentation .......................................................... 109
9.2
Protocol Deviations.............................................................. 110
9.3
Site Inspections ................................................................... 110
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 110
9.5
Protocol Amendments ......................................................... 111
10. REFERENCES ......................................................................................... 112
LIST OF TABLES
Table 1
Age-adjusted Starting Doses Based on PBPK Model................. 54
Table 2
Updated Age-Adjusted Doses Based on PK Data ...................... 54




Balovaptan—F. Hoffmann-La Roche Ltd
12/Protocol BP30153, Version 6
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, 24-WEEK, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF BALOVAPTAN
(RO5285119) IN CHILDREN AND ADOLESCENTS AGE 
5-17 WITH AUTISM SPECTRUM DISORDER (ASD)
PROTOCOL NUMBER:
BP30153
VERSION NUMBER:
6
IND NUMBER:
116,483
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, Ph.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 keep the signed original form in your study files, and return a copy to your local 
Study Monitor.


Balovaptan—F. Hoffmann-La Roche Ltd
13/Protocol BP30153, Version 6
PROTOCOL SYNOPSIS
TITLE:
A PHASE II MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
24-WEEK, PARALLEL GROUP, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY AND SAFETY OF 
BALOVAPTAN (RO5285119) IN CHILDREN AND ADOLESCENTS 
AGE 5-17 WITH AUTISM SPECTRUM DISORDER (ASD)
PROTOCOL NUMBER:
BP30153
VERSION:
6
EUDRACT NUMBER:
N/A
IND NUMBER:
116,483
TEST PRODUCT:
Balovaptan (RO5285119)
PHASE:
II
INDICATION:
Autism Spectrum Disorder (ASD)
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES 
Primary Objectives
The primary objectives of this study are as follows:

To evaluate the efficacy of 24-week treatment with balovaptan (RO5285119) 10 mg 
equivalent compared to placebo as measured by the change from baseline on the 
Vineland-II Adaptive Behavior Scales, second edition (Vineland-II) Two Domain 
Composite (2DC) (average of Communication and Socialization domains)
Secondary Objectives
The secondary objectives for this study are as follows:

To evaluate the efficacy of treatment with balovaptan 10 mg equivalent vs. placebo on:
o
Change from baseline on the Vineland-II Composite standard score after 12 weeks 
and 24 weeks of treatment
o
Change from baseline in the Vineland-II Communication, Socialization, and Daily 
Living Skills domain standard scores after 12 weeks and 24 weeks of treatment
o
Proportion of subjects with ≥6-point improvement in the Vineland-II 2DC score to 
evaluate clinically meaningful response
o
Change from baseline in severity of clinical impressions as measured by CGI-S (Clinical 
Global Impressions-Severity) and OACIS-S (Ohio Autism Clinical Impressions Scale-
Severity) after 12 weeks and 24 weeks of treatment
o
Improvements in clinical impressions as measured by CGI-I (Clinical Global 
Impressions-Improvement) and OACIS-I (Ohio Autism Clinical Impressions Scale-
Improvement) after 12 weeks and 24 weeks of treatment
o
Patient-reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale after 
12 weeks and 24 weeks of treatment
o
Change from baseline in the Vineland-II) Composite standard score in adolescents 
and children independently after 12 weeks and 24 weeks of treatment


Balovaptan—F. Hoffmann-La Roche Ltd
14/Protocol BP30153, Version 6
o
Change from baseline on the Vineland-II Adaptive Behavior Scales, second edition 
(Vineland-II) 2DC score after 12 weeks of treatment

To evaluate safety and tolerability of 24 and up to 76 weeks of treatment with balovaptan

To evaluate the pharmacokinetics and exposure-response relationships of balovaptan and 
its metabolites, if appropriate
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the effect of treatment with balovaptan on:
o
Change from baseline on the VinelandTM-II Adaptive Behavior Scales, second edition 
(VinelandTM-II) Two Domain Composite (2DC) 
o
Change from baseline on the VinelandTM-II Composite standard score after 12 weeks 
and 24 weeks of treatment
o
Change from baseline in the VinelandTM-II Communication, Socialization, and Daily 
Living Skills domain standard scores after 12 weeks and 24 weeks of treatment
o
Change from baseline in behaviors as measured by Aberrant Behavior Checklist (ABC) 
Lethargy/Social withdrawal subscale after 12 weeks and 24 weeks of treatment
o
Change from baseline in repetitive behaviors as measured by Repetitive Behavior 
Scale-Revised (RBS-R) after 12 weeks and 24 weeks of treatment
o
Change from baseline to Week 76 (52 weeks of open-label treatment) as measured by 
Vineland-II 2DC score
o
Change from Week 24 to Week 76 (52 weeks of open-label treatment) as measured by 
Vineland-II 2DC score
o
Proportion of subjects with 4-point improvement in Vineland-II 2DC score
o
Proportion of subjects with 8-point improvement in Vineland-II 2DC score
o
Maintenance of efficacy 6 weeks after end of study treatment as measured by 
Vineland-II Composite standard score
o
Social symptoms, communication, and behavior assessed by Exit Interviews
o
Change from baseline in behaviors as measured by ABC Irritability, Stereotypic 
Behavior, Hyperactivity/Noncompliance, and Inappropriate Speech subscales after 
12 weeks and 24 weeks of treatment
o
Patient-reported PedsQL Cognitive Functioning Scale and parent-reported PedsQL 
Family Impact Scale after 12 weeks and 24 weeks of treatment
o
Caregiver-reported Global Impression of Change on communication skills, social skills, 
daily living skills, and overall autism symptoms (CaGI) after 12 weeks and 24 weeks of 
treatment

To evaluate whether genetic variants in the AVPR1A gene affect the efficacy or safety of 
balovaptan

To evaluate the palatability of study medication
STUDY DESIGN
Description of Study
For all subjects enrolled prior to Version 6 of the protocol, this is a Phase II multi--center, 
randomized, double-blind, 24-week, 3-arm, parallel group, placebo-controlled study to 
investigate the efficacy, safety, and PK of balovaptan in children and adolescents aged 
517 years with ASD who are high functioning (IQ ≥70). 
For subjects enrolled in accordance to Version 6 of the protocol, this is a Phase II multi-center, 
randomized, double-blind, 24-week, parallel group, placebo-controlled, 2-arm study with 
subjects assigned to a single dose of balovaptan (10 mg or equivalent) or placebo.  All other 
parameters of the study design will remain as outlined.
Approximately 340 children and adolescents aged 517 years with ASD will be recruited to 
ensure a total of 160 evaluable subjects with placebo or 10 mg eq after 24 weeks of treatment.


Balovaptan—F. Hoffmann-La Roche Ltd
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All individuals who received doses of balovaptan that were not equivalent to 4 mg or 10 mg 
will not be included in the primary analysis.
Randomization will be stratified by age group and sex. The ratio between adolescents (aged 
1317 years) and children (aged 512 years) will be approximately 1:1.  The children’s cohort 
should contain up to approximately 30 subjects of whom up to approximately 16 should be aged 
between 5 and 7 years old. Additionally, the proportion of female subjects will be balanced in 
each treatment group and limited to a maximum of 20% of the entire study population.
Dose-exposure relationship in adolescents and in children will be confirmed independently. 
Enrollment will be staggered, starting first with adolescents (aged 13 to 17 years) and then with 
children (aged 5 to 12 years). Initially, a first cohort of approximately 24 adolescents will be 
enrolled together. Once the Internal Monitoring Committee (IMC) and the Scientific Oversight 
Committee (SOC) agree on acceptable safety and tolerability in the first adolescent cohort and 
determine the final doses, enrollment of adolescents will resume and the enrollment of a first 
cohort of up to approximately 30 children (aged 5 to 12 years) can commence. Once the IMC 
and SOC agree on acceptable safety and tolerability in the first children cohort and determine 
the final doses, enrollment of children for the main study will start. If IMC and SOC review of 
data determines the final dose and agreement on acceptable safety and tolerability in a 
subgroup of children (e.g., 812 years old) but not the full cohort aged 512 years, enrollment of 
children in this subgroup for the main study may start.  Enrollment of the other subgroup for 
confirmation of dose-exposure relationship will continue until IMC and SOC review determines 
final doses and agreement on acceptable safety and tolerability in that subgroup.  Children will 
not receive treatment for a period beyond what is supported by the non-clinical toxicology 
package.
Subjects who complete or have completed the double-blind 24-week treatment period will able 
to participate in an optional 52-week open-label extension (OLE) period where they will receive 
open-label balovaptan treatment.
NUMBER OF SUBJECTS
A total of approximately 340 subjects: for 80 evaluable subjects on balovaptan 10 mg eq and 
80 evaluable subjects on placebo at Week 24.
TARGET POPULATION
High functioning (IQ ≥ 70) children and adolescents (aged 517 years) with ASD according to 
DSM-5 or ICD10 criteria. 
INCLUSION CRITERIA
Subjects must meet the following criteria for study entry:
1.
Males or females aged 517 years at randomization
2.
Fluent in English 
3.
DSM-5 criteria for ASD or ICD10 criteria for Autism diagnosis confirmed by ADOS-2 criteria
4.
SRS-2 (T-score) ≥ 66
5.
CGI-S ≥ 4 (moderately ill) at screening
6.
IQ ≥ 70 as assessed by WASI-II or WPPSI-IV intelligence test 
7.
Language, hearing, and vision compatible with the study measurements as judged by the 
Investigator
8.
In the Investigator’s opinion, the subject must be able to participate and is deemed 
appropriate for participation in the study, capable of following the study schedule of 
assessments 
9.
Availability of a parent or other reliable caregiver who is fluent in English and has frequent 
and sufficient contact with the subject. The same person must agree to accompany the 
subject to all clinic visits and provide information about the subject’s behavior and 
symptoms and must agree to oversee the subject’s adherence with protocol-specified 
procedures and study medication dosing
10. Parent or legal guardian/representative and caregiver willing and able to give written 
informed consent according to local requirements and subject willing and able to provide 
informed assent or consent according to local requirements


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11. Female subjects who have experienced menarche: 
o
Must have a negative urine pregnancy test at screening and are not breast feeding
o
Must agree to either remain completely sexually abstinent or use two effective 
contraceptive methods from screening until 28 days after the last dose of study 
treatment. Methods include:

An intrauterine device (IUD) implanted at least 2 months prior to screening

Established hormonal contraception (oral, vaginal, implanted, or injectable)

Spermicidal agent (foam, gel, cream, or suppository) 

Barrier method, such as a condom, diaphragm, cervical/vault cap, or vaginal 
sponge
Notes:
The Sponsor does not require male contraception because of the minimal seminal dose 
transmitted via sexual intercourse.
Female subjects who experience menarche during the study must comply from this time 
onwards with the same requirements as outlined above, i.e., use 2 forms of effective 
contraception or agree to remain completely abstinent until 28 days after last dose.
EXCLUSION CRITERIA
Subjects who meet any of the following criteria will be excluded from study entry:
Neurological/psychiatric: 
1.
Initiation of a major change in psychosocial intervention (including investigational) within 
4 weeks prior to screening. Minor changes in ongoing treatment (e.g., missed therapy 
sessions due to holiday/vacation; planned break in therapy due to school holidays; changes 
in college/school programs) are not considered significant.
2.
Unstable or uncontrolled clinically significant psychiatric and / or neurological disorder that 
may interfere with the safety or efficacy endpoints
3.
Known personal or family history (first or second degree relatives) of cerebral aneurysm
4.
Risk of suicidal behavior in the opinion of the Investigator or as evidenced by a "yes" to 
questions 4 and / or 5 of C-SSRS taken at screening and baseline with respect to the last 
12 months, or any suicide attempt in medical history
5.
Seizure within the past 6 months 
6.
Medical history of alcohol or substance abuse/dependence
Cardio-vascular:
7.
Concurrent cardio-vascular disease not considered well controlled by the Investigator
8.
Confirmed (e.g., 2 consecutive measurements) clinically significant abnormality on ECG at 
screening. That includes but is not limited to a QTcF of ≥ 450 milliseconds, absence of 
dominating sinus rhythm, AV-block II° or III°
Other organ systems:
9.
Concomitant disease or condition (pulmonary, gastro-intestinal, hepatic, renal, metabolic, 
immunological system, or obesity (Body Mass Index [BMI] at or above the 99th percentile 
for the same age and sex) that could interfere with, or treatment of which might interfere 
with, the conduct of the study; or discontinuation of prohibited medication might pose 
unacceptable risks to the subject in the opinion of the Investigator
10. Evidence for current GI bleeding, e.g., active stomach ulcer disease
11. History of coagulopathies, bleeding disorders, or blood dyscrasias




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LENGTH OF STUDY
The total duration of the study (from screening through to study completion) for each subject will 
be approximately 87 weeks divided as follows:

Screening period (first adolescent/ children cohorts): Approximately 4 weeks
o
At least 1 week and up to 4 weeks prior to randomization

Screening period (main study): Approximately 4 weeks
o
At least 1 week and up to 4 weeks prior to randomization

Treatment phase*: 24 weeks

Optional OLE: Approximately 52 weeks

Follow-up:  At least 6 weeks and up to 7 weeks after last dose
* A small group of subjects may receive blinded treatment for up to 32 weeks. These are 
subjects from first PK cohort who stopped treatment prior to determination of final doses by the 
IMC and SOC, and have the opportunity to re-start in the main study.
END OF STUDY
For primary analysis purposes, and for the clinical study report, the end of the study is defined 
as 31 weeks after the last subject is enrolled into the main part of the study. 
For subsequent analyses and for the clinical study report addendum, the end of the study is 
defined as the date when the last subject last observation (LSLO) occurs.  LSLO is expected to 
occur approximately 83 weeks after the last subject is enrolled into the main part of the study.
OUTCOME MEASURES
EFFICACY OUTCOME MEASURES
The efficacy outcome measures for this study are as follows:

Vineland-II Adaptive Behavior Scales, second edition (Vineland-II)

Clinical Global Impressions: Severity (CGI-S) and Improvement (CGI-I)

Ohio Autism Clinical Impressions Scale: Severity (OACIS-S) and Improvement (OACIS-I)

Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale
EXPLORATORY OUTCOME MEASURES
The exploratory outcome measures for this study are as follows:

Pediatric Quality of Life (PedsQL) Cognitive Functioning Scale

Pediatric Quality of Life PedsQL Family Impact Scale

Caregiver-reported Global Impression of Change (CaGI)

Aberrant Behavior Checklist (ABC)

Repetitive Behavior Scale-Revised (RBS-R)

Exit interviews

Evaluation of safety and/ or efficacy data in the context of genetic variants in the AVPR1A 
gene

Palatability test of study medication
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence, nature, and intensity of adverse events

Incidence and nature of laboratory abnormalities, based on hematology, clinical chemistry, 
, coagulation monitoring, and urinalysis testing

Tanner staging

Physical examination (including body height and weight) and neurological examination 




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For subjects enrolling in the first adolescent/first children cohorts, Baseline visit will take place at 
least 1 week and up to 4 weeks after Screening visit.  The first dose of study medication will be 
given after completion of all pre-dose baseline assessments. 
Treatment: During the 24-week treatment period, subjects will take double-blinded study 
medication once a day. Specific hematological and CPK safety labs will be taken at least every 
4 weeks. These samples can be taken at home. During this period safety and efficacy 
assessments will be performed according to the schedule of assessments.
In each population of adolescents and children, a first cohort of approximately 24 subjects
(adolescents) and up to approximately 30 subjects (children’s cohort) will be enrolled in order to 
determine the final doses and to confirm acceptable safety and tolerability. At this early stage of 
the study the specific hematological and CPK safety labs will be taken every week. 
Follow-Up: Subjects will be followed-up for at least 6 weeks after their last dose of study 
treatment.
STATISTICAL METHODS
PRIMARY ANALYSIS
Inferential statistical analysis will be performed on pooled data from patients taking 
balovaptan 10 mg eq dose compared with those from the concurrently randomized placebo in 
the corresponding randomization stage.  The primary analysis will be performed on the 
modified intent-to-treat (mITT) population. The primary efficacy endpoint is absolute change 
from baseline after 24 weeks of treatment in Vineland-II 2DC.
Mixed-effects model repeated measures (MMRM) methods will be used to compare treatment 
effects for the primary and continuous secondary efficacy endpoints on the overall population of 
adolescents and children. The model will include treatment and visit as main effects, individual 
age and baseline score (where available) as covariates, treatment-by-visit and baseline-by-visit 
as interaction terms, with visit week as a repeated effect. Treatment differences will be 
estimated together with their 90% confidence intervals.
The proportion of subjects with 6-point improvement in the Vineland™-II 2DC score 
(clinically meaningful response) will be analyzed using logistic regression.  The odds ratio 
will be presented for descriptive purposes along with the corresponding 90% confidence 
interval and p-value for the comparison between balovaptan 10 mg eq and placebo after 
24 weeks of treatment as well as at intermediate visits.
SAFETY ANALYSES
All safety analyses will be based on the safety population, that is, on all randomized subjects 
who received at least one dose of study medication. As appropriate, listings, summary tables,
and graphs will be provided for safety and tolerability assessments.
PHARMACOKINETIC ANALYSES
Individual and mean plasma concentration data per time-point will be listed. Nonlinear mixed 
effects modeling will be used to analyze the sparse sampling dose-concentration-time data 
collected for balovaptan (and its metabolites as appropriate). Population and individual 
pharmacokinetic parameters will be estimated and the influence of various covariates on these 
parameters will be investigated. Additional PK, PK-PD, or dose/exposure-response analyses 
will be conducted as appropriate.
SAMPLE SIZE JUSTIFICATION
Prior to Version 6 of the protocol, a sample size of 240 ASD patients (80 per treatment arm) 
providing evaluable data at Week 24 ensured the study 80% power to detect as statistically 
significant, at 1-sided 5% significance level, a difference between each active dose and placebo 
with an effect size of at least 0.4. No adjustment for multiple doses was performed.  Considering 
a withdrawal rate of around 15-20%, it was planned to recruit approximately 300 subjects overall.
In accordance to Version 6 of the protocol, 80 subjects per treatment arm (balovaptan 
10 mg eq and placebo) will be required, for a total sample size of approximately 160 subjects 
with ASD with evaluable data at Week 24.  To maintain the number of evaluable subjects, the 
sample size will be increase to approximately 340 subjects overall.


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21/Protocol BP30153, Version 6
Interim Analyses
Interim analyses for PK and safety in the first cohort of approximately 24 adolescents and 
subsequently in the first cohort of up to approximately 30 children are planned.
An efficacy and safety interim analysis is planned once approximately 80 subjects taking either 
balovaptan 10 mg eq or placebo (i.e., approximately 40 subjects per treatment arm) have 
completed their 12 week visit without dose interruptions or adjustments to allow internal 
decisions for the next steps of the development plan.
Given the hypothesis generating nature of this study, the Sponsor may conduct up to two 
interim analyses beyond what is specified elsewhere in this protocol. The decision to conduct 
such an interim analysis and its timing will be documented in the Sponsor’s study master file 
prior to the conduct of the interim analysis. The clinical study report will also document that 
such an interim analysis occurred. Interim analyses will be performed and interpreted by the 
IMC and SOC members (as required), who will have full access to unblinded data. Recruitment 
will continue during the efficacy and safety interim analyses.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABC 
Aberrant Behavior Checklist
ADOS-2
Autism Diagnostic Observational Schedule
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASD
autism spectrum disorder
AST
aspartate aminotransferase
AUC
area under the curve
AUCtau,ss
area under the concentration-time curve during the 
dosing interval tau at steady state
AVP
arginine vasopressin
AVPR1A
arginine vasopressin receptor 1A
AVR
microsatellite polymorphism at the AVPR1A gene
BMI
Body Mass Index
BP
blood pressure
CaGI
Caregiver-reported Global Impression
cAMP
cyclic adenosine monophosphate
CGI-I
Clinical Global Impressions of Improvement
CGI-S
Clinical Global Impressions of Severity
CL
clearance
CNTNAP2 KO
Knock out mutant for contact in associated protein-like 
2 gene
Cmax
maximum plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
CRH
corticotropin-releasing hormone
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP2D6
cytochrome P450 2D6
CYP3A4
Cytochrome P450 3A4
DAS
Data Acquisition Specialist
DDI
drug-drug interaction


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Abbreviation
Definition
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition
DSUR
Development Safety Update Report
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO
electronic patient-reported outcome
ESF
Eligibility Screening Form
EU
European Commission
FE
food effect
FDA
U.S. Food and Drug Administration
GI
gastrointestinal
GLP
Good Laboratory Practice
HbA1c
glycated hemoglobin
HBcAb
total hepatitis B core antibody
HBsAg
hepatitis B surface 
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICD-10
International Statistical Classification of Diseases and 
Related Health Problems, Tenth Revision
IC20
concentration required for 20% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation
IQ
intelligence quotient
IUD
intrauterine device
LDH
Lactate dehydrogenase
IEC
independent Ethics Committee
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)


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Abbreviation
Definition
IRB
Institutional Review Board
ITT
intent to treat
mITT
modified intent to treat
IxRS
Interactive voice or web-based response system
Ki
inhibitory constant
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LLN
lower limit of normal
MAD
multiple ascending doses (study)
MedDRA
Medical Dictionary for Regulatory Activities 
mg eq
age adjusted dose equivalent to adult dose
MMRM
mixed-effect model for repeated measures
NOAE-AUC
no-observed adverse effectarea under the curve
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
OACIS –I or S
Ohio Autism Clinical Impressions Scale Improvement 
or Severity
OCD
obsessive-compulsive disorder
PBPK
physiologically based pharmacokinetic 
PD
pharmacodynamic
PedsQL
Pediatric Quality of Life
P-gp
P-glycoprotein
PK
pharmacokinetic
PNS
peripheral nervous system
POC
proof-of-concept
POM
proof of mechanism
PopPK
population pharmacokinetic
PP
per protocol
PR
pulse rate
PRO
patient-reported outcome
PT
prothrombin time
Q2W
every 2 weeks
Q4W
every 4 weeks
QRS
QRS interval on an electrocardiogram (ECG)
QT
QT interval on ECG
QTcB
QT interval on ECG with Bazett correction
QTcF
QT interval on ECG with Fridericia correction


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Abbreviation
Definition
RBS-R 
Repetitive Behavior Scale-Revised
RNA
ribonucleic acid
RR
RR interval
RS1
microsatellite polymorphism at the AVPR1A gene
RS3
microsatellite polymorphism at the AVPR1A gene
SAD
single-ascending dose (study)
SAE
serious adverse event
SI
International System of Units
SoA
Schedule of Assessments
SOC
Scientific Oversight Committee
SMT
Study Management Team
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SRS-2
Social Responsiveness Scale, Second Edition
Tmax
time to maximum plasma concentration
TSH
thyroid stimulating hormone
T4
thyroxine
ULN
upper limit of normal
VABS-II
VinelandTM-II Adaptive Behavior Scales, Second 
Edition
VinelandTM-II
VinelandTM-II Adaptive Behavior Scales, Second 
Edition
VPA
valproate
Vss
volume of distribution at steady state
V1a
vasopressin receptor type 1a
V1b
vasopressin receptor type 1b
V2
vasopressin receptor 2
WASI-II
Wechsler Abbreviated Scale of Intelligence Scale, 
Second Edition
WBC
white blood cell
WGS
whole genome sequencing
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence, 
Fourth Edition


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1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
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 ASDs is between 1 in 50 to 
1 in 88 children [1, 2]. Core symptoms of ASD are usually observed by three years of 
age, although typical language development might delay identification of symptoms. 
Moreover, although initial symptoms may be identified between 12 and 24 months, 
typically this does not manifest as a formal diagnosis and even if a diagnosis is made, 
this may not be stable [3, 4]. 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 may include a delay in verbal language 
development, impaired expressive language, deficient language pragmatics, as well as 
stereotyped, repetitive, or idiosyncratic use of language. Stereotyped and repetitive 
behavior manifests as a preoccupation with stereotyped or restricted interests, 
adherence to routines, rigidity, perseveration, motor mannerisms, and preoccupation or 
fascination with parts of items and unusual visual exploration. In addition to these core 
deficits, individuals with ASD may suffer from a range of co-morbid conditions and 
associated behavioral problems, including irritability, depression or anxiety, attention 
deficits, obsessive compulsive symptoms, seizures and sleep disruption. 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, making ASD the neuropsychiatric disorder most affected by 
genetic factors [2].
At present, no pharmacological treatment has been approved by Health Authorities to 
treat the core deficits of ASD, and currently available drugs address only associated 
behavioral problems [5]. Non-pharmacological treatments have been developed to 
address the core symptoms; however, clear efficacy has been difficult to demonstrate in 
large controlled clinical trials [6]. Accordingly, there is a high unmet medical need for 
pharmacological treatments of these core symptoms of the disorder.
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 (V1a, V1b and 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 (cAMP) production. V1a receptors are the 
primary subtype found in the central nervous system (CNS), expressed in several areas 
of the limbic system (hypothalamus, septum, hippocampus, amygdala) but are also 


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present in several tissues (vascular smooth muscle, liver, kidney, platelets, spleen) 
[7, 8, 9]. V1b receptors are also present in several brain regions, but appear to be most 
important for the increase in corticotropin-releasing hormone (CRH)-induced 
adrenocorticotropic hormone (ACTH) 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 [10]. 
Central administration of a V1 peptide antagonist has shown anxiolytic effects in the 
elevated plus-maze, a standard animal model of anxiety [11] and antidepressant-like 
effects in the Forced Swim Test, a model of depressive behavior. Similarly, V1a receptor 
knock-out mice also show reduced anxiety in open-field, light-dark box and elevated 
plus-maze tests [12, 13]. In addition, central injection of arginine vasopressin (AVP) in 
rodents (voles and hamsters), has been shown to induce offensive aggressive behavior 
[14, 15], which can be prevented by a V1a receptor antagonist [16]. Scratching and 
grooming, reminiscent of obsessive-compulsive behavior, can also be observed in mice 
after central injection of vasopressin [17]. 
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 [18]. Consistent with 
behavioral studies in animals (see above), these risk alleles have been found to 
modulate activation of the amygdala during emotional face processing [19] and to be 
associated with specific personality traits in healthy volunteers [21]. 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 subgenual cingulate 
regions [22]. 
Further 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 (OCD) and aggressive behavior [22]. Also, increased 
levels of AVP in plasma of subjects with ASD have been reported [23], although other 
researchers failed to replicate this observation.
1.2
BACKGROUND ON BALOVAPTAN (RO5285119)
Balovaptan is a potent and highly selective human vasopressin 1a (V1a) receptor 
antagonist that blocks the activation of the V1a G protein-coupled receptor. 


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1.2.2
Previous and Ongoing Clinical Studies
1.2.2.1
Safety and Tolerability
To date, balovaptan has been investigated in healthy subjects in five completed clinical 
pharmacology studies (Studies BP25694, BP28318, BP28977, BP29279, and WP40038) 
and one completed proof of mechanism study (Study BP29412).  Clinical pharmacology 
studies (WP40608 and WP40609) are clinically complete.
Additionally, balovaptan has been investigated n a completed Phase II study in adult 
male patients with ASD (Study BP28420 [VANILLA]).  Recruitment for this Phase II 
study in 5 to 17 year-old children and adolescent patients with ASD was initiated in 
November 2016 and is ongoing (Study BP30153 [aV1ation]).  Approximately 
340 patients are planned to be randomized. Treatment duration is 24 weeks with an 
optional open label extension of 52 weeks.
In addition, balovaptan is currently being investigated in a global Phase III study in 
adult patients with ASD (Study WN39434, V1aduct).  Recruitment was initiated in 
August 2018 and is ongoing.
To date, no drug-related safety concerns have emerged from Adverse Events (AE) 
reporting, vital signs monitoring or assessment of hematology, clinical chemistry, and 
urinalysis. The maximum tolerated dose was not reached in the SAD (highest dose: 
76 mg) or in the MAD (highest dose: 52 mg/day for 2 weeks). When balovaptan (12 mg 
single dose) was co-administered with multiple doses of fluoxetine (20 mg/day), an 
increased number of euphoric and asthenia AEs was reported; however, this has not 
been reported in patients taking SSRIs in Study BP28420 (see below).


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Study BP28420 (VANILLA) is a completed Phase II study in 223 adult ASD patients. 
The scheduled treatment duration of 12 weeks was completed by 25 subjects 
randomized to a once daily dose of 1.5 mg, by 69 subjects treated once daily with 4 mg, 
by 29 subjects treated with 10 mg once daily, and by 64 subjects randomized to placebo. 
Analyses of AEs reported, including those considered serious or a non-serious adverse 
events of special interest (AESIs) and those that resulted in premature withdrawal from 
treatment, as well as analyses of laboratory results and physical and neurological 
examinations did not reveal any safety signal thought to be associated with the 
administration of balovaptan.
  
 
 
 
 
 
 
 
 
 
 
  
 
 
1.2.2.2
Efficacy
Efficacy of balovaptan has been investigated in a Phase II study in adult male patients 
with ASD (Study BP28420 [VANILLA]).
No significant treatment effects were observed on the SRS-2, the primary efficacy 
endpoint, in individuals with ASD after 12 weeks of treatment with balovaptan compared 
with placebo, and a large placebo effect was observed on the Total t-score and the five 
sub-scales. 


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The evaluation of change from baseline in adaptive functioning and skills was measured 
by the Vineland-II. Improvement from baseline after 12 weeks of treatment was 
observed in adaptive behaviors as assessed by the Vineland-II Composite Standard 
Score (see below). Greater improvement was observed with increasing doses of 
balovaptan as assessed by the estimated treatment difference on the Vineland-II 
Adaptive Behavior Composite Score (90% confidence intervals) between balovaptan 
treatment and placebo as follows: 

1.5 mg: 1.96 (2.00, 5.92)

4 mg:  3.95 (1.66, 6.24)

10 mg: 4.87 (0.40, 9.33)
Greater improvement with increasing doses of balovaptan has also been observed in the 
Socialization and Communication domains. Among exploratory analyses, results 
suggested an improvement in the Pediatric Quality of Life (PedsQL)™ generic core 
scales, cognitive functioning scale, and family impact total score in 10 mg/day 
balovaptan group compared with placebo.
For further details regarding Study BP28420, please see the IB [45].
1.2.2.3
Pharmacokinetics
Plasma exposure of balovaptan increased in a greater than dose-proportional manner 
following single doses of 0.5 to 76 mg, whereas an approximately linear increase in 
exposure was observed after repeated dosing with 12 to 52 mg/day for 14 days. 
balovaptan was rapidly absorbed with a median Tmax between 1 and 4.5 hours after 
administration of single doses, and between 3 to 4 hours after multiple dosing. Steady 
state was achieved after approximately 7 days of daily dosing. Food had no relevant 
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. A further 30% of the administered dose was recovered in feces.
 
 
 
 
 
 


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2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objectives of this study are as follows:

To evaluate the efficacy of 24-week treatment with balovaptan (RO5285119) 10 mg 
equivalent compared to placebo as measured by the change from baseline on the 
Vineland-II Adaptive Behavior Scales, second edition (Vineland-II) Two Domain 
Composite (2DC) (average of Communication and Socialization domains)
2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:

To evaluate the efficacy of treatment with balovaptan 10 mg equivalent vs. placebo 
on:
o
Change from baseline on the Vineland-II Composite standard score after 
12 weeks and 24 weeks of treatment
o
Change from baseline in the Vineland-II Communication, Socialization, and 
Daily Living Skills domain standard scores after 12 weeks and 24 weeks of 
treatment
o
Proportion of subjects with 6-point improvement in the Vineland-II 2DC score 
to evaluate clinically meaningful response
o
Change from baseline in severity of clinical impressions as measured by CGI-S 
(Clinical Global Impressions-Severity) and OACIS-S (Ohio Autism Clinical 
Impressions Scale-Severity) after 12 weeks and 24 weeks of treatment
o
Improvements in clinical impressions as measured by CGI-I (Clinical Global 
Impressions-Improvement) and OACIS-I (Ohio Autism Clinical Impressions 
Scale-Improvement) after 12 weeks and 24 weeks of treatment
o
Patient-reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale 
after 12 weeks and 24 weeks of treatment


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o
Change from baseline in the Vineland-II Composite standard score in 
adolescents and children independently after 12 weeks and 24 weeks of 
treatment
o
Change from baseline on the Vineland-II 2DC score after 12 weeks of 
treatment

To evaluate safety and tolerability of 24 and up to 76 weeks of treatment with 
balovaptan

To evaluate the pharmacokinetics and exposure-response relationships of 
balovaptan and its metabolites, if appropriate
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the effect of treatment with balovaptan on:
o
Change from baseline on the VinelandTM-II Adaptive Behavior Scales, second 
edition (VinelandTM-II) Two Domain Composite (2DC) 
o
Change from baseline on the VinelandTM-II Composite standard score after 
12 weeks and 24 weeks of treatment
o
Change from baseline in the VinelandTM-II Communication, Socialization, and 
Daily Living Skills domain standard scores after 12 weeks and 24 weeks of 
treatment
o
Change from baseline in behaviors as measured by Aberrant Behavior Checklist
(ABC) Lethargy/Social withdrawal subscale after 12 weeks and 24 weeks of 
treatment
o
Change from baseline in repetitive behaviors as measured by Repetitive 
Behavior Scale-Revised (RBS-R) after 12 weeks and 24 weeks of treatment
o
Change from baseline to Week 76 (52 weeks of open-label treatment) as 
measured by Vineland-II 2DC score
o
Change from Week 24 to Week 76 (52 weeks of open-label treatment) as 
measured by Vineland-II 2DC score
o
Proportion of subjects with ≥4-point improvement in Vineland-II 2DC score
o
Proportion of subjects with ≥8-point improvement in Vineland-II 2DC score
o
Maintenance of efficacy 6 weeks after end of study treatment as measured by 
Vineland-II Composite standard score
o
Social symptoms, communication, and behavior assessed by Exit Interviews
o
Change from baseline in behaviors as measured by ABC Irritability, Stereotypic 
Behavior, Hyperactivity/Noncompliance, and Inappropriate Speech subscales 
after 12 weeks and 24 weeks of treatment


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o
Patient-reported PedsQL Cognitive Functioning Scale and parent-reported 
PedsQL Family Impact Scale after 12 weeks and 24 weeks of treatment
o
Caregiver-reported Global Impression of Change on communication skills, social 
skills, daily living skills, and overall autism symptoms (CaGI) after 12 weeks and 
24 weeks of treatment

To evaluate whether genetic variants in the AVPR1A gene affect the efficacy or 
safety of balovaptan 

To evaluate the palatability of study medication
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
For all subjects enrolled prior to Version 6 of the protocol, this is a Phase II 
multi--center, randomized, double-blind, 24-week, 3-arm, parallel group, 
placebo-controlled study to investigate the efficacy, safety, and PK of balovaptan in 
children and adolescents aged 517 years with ASD who are high functioning (IQ ≥70). 
For subjects enrolled in accordance to Version 6 of the protocol, this is a Phase II 
multi-center, randomized, double-blind, 24-week, parallel group, placebo-controlled,
2-arm study with subjects assigned to a single dose of balovaptan (10 mg or equivalent)
or placebo. All other parameters of the study design will remain as outlined.
3.1.1
Overview of Study Design
The total duration of the study (from screening through to study completion) for each 
subject will be approximately 87 weeks divided as follows:

Screening period (first adolescent/children cohorts): Approximately 4 weeks 
o
at least 1 week and up to 4 weeks prior to randomization

Screening period (main study): Approximately 4 weeks 
o
at least 1 week and up to 4 weeks prior to randomization

Treatment phase*: 24 weeks 

Optional OLE: Approximately 52 weeks

Follow-up: At least 6 weeks and up to 7 weeks after last dose
* A small group of subjects may receive blinded treatment for up to 32 weeks. These 
are subjects from the first PK cohort who stopped treatment prior to determination of 
final doses by the IMC and SOC, and have the opportunity to re-start in the main study 
(see protocol Section 3.1.3.1).
Approximately 340 children and adolescents aged 517 years with ASD will be recruited 
to ensure a total of 160 evaluable subjects with placebo or 10 mg eq after 24 weeks of 
treatment (see Figure 1and Figure 2).  All individuals who received doses of balovaptan 
that were not equivalent to 4 mg or 10 mg will not be included in the primary analysis.


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Randomization will be stratified by age group and sex.  The ratio between adolescents 
(aged 1317 years) and children (aged 512 years) will be approximately 1:1.  The 
children’s cohort should contain up to approximately 30 subjects of whom up to 
approximately 16 should be aged between 5 and 7 years old.  Additionally, the 
proportion of female subjects will be balanced in each treatment group and limited to a 
maximum of 20% of the entire study population. 
Figure 1
Study Design for Subjects Enrolled prior to Version 6
Subjects will be randomized in a ratio of 1:1:1 and receive doses providing an exposure 
approximately equivalent to the 4 mg/day and 10 mg/day or placebo exposures 
observed in adults (see Table 1 for predicted doses).  Age-adjusted doses were derived 
using a physiologically-based pharmacokinetic (PBPK) model.
Figure 2
Study Design for Subjects Enrolled in Accordance to Version 6
eq equivalent.
Subjects will be randomized in a ratio of 1:1 and receive doses equivalent to the 
10 mg/day or placebo exposures observed in adults (see Table 2 for predicted doses).
Dose-exposure relationship in adolescents and in children will be confirmed 
independently. Enrollment will be staggered, starting first with adolescents (aged 13 to 
17 years) and then with children (aged 5 to 12 years). Initially, a first cohort of 
Screening
10 mg eq
Placebo
Open-Label Extension
Follow-Up
8 weeks
24 weeks
52 weeks
6 weeks
4 mg eq
Screenin
10 mg eq
Placebo
Open-Label Extension
Follow-Up
4 weeks
24 weeks
52 weeks
6 weeks




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3.1.3.2
Efficacy Interim Analyses
In accordance to Version 6 of the protocol, an efficacy and safety interim analysis is 
planned once approximately 80 subjects have taken either 10 mg eq or placebo 
(i.e., approximately 40 subjects per treatment arm) have completed the 12-week visit 
without interruptions or dose adjustments to allow internal decisions for the next steps of 
the development plan (see also Section 6.8).
 
 
 
 
3.1.5
Open-Label Extension
Subjects who complete the double-blind 24-week treatment period will able to participate
in an optional 52-week OLE period where they will receive open-label balovaptan
treatment. 
Participation in the OLE will also be permitted for all subjects who have completed 
treatment to Week 24, prior to implementation of the OLE. Furthermore, individuals who 
participated in the PK cohort and were required to stop dosing before week 8, and then 
did not participate further in BP30153, will be allowed to participate in the OLE
(see Section 4.2.4 for detailed eligibility criteria).  All subjects meeting these 
requirements will need to be re-consented for participation in the OLE after meeting 
requirements specified in Appendix 11. 
Subjects who do not want to participate in the OLE will complete the follow-up visits as 
detailed in the Schedule of Assessments (see Appendix 1).  Subject treatment allocation 
during the blinded treatment period will not be unblinded until all patients have 
completed the double-blind period.  
During the OLE portion of the study, all subjects will be provided with 10 mg eq
balovaptan irrespective of previous treatment allocation.
3.2
END OF STUDY
For primary analysis purposes, and for the clinical study report, the end of the study is 
defined as 31 weeks after the last subject is enrolled into the main part of the study; see 
also Section 3.1.1. 
For subsequent analyses and for the clinical study report addendum, the end of the 
study is defined as the date when the last subject last observation (LSLO) occurs. LSLO 




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3.3.3
Rationale for Use of Single Dose in Subjects Enrolled in 
Accordance to Version 6
Study BP30153 was initiated as a 3-arm study, two doses of balovaptan (10 mg eq and 
4 mg eq) and placebo. These doses were adjusted per age (see Section 3.1.3 and Table 1).  
Following the IMC and SOC review in July 2018, data showed that subjects received 
doses that produced exposures lower than those targeted from Study BP28420.  To 
ensure that 10 mg is adequately characterized, the 4 mg dose arm will be discontinued,
and all subjects who enroll after Version 6 approval will receive either 10 mg eq or 
placebo.
Balovaptan 10 mg eq/day (age adjusted dose equivalent to adult dose) has been selected 
as the single dose to be studied. Results from Study BP28420 suggested that 10 mg 


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balovaptan once daily showed consistent efficacy across multiple domains of the 
Vineland-II and other instruments explored. The safety profile of balovaptan across 
doses was similar. The 10-mg balovaptan once daily 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 the Socialization and Communication domains of the 
Vineland-II scales. 
3.3.4
Rationale for Study Population
Young subjects with ASD (age 517) will be enrolled in this study to assess efficacy in 
this pediatric population and to generate a safety and tolerability database in this 
population. The study population includes cognitively high functioning (IQ ≥ 70) children 
and adolescents (aged 517 years) with clinical diagnosis of ASD confirmed by Autism 
Diagnostic Observational Schedule (ADOS-2). 
The lower age limit (5 years) will allow building a significant safety database from older 
pediatric population before exposing preschool children and toddlers to balovaptan. 
Furthermore, although initial symptoms may be identified very early, typically this does 
not lead to a formal diagnosis and even if a diagnosis is made, this may not be stable 
over time [4]. In conclusion, although data suggest that the diagnosis of ASD is possible 
below the age of 5, the diagnosis is less reliable and may not be stable, and as a 
consequence, younger subjects may be included later in future trials in the development 
program.
Cognitively high functioning (IQ 70) individuals define a more homogeneous population 
that will facilitate signal detection and it is expected that this population may benefit more 
from a therapy improving social and communication aspects of ASD. Subjects with 
significant social and communication deficits will be recruited to ensure room for 
potential treatment-mediated improvements. To this aim, only subjects with SRS-2 
T-scores ≥ 66 and CGI-S ≥ 4 (at least moderately-ill) at screening will be enrolled. 
Individuals with prominent social and communication deficits will be recruited since this 
group has more need for improvement in social and communication deficits. 
3.3.5
Rationale for Use of Vineland™-II Adaptive Behavior Scales 
2-Domain Composite Score as the Primary Efficacy Endpoint
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 
parent [50].  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 [33] and have been used 
independently as endpoints in clinical trials of ASD [49].  To explore the measurement 


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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 support the 
Sponsor’s proposal to combine the two domains into a single endpoint.  The use of the 
2DC has been discussed with both FDA and EMA.
3.3.6
Rationale for Open-Label Extension
At the time that study BP30153 was initiated, there was no evidence supporting the 
efficacy of balovaptan in individuals with ASD.  However, study BP28420 has provided 
preliminary evidence that balovaptan may have efficacy on the social and 
communication deficits observed in adults with ASD (see Section 1.2.2.2). 
Consequently, the Sponsor now proposes to include a 52-week OLE to evaluate effects 
of balovaptan in children over a longer time period.  Therefore, the treatment duration 
will be extended to 76 weeks with the following treatment periods: double-blind from 
baseline to Week 24; and open-label from Week 24 to Week 76.
All children will receive 10 mg (age-equivalent) balovaptan during the OLE. The dose 
selection was based on preliminary evidence from Study BP28420 in adult ASD patients,
which indicated consistent and potentially clinically relevant changes in the Socialization 
and Communication domains of the Vineland-II Scales without having revealed 
relevant safety liabilities. To date, there is no indication from this ongoing BP30153 
study that the safety profile would be different in children and adolescents, respectively.
3.3.7
Rationale for Use of Responder Definition
A clinically meaningful response (or “responder”) is defined as ≥6 point improvement on 
the Vineland-II 2DC at Week 24. This threshold was determined through anchor- and 
distribution-based analyses conducted on Study BP28420 data. 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 x Standard Error of 
Measurement (SEM) 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.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

VinelandTM-II Adaptive Behavior Scales, second edition (VinelandTM-II) 

Clinical Global Impressions: Severity (CGI-S) and Improvement (CGI-I)


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
Ohio Autism Clinical Impressions Scale: Severity (OACIS-S) and Improvement 
(OACIS-I)

Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale 
3.4.2
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Pediatric Quality of Life (PedsQL) Cognitive Functioning Scale.

Pediatric Quality of Life PedsQL Family Impact Scale

Caregiver-reported Global Impression of Change (CaGI)

Aberrant Behavior Checklist (ABC) 

Repetitive Behavior Scale-Revised (RBS-R)

Exit interviews

Evaluation of safety and/ or efficacy data in the context of genetic variants in the 
AVPR1A gene

Palatability test of study medication
3.4.3
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and intensity of adverse events

Incidence and nature of laboratory abnormalities, based on hematology, clinical 
chemistry, 
, coagulation monitoring, and urinalysis testing

Tanner staging (see Appendix 6)

Physical examination (including body height and weight) and neurological 
examination (see Appendix 5) 

Vital signs, i.e., systolic and diastolic blood pressure, pulse rate in supine position, 
and orthostatic hypotension

Frequency of body temperature exceeding 38°C (100.4°F) lasting for longer than 
1 hour differentiated according to whether or not this presents with an absolute 
neutrophil count (ANC) below 1,000/µL (confirmed)
 

Suicidality evaluated by the Columbia-Suicide Severity Rating Scale (C-SSRS) or as 
evaluated by dedicated questions on suicidal ideation and behavior or as reported 
through AE
3.4.4
Pharmacokinetic (PK) Outcomes
The observed plasma concentrations of balovaptan and its metabolites M3 and M2 
(as applicable) (and other metabolites as appropriate) will be summarized by dose and 
observation time, and the ratio of metabolite to parent drug concentration (molecular 
weight corrected) will be reported. 


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A population PK modeling approach will be used to characterize the pharmacokinetics 
and variability of balovaptan (and its metabolites, if warranted) in the pediatric population. 
The key PK outcome measures for balovaptan will be:

Apparent clearance (CL) and volume of distribution (VD)

Covariate (e.g., age, weight) effects on CL and VD

Exposure at steady-state (AUC0-24,ss)
Other individual exposure estimates (e.g., Cmax, Tmax, AUC for a specific time interval) 
may also be derived as appropriate.
Apparent CL and exposure (AUC0-24,ss) estimates for dose confirmation in the first cohort 
of adolescents and a subgroup of children will be derived in a Bayesian feedback 
approach based on an adult PopPK model.
The results of population PK model derived outcome measures may be reported in a 
document separate from the clinical study report.
3.4.5
Biomarker/Genotyping Sample Collection
3.4.5.1
Clinical Genotyping (CG) Samples
A mandatory pre-dose whole blood sample will be taken for DNA extraction from every 
participant on Day 1. The DNA will be used to evaluate if genetic variants of the 
AVPR1A gene affect the efficacy/safety and/or PK of balovaptan. CG samples and 
derived analytical materials will be destroyed no later than 2 years after the date of the 
final clinical study report. 
3.4.5.2
Research Biosample Repository 
Subjects enrolled in the study will be asked to donate one optional blood sample for the 
Research Biosample Repository (Section 4.6.1.13). Specimens will be used to promote, 
facilitate, and improve individualized healthcare by better understanding/predicting drug 
efficacy, dose response, safety, mode of actions, disease biology, and progression.
Samples will be collected from consenting subjects at the time points indicated in the 
Schedule of Assessments. Specimens will be stored and used until no longer needed or 
until they are exhausted.
4.
MATERIALS AND METHODS
4.1
CENTER
This is a multi-center study to be conducted in the United States.
Administrative and Contact Information and List of Investigators are provided separately.


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4.2
STUDY POPULATION
The study will include children and adolescents between 5 to 17 years of age with a 
diagnosis of ASD according to the DSM-5 or ICH 10 criteria who are high functioning 
(IQ 70).
4.2.1
Recruitment Procedures 
A total of approximately 340 children and adolescents with ASD will be stratified by age 
and sex and randomized in order to obtain evaluable data after 24 weeks of treatment 
from approximately 160 subjects, considering a withdrawal rate of approximately 
15%20%.  Individuals who received doses lower than intended will not be evaluable 
for the primary objective.
Subjects in first adolescent/first children cohorts with dose adjustments, or who stopped 
and re-started treatment in the context of the interim PK and safety reviews (see 
Section 3.1.3), will not contribute to the approximately 160 evaluable subjects 
(80 subjects balovaptan 10 mg eq and 80 subjects placebo) for the primary efficacy 
analysis.  Additional subjects will be recruited until approximately 160 evaluable subjects 
is reached (Section 6.3.3).
Subjects who have been discontinued for reasons of dose confirmation, prior to Week 8, 
will be eligible to re-screen for the OLE without having to complete the 24 weeks of 
double-blind treatment.
Subjects must meet all of the inclusion criteria and none of the exclusion criteria to 
qualify for the study. Unless otherwise stated, inclusion and exclusion criteria refer to 
screening.
Abbreviated re-screening (written informed consent/assent, medical history, physical 
examination, substance use, alcohol test, fasted laboratory safety, coagulation, serology, 
urinalysis, inclusion / exclusion criteria) may be allowed under circumstances in which 
the subject is screen-passed but could not be randomized within the 4-week screening 
window due to a study halt, logistical, personal, or technical reason. At no time shall the 
duration between the original screening visit and the abbreviated re-screening visit 
exceed 3 months. Abbreviated re-screening will only be permitted by the Sponsor 
(Medical Monitor or designee) in cases where this poses no safety risk to the subject. 
Screen-failed subjects can be re-screened with Sponsor permission (Medical Monitor
or designee) if there is a substantial change in the subject’s general condition 
(e.g., prohibited medication was stopped or weight loss) and if recruitment for the study 
is still ongoing. Re-screening will not be allowed if the subject failed earlier to meet the 
disease specific inclusion criteria (e.g., SRS-2 T-score).


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Safety laboratory tests which would exclude the subject at screening may be repeated 
once (as unscheduled labs) if it is suspected that the abnormal result is transient and 
likely to be normal at repeat testing.
Individuals are not permitted to be re-randomized to receive a second course of 
treatment. However, subjects from first adolescent and first children cohorts, who 
stopped treatment in the context of the interim safety and PK decisions, (see 
Section 3.1.3) will be allowed to re-start in the same treatment arm, according to their 
original randomization, for 24 weeks in the main study. Subjects may only re-start if the 
Investigator can exclude relevant changes in the subject’s general condition, i.e., no 
change in risk-benefit for treatment of the individual subject in study BP30153.  In case 
of uncertainty the Investigator should discuss the case with the Sponsor (Medical 
Monitor or designee). Re-starting subjects will have a new, abbreviated baseline visit, 
and will continue with all subsequent visits according to the schedule of assessments 
(Appendix 1).
Study subjects may be identified for potential recruitment using pre-screening enrollment 
logs, IRB approved newspaper/radio advertisements and mailing lists prior to consenting 
to take place on this study.
4.2.2
Inclusion Criteria
Subjects must meet the following criteria for study entry:
1.
Males or females aged 517 years at randomization
2.
Fluent in English 
3.
DSM-5 criteria for ASD or ICD10 criteria for Autism diagnosis confirmed by 
ADOS-2 criteria
4.
SRS-2 (T-score) 66
5.
CGI-S 4 (moderately ill) at screening
6.
IQ 70 as assessed by WASI-II or WPPSI-IV intelligence test
7.
Language, hearing, and vision compatible with the study measurements as judged 
by the Investigator
8.
In the Investigator’s opinion, the subject must be able to participate and is deemed 
appropriate for participation in the study, capable of following the study schedule of 
assessments
9.
Availability of a parent or other reliable caregiver who is fluent in English and has 
frequent and sufficient contact with the subject. The same person must agree to 
accompany the subject to all clinic visits and provide information about the subject’s 
behavior and symptoms and must agree to oversee the subject’s adherence with 
protocol-specified procedures and study medication dosing


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10. Parent or legal guardian/representative and caregiver willing and able to give written 
informed consent according to local requirements and subject willing and able to 
provide informed assent or consent according to local requirements
11. Female subjects who have experienced menarche:
–
Must have a negative urine pregnancy test at screening and are not breast 
feeding
–
Must agree to either remain completely sexually abstinent or use two effective 
contraceptive methods from screening until 28 days after the last dose of study 
treatment. Methods include:

An intrauterine device (IUD) implanted at least 2 months prior to screening

Established hormonal contraception (oral, vaginal, implanted, or injectable)

Spermicidal agent (foam, gel, cream, or suppository) 

Barrier method, such as a condom, diaphragm, cervical/vault cap, or 
vaginal sponge
Notes: 

The Sponsor does not require male contraception because of the minimal 
seminal dose transmitted via sexual intercourse [46, 47 and see also 
Section 1.2.1].

Female subjects who experience menarche during the study must comply from 
this time onwards with the same requirements as outlined above, i.e., use 
2 forms of effective contraception or agree to remain completely abstinent until 
28 days after last dose.
4.2.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
Neurological/psychiatric: 
1.
Initiation of a major change in psychosocial intervention (including investigational) 
within 4 weeks prior to screening. Minor changes in ongoing treatment (e.g., missed 
therapy sessions due to holiday/vacation; planned break in therapy due to school 
holidays; changes in college/school programs) are not considered significant.
2.
Unstable or uncontrolled clinically significant psychiatric and / or neurological 
disorder that may interfere with the safety or efficacy endpoints
3.
Known personal or family history (first or second degree relatives) of cerebral 
aneurysm
4.
Risk of suicidal behavior in the opinion of the Investigator or as evidenced by a "yes" 
to questions 4 and / or 5 of C-SSRS taken at screening and baseline with respect to 
the last 12 months, or any suicide attempt in medical history
5.
Seizure within the past 6 months 
6.
Medical history of alcohol or substance abuse/dependence


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Cardio-vascular:
7.
Concurrent cardio-vascular disease not considered well controlled by the 
Investigator
8.
Confirmed (e.g., 2 consecutive measurements) clinically significant abnormality on 
ECG at screening. That includes but is not limited to a QTcF of 450 milliseconds, 
absence of dominating sinus rhythm, AV-block II° or III
Other organ systems:
9.
Concomitant disease or condition (pulmonary, gastro-intestinal, hepatic, renal, 
metabolic, immunological system, or obesity (Body Mass Index [BMI] at or above 
the 99th percentile for the same age and sex [see Section 4.6.1.2]) that could 
interfere with, or treatment of which might interfere with, the conduct of the study; or
discontinuation of prohibited medication might pose unacceptable risks to the 
subject in the opinion of the Investigator
10. Evidence for current GI bleeding, e.g., active stomach ulcer disease
11. History of coagulopathies, bleeding disorders, or blood dyscrasias
12. Positive serology for hepatitis B (HBV), hepatitis C (HCV), HIV 1, or HIV 2.
Subjects who test positive for hepatitis B core antibodies may still be eligible if 
the subject has a combination of a negative hepatitis B surface antigen and/or 
hepatitis B cDNA test, no history of hepatitis, and no indication of liver 
dysfunction through liver enzyme or coagulation results.
13. Confirmed clinically significant abnormality in parameters of hematology, clinical 
chemistry, coagulation, or urinalysis 
 
 
14. Medical history of malignancy if not considered cured
Other exclusion criteria
15. Participation in an investigational drug study within 90 days or 5 times the half-life of 
the investigational molecule (whichever is longer) prior to randomization or 
participation in a study testing an investigational medical device within 90 days prior 
to randomization or if the device is still active.
a)
Subjects from first adolescent and first children cohorts, who stopped treatment 
in the context of the IMC/SOC dose determination decision (see Section 3.1.3.1), 
are allowed to re-start originally assigned treatment for an additional 24 weeks 
in the main part of the study.
16. Loss of blood over 250 mL within three months prior to screening
17. Allowed medications have not been stable since 4 weeks before screening, and 
allowed medications for treatment of epilepsy have not been stable since 3 months 
before screening. 


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18. Use of prohibited medications within 2 weeks prior to screening visit or 5 times the 
half-life prior to randomization (whichever is longer) 
19.
 
4.2.4
Eligibility for Open-Label Extension Phase
Subjects who meet the following criteria may participate in the OLE:
Subjects who complete the double-blind 24-week treatment period will able to participate 
in an optional 52-week OLE period where they will receive open-label balovaptan 
treatment.  All subjects that have previously completed or were required to stop dosing 
prior to Week 8 for non-safety reasons will need to be re-consented and meet the 
eligibility requirements specified in Appendix 11.
Subjects must satisfy both criteria:
1.
Either completed the blinded treatment phase (Week 24) OR were required to stop 
dosing by the Sponsor at or before Week 8.
2.
Have no relevant adverse events including laboratory abnormalities in the opinion of 
the investigator that are prohibitive for starting the OLE
If a subject with ASD reaches the age of 18 during the study, they will still be eligible for 
participation in the OLE provided that they meet all the criteria above.
Where possible, all subjects should continue directly from the blinded phase to the 
open-label phase.  For subjects that enter the OLE, the treatment follow-up visit will be 
completed at the end of OLE phase.
Under specific circumstances, a subject may need to have treatment interrupted at the 
end of the double-blind phase before entering the OLE.  These cases should be discussed 
with the Medical Monitor or designee.
Any subject who had treatment interruption due to lack of dose confirmation or for 
whom the OLE was not available will be able to enter the open label phase until the 
final subject recruited reaches Week 24.
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
stratified by age group and sex and randomized in a 1:1 ratio (10 mg eq:placebo) to 
receive of 10 mg/day (age adjusted dose equivalent to adult dose) 24 weeks as 
double-blinded study medication or placebo. The allocation to individual treatment will be 
implemented using an Interactive (voice/web) Response System (IxRS).


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Approximately equal numbers of children (aged 5–12 years) and adolescents (aged 
1317 years) will be enrolled. Additionally, the proportion of female subjects will be 
limited to a maximum of 20% of the entire study population. Furthermore, stratification 
will guarantee (for exposure checks purpose, see Section 3.1.3.1) that, in the first 
30 children cohort and first 24 adolescent cohort, 10 of the youngest subjects 
13-14 years old in adolescent group and approximately 10 of the 5–7 years old in 
children group will take active treatment.  However, if final doses cannot be determined 
for the subgroup or cohort, and additional subjects are required for dose confirmation to 
occur, the size of the cohort will increase (see Section 3.1.3.1 for further details).  The 
children’s cohort should contain up to approximately 16 subjects aged between 5 and 
7 years old.  Subjects from first adolescent and first children cohorts, who stopped 
treatment in the context of the interim safety and PK decisions, (see Section 3.1.3) will 
be allowed to re-start in the same treatment arm, according to their original 
randomization, for an additional 24 weeks in the main study, provided the Investigator 
can exclude relevant changes in the subject’s general condition (see Section 4.2.1). 
Unblinding should not occur except in the case of emergency situations. Unblinding will 
be performed by means of the IxRS.
As per regulatory reporting requirements, Roche will unblind the identity of the study 
medication for all unexpected serious adverse events that are considered by the 
Investigator to be related to study drug as per safety reference document(s), 
i.e., Investigator Brochure [45]. Details of subjects who are unblinded during the study 
will be included in the Clinical Study Report.
Whenever disclosure of the identity of the study medication 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 date, reason for 
identifying the drug, and the name of all person(s) who had to be unblinded.
With the exceptions described below and in the IMC+SOC agreement (see also 
Section 3.1.2), the randomization list will not be available to the Roche project and study 
team or any personnel at the study centers. Access to potentially unblinding data 
(e.g., PK data) will be restricted as described below.
PK/PD data can be received and cleaned on an ongoing basis by an unblinded Data 
Acquisition Specialist (DAS). In addition, a pharmacometrician may be unblinded to 
enable the frontloading of modeling activities. These activities are solely for building the 
pharmacometric models and frontloading the analyses.
Subjects, Investigators, and all other individuals directly involved in this study will remain 
blinded until the end of the study when the final analysis becomes available.


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4.4
STUDY TREATMENT
 
 
 
 
 
 
 
 
 
 
 
4.4.2
Dosage, Administration, and Compliance
4.4.2.1
Age-adjusted Doses
Subjects enrolled before Version 6 will receive age-adjusted total daily dose 
approximately equivalent to the adult doses of either 4 mg/day or 10 mg/day of 
balovaptan or placebo:
The median exposures achieved in adults at doses of 4 mg/day and 10 mg/day, 
respectively, will be targeted in the adolescents and children enrolled in this study. The 
following age-adjusted doses are therefore planned as starting doses based on PBPK 
model predictions, to achieve exposures similar to those in adults at 4 mg/day and at 
10 mg/day:
Subjects enrolled under Version 6 will receive age-adjusted total daily dose 
approximately equivalent to the adult doses of 10 mg/day of balovaptan or placebo.


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Table 1
Age-adjusted Starting Doses Based on PBPK Model
Age (years)
4 mg eq*
Dose (mg)
10 mg eq*
Dose (mg)
57
1.5
3
811
2
5
1214
3
7
1517
4
10
*eq dose predicted to achieve exposures equivalent to 4 mg/day or 10 mg/day, respectively, in 
adults.
Following IMC and SOC reviews, the starting doses were shown to not achieve the 
target exposure in children aged between 5 and 14 years.  Therefore, new doses were 
identified to produce exposures equivalent to the 4 mg and 10 mg doses used in adults 
(Study BP28420).  See Table 2 for details.
Table 2
Updated Age-Adjusted Doses Based on PK Data
Age (years)
4 mg eq
Dose (mg)
10 mg eq
Dose (mg)
57 a
3
7
817
4
10
eq age adjusted dose equivalent to adult dose; PK pharmacokinetic.
a
Dose predicted to achieve exposures equivalent to 4 mg/day or 10 mg/day, respectively, in 
adults.  Note:  Dose is not confirmed—the IMC and SOC will recommend the final dose 
based on review of data (see Section 3.1.3.1) to achieve equivalent adult exposures.  Any 
changes will be communicated to all parties.
The starting doses have been taken by the first cohort of 24 adolescents and the first 
cohort of approximately 30 children. Enrollment will be staggered by age, starting first 
with adolescents. The exposures will be monitored closely by the IMC and SOC 
throughout the study. The age at inclusion in the double-blind portion or the age at 
inclusion in the OLE will be relevant for selection of doses.
The total daily doses of the blinded treatment phase will be administered as tablets of 
balovaptan or placebo once daily.
Following an ad-hoc interim assessment of the PK data by the IMC and SOC, 
adolescents and children 8 years and above will receive higher starting doses as 
outlined in Table 2. Subjects already enrolled should receive the adjusted doses
(4 or 10 mg eq) as soon as practicable, per his or her randomized assignment.


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Subjects enrolled in accordance with earlier protocol versions will continue with his or 
her assigned dose until Week 24. All newly enrolled subjects (in accordance to 
Version 6) will be given either 10 mg eq or placebo.
In the OLE phase, subjects will receive 10 mg eg/day of balovaptan (see Table 2 for 
further details). Details of tablet administration will be provided in the Instructions for 
Use.
Guidelines for treatment interruption or discontinuation are provided in Section 5.2.
4.4.2.2
Administration and Compliance
Study medication (balovaptan or placebo) should be taken once per day in the morning 
with or without food. The dispersible tablets can either be swallowed whole with 
something to drink or with a small amount of soft food such as yogurt on a spoon, or can 
first be dispersed in 5 mL of water, orange or apple juice using a provided cup (for more 
details please see document ‘Instructions for pediatric use’). Administration with larger 
amounts of food should be avoided as the tablets should be taken as whole tablets in 
one mouthful avoiding chewing. Tablets taken with soft food must be swallowed 
immediately after adding the tablets to the soft food on a spoon and must not be stored 
for future use. At inclusion of each subject to the blinded portion of the study, a decision 
will be made for the entire study whether the subject will swallow the study medication 
as a whole or after dispersion in a liquid and that decision will be recorded on the eCRF 
and drug diary.
The first dose of the study medication will be administered on Day 1, after all pre-dose 
baseline assessments have been conducted. Compliance regarding administration of 
study medication at home will be monitored by the completion of a diary card by the 
subject or caregiver. Diary cards will be reviewed at each clinic and home visit.
If, during the first adolescent/first children cohorts, it is not possible to collect a pre-dose 
PK sample during home visits in Week 1, Week 2, and Week 4, the dose must be taken 
as normal and a post-dose PK sample should be taken at a convenient time. It is 
important that the exact time of dosing is recorded (see also Section 4.6.1.8 and 
Appendix 2).
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose according to the randomization schedule. This individual will write the date 
dispensed, subject number, and initials on the study drug vial label and on the Drug 
Accountability Record. This individual will also record the study drug batch or lot number 
received by each subject during the study.
4.4.2.3
Treatment in the Open-Label Extension, Including 
Age-Adjusted Doses
Subjects will receive 10 mg/day equivalent of balovaptan (see Table 1 and Table 2 for 
further details). 


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Study medication (balovaptan) should be taken once per day in the morning with or 
without food (for more details, please see document “Instructions for pediatric use”). 
At inclusion of each subject, a decision will be made for the entire OLE whether the 
subject will swallow the study medication as a whole or after dispersion in a liquid, and 
that decision will be recorded on the eCRF and drug diary.
The first dose of the study medication in the OLE will be administered at the Week 24 
visit for those that are continuing directly into the OLE and following completion of 
eligibility assessments in the OLE for those that are returning to the study (see
Appendix 11). Administration will take place after all assessments have been conducted 
on the visit. Compliance regarding administration of study medication at home will be 
monitored by the completion of a diary card by the subject or caregiver. Diary cards will 
be reviewed at each clinic and home visit.
4.4.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(balovaptan and placebo) will be provided by the Sponsor. The investigational site will 
acknowledge receipt of IMPs, to confirm the shipment condition and content. Any 
damaged shipments will be replaced.
The investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the subject to whom the study drug was dispensed (for example 
subject initials and date of birth)

The date(s), quantity of the study drug dispensed to the subject

The date(s) and quantity of the study drug returned by the subject

All records and drug supplies must be available for inspection by the Roche Monitor 
[at every monitoring visit]
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. In these cases, it may be acceptable for investigational study 
site staff to destroy dispensed investigational product before a monitoring inspection 
provided that source document verification is performed on the remaining inventory and 
reconciled against the documentation of quantity shipped, dispensed, returned, and 
destroyed, and provided that adequate storage and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.


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Written documentation of destruction must contain the following:

Identity [batch numbers or study subject numbers] of investigational product[s] 
destroyed

Quantity of investigational product[s] destroyed

Date of destruction

Method of destruction

Name and signature of responsible person [or company] who destroyed 
investigational product[s]
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
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.
4.5
CONCOMITANT THERAPY
Adding a new medication or changing the dose of a medication after signing the 
Informed Consent Form (ICF) 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-
medication interventions (e.g. individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, and rehabilitative therapy) used by a subject from 12 weeks 
prior to screening until the follow-up visit. 
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF). All therapy and/or 
medication administered to manage adverse events should be recorded on the Adverse 
Event eCRF.
4.5.1
Permitted Therapy 
As a general rule, no concomitant medication will be permitted, with the exception of 
medications listed in this section, unless the rationale for exception is discussed and 
clearly documented between the Investigator and the Sponsor (Medical Monitor or 
designee). Subjects must be on a stable prescribed medication regimen for 4 weeks 
before screening, with the exception of antiepileptic treatments in which subjects need to 
be on a stable regimen for at least 3 months prior to screening. Any stable prescribed 
medication at screening should remain stable throughout the study. However, dose 
changes due to adjustments for change in body weight / age and or triggered by 
therapeutic monitoring will be allowed. Other changes in prescribed medication need to 
be approved by the Sponsor (Medical Monitor or designee).


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Examples of allowed medications:

Selective Serotonin Reuptake Inhibitor / Serotonin-Norepinephrine Reuptake 
Inhibitor (SSRI/SNRI), including fluoxetine

Melatonin 

Benzodiazepines when used to treat anxiety

Aripiprazole

Risperidone

ADHD medications including psychostimulants like methylphenidate

Hypnotics for insomnia, falling asleep problems (only on an as needed basis, limited 
to 3 times per week)

Antiepileptic drugs (AED) used for treatment of epilepsy including valproic acid and 
oxcarbazepine may be used provided they have been given at stable dosage for at 
least 3 months prior to screening and were well tolerated

Occasional use of paracetamol/acetaminophen

Topical application of local anesthetic is permitted if necessary as pain relief for all 
blood samples, including hematology and PK
Any other medications and cases of polypharmacy require the approval from the 
investigator and the Medical Monitor or designee.
4.5.2
Non-Pharmacological Interventions 
Non-pharmacological interventions must be stable for 4 weeks prior to screening and 
must remain stable throughout the ongoing study (e.g., subject psychotherapy, cognitive 
behavioral therapy, and rehabilitative therapy). Minor changes in ongoing treatment 
(e.g., missed therapy sessions due to holiday/vacation; planned break in therapy due to 
school holidays; changes in college/school programs) are not considered significant and 
need not to be discussed with the Sponsor (Medical Monitor or designee).
4.5.3
Prohibited Therapy
These therapies are not allowed during the study and must be stopped 2 weeks prior to 
screening to ensure a washout of at least 4 weeks prior to Baseline assessment or must 
be stopped earlier to ensure a washout of 5 times the medication half-life before 
randomization (whichever is longer).
Examples of prohibited medications:

Strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, grapefruit juice) 


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
Moderate inhibitors of CYP3A4 (e.g., erythromycin, ciprofloxacin, diltiazem) 
o
For treatment duration of no more than approximately 10 days (e.g. in the 
context of an Adverse Event), moderate inhibitors of CYP3A4 may be used after 
discussion with, and agreement by, the Sponsor (Medical Monitor or designee). 
The reasons for and approval of such use must be documented. 

Strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, St. John’s Wort

Quinidine

Chronic adrenocorticoid or glucocorticoid use (use of inhaled or topical formulations 
are allowed)

Oxytocin

Agents inhibiting vasopressin receptors (e.g., tolvaptan, conivaptan)

Desmopressin (DDAVP)

Hematotoxic drugs requiring frequent hematological monitoring of white blood cells 
(e.g., clozapine)

Neurotoxic drugs that per warning/precaution section of U.S. label are considered to 
have a risk of peripheral neuropathy

Herbal therapies and dietary supplements (unless allowed by the medical monitor or 
designee)
4.5.4
Caution Regarding P-gp Substrates
Based on in vitro experiments, quinidine should not be given with balovaptan, but no 
systemic interactions are predicted with cetirizine, dabigatran etexilate, or digoxin. 
Caution is advised when using balovaptan together with other medications known to be 
clinically-relevant substrates of P-gp, in particular for those medications that have a 
narrow therapeutic window (e.g., loperamide). However, when such medications are 
dosed 5 or more hours after administration of balovaptan, the risk of pharmacokinetic 
interaction is predicted to be small.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the schedule of 
assessments outlined in Appendix 1, Appendix 2, Appendix 9, and Appendix 10.
4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases experienced up to Screening 
plus for the previous 5 years: developmental history, date of diagnosis with ASD, 
smoking history, use of alcohol and drugs of abuse, medical interventions 
(e.g., immunizations/vaccines and surgeries). 


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All medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the subject within 12 weeks prior to the 
screening visit as well as details of psychosocial/non-pharmacological interventions used 
over the past year are to be documented.
Demographic data will include age, sex, and self‑reported race/ethnicity as well as 
applicable information about residential setting, school or employment status, day care 
facilities, level of education, participation in educational or day programs, and any non-
medical hospitalizations.
General information will also be collected on the caregiver who will oversee the subject’s 
adherence with protocol-specified procedures and study medication, and report on the 
subject’s status. This will include, for example, their relationship to the subject, time 
spent with the subject, and whether they live in the same residence.
4.6.1.2
Physical and Neurological Examinations
At the time-points listed in the Schedule of Assessments (Appendix 1, Appendix 2, 
Appendix 9, and Appendix 10) a complete physical examination will be performed at 
screening and Week 24 or early withdrawal visit and will include an evaluation of the 
head, eyes, ears, nose, throat, neck, and lymph nodes and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. 
At other clinic visits listed in Appendix 1, Appendix 2, Appendix 9, and Appendix 10 or as 
clinically indicated, limited, symptom-directed physical examinations should be 
performed. Changes from baseline abnormalities should be recorded in subject’s notes. 
The physical exam will not include pelvic, rectal, or breast exams.
At all time-points listed in the Schedule of Assessments (Appendix 1, Appendix 2, 
Appendix 9, and Appendix 10), a complete and neurological examination including an 
examination for symptoms of peripheral neuropathy will be performed, see Appendix 5
and Section 5.2.3).
Any abnormality identified at screening should be recorded on the General Medical 
History and Baseline Conditions eCRF section and carefully evaluated in terms of 
eligibility of subject for enrollment into this study.
Body height and weight will be recorded as specified in Appendix 1, Appendix 2, 
Appendix 9, and Appendix 10. Body Mass Index (BMI) including age and sex specific 
BMI Percentiles relevant for inclusion will be derived at screening. These 
anthropometric parameters will be determined according to 
https://nccd.cdc.gov/dnpabmi/Calculator.aspx. Screenshots of this derivation will be kept 
in the source data.


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Results from these examinations will be documented in the eCRF forms and new or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
 
 
4.6.1.3
Tanner Staging
Tanner stages will be determined in subjects aged at least 7 years, but not after 
menarche in female and not after voice break in male subjects, and based upon 
agreement/approval by the Principle Investigator, legally authorized representative, 
patient and IRB as outlined in Appendix 6 and at the time points specified in the 
Schedule of Assessments (Appendix 1, Appendix 2, Appendix 9, and Appendix 10).
4.6.1.4
Palatability Test
Palatability (taste and acceptability) testing of the dispersible tablet formulation of the 
study medication will include questions directed to the subjects to capture subjective 
experiences with the dispersible tablets. The input of the care-giver will also be sought to 
aid interpretation of the experience or reaction of the subjects. 
Palatability assessments will be performed at the time points specified in the Schedule of 
Assessments (Appendix 1) after administration of study medication.
4.6.1.5
Vital Signs
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure after the subject has been in supine position for at 
least 5 minutes. Additionally, orthostatic function will be assessed post dose at selected 
visits comparing the blood pressure and the pulse rate after at least 5 minutes in supine 
position and again 3 minutes after having rapidly changed into standing position.
Vital signs will be recorded at the time points specified in the Schedule of Assessments, 
(Appendix 1, Appendix 2, Appendix 9, and Appendix 10). 
When vital signs and a blood draw are scheduled at the same time, the vital signs 
should be measured prior to blood draw or at least 10 minutes after the last blood draw. 
When possible, the same arm should be used for all blood pressure measurements.
Blood pressure, pulse rate, and respiratory rate should be obtained in a quiet room at a 
comfortable temperature, with the subject's arm unconstrained by clothing or other 
material. All measurements will be obtained from the same arm and using a well-
calibrated automatic instrument with a digital readout, throughout the study. Cuff size 
should be selected as appropriate for age/arm circumference thus that cuff bladder width 


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is about 40% and cuff bladder length is about 80% of arm circumference. As the 
subjects grow during study participation, the Investigator should check for appropriate 
cuff size according to this guide. 
Temperature assessments (home): body temperature is to be measured using a 
tympanic thermometer in a closed room at room temperature. Body temperature should 
be recorded in a patient diary provided for that purpose.
4.6.1.6
Electrocardiograms
Triplicate ECG recordings (i.e., three useful ECGs without artifacts) will be obtained at 
the Baseline visit before first dosing with approximately 25 minutes between each 
recording. For the triplicate recordings at baseline, the average of the three readings will 
be used to determine ECG intervals (e.g., PR, QRS, QT).
Single ECG recording will be performed at screening and the other time-points listed in 
the Schedule of Assessments (Appendix 1, Appendix 2, Appendix 9, and Appendix 10). 
To minimize variability, it is important that subjects be in a resting position for at least 
5 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG
resting period and during ECG recording. ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the subject’s 
permanent study file at the site.  If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
The recordings will be electronically transferred to a central ECG analysis vendor. The 
following parameters will be obtained from the digital recordings: heart rate, QRS 
duration, PQ (PR), RR and QT intervals (QTcB (Bazett’s correction) and QTcF 
(Fridericia’s correction)) as well as information on T-wave and U-wave and overall ECG 
interpretation.
4.6.1.7
Laboratory Assessments
Normal ranges for the study laboratory parameters, by age and sex where appropriate, 
must be supplied to the Sponsor before relevant assessments are completed. 
Laboratory safety tests shall be collected at time-points specified in the Schedule of 
Assessments (Appendix 1, Appendix 2, Appendix 9, and Appendix 10).
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 


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additional testing to monitor subject safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse, e.g., previous occasional intake of a medication or 
food containing for example codeine, benzodiazepines or opiates, the test could be 
repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. 
 
 
  Results of clinical laboratory testing will be recorded on the eCRF or be 
received as electronically produced laboratory reports submitted directly from the local or 
central laboratory, if applicable.

Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count [neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells].  
Additional hematology monitoring will be performed at so called “home visits” 
(Appendix 1, Appendix 2, Appendix 9, Appendix 10, and Section 5.2.1).

Serum chemistry:
As specified in the schedule of assessments (see Appendix 1, Appendix 2, 
Appendix 9, and Appendix 10), different serum chemistry assessments will be
performed at specific visits:
o
Full Serum chemistry panel: sodium, potassium, chloride, bicarbonate, glucose 
(fasting for at least 4 hours at screening only), urea, creatinine, phosphate, 
calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, protein, 
albumin, urate, LDH, CPK, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides. 
Additionally, HbA1c, TSH, and free T4 will be assessed at screening, 
Week 24/76 early withdrawal, and 6-week follow-up visits.
  
 
 
 
 
 
 

Coagulation: INR, aPTT, PT


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
Viral serology:
o
HIV (specific tests HIV-1 Antibody, HIV-1/2 Antibody, HIV-2 Antibody)
o
Hepatitis B surface antigen (HBsAg) or hepatitis B cDNA
o
Total hepatitis B core antibody (HBcAb)
–
Any positive HBV serology will be followed by confirmatory assays.
o
Hepatitis C virus (HCV) antibody

Urinalysis, including dipstick: pH, specific gravity, glucose, protein, ketones, blood 
will be performed at the study center. If there is a clinically significant positive blood 
or protein result, urine 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, and PCP. Drug screen and alcohol test will be mandatory for adolescents 
at screening and may be performed in any subject at any visit at the discretion of the 
study physician.

Pregnancy test: All females with menarche (including those who have had a tubal 
ligation) will have a urine pregnancy test at screening and specified sub-sequent 
visits. 

Unscheduled Visit: In the event that additional laboratory parameters are required to
interpret any adverse events or abnormal hematology/chemistry, the following 
assessments may be included:
o
Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)
o
Full serum chemistry panel: sodium, potassium, chloride, bicarbonate, glucose 
(fasting for at least 4 hours at screening only), urea, creatinine, phosphate, 
calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, protein, 
albumin, urate, LDH, CPK, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides 
 
 
 


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The procedures for the collection, handling, and shipping of samples will be provided in 
the Central Laboratory Manual.
4.6.1.8
Pharmacokinetic Assessments
Blood samples for pharmacokinetic determination of plasma concentrations of 
balovaptan and its metabolite M3 and M2 (as applicable) (and other metabolite(s) as 
relevant) will be collected as specified in the Schedule of Assessments and the PK 
sampling schedule detailed below by qualified personal. Samples scheduled at least 
4 hours post dose on a clinic visit day can be taken by a nurse at home.
Topical application of local anesthetic is permitted if necessary. See also lab manual for 
further details.
PK sampling for first cohorts of 24 adolescents and 30 children 
Two first cohorts of 24 adolescents and approximately 30 children will undergo over the 
first 4 weeks a more intense PK sampling until the IMC and SOC confirms the final 
doses for each age group (see also Appendix 2 and see Section 3.1.3.1):

Week 1, one sample: pre-dose at home together with

Week 2, four samples: pre-dose, 2 (0.5) hours post-dose, 4 (0.5) hours 
post-dose, and at least 6 hours post-dose; PK samples need to be at least 2 hours 
apart.

Week 4, one sample: pre-dose at home

End of Treatment visit (if needed), one sample anytime during the visit
PK sampling for second cohorts of adolescents and children after confirmation of 
final doses by IMC and SOC:
All subjects in this study will follow at least a minimal PK sampling scheme (to obtain 
adequate estimates of key PK parameters, i.e., apparent clearance and volume of 
distribution). PK samples will be taken from all subjects on the following visits (see also 
Appendix 1, Appendix 9, and Appendix 10):

Week 8, 1 sample: post-dose in the evening at home together with safety labs 
(the dose will be taken in the morning)

Week 12 and 24, three samples: pre-dose, 2 hours post-dose, and at the end of the 
clinic visit but at least 4 hour post-dose

Early withdrawal visit: one sample anytime during the visit
 
The actual time of the PK blood sampling, together with the exact time for dosing on day 
before and on day of PK sampling, needs to be precisely entered into the corresponding 
eCRF section.


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Plasma concentrations of balovaptan and its metabolite M3 and M2 (as applicable) will 
be measured by a specific and validated LC-MS/MS method. Other balovaptan-derived 
metabolites in plasma may be investigated as appropriate by an exploratory method.
PK samples will be destroyed no later than 2 years after the date of the final clinical 
study report.
4.6.1.9
Clinical Genotyping Samples
A mandatory whole blood sample will be taken for DNA extraction from every subject on 
Day 1. The DNA will be used to evaluate if genetic variants in the AVPR1A gene affect 
the efficacy or safety of balovaptan. The sample may be used also to assess if genetic 
variants (e.g., in CYP3A4 or CYP2D6) can be related to the PK and safety of balovaptan. 
Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to the confidentiality standards described in Section 8.4. CG samples and 
derived analytical materials will be destroyed no later than 2 years after the date of the 
final clinical study report. 
4.6.1.10
Disease-Specific Assessments
Caregivers and clinicians will use an electronic device to capture disease specific 
questionnaires. The data will be transmitted electronically to a centralized database at 
the electronic PRO (ePRO) vendor. 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 and the caregiver should be requested to complete any 
blank items. Changes to the form should not be made once the caregiver has left the site 
for that visit.
4.6.1.10.1
Requirements for Caregivers
All disease specific assessments will take place on-site at the clinic. The same 
caregiver will provide feedback on all informant based assessments throughout the 
study as established at baseline. If a caregiver visit cannot be completed as 
arrangede.g., the caregiver is delayed in transitvisits should be rescheduled as soon 
as possible after the original appointment. Caregiver completed assessments cannot be 
conducted over the telephone. Caregiver initials will be reported on eCRF at all 
assessments.
The reliable caregiver or parent must live with the subject or have substantial and 
sufficient periods of contact with the subject and is willing and able to attend the on-site 
visits when required. The reliable caregiver or parent must oversee the subject’s 
adherence with protocol-specified procedures and study medication dosing, and report 
on the subject’s status via completion of study assessments.
If the caregiver is not living with the subject, the Investigator has to be satisfied that the 
subject can contact the caregiver readily during the times when the caregiver is not with 
the subject. If in doubt about whether a subject’s care arrangements are suitable for 


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inclusion, the Investigator should discuss this with Sponsor (Medical Monitor or 
designee). A non-cohabitating caregiver must spend sufficient time with the subject so 
that, in the opinion of the Investigator, the caregiver can reliably assess the subject’s 
mental status, activities and behavior, and report on the subject’s adherence and health. 
This would normally be possible when the caregiver spends a few hours each day with 
the subject.
4.6.1.10.2
Wechsler Abbreviated Scale of Intelligence ScaleSecond 
Edition (WASI-II)
The WASI-II is a tool used to evaluate an individual’s cognitive functioning and generate 
IQ scores [29] and will be administered by a certified rater at screening only. 
For subjects older than 7:7 years the WASI-II will be the only choice at screening. For 
children from 6 to 7:7 years the WASI-II will be the first choice to determine eligibility at 
screening and for children aged 5 years only the WPPSI-IV can be used (see 
Section 4.6.1.10.3).
If the WASI or an equivalent assessment (e.g., the Wechsler Intelligence Scale for 
Children (WISC) or the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) 
has been performed by a certified rater and documented within 12 months of the 
screening visit, there will be no requirement to repeat it.
The assessment will take approximately 30 minutes to complete. 
4.6.1.10.3
Wechsler Preschool and Primary Scale of IntelligenceFourth 
Edition (WPPSI-IV)
The WPPSI-IV is a tool used to evaluate cognitive functioning and generate IQ scores in 
preschoolers and young children [30] and will be administered by a certified rater at 
screening only.
If the WPPSI has been performed by a certified rater and documented within 12 months 
of the screening visit, there will be no requirement to repeat it.
The assessment will take approximately 45-60 minutes to complete. 
4.6.1.10.4
Autism Diagnostic Observation Schedule (ADOS-2)
The ADOS second edition is a diagnostic tool used to document the presence of ASD 
[31, 32]. During a semi-structured evaluation, the individual is observed in a naturalistic 
social situation and assessed across areas of social communication, imagination, and 
restricted and/or repetitive behaviors. 
The ADOS includes four modules for use with different age groups and language levels; 
module 2, 3, and 4 will be used in this study. The appropriate module of the ADOS will 
be administered by a certified rater at screening.


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If the ADOS assessment has been performed by a certified rater and documented within 
12 months of the screening visit, there will be no requirement to repeat it.
The assessment will take approximately 35 to 40 minutes to complete.
4.6.1.10.5
Social Responsiveness Scale Second Edition (SRS-2)
The SRS-2 is a 65-item informant-based rating scale designed specifically for use in 
ASD to quantitatively measure an individual’s ability to engage in emotionally 
appropriate reciprocal social behavior in a naturalistic social setting [35]. Each item on 
the scale inquires about an observed aspect of reciprocal social behavior that is rated on 
a scale from 1 (not true) to 4 (almost always true). Social skill levels are assessed over 
five domains: Social Awareness, Social Cognition, Social Communication, Social 
Motivation, and Autistic Mannerisms. The total score generated serves as an index of 
severity of social deficits in the autism spectrum. 
The reliable caregiver will complete the rating scale at screening. A clinician will be 
available to assist the caregiver during completion of the questionnaire.
This assessment will take approximately 15-20 minutes.
4.6.1.10.6
Vineland-II Adaptive Behavior Scales, Second Edition 
(VinelandTM-II)
The VinelandTM-II is an instrument that measures communication, daily living skills, 
socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed 
in this study) behavior of individuals with developmental disabilities [33]. The Survey 
Interview Form (i.e., semi -structured interview) will be administered to a subject’s 
reliable caregiver in this study, during which the rater or clinician will ask to the caregiver 
open ended questions relating to the subject’s activities and behavior. Domain scores 
will be obtained for the individual domains of Socialization, Communication, Daily Living 
Skills, and motor skills (up to 6 years only) and used to calculate the VinelandTM-II 
Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior 
composite range from 20-160 with higher scores indicating better functioning. 
The same rater or clinician will perform the VinelandTM-II together with the same 
caregiver throughout the study as established at baseline visit. The initials from 
caregiver and rater will be reported on eCRF at all assessments.
This interview will take approximately 45-60 minutes to complete. At a clinic visit the 
VinelandTM-II should be performed as the first of all informant based assessments with 
the caregiver (see Section 4.6.2.2).
4.6.1.10.7
Aberrant Behavior Checklist (ABC)
The ABC is an informant-based questionnaire consisting of 58 items subdivided 
amongst 5 scales: irritability, lethargy and social withdrawal, stereotypic behavior, 
hyperactivity/non-compliance, and inappropriate speech [34]. A score for each item 


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ranges from 0 indicating “no problem” to 3 indicating “severe problem”. Scale scores are 
calculated by summing the items within that scale. Higher scores indicate greater 
impairment. 
The reliable caregiver identified upon subject’s screening visit will complete the rating 
scale. A clinician will be available to assist the caregiver during completion of the 
questionnaire.
This assessment will take approximately 10-20 minutes to complete.
4.6.1.10.8
Ohio Autism Clinical ImpressionsSeverity (OACIS-S) and 
Improvement (OACIS-I)
The OACIS-S and -I are 10-item, clinician-completed measures based upon interview 
and/or observation [38]. 
The OACIS-S and OACIS-I assess severity and improvement, respectively, in social 
interaction, aberrant behavior, repetitive or ritualistic behavior, verbal communication, 
nonverbal communication skills, hyperactivity and inattention, anxiety and fearfulness, 
sensory sensitivities, restricted and narrow interests, and a global rating of autism. 
Each item of the OACIS-S is rated on a 7-point scale ranging from no symptoms (1) to 
very severe symptoms (7). The OACIS-I is used to assess the clinical change as 
compared to symptoms at baseline using a 7-point scale, ranging from very much 
improved (1) to very much worse (7). 
4.6.1.10.9
Clinical Global ImpressionSeverity (CGI-S) and Improvement 
(CGI-I)
The CGI rating scales are tools used to evaluate both the severity of illness and change 
from baseline [39]. The CGI-S reflects the rater’s impression of the subject’s current 
autism severity on a 7-point scale ranging from no symptoms (1) to very severe 
symptoms (7). The CGI-I is used to assess the clinical change as compared to 
symptoms at baseline using a 7-point scale, ranging from very much improved (1) to 
very much worse (7). For this study modified versions will be used [40, 41].
Whenever possible, for any individual, these assessments should be done by the same 
rater throughout the study.
4.6.1.10.10
Caregiver-reported Global Impression (CaGI)
The Caregiver Global Impression (CaGI) is a four item informant-based questionnaire 
assessing the caregiver's impression about changes in subject’s communications skills, 
social skills, daily living skills and overall symptoms associated with autism as compared 
to Baseline. The CaGI items utilize a 7-point scale, ranging from very much improved 
(1) to very much worse (7) to report the changes as compared to Baseline. For this 
study an adapted version for Autism will be used (see Appendix 4 and [42]). 


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This scale will take up to 5 minutes to complete.
4.6.1.10.11
Repetitive Behavior ScaleRevised (RBS-R)
The RBS-R is a 43-item informant-based questionnaire assessing the variety of 
restricted and repetitive behaviors observed in individuals with ASD [43]. The scale is 
grouped into six subscales: Stereotyped, Self-injurious, Compulsive, Ritualistic, 
Sameness, and Restricted Behaviors.
This scale will take approximately 2030 minutes to complete.
4.6.1.10.12
PedsQL Family Impact Scale
The Pediatric Quality of Life Inventory (PedsQL™) Family Impact Module version 2 [44] 
is a 36-item questionnaire which is completed by the caregiver and was developed to 
measure parent and family functioning. It encompasses six scales covering 1) Physical 
Functioning (6 items), 2) Emotional Functioning (5 items), 3) Social Functioning (4 items), 
4) Cognitive Functioning (5 items), 5) Communication (3 items), 6) Worry (5 items), and 
2 scales measuring parent reported family functioning; 7) Daily Activities (3 items) and 
8) Family Relationships (5 items). For each item a 5-point response scale is utilized 
(0never a problem; 4 = always a problem). Items are then reverse-scored and linearly 
transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher 
scores indicate better functioning (less negative impact). 
Scale Scores are computed as the sum of the items divided by the number of items 
answered (this accounts for missing data). If more than 50% of the items in the scale 
are missing, the Scale Score is not computed. A Total Score, a Parent HRQOL 
Summary Score, and a Family Summary Score can also be computed by averaging 
across the relevant domains (Total Score by averaging across all items, Parent HRQOL 
Summary Score by averaging the 20 items in Physical, Emotional, Social, and Cognitive 
Functioning, and the Family Summary Score by averaging 8 items in Daily Activities and 
Family Relationships). The acute form with a recall period of 7 days will be employed in 
this trial.
 
 
 
 
 
 
 
 


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4.6.1.11
Patient-Reported Outcomes
Subjects will use an electronic device to capture PRO questionnaire data. The data will 
be transmitted electronically to a centralized database at the electronic PRO (ePRO) 
vendor. 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 and the patient should be requested to complete any blank items. Changes to the 
form should not be made once the subject has left the site for that visit.
4.6.1.11.1
Pediatric Quality of Life Inventory (PedsQLTM) Generic Core & 
Cognitive Functioning Scales
The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment 
consists of a 23 item questionnaire encompassing 4 core scale domains: Physical 
Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and 
School Functioning (5 items). Additionally, the PedsQL Cognitive Functioning Scale 
which contains 6 items will also be completed. The acute self-completed forms with a 
recall period of 7 days will be employed in this trial [44]. Different versions exist for 57, 
812, and 1318 year age ranges. 
For children aged 8 years and above, the PedsQL items are scored on a 5 point 
Likert-type response scale (0never a problem; 1almost never a 
problem; 2sometimes a problem; 3often a problem; and 4almost always a problem). 
For children aged 5-7 years, scoring is based on a three-point scale (0Not at all, 
2Sometimes, 4A lot). Once scored, items will be reverse scored and linearly 
transformed to a 0-100 scale (0100, 175, 250, 325, 40), so that higher scores 
indicate better health-related quality of life. 
For children aged 57 years, an administrator will read out the questions and the child 
will respond by pointing to one of three smiley faces. Children aged 8 years and above 
complete the questionnaire themselves. Subjects should complete the same version of 
the questionnaire throughout the study even if they have moved up an age group. 
After completion of the PedsQL at Week 24, Week 76, or Early Withdrawal visit (see 
Schedule of Assessments, Appendix 1 or Appendix 10), subjects will be asked up to two 
additional open-ended questions on their perception of change from baseline. 
 
 
The questions are as follows:

"Have you noticed any changes since starting the study medication?”

If yes, “Can you tell me about these changes?”


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This information will be recorded verbatim from the subject on an electronic device and 
transcribed. 
4.6.1.12
Columbia Suicide Severity Rating Scale (C-SSRS)
The assessment for suicidality in clinical trials is a requirement for CNS active molecules 
requested by Health Authorities.
The C-SSRS (http://www.cssrs.columbia.edu) is a clinician-rated tool recommended by 
Health Authorities including the FDA to assess previous suicidality of a subject at 
screening (C-SSRS screening to be used at screening) as well as any new instances of 
suicidality during the clinical study (C-SSRS since last visit, 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. 
Age specific versions of the C-SSRS will be used.
The pediatric version will be used for children 511 years old. After completion of the 
pediatric questionnaire, the Investigator will ask both the caregiver and the child the 
following additional questions relating to the areas of suicidal ideation, suicidal behavior, 
and self-injurious behavior:

Suicidal Ideation: 
Has the child wished he/she were dead or wished they could go to sleep and not 
wake up?

Suicidal Behavior: 
Has the child made a suicide attempt? 
Has he or she done anything to harm him or herself?

Self-injurious Behavior: 
Has the child engaged in nonsuicidal self-injurious behavior?
If the Investigator concludes on a suicidality risk of the subject, the Investigator must 
take care for further evaluation of the risk which may involve local experts in the field of 
suicidality.
4.6.1.13
Samples for Research Biosample Repository
Overview of the Research Biosample Repository
The Roche Research Biosample Repository is a centrally administered group of facilities 
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 these 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.


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Specimens will be collected from subjects who give specific consent to participate in this 
optional Research Biosample Repository. Collected 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

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
These samples may be used to explore the associations of variants of genes implicated 
in susceptibility and pathogenesis of ASD. The pharmacogenetic information gathered 
through the analysis of specimens in the Research Biosample Repository is hoped to 
improve subject’s outcomes by predicting which subjects are more likely to respond to 
specific drug therapies, predicting which subjects are susceptible to developing adverse 
side-effects, and/or predicting which subjects are likely to progress to more severe 
disease states.
The results of specimen analysis from the Research Biosample Repository may 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.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the Research Biosample Repository is contingent upon the review and 
approval of the exploratory research and the Research Biosample Repository portion of 
the Informed Consent and assent 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 Research Biosample Repository sampling, this 
section of the protocol will not be applicable at that site.
Sample Collection
One optional sample for DNA extraction will be collected per Appendix 1 and Appendix 2, 
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 used for whole genome sequencing 
(WGS) and other genetic analysis and may be sent to one or more laboratories for 
analysis. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 


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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 all samples, dates of consent and specimen collection should be recorded on the 
associated Research Biosample Repository page of the eCRF. For sampling procedures, 
storage conditions, and shipment instructions, see the separate laboratory manual. 
Research Biosample Repository specimens will be stored and used until no longer 
needed or until they are exhausted. The Research Biosample Repository storage period 
will be in accordance with the IRB/EC-approved Informed Consent Form and applicable 
laws (e.g., Health Authority requirements). 
The repository specimens will be subject to the confidentiality standards described in 
Section 8.4.
Confidentiality
Data generated from Research Biosample Repository specimens must be available for 
inspection upon request by representatives of national and local Health Authorities, and 
Roche monitors, representatives, and collaborators, as appropriate.
Subject medical information associated with Research Biosample Repository specimens 
is confidential and may only be disclosed to third parties as permitted by the Informed 
Consent Form (or separate authorization for use and disclosure of personal health 
information) signed by the subject, unless permitted or required by law.
Data derived from Research Biosample Repository specimen analysis on individual 
subjects will generally not be provided to study Investigators unless a request for 
research use is granted. The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Patients will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or patients unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the Research Biosample Repository specimen data will become and remain 
the exclusive and unburdened property of Roche, except where agreed otherwise.


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Consent to Participate in the Research Biosample Repository
The Informed Consent and assent Form will contain a separate section that addresses 
participation in the Research Biosample Repository. The Investigator or authorized 
designee will explain to each subject the objectives, methods, and potential hazards of 
participation in the Research Biosample Repository. Subject will be told that they are 
free to refuse to participate and may withdraw their specimens 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 Research Biosample Repository 
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 by completing the Research Biosample Repository Sample Informed Consent 
eCRF.
In the event of death or loss of competence of a subject who is participating in the 
research, the participant's specimens and data will continue to be used as part of the 
Research Biosample Repository research.
Withdrawal from the Research Biosample Repository
Subjects who give consent to provide specimens for the Research Biosample Repository 
have the right to withdraw their specimens at any time for any reason. If a subject wishes 
to withdraw consent to the testing of his or her specimens, the Investigator must inform 
the Monitor in writing of the subject’s wishes using the Research Biosample Repository 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
Research Biosample Repository Withdrawal of Informed Consent eCRF. The subject will 
be provided with instructions on how to withdraw consent after the trial is closed. 
A Study Subject's withdrawal from Study BP30153 does not, by itself, constitute 
withdrawal of specimens from the Research Biosample Repository. Likewise, a Study 
Subject’s withdrawal from the Research Biosample Repository does not constitute 
withdrawal from Study BP30153. Data already generated before time of withdrawal of 
consent to Research Biosample Repository will still be used.
Monitoring and Oversight
Specimens collected for the Research Biosample Repository 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. Roche 
monitors and auditors will have direct access to appropriate parts of records relating to 
Study Subject participation in the Research Biosample Repository for the purposes of 
verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the samples.


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4.6.2
Timing of Study Assessments
The Schedules of Assessments can be found in Appendix 1, Appendix 2, Appendix 9, 
and Appendix 10.
The first cohorts of 24 adolescents and up to approximately 30 children will follow at 
study start a specific Schedule of Assessments (see Appendix 2) with additional 
assessments until the IMC and SOC determines the final doses for each age group 
(see protocol Section 3.1.3.1). After determination of the final doses for the cohort these 
subjects will continue following the Schedule of Assessments for the entire study 
(Appendix 1). If the dose is judged acceptable on an individual level, the subject may 
continue on that dose and follow the Schedule of Assessments for the entire study. 
During the early interim Pharmacokinetic and safety reviews the IMC and SOC may 
decide to stop treatment (see Section 3.1.3.1).
If necessary, site visits (Week 6, Week 12, Week 18, Week 24, Week 48, Week 64,
Week 76, Early Withdrawal Visit, and Follow-Up Visit) can be performed over two 
consecutive days. Assessments at screening can be performed at any time during the 
screening period. Baseline assessments can be performed up to 1 week prior to first 
dose (see Appendix 1, Appendix 2, Appendix 9, and Appendix 10).
4.6.2.1
Screening and Pretreatment Assessments
Written informed consent and Assent for participation in the study must be obtained 
before performing any study‑specific screening tests or evaluations. Informed Consent 
Forms and Assent Forms for enrolled subjects and for subjects who are not 
subsequently enrolled will be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that subjects meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all subjects screened and to confirm eligibility or record reasons 
for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Abbreviated re-screening (written informed consent, medical history, physical 
examination, substance use, alcohol test, fasted laboratory safety, coagulation, serology, 
urinalysis, inclusion/exclusion criteria) may be allowed under circumstances where the 
subject is screen-passed but could not be randomized within the 4-week screening 
window due to a study halt, logistical, personal, or technical reasons. At no time should 
the duration between the original screening visit and the abbreviated re-screening visit 
exceed 3 months. Abbreviated re-screening will only be permitted in cases where this 
poses no safety risk to the subject. 


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Screen-failed subjects can be re-screened if there is a substantial change in the 
subject’s general condition (e.g., prohibited medication was stopped or weight loss) and 
if recruitment for the study is still ongoing. Re-screening will not be allowed if the subject 
failed earlier to meet the disease specific inclusion criteria (e.g., SRS-2 T-score).
Safety laboratory tests which would exclude the subject at screening may be repeated 
once (as unscheduled labs) if it is suspected that the abnormal result is transient and 
likely to be normal at repeat.
Subjects from first adolescent and first children cohorts, who stopped treatment in the 
context of the interim safety and PK decisions, (see Section 3.1.3) will be allowed to 
re-start in the same treatment arm, according to their original randomization, for 
24 weeks in the main study, provided the Investigator can exclude relevant changes in 
the subject’s general condition (see Section 4.2.1). These subjects will have a new, 
abbreviated Baseline visit, and will continue with all subsequent visits according to the 
schedule of assessments until completion of their time on the study (Appendix 1).
In addition, re-starting subjects will be assigned a new subject number. Some data from 
their original screening visit will be required to be re-entered in the eCRF under the new 
subject number.
A screening examination will be performed approximately 4 weeks (at least 3 weeks and 
up to 4 weeks) before the first drug administration (Day 1) per the Schedule of 
Assessments, (see Appendix 1). Subjects must fulfill all entry criteria to be accepted into 
the study.
For subjects enrolling in first adolescent/first children cohorts (see Section 3.1 and 
Section 3.1.3.1), a screening examination will be performed approximately 4 weeks 
(at least 1 week and up to 4 weeks) before the first drug administration (Day 1) per the 
Schedule of Assessments (Appendix 2).
The Investigator, or designee, will use the eCRF with the assigned subject number and 
enter the corresponding number for allocation to the treatment group in the appropriate 
place on each subject’s eCRF.
The randomization numbers are to be allocated sequentially in the order in which the 
subjects are enrolled. A Subject Enrollment and Identification Code List must be 
maintained by the Investigator.
4.6.2.2
Assessments during Treatment
All assessments must be performed as per Schedule of assessments (see Appendix 1, 
Appendix 2, Appendix 9, and Appendix 10).
Subjects will arrive at each study visit without having taken their daily dose of study 
medication. Following collection of the pre-dose PK blood sample, and the safety labs 


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subjects will take their next dose of study medication. Site staff will record the actual 
date and time of the dose intake. The last dose of study medication will be administered 
at the Week 76 visit.
When blood samples are scheduled for the same nominal time as other assessments 
the following order should be followed:

12-lead ECGs

Vital signs

Blood samples
As a general rule, the test sequence for all disease specific assessments should remain 
the same for a given subject as established at screening and Baseline. Additionally, 
testing should occur around the same time of the day at each visit. 
For the informant based assessments the following order will be followed:

Always the VinelandTM-II will be the first informant based assessment with the 
caregiver. 

For all other informant based assessments there is no restriction in the order, 
however a sequence established at screening and Baseline should remain the same 
for a given subject.
The patient reported outcome measures can be performed in parallel with the informant 
based assessments. The following sequence is proposed: first the C-SSRS followed by 
the PedsQL. Ideally these assessments should be performed before administration of 
study medication or within 1 hour after administration.
The remaining clinician-completed measures will be completed after all other disease 
specific assessment to minimize any possible bias on caregiver reported assessments.
4.6.2.3
Assessments at Study Completion/Early Withdrawal Visit
Subjects who complete the study treatment period (defined as completion of 24 weeks of 
study treatment) or discontinue from the study early, will perform with the caregiver all 
assessments for the Week 24 or the Early Withdrawal visit with the caregiver, as per the 
schedule of assessments (see Appendix 1 and Appendix 10).
4.6.2.4
Follow-Up Assessments
As per the schedule of assessments, all subjects will have safety hematology/CPK blood 
samples taken 2 weeks after last dose and a clinic visit 6 weeks after last dose (see 
Appendix 1 or Appendix 10). After the study completion/Early Withdrawal visit, adverse 
events should be followed as outlined in Sections 5.5 and 5.6.


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4.7
SUBJECT, STUDY, AND SITE DISCONTINUATION
4.7.1
Subject Discontinuation
The Investigator has the right to discontinue a subject from balovaptan or withdraw a 
subject from the study at any time. In addition, subjects have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason. Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following:

Subject withdrawal of consent at any time

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the subject’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the subject

Subject non-compliance
4.7.1.1
Discontinuation from Study Drug
The Investigator must diligently review incoming safety data. In particular hematological 
or neurological abnormalities should be considered as a potential reason to withdraw a 
patient from further trial participation. 
Subjects must be discontinued from study drug in case of: 

Subject unable to continue to comply with study requirements
Subjects who discontinue study drug prematurely will be asked to return to the clinic for 
a study completion/Early Withdrawal visit as soon as possible (see Section 4.6.2.3) 
including detailed safety and efficacy assessments (see Schedule of Assessments, 
Appendix 1 and Appendix 2) and may undergo follow-up assessments (see 
Section 4.6.2.4). The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF. 
4.7.1.2
Withdrawal from Study
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 5.1.3 documented on 
the appropriate eCRF.
Subjects will not be followed for any reason after full consent has been withdrawn.
When a subject voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless the subject 
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destruction. A subject's withdrawal from Study BP30153 does not, by itself, constitute 
withdrawal of specimens donated to the Research Biosample Repository. 
4.7.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects

Subject enrollment is unsatisfactory

Three or more subjects (delta between active and placebo arm) are pre-maturely 
withdrawn from the study because of serious adverse events or adverse events of 
special interest that are of similar nature and considered related to the intake of 
balovaptan (see also Appendix 3).
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
The Sponsor has the right to close or replace a site at any time. Reasons for replacing or 
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
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events, and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.1.1
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), except as described in 
Section 5.3.5.8.

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).
5.1.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

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)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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 (rated as mild, moderate, or severe (see Section 5.3.3); the event itself 
may be of relatively minor medical significance (such as severe headache without any 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions). Adverse events of special interest 
for this study include the following:
 
 
 
 
 
 
 

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in 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 
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 patient exposed to a medicinal product.
This term applies only when a contamination of the study drug is suspected.
5.2
SAFETY PLAN
 
 
 


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5.2.2
Blood Pressure and ECG Monitoring
While the overview of available respective clinical experience does not indicate an effect 
of balovaptan on heart rate and blood pressure, hypothetically antagonism of V1a could 
result in a decrease in blood pressure and impairment of orthostatic function. 

Blood pressure and pulse rate in supine position and in context of orthostatic 
challenge testing will be monitored in this study in pediatric patients. 
As a standard policy of clinical trials sponsored by Roche, and not because of any 
specific concern of balovaptan, the following stopping rule is implemented with respect 
to QTc: 

A confirmed value for QTcF above 500 ms or a change from baseline by more than 
60 ms will result in drug discontinuation (to confirm the initial abnormal value the 
ECG should be repeated within 30 minutes).
 
 
 
 
 
 


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5.2.6
Tanner Staging
Animal studies do not point to any adverse effects of balovaptan with respect to sexual 
maturation. As a matter of routine monitoring, Tanner stages will be determined in 
subjects aged at least 7 years, but no longer after menarche in female and no longer 
after voice break in male subjects, and based upon agreement/approval by the site 
Principle Investigator, legally authorized representative, patient, and IRB as outlined in 
Appendix 6. 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1.1 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 to 5.6. For each 
adverse event recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each subject contact. All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject’s medical record. Adverse events will then be reported on the 
Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies). Any 
other adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 6 weeks after the last dose of study drug.
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 time‑points. Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”


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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 5.1.2).
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 or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or re-introduction of study drug (where 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 subject receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
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 


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on the Adverse Event eCRF. If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
subject evaluation time‑points. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between subject evaluation time‑points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the Investigator’s judgment
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal (ULN) 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the Investigator’s judgment
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3 ULN in combination with total 
bilirubin2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
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").
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 


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that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
5.3.5.9
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient 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 5.3.5.9), 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 suffered an adverse event

Prolonged hospitalization due to lack of home care facilities, caregiver issues, 
transport issues, etc.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.10
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data 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 5.1.2; see Section 5.4.2 for details on 
reporting requirements)


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
Non-serious adverse events of special interest (defined in Section 5.1.3; see 
Section 5.4.2 for details on reporting requirements)

Pregnancies (see Section 5.4.3)

Overdoses, medication errors, drug abuse, or drug misuse (see 5.4.4 for details on 
reporting requirements)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, Ph.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D. (Secondary) 
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, 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 
Non-Serious Adverse Events of Special Interest
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3), Investigators should record all case details that can be 


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gathered on the Serious Adverse Reporting Form and forward this form to the SAE 
Responsible within 24 hours.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Subjects
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 Clinical Trial Pregnancy Reporting Form should be completed by 
the Investigator and submitted to the Sponsor within 24 hours after learning of the 
pregnancy. Pregnancy should not be recorded on the Adverse Event eCRF. The 
Investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy.
5.4.3.2
Pregnancies in Female Partners of Male Subjects
Male subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of study drug. A paper Clinical Trial Pregnancy Reporting 
Form should be completed by the investigator 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. Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male subject exposed to 
study drug. When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy. If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available. An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Abortions
Any spontaneous abortion in a pregnant female subject or a female partner of a male 
subject should be classified as a serious adverse event (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.4.3.4
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).


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5.4.4
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 patient, drug misuse could 
involve the drug being administered to someone other than the patient.
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 and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

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.


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
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 patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
For balovaptan, 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).  For 
balovaptan, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

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.
5.5
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 patient 


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is lost to follow-up, or the patient 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 patient’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, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor subjects for adverse events after the 
end of the adverse event reporting period (defined as 6 weeks after the last dose of 
study drug). However, the Sponsor should be notified if the Investigator becomes aware 
of any death or any other serious adverse event occurring after the end of the adverse 
event reporting period, if the event is believed to be related to prior study drug treatment.
The Investigator should report these events directly to the Sponsor or its designee, 
either by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event 
of Special Interest Reporting Form using the fax number or email address provided to 
Investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to Investigators, IRBs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events to balovaptan, which is the only IMP studied in 
this trial, using the following reference document as “Reference Safety Information”: 

Section 6.4 of the IB. [45]


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Independent from the causality assessment, the following SAEs and non-serious AESIs 
will be reported to FDA on an expedited basis: 
Death, arrhythmia, syncope, dyspnea, palpitations, and chest pain
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.
The IMC and the independent SOC will monitor the incidence of these expected 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
6.1
DETERMINATION OF SAMPLE SIZE
Prior to Version 6 of the protocol, a sample size of 240 ASD patients (80 per treatment 
arm) providing evaluable data at Week 24 ensured the study 80% power to detect as 
statistically significant, at 1-sided 5% significance level, a difference between each active 
dose and placebo with an effect size of at least 0.4. No adjustment for multiple doses 
was performed.  Considering a withdrawal rate of around 15-20%, it was planned to 
recruit approximately 300 subjects overall.
In accordance to Version 6 of the protocol, 80 subjects per treatment arm (balovaptan 
10 mg eq and placebo) will be required, for a total sample size of approximately 
160 subjects with ASD with evaluable data at Week 24.  To maintain the number of 
evaluable subjects, the sample size will be increase to approximately 340 subjects 
overall.
6.2
SUMMARIES OF CONDUCT OF STUDY
Inclusion/exclusion criteria violations and the use of prohibited co-medication during the 
study will be summarized descriptively to check the quality and integrity of the conduct of 
the study. 
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All subjects who have received at least one dose of the study medication, whether 
prematurely withdrawn from the study or not, will be included in the safety analysis 
population. Data will be analyzed according to the treatment as randomized. Any dosing 
error will be reviewed and the implications of such errors on safety interpretation will be 
assessed.


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6.3.2
Pharmacokinetic Analysis Population
All subjects providing pharmacokinetic data will be included in the PK Population. 
Subjects will be excluded if they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol or if data are unavailable or incomplete which may 
influence the pharmacokinetic analysis. Excluded cases will be documented together 
with the reason for exclusion. 
6.3.3
Efficacy Analysis Population
6.3.3.1
For All Subjects Enrolled prior to Version 6 of the Protocol:
Modified Intent-To-Treat Population
The modified intent-to-treat (mITT) population is defined as consisting of all subjects who 
give informed consent, are randomized, received at least one dose of double-blind 
medication, and for whom a baseline and at least one post-dose assessment is available. 
Subjects in first adolescent/first children cohorts with dose adjustments, or who were on 
a different dose than the final dose for their age group, will be excluded from the primary 
efficacy analysis, and will not contribute to the approximately 160 evaluable subjects 
expected in the mITT population (see Section 4.2.1). Data will be analyzed according to 
the treatment as randomized.
The mITT population is the primary population of interest.
Per-Protocol Population
The Per-Protocol (PP) population will be precisely defined in the statistical analysis plan, 
which will be finalized before database closure, as the subset of the mITT population 
without major protocol deviations. 
The PP population will not be analyzed if this population comprises more than 90% or 
less than 50% of the mITT population. Only the key efficacy outcome measures (see 
Section 3.4.1) will be analyzed using the PP population.
6.3.3.2
For Subjects Enrolled in Accordance to Version 6 of the 
Protocol:
Intent-To-Treat Population
The intent-to-treat (ITT) population is defined as consisting of all subjects who give 
informed consent, are randomized, and receive at least one dose of double-blind 
medication.  Subjects with dose adjustments or interruptions, or who were on a 
different dose than the final dose for their age group, will be excluded from the primary 
efficacy analysis and will not contribute to the approximately 160 evaluable subjects 
expected after 24 weeks.  Data will be analyzed according to the treatment as 
randomized.
The ITT population is the primary and the population assessed for efficacy.


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6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographics, baseline characteristics (including subject disposition and medical 
history) and all baseline laboratory values will be summarized descriptively by treatment 
using frequency tables and summary statistics providing means, medians, standard 
deviations, and extreme values.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
As appropriate, listings, summary tables, and graphs by treatment will be provided for 
safety and tolerability assessments, including

Incidence of adverse events (overall, by intensity, and by relationship to study 
medication). 

Serious adverse events and adverse events of special interest will be reported 
separately.
 

Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, and 
orthostatic effects)
 

Physical examination (height, weight, neurological examination)

Safety laboratory values (including hematology, blood chemistry, 
, 
coagulation, and urinalysis parameters)

Incidence of marked laboratory abnormalities

Clinical assessment of suicidality (C-SSRS)
6.5.1
Adverse Events
Verbatim descriptions of adverse events recorded on the eCRF by the Investigator
during the study period will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms. All adverse events will be tabulated by body system and 
preferred term for individual events within each body system. Adverse events will also be 
tabulated by severity and relationship to the study medication. Serious adverse events 
will be summarized separately.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Subjects’ listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 


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d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
6.5.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters the measured laboratory test result 
will be assessed directly using the Roche standard reference range. A transformation 
will be performed on some laboratory tests that lack sufficiently common procedures and 
have a wide range of Investigator ranges, e.g., enzyme tests that include AST, ALT, and 
alkaline phosphatase and total bilirubin. If the standard reference ranges for these 
parameters have a lower limit of zero only the upper limits of the ranges will be used in 
transforming the data.
6.5.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range.
Laboratory 
values falling outside this standard reference range will be labeled “H” for high or “L” for 
low in study subject listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a subject, the midpoint of the standard reference range will be used as the 
subject’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the subject listings as 
“HH” for very high or “LL” for very low.
 
 


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6.5.3
Vital Signs and ECG
Vital signs and ECG will be presented by individual listings and summary tables of raw 
values and change from baseline.
6.5.4
Concomitant Medications
The original terms recorded on the study subjects’ eCRF by the Investigator for 
concomitant medications will be standardized by the Sponsor by assigning preferred 
terms. Concomitant medications will be presented in summary tables and listings.
6.6
EFFICACY ANALYSES
All efficacy data will be summarized by treatment and time (visit). Listings, summary 
tables of descriptive statistics, frequency tables of raw values and of change from 
baseline (if available) and corresponding graphs will be provided as appropriate.
Inferential statistical analysis will be performed on pooled data from patients taking 
balovaptan 10 mg eq dose compared with those from the concurrently randomized 
placebo in the corresponding randomization stage.  The primary efficacy endpoint, 
absolute change from baseline of VinelandTM-II 2DC, as well as VinelandTM-II Composite 
Standard score and domains standard scores (Communication, Socialization, and Daily 
Living Skills) and the factors obtained from ABC, RBS-R, and PedsQL will be analyzed 
using MMRM (Mixed Model Repeat Measurements) on the overall population of 
adolescents and children. The MMRM model will include treatment and visit (week) as 
main effects, individual age and baseline score (where available) as covariates, and 
treatment-by-visit and baseline-by-visit as interaction terms. An unstructured correlation 
will be employed to allow for correlation among repeated observations within a patient. 
In the event that the model fails to reliably fit, alternative models may be considered. 
All main effects and interactions will be retained in the final model regardless of their 
statistical significance. The results of the analysis will be presented as point estimates, 
90% confidence intervals and associated p-values for the adjusted mean differences 


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between balovaptan 10 mg eq and placebo after 24 weeks of treatment as well as at 
intermediate visits. 
 
 
 
 
 
Further details on the data analysis will be provided in the Statistical Analysis Plan.
6.7
PHARMACOKINETIC ANALYSES
The observed plasma concentrations of balovaptan and its metabolite M3 and M2 
(as applicable) (and other metabolites as appropriate) will be summarized by dose and 
observation time, and the ratio of metabolite to parent drug concentration (molecular 
weight corrected) will be calculated.
A population PK modeling approach (nonlinear mixed-effect modeling) will be used to 
characterize the pharmacokinetics and variability of balovaptan (and its metabolites, if 
warranted) in the pediatric population. The structural PK model will be built based on 
prior information in adults. Key pharmacokinetic parameters, (i.e. apparent clearance 
and volume of distribution) and variability will be reported and the influence of covariates 
(e.g., age, body size, genetic variability of CYP3A4) on the population PK parameters 
will also be investigated, as appropriate. The pediatric data in this study (BP30153) may 
be combined with balovaptan exposure data in adults as needed to adequately 
characterize the PK in the pediatric population. Individual exposure at steady-state 
(AUCss) will be derived from the model. Other individual exposure estimates (e.g. Cmax, 
Tmax, AUC for a specific time interval) may also be derived from the model or from the 
observed data, if possible.
Apparent CL and exposure (AUCss) estimates for dose confirmation in the first cohort of 
adolescents and children will be derived in a Bayesian feedback approach based on an 
adult PopPK model.
Additional PK, PK-PD, or dose/exposure response analyses will be conducted as 
appropriate.
The results of population PK and PK-PD modeling may be reported separately.
6.8
INTERIM ANALYSES
Interim analyses for PK and safety in the first cohort of approximately 24 adolescents 
and subsequently in the first cohort of up to approximately 30 children are planned 
(see Section 3.1.3.1).


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An efficacy and safety interim analysis is planned once approximately 80 subjects taking 
either balovaptan 10 mg eq or placebo (i.e., approximately 40 subjects per treatment 
arm) have completed their 12 week visit without dose interruptions or adjustments to 
allow internal decisions for the next steps of the development plan.
Given the hypothesis generating nature of this study, the Sponsor may conduct up to 
two interim analyses beyond what is specified elsewhere in this protocol. The decision to 
conduct such an interim analysis and its timing will be documented in the Sponsor’s 
study master file prior to the conduct of the interim analysis. The clinical study report will 
also document that such an interim analysis occurred. Interim analyses will be 
performed and interpreted by the IMC and SOC members (as required), who will have 
full access to unblinded data. Recruitment will continue during the efficacy and safety 
interim analyses.
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. Sites will be responsible for data entry into the EDC system.
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Central laboratory data or 
Other electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line Electronic Data Capture (EDC) system. 
The data collected in the source documents is entered onto the study eCRF. An audit 
trail will maintain a record of initial entries and changes made; reasons for change; time 
and date of entry; and user name of person authorizing entry or change. For each 
subject enrolled, an eCRF must be completed and electronically signed by the principal 
Investigator or authorized delegate from the study staff. If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study 
because of a treatment‑limiting adverse event, thorough efforts should be made to 
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The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Subjects will use an ePRO device to capture PRO data. The data will be transmitted 
electronically to a centralized database at the ePRO vendor. The data can be reviewed 
by site staff via secure access.
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived. The Investigator will receive patient 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 patient data in a 
machine-readable format on a compact disc.
ePRO data will be collected using an electronic device provided by an ePRO vendor. 
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11). The ePRO device data are available for view 
access only via secure access. Only identified and trained users may view the data, and 
their actions 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.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which 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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
subject files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.


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Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. No records may be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
If audio recordings have been used, they will be maintained on a secure server 
throughout the duration of the study and will be destroyed one year after study 
completion on approval by the Sponsor.
For countries where ethics committees or the Ministry of Health will not approve audio 
recording of subject interviews, review of the scale worksheets, submitted as part of the 
assessment source information, will be performed to verify accuracy of scoring and 
adherence to study conventions.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. 
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
In this study, caregiver specific information will be collected to evaluate caregiver burden 
requiring that a separate written informed consent be obtained from the caregiver.
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 


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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 of 1996 (HIPAA). 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.
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 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive 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 only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 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.


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Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the
course of the study and for one year after completion of the study (i.e., Last Subject 
Last Visit).
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, which includes an audit trail containing a complete record of all 
changes to data.
Roche shall also submit as a periodic safety report once a year a Development Safety 
Update Report (DSUR) to the IEC and regulatory authorities according to local 
regulatory requirements and timelines of each country participating in the study.
Sampling for the Research Biosample Repository is contingent on review and approval 
for the exploratory biomarker assessments and written informed consent by an 
appropriate regulatory body (depending on the country where the study is performed) 
and a site’s Institutional Review Board (IRB) / Ethics Committee (EC). If a regulatory or 
site’s IRB/ EC does not approve the sampling for the exploratory assessments the 
section on biomarker sampling will not be applicable.
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 Institutional Review Board (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 also whenever subsequent amendments 
/modifications are made to the protocol. 
A Clinical Study Report (CSR) will be written and submitted to relevant Institutional 
Review Board (IRB) / Ethics Committee (EC) and regulatory authorities in accordance 


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with local requirements. To fulfill the requirements for the EU Directive No 75/318/EEC 
the CSR 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 patient 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.
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
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, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  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 patients 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 patients 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.
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.


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


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10.
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Appendix 1
Schedule of Assessments
For all Subjects after Confirmation of Final Doses by IMC and SOC (cont.)
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5. See protocol Section 4.6.1.7 and lab manual for more details about full serum chemistry.
6. At screening, Week 24/Early Withdrawal Visit and Follow-Up Visit (6 weeks), glycated hemoglobin (HbA1c), thyroid stimulating hormone (TSH), 
and free thyroxine (T4) will be assessed. 
 
7. ECG at Week 6 and Week 24 will be performed 3 hours post-dose.
8. ADOS-2 and IQ test up to 12 months old can be accepted at screening; Wechsler Abbreviated Scale of Intelligence Scale, Second Edition 
(WASI-II) or Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) intelligence test will be used at screening.
9. Alcohol test and substance use tests are mandatory at screening for adolescents. At other visits and for children, only to be performed if 
deemed necessary by investigator.
10.Vital signs will be done pre-dose and 3 hours post-dose. Additionally, orthostatic function will be assessed pre-dose and 3 hours post-dose at 
baseline/abbreviated baseline, and 3 hours post-dose at Week 6 and Week 24 or Early Withdrawal Visit.
11.Planned as off-site/home visit and can be done by a nurse, however can also be performed as clinic visits.
12.Tanner staging will be done in patients 7 years and older, but not after menarche in female patients and not after voice break in male patients.
13.Pregnancy tests will be performed in female patients after menarche only.
14.PK samples: Week 8: in the evening post-dose together with safety labs; Week 12 and Week 24: pre + 2 hours post-dose + end of visit but at
least 4 hours post-dose; Early Withdrawal Visit: one at any time.  Samples scheduled at least 4 hours post-dose on a clinic visit day can be 
taken by a nurse at home.
15.Subject and caregiver will provide feedback on palatability of study medication.
16.Subjects will be asked additional questions after completion of the PedsQL.
17.RBR and CG samples should be taken at baseline upon consent, but if missed, may be taken at any visit after.
18.For children 511 years old, additional questions will be asked in context of Columbia-Suicide Severity Rating Scale (C-SSRS; see Section 
4.6.1.12).
19.Subjects from first adolescent/first children cohorts who stopped treatment on or before Week 8 in the context of the IMC/SOC dosing decision 
(see Appendix 2, Section 3.1.3.1) will be allowed to restart for an additional 24 weeks in the main study in the same treatment arm without new 
randomization, provided the investigator can exclude relevant changes in patient's general condition (see Section 4.2.1). These patients will 
have a new, abbreviated baseline visit, and will continue with all subsequent visits according to the schedule of assessments. In this 
abbreviated baseline visit, a single ECG should be taken.
20.For those subjects who consent to the OLE and are able to proceed directly into the OLE, medication will be administered after all assessments 
are complete. This will be defined as Day 1 of the OLE.


Appendix 1
Schedule of Assessments
For all Subjects after Confirmation of Final Doses by IMC and SOC (cont.)
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21.Safety monitoring will follow semi-structured interview as listed in Appendix 8.  This will include a check on compliance with body temperature 
monitoring.  
22. If these hematology samples are required, visits must be conducted either at the site or by a home nurse if appropriate.
23. Blood samples indicated in parentheses are applicable only in the event that temperature monitoring could be implemented or individuals are 
not compliant.










Appendix 2
Schedule of Assessments
For First Cohorts of 24 Adolescents and 30 Children
until Confirmation of Final Doses by IMC/SOC (cont.)
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3. Triplicate ECG at baseline only.
4. Demography includes Educational Level, Diagnosis of ASD, Caregiver Information, Employment and/or school Status and Living 
Arrangements.
5. See protocol Section 4.6.1.7 and lab manual for more details about full and abbreviated serum chemistry.
6. At screening and Follow-Up Visit (6 weeks) glycated hemoglobin (HbA1c), thyroid stimulating hormone (TSH), and free thyroxine (T4) will be 
assessed. 
 
7. At Week 2 and Week 6, a single ECG 3 hours post-dose; at Week 4 a single ECG preferably pre-dose.
8. ADOS-2 and IQ test up to 12 months old can be accepted at screening; Wechsler Abbreviated Scale of Intelligence Scale, Second Edition 
(WASI-II) or Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) intelligence test will be used at screening.
9. Alcohol test and substance use tests are mandatory at screening for adolescents. At other visits and for children only to be performed if 
deemed necessary by investigator.
10.Vital signs will be done pre-dose and additionally 3 hours post-dose at baseline, Week 2 and Week 6. Orthostatic function will be assessed 
3 hours post-dose at baseline and Week 6.
11.Planned as off-site/home visit and can be done by a nurse, however can also be performed as clinic visits.
12.Tanner staging will be done in patients 7 years and older, but not after menarche in female patients and not after voice break in male patients.
13.Pregnancy tests will be performed in female patients after menarche only.
14.PK samples: Week 1: pre-dose; Week 2: pre; + 2 (+/- 0.5); hour + 4 (+/- 0.5) hour + at least 6 hours post-dose; PK samples need to be at least 
2 hours apart; Week 4: pre-dose; End of Treatment Visit: one at any time.  Samples scheduled at least 4 hours post-dose on a clinic visit day 
can be taken by a nurse at home.
15.If treatment continues without halt and with final doses determined, ongoing patients will have their next visit (e.g., visit Week 8) according to 
Appendix 1 and continue from thereafter according to Appendix 1.
16.Subjects can continue in the study beyond 8 weeks, even if dose confirmation has not occurred, as long as individual review of PK has been 
completed and exposure is within agreed limits.
17.RBR and clinical genotyping (CG) samples should be taken at baseline upon consent, but if missed, may be taken at any visit after.
18.For children 511 years old additional questions will be asked in context of Columbia-Suicide Severity Rating Scale (C-SSRS; see 
Section 4.6.1.12).


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Appendix 6
Tanner Stages [48]
Stage
Male Genitalia
Pubic Hair
Female Breasts
1
Preadolescent 
testes, scrotum, and 
penis are childlike in 
size
None; may be vellus 
hair, as over 
abdomen
Preadolescent elevation of 
papilla only
2
Slight enlargement of 
scrotum with 
reddening of skin; 
little or no 
enlargement of penis
Sparse growth of 
long, slightly 
pigmented, downy 
hair, straight or 
slightly curled, 
primarily at base of 
penis or along labia
Breast bud stage; breast and 
papilla form a small mound; 
areolar diameter enlarges
3
Further enlargement 
of scrotum; penis 
enlarges, mainly in 
length
Hair considerably 
darker, coarser, and 
more curled; spreads 
sparsely over 
junction of pubes
Further enlargement of breast 
and areola with no separation 
of their contours
4
Further enlargement 
and darkening of 
scrotum; penis 
enlarges, especially 
in breadth; glans 
develops
Adult-type hair that 
does not extend onto 
thighs, covering a 
smaller area than in 
adult
Areola and papilla project to 
form a secondary mound above 
the contour of the breast; stage 
4 development of the areolar 
mound does not occur in 10% 
of girls and is slight in 20%; 
when present, it may persist 
well into adulthood
5
Adult in size and 
shape
Adult in quantity and 
type with extension 
onto thighs but not 
up linea alba
Mature female; papilla projects 
and areola recesses to general 
contour of breast
In boys, if different scores are obtained for pubic hair and genitalia, the score for 
genitalia should be used.
In girls, if different scores are obtained for pubic hair and breast development, the score 
for breast development should be used.
In this study Tanner staging will be done in subjects 7 years and older, but not after 
menarche in female and not after voice break in male subjects


Balovaptan—F. Hoffmann-La Roche Ltd
135/Protocol BP30153, Version 6
Appendix 7
Strong and Moderate Inhibitors and Inducers of CYP3A [37]
Concomitant administration of strong Cytochrome P450 3A4 (CYP3A) inducers or 
inhibitors is prohibited. Moderate CYP3A inhibitors are also prohibited, but for treatment 
duration of shorter than approximately 10 days (e.g., in the context of an adverse event) 
possible exceptions can be discussed with the Sponsor (Medical Monitor or designee). 
Based on in vitro experiments, quinidine should not be given with balovaptan, but no 
systemic interactions are predicted with cetirizine, dabigatran etexilate, or digoxin.  
Caution is advised when using balovaptan together with other medications known to be 
clinically-relevant substrates of P-gp, in particular for those medications that have a 
narrow therapeutic window (e.g., loperamide). However, when such medications are 
dosed 5 or more hours after administration of balovaptan, the risk of pharmacokinetic 
interaction is predicted to be small.
CYP3A Inhibitor*
CYP3A Inducer*
Itraconazole
St John’s wort
Clarithromycin
Dexamethasone
Ketoconazole
Retinoic acid
Grapefruit juice
Carbamazepine
Erythromycin
Phenytoin
Diltiazem
Rifampin
Verapamil
Ciprofloxacin
Clotrimazole
Fluconazole
Tofisopam
* This table is not exhaustive.


Balovaptan—F. Hoffmann-La Roche Ltd
136/Protocol BP30153, Version 6


Balovaptan—F. Hoffmann-La Roche Ltd
137/Protocol BP30153, Version 6






Appendix 9
Schedule of Assessments:  Open-Label Extension to Week 52 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
140/Protocol BP30153, Version 6
ABCAberrant Behavior Checklist; CaGICaregiver-reported Global Impression; CGI-IClinical Global Impressions of Improvement; CGI-
SClinical Global Impressions of Severity; CPKcreatinine phosphokinase; ECG electrocardiogram; EW Early Withdrawal; FUFollow-Up; 
T; PedsQLPediatric Quality of Life; PKpharmacokinetic; RBS-RRepetitive Behavior 
Scale-Revised; SAEserious adverse event; W Week(s).

Phone call interview
P
Pre-dose.  The first dose of study medication has to be taken after all pre-dose assessments.
1
These assessments can be performed at or within 1 week prior to first dose.
2
If necessary, these clinic visits (Week 30, Week 36, Week 42, Week 52, Early Withdrawal Visit, and 6-week Follow-Up Visit) can be performed over 
2 consecutive days; assessments at screening can be performed over the entire screening time window.  After premature discontinuation, an Early 
Withdrawal Visit should be arranged as soon as possible (see also Section 4.7.1.1).
3
Triplicate ECG at rescreening (substudy) only.
4
Demography includes Educational Level, Diagnosis of ASD, Caregiver Information, Employment and/or school Status, and Living Arrangements
5
See Section 4.6.1.7 and lab manual for more details about full serum chemistry
. 
6
At rescreening (substudy only), Week 76/Early Withdrawal Visit and Follow-Up Visit (6 weeks), glycated hemoglobin (HbA1c), thyroid stimulating 
hormone (TSH), and free thyroxine (T4) will be assessed.  
 
7
ECG at Week 30 will be performed 3 hours post-dose.
8
Alcohol test and substance use tests are mandatory at screening for adolescents.  At other visits and for children, only to be performed if deemed 
necessary by investigator.
9
Pregnancy tests will be performed in female patients after menarche only.
10
Vital signs will be done pre-dose and 3 hours post--dose.  Additionally, orthostatic function will be assessed pre-dose and 3 hours post-dose at 
Week 30.
11
Planned as off-site/home visit and can be done by a nurse, however can also be performed as clinic visits.
12
Tanner staging will be done in patients 7 years and older, but not after menarche in female patients and not after voice break in male patients.
13
PK samples should be collected in those that withdraw from the study early as long as ≤7 days after last dose.
14
For children 511 years old, additional questions will be asked in context of Columbia-Suicide Severity Rating Scale (C-SSRS; see 
Section 4.6.1.12).
15
Patients will be asked additional questions after completion of the PedsQL.
16
Safety interview will occur either at site or during telephone visit and will follow semi-structured interview as listed in Appendix 8.  It will include a 
check on compliance with body temperature monitoring.
17
If these hematology samples are required, visits must be conducted either at the site or by a home nurse if appropriate.


Balovaptan—F. Hoffmann-La Roche Ltd
141/Protocol BP30153, Version 6
Appendix 10
Schedule of Assessments: Open-Label Extension from Weeks 52 to 76
Week
Site
Site
Site
FU
(2 W)
FU
(6 W)
64 2
76 2
EW 2
78
88 2
Day
449
533
NA
Time window (days)


NA


Study site visits
x
x
x
x
Informed consent
Physical and neurological examination
x
x
x
x
Tanner staging 3
x
Anthropometric measurements
x
x
x
x
Vital signs
x
x
x
ECG-12 lead
x
x
x
Hematology
P
x
x
x
x
Full serum chemistry 5
P
x 6
x 6
x 6
Safety questions 1
x
x
x
x
Coagulation
x
x
Urinalysis
x
x
x
Pregnancy test 4
x
x
x
x
Dispensing of study medication
x
Administration of study medication
x
x
x
PK blood samples 
x
x 7


Appendix 10
Schedule of Assessments: Open-Label Extension to Week 76 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
142/Protocol BP30153, Version 6
Week
Site
Site
Site
FU
(2 W)
FU
(6 W)
64 2
76 2
EW 2
78
88 2
Day
449
533
NA
Time window (days)


NA


Vineland–II (survey)
x
x
x
x
ABC
x
x
x
x
RBS-R
x
x
x
x
CaGI
x
x
x
PedsQL (Family Impact Scale)
x
x
x
C-SSRS 8
x
x
x
x
PedsQL (Core and Cognitive Scale) 9
x
x 9
x 9
CGI-S
x
x
x
x
CGI-I
x
x
x
x
Adverse events
Previous and concomitant treatments
ABCAberrant Behavior Checklist; CaGICaregiver-reported Global Impression; CGI-IClinical Global Impressions of Improvement; CGI-
SClinical Global Impressions of Severity; ECGelectrocardiogram; EW Early Withdrawal; FUFollow-Up; PedsQLPediatric Quality of Life; 
PKpharmacokinetic; RBS-RRepetitive Behavior Scale-Revised; W Week(s).

Phone call interview
P
Pre-dose.  The first dose of study medication has to be taken after all pre-dose assessments.
1
Safety interview will occur either at site or during telephone visit and will follow semi-structured interview as listed in Appendix 8.


Appendix 10
Schedule of Assessments: Open-Label Extension to Week 76 (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
143/Protocol BP30153, Version 6
2
If necessary these clinic visits (Week 64, Week 76, Early Withdrawal Visit, and 6-week Follow-Up Visit) can be performed over 2 consecutive days;
assessments at screening can be performed over the entire screening time window.  After premature discontinuation, an Early Withdrawal Visit 
should be arranged as soon as possible (see also Section 4.7.1.1)
3
Tanner staging will be done in patients 7 years and older, but not after menarche in female patients and not after voice break in male patients.
4
Pregnancy tests will be performed in female patients after menarche only.
5
See Section 4.6.1.7  and lab manual for more details about full serum chemistry.
6
At rescreening (substudy only), Week 76/Early Withdrawal Visit, and Follow-Up Visit (6 weeks), glycated hemoglobin (HbA1c), thyroid stimulating 
hormone (TSH), and free thyroxine (T4) will be assessed.
7
PK samples should be collected in those that withdraw from the study early.
8
For children 511 years old, additional questions will be asked in context of Columbia-Suicide Severity Rating Scale (C-SSRS; see 
Section 4.6.1.12).
9
Patients will be asked additional questions after completion of the PedsQL.


Balovaptan—F. Hoffmann-La Roche Ltd
144/Protocol BP30153, Version 6


Balovaptan—F. Hoffmann-La Roche Ltd
145/Protocol BP30153, Version 6


Balovaptan—F. Hoffmann-La Roche Ltd
146/Protocol BP30153, Version 6


Balovaptan—F. Hoffmann-La Roche Ltd
147/Protocol BP30153, Version 6

SAP_001.pdf: 
Official Title: A Phase II Multi-Center, Randomized, Double-Blind, 24 Week, 
Parallel Group, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of Balovaptan (RO5285119) in Children and 
Adolescents Age 5-17 With Autism Spectrum Disorder (ASD) 
NCT Number: NCT02901431 
Document Date: SAP Version 2: 14-May-2019 




2 
 
Table of Contents 
1 
BACKGROUND .................................................................................................. 4 
2 
STUDY DESIGN ................................................................................................. 4 
Figure 1. 
Study Design for subjects enrolled up to Version 5 .......................... 5 
Table 1.  
Age-adjusted Starting Doses Based on PBPK Model ...................... 5 
Table 2.  
Updated Age-adjusted Doses Based on PK Data ............................ 5 
Figure 2. 
Study Design for subjects enrolled in accordance to Version 6 ....... 6 
Table 3.   
Study Treatments in the 24-weeks Main Part (Study Part 2) ........... 7 
2.1 
OBJECTIVES ............................................................................................... 8 
2.1.1 
Primary Objective .................................................................................... 8 
2.1.2 
Secondary Objectives ............................................................................. 8 
2.2 
OUTCOME MEASURES............................................................................... 8 
2.2.1 
Primary Efficacy Endpoint ...................................................................... 8 
2.2.2 
Secondary Efficacy Endpoints ............................................................... 9 
2.2.3 
Exploratory Efficacy Endpoints .............................................................. 9 
2.2.4 
Pharmacokinetic Endpoints .................................................................... 9 
2.2.5 
Safety Endpoints ...................................................................................... 9 
2.3 
DETERMINATION OF SAMPLE SIZE ....................................................... 10 
2.4 
ANALYSIS TIMING .................................................................................... 10 
3 
STUDY CONDUCT ........................................................................................... 10 
3.1 
RANDOMIZATION CONSIDERATIONS .................................................... 10 
3.2 
TREATMENT GROUPING .......................................................................... 11 
3.3 
TIME-WINDOWS ........................................................................................ 12 
4 
STATISTICAL METHODS ................................................................................ 12 
4.1 
ANALYSIS DATASETS .............................................................................. 12 
Table 4.  Patterns of subjects’ disposition ......................................................... 13 
4.2 
ANALYSIS POPULATIONS ....................................................................... 13 
4.2.1 
Safety Population ................................................................................... 14 
4.2.2 
Efficacy Population ................................................................................ 14 
Table 5.  Patterns of subjects’ disposition identifying Safety and Efficacy 
Analysis Population/Dataset ............................................................................. 15 
4.2.3 
PK/PD Population .................................................................................. 15 
4.3 
ANALYSIS OF STUDY CONDUCT ............................................................ 15 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY ........................ 15 
4.5 
EFFICACY ANALYSES .............................................................................. 15 
4.5.1 
Subgroup Analyses ............................................................................... 16 


3 
 
4.5.2 
Interim Analysis ..................................................................................... 17 
4.5.3 
PK/PD Analyses ..................................................................................... 17 
4.6 
SAFETY ANALYSES ................................................................................. 17 
5 
DERIVED ENDPOINTS .................................................................................... 19 
 
 
 


4 
 
1 
BACKGROUND  
This document describes the methods of summarizing and analyzing the data collected in 
Study BP30153.  The main purpose of this document is to describe the data handling rules, 
derivation rules and statistical analysis methods for the final analysis of the double-blind, 24-
week, placebo-controlled period that will be performed by Biostatistics and Statistical 
Programming and Analysis and that will be reported in the Clinical Study Report.  An 
independent document will be prepared to describe the methods that will be used to 
summarize the open-label extension (OLE) data.  Rules and methods here described will be 
applied, as appropriate, for any efficacy and safety interim analysis allowed by the study 
protocol.  
Details on the PK and PK/PD analyses performed by the Pharmacometrics group within 
Clinical Pharmacology may be reported in a document separate from the Clinical Study 
Report. 
This version 2.0 has been developed based on version 1.0, issued on 6-Aug-2018, on study 
protocol BP30153 version 6, issued on 19-Dec-2018, and on Study File Note “Dose 
Adjustment Following Review of PK Data by the IMC SOC” issued on 19-Jan-2019.    
 
2 
STUDY DESIGN 
Study protocol BP30153 version 1-5 were conceived as “A PHASE II MULTI-CENTER, 
RANDOMIZED, DOUBLE-BLIND, 24-WEEK, 3-ARM, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
BALOVAPTAN (RO5285119) IN CHILDREN AND ADOLESCENTS AGE 5-17 WITH 
AUTISM SPECTRUM DISORDER (ASD)”, and version 6 as “A PHASE II MULTI-CENTER, 
RANDOMIZED, DOUBLE-BLIND, 24-WEEK, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
BALOVAPTAN (RO5285119) IN CHILDREN AND ADOLESCENTS AGE 5-17 WITH 
AUTISM SPECTRUM DISORDER (ASD)” with recruitment to the balovaptan 4mg equivalent 
treatment arm closed. 
The overall study design was built by staggering enrollment by subject’s age, starting first 
with adolescents (aged 13 to 17 years) and then with children (aged 5 to 12 years).  Once 
the Internal Monitoring Committee (IMC) and the Scientific Oversight Committee (SOC) 
agreed on acceptable safety and tolerability in the first adolescent cohort (based on data 
from 8 weeks of treatment, First Study part) and determined the final doses, enrollment of 
adolescents resumed (for 24 weeks of treatment, Main Study part) and enrollment of a first 
cohort of younger subjects commenced.  Similar process occurred for the first children 
cohort.  See the Study Protocol for more details. 
Approximately 340 children and adolescents aged 5 – 17 years with ASD are expected to be 
recruited to ensure a total of 160 evaluable subjects with placebo or 10 mg equivalent after 
24 weeks of treatment.  


5 
 
Subjects who complete the double-blind 24-week treatment period are allowed to participate 
in an optional 52-week Open-Label Extension (OLE) period where they receive open-label 
balovaptan treatment (from Week 24 to Week 76).   
For all subjects enrolled prior to protocol version 6, study design can be visualized as 
follows: 
Figure 1. 
Study Design for subjects enrolled up to Version 5 
 
Doses were initially administered as follows: 
Table 1.  
Age-adjusted Starting Doses Based on PBPK Model 
 
During the study, at planned IMC and SOC reviews of accrued data, the starting doses in 
Table 1 were shown to not achieve the target exposure in children aged between 5 and 14 
years.  Therefore, new doses were identified to produce exposures equivalent to the 4 mg 
and 10 mg doses used in adults (Study BP28420) as described by the following Table: 
Table 2.  
Updated Age-adjusted Doses Based on PK Data 
 
 


6 
 
For subjects enrolled in accordance to protocol version 6, study design can be 
visualized as follows: 
Figure 2. 
Study Design for subjects enrolled in accordance to Version 6 
 
For subjects randomized in accordance to protocol version 5 but after the 1st of 
October 2018 the dose is given, once the local IRB approved the plan described in the 
“Dose Adjustment Following Review of PK Data by the IMC SOC”, at the age-adjusted dose 
level as described in Table 2.   
For subjects still on-treatment in accordance to protocol version 5 after the 1st of 
October 2018 the dose is increased, once the local IRB approved the plan described in the 
“Dose Adjustment Following Review of PK Data by the IMC SOC”, to the age-adjusted dose 
level as described in Table 2.  
The following Table describes the disposition of subjects in relationship with study treatment 
in the Main study part, 24-weeks period. 
 




8 
 
2.1 
OBJECTIVES 
2.1.1 
Primary Objective 
The primary objectives of this study is: 
• 
To evaluate the efficacy of 24-week treatment with balovaptan (RO5285119) 10 mg 
equivalent compared to placebo as measured by the change from baseline on the 
Vineland-II Adaptive Behavior Scales, second edition (Vineland-II) Two Domain 
Composite (2DC) (average of Communication and Socialization domains)  
2.1.2 
Secondary Objectives 
The secondary objective of this study are as follows: 
• 
To evaluate the efficacy of treatment with balovaptan 10 mg equivalent vs. placebo on: 
o Change from baseline on the Vineland™-II Composite standard score after 12 weeks 
and 24 weeks of treatment 
o Change from baseline in the Vineland™-II Communication, Socialization and Daily 
Living Skills domain standard scores after 12 weeks and 24 weeks of treatment 
o Proportion of subjects with ≥6-point improvement in the Vineland™-II 2DC score 
(clinically meaningful response) 
o Change from baseline in severity of clinical impressions as measured by CGI-S 
(Clinical Global Impressions-Severity) and OACIS-S (Ohio Autism Clinical 
Impressions Scale-Severity) after 12 weeks and 24 weeks of treatment 
o Improvements in clinical impressions as measured by CGI-I (Clinical Global 
Impressions-Improvement) and OACIS-I (Ohio Autism Clinical Impressions Scale-
Improvement) after 12 weeks and 24 weeks of Treatment 
o Change from baseline in patient- or parent-reported Pediatric Quality of Life 
(PedsQL) v4.0 Generic Core Scale after 12 weeks and 24 weeks of treatment 
o Change from baseline in the Vineland™-II Composite standard score in adolescents 
and children independently after 12 weeks and 24 weeks of treatment 
o Change from baseline on the Vineland™-II 2DC score after 12 weeks of treatment 
• 
To evaluate safety and tolerability of 24 and up to 76 weeks of treatment with 
balovaptan 
• 
To evaluate the pharmacokinetics and exposure-response relationships of balovaptan 
and its metabolites, if appropriate 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline at Week 24 on the Vineland™-II 
Adaptive Behavior Scales 2-Domain Composite (2DC) Score, defined as the mean of the 
Communication domain standard score and the Socialization domain standard score. 


9 
 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as identified in the list of secondary objectives (see 
Section 2.1.2) 
2.2.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are as follows: 
• 
Change from baseline in behaviors as measured by Aberrant Behavior Checklist 
(ABC) Lethargy/Social withdrawal subscale after 12 weeks and 24 weeks of 
treatment 
• 
Change from baseline in repetitive behaviors as measured by Repetitive Behavior 
Scale-Revised (RBS-R) after 12 weeks and 24 weeks of treatment 
• 
Change from baseline to Week 76 (52 weeks of open-label treatment) as measured 
by Vineland™-II 2DC score 
• 
Change from Week 24 to Week 76 (52 weeks of open-label treatment) as measured 
by Vineland™-II 2DC score 
• 
Proportion of subjects with ≥4-point improvement in Vineland™-II 2DC score 
• 
Proportion of subjects with ≥8-point improvement in Vineland™-II 2DC score 
• 
Data (social symptoms, communication, and behavior) from Exit Interviews 
• 
Change from baseline in behaviors as measured by ABC Irritability, Stereotypic 
Behavior, Hyperactivity/Noncompliance, and Inappropriate Speech subscales after 
12 weeks and 24 weeks of treatment 
• 
Change from baseline in patient- or parent-reported PedsQL Cognitive Functioning 
Scale and parent-reported PedsQL Family Impact Scale after 12 weeks and 24 
weeks of treatment 
• 
Change from baseline in caregiver-reported Global Impression (CaGI) severity on 
communication skills, social skills, daily living skills and overall autism symptoms 
after 12 weeks and 24 weeks of treatment 
• 
Improvements in caregiver-reported Global Impression (CaGI) impression on 
communication skills, social skills, daily living skills and overall autism symptoms 
after 12 weeks and 24 weeks of treatment 
• 
Palatability assessments (taste and acceptability) 
2.2.4 
Pharmacokinetic Endpoints 
The pharmacokinetic endpoints are as follows: 
• 
Apparent clearance (CL) and volume of distribution (VD) 
• 
Exposure at steady-state (AUC0-24,ss) 
• 
Other individual exposure estimates (e.g., Cmax, Tmax, AUC for a specific time 
interval) may also be derived as appropriate 
2.2.5 
Safety Endpoints 
Safety will be assessed through: 


10 
 
• 
Occurrence, nature and intensity of adverse events, serious adverse events and non-
serious adverse events of special interest, as determined using the Adverse Event 
Severity Grading Scale  
• 
Physical and neurologic examinations, vital signs, hematology, blood chemistry and 
urinalyses, ECGs and C-SSRS 
2.3 
DETERMINATION OF SAMPLE SIZE 
Prior to protocol version 6, a sample size of 240 subjects with ASD (80 per treatment arm) 
providing evaluable data at Week 24 ensured the study 80% power to detect as statistically 
significant, at 1-sided 5% significance level, a difference between each active dose and 
placebo with an effect size of at least 0.4.  For the Vineland™-II 2DC score, assuming a 
standard deviation of about 12.5 points, then the effect size of 0.4 corresponds to 5 points.  
No adjustment for multiple doses was performed.  Considering a withdrawal rate of around 
15-20%, it was planned to recruit approximately 300 subjects overall. 
In accordance to protocol version 6, 80 subjects per treatment arm (balovaptan 10 mg 
equivalent and placebo) are required, for a total sample size of approximately 160 subjects 
with ASD with evaluable data at Week 24.  To achieve this number of evaluable subjects, 
the overall sample size in the study since it started is expected to increase to approximately 
340 subjects. 
2.4 
ANALYSIS TIMING 
The primary analysis will be conducted when the double-blind 24-week treatment period 
ends.  Database lock 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.   
An efficacy and safety interim analysis is planned once approximately 80 subjects taking 
either balovaptan 10 mg equivalent or placebo (i.e., approximately 40 subjects per treatment 
arm) have completed their 12-week visit without dose interruptions or adjustments to allow 
internal decisions for the next steps of the development plan. 
Given the hypothesis generating nature of this study, the Sponsor may conduct up to two 
interim analyses beyond what is specified elsewhere in this protocol.  The decision to 
conduct such an interim analysis and its timing will be documented in the Sponsor’s study 
master file prior to the conduct of the interim analysis.  The clinical study report will also 
document that such an interim analysis occurred.  Interim analyses will be performed and 
interpreted by the IMC and SOC members (as appropriate), who will have full access to 
unblinded data.   
 
3 
STUDY CONDUCT  
3.1 
RANDOMIZATION CONSIDERATIONS  
After all subjects have been randomized, the data entered into the IxRS system will be 
reviewed for consistency with the data entered into the Case Report Form (CRF).  In 


11 
 
particular, the randomization dates and stratification factors (sex and age) will be checked 
and a summary of the discrepancies between the IxRS and CRF will be reviewed.  
3.2 
TREATMENT GROUPING 
As the starting doses in children aged between 5 and 14 years were shown to not achieve 
the target adult exposure, the treatment grouping originally expected - Placebo, balovaptan 4 
mg equivalent and balovaptan 10 mg equivalent - is no longer tenable.   
Given the numerous different dose regimens occurred in the study, as described in Table 3, 
the individual treatment level will be ultimately identified based on individual subject’s PK 
exposure, estimated as the average plasma concentration (Cave) since treatment start.   
Cave was not specifically listed in the Pharmacokinetic endpoints section of the protocol, 
however, in the situation of possible dose adaptations within an individual during the course 
of the study, Cave is the PK exposure measure that reflects most realistically the individual 
exposure. Moreover, Cave  also takes into account potential dose interruptions during 
treatment. For subjects without dose changes or dose interruptions, Cave is approximately 
equal to AUC0-24,ss divided by 24 hrs. Individual Cave will be estimated by the 
pharmacometrics group in Clinical Pharmacology for all subjects with at least one 
adequately documented PK measurement at steady-state, using a population PK modeling 
approach.  Cave at week 12 will be used as a classification factor to split the subjects 
receiving balovaptan into three equally sized exposure sub-groups: Low Tertile, Medium 
Tertile and High Tertile.     
If insufficient exposure data are available for a subject and Cave cannot be derived (this can 
happen, for example, to withdrawals or in case of issues with PK sample analyses), then 
his/her data will contribute to the same treatment group of the majority of his/her coetaneous 
taking the same regimen as per randomisation.  For example, if a 6 years-old initially 
randomized to 1.5mg switched to 3mg and no PK data are available for him/her, then his/her 
data will be attributed to the Low Tertile if most of the 5-7 years-old subjects taking the same 
regimen are allocated, based on their available exposure, to the Low Tertile.  In case no 
other coetaneous providing exposure data went through the same regimen pattern (as in the 
example, increasing dose from 1.5mg to 3mg) then data will be attributed to the same 
exposure sub-group of the majority of his/her coetaneous taking the same final dose (in the 
example, 3mg). 
This treatment grouping will be used for descriptive (ie, not inferential) statistical reporting 
purposes of efficacy and safety data. 
For pharmacometric exploratory graphical analyses, missing PK information will not be 
inputed. In case of missing PK information for subjects assigned to a starting dose other 
than Placebo, the subject with missing PK information will be excluded from exposure-
efficacy analyses.  
 
 


12 
 
3.3 
TIME-WINDOWS 
Efficacy and safety analyses will be performed according to the data collected at the 
originally scheduled visit.   
In case of deviations from the visit date scheduled as per protocol the following boundaries 
will be implemented to identify time-windows: 
Site  
Visit 
Time-window 
(days) 
Range  
(days) 
Baseline 
Before or soon 
after Start Dosing 
Up to the 1st day  
of dosing 
Week   6 
43 ± 21 
 23 –   64 
Week 12 
85 ± 21 
 65 – 106 
Week 18 
127 ± 21 
107 – 148 
Week 24 
169 ± 21 
149 – at most 21 days  
after last double-blind Dose and prior to  
OLE Screening 
 
For Screening, the scheduled visit will be used regardless of the actual assessment days 
relative to the first day of study drug. 
Baseline Definition 
Unless otherwise stated, baseline is defined as the last non-missing value recorded before 
the first study drug administration of each repeated study drug period (ie. 8 weeks for the 
First Part, and 24 weeks for the Main Part) or soon after the start of the dosing (see Table 
above).  The last observation can be an unscheduled / repeated measurement.  
Baseline for Electrocardiograms (ECGs) is derived as the mean of the triplicate 
measurements of pre-dose assessments.   
Unscheduled Measurements 
Unscheduled measurements will be included in the listings. Except for unscheduled 
measurements used for baseline, unscheduled measurements will be excluded from the 
descriptive statistics and statistical analysis. 
 
4 
STATISTICAL METHODS 
4.1 
ANALYSIS DATASETS 
According to the protocol, the disposition of subjects in relationship with each Study Part 
may be as follows:  




14 
 
 
4.2.1 
Safety Population 
• 
Safety Global 
The “Safety Global” population consists of all subjects who gave informed consent and 
received at least one dose of study medication, whether prematurely withdrawn from the 
study or not.   
Data will be summarized according to treatment classified as derived from PK exposure: 
Placebo, Low Tertile, Medium Tertile, High Tertile and All Treated with Active. 
• 
Safety Inferential 
The “Safety Inferential” population consists of the subset of the “Safety Global” population 
that is identified to address the primary efficacy study objective.   
Data will be summarized according to treatment classified as: Placebo, 10mg equivalent.   
4.2.2 
Efficacy Population 
• 
Efficacy ITT Global 
The “Efficacy Global” population consists of all subjects who gave informed consent and 
received at least one dose of study medication, whether prematurely withdrawn from the 
study or not.   
Data will be summarized according to treatment classified as derived from PK exposure: 
Placebo, Low Tertile, Medium Tertile, High Tertile.   
• 
Efficacy ITT Inferential 
The “Efficacy ITT Inferential” population is the primary population of interest.  It consistsof 
the subset of the “Efficacy Global” population obtained by pooling data from subjects taking 
balovaptan 10 mg equivalent or the concurrently randomized placebo in the corresponding 
age band and in the same randomization stage, as highlighted in orange in Table 3, and 
belonging to patterns c) or d), as highlighted in yellow in Table 4.  Subjects with dose 
adjustments or interruptions, or on a different dose than the final dose for their age group, 
are excluded and do not contribute to this analysis population. 
Data will be summarized according to treatment classified as: Placebo, 10mg equivalent. 


15 
 
The following Table shows the combination of subjects’ patterns (described in Table 4) to 
identify the Safety and Efficacy analyses population/dataset: 
Table 5.  Patterns of subjects’ disposition identifying Safety and Efficacy 
Analysis Population/Dataset 
Analysis Population: 
Analysis dataset: 
First Part (8 weeks) 
Main Part (24 weeks) 
Safety Global 
a + 1st part of b 
2nd part of b + c + d 
Safety Inferential 
- 
c + d 
Efficacy ITT Global 
- 
2nd part of b + c + d 
Efficacy ITT Inferential 
- 
c + d 
4.2.3 
PK/PD Population 
The PK/PD population will be used for exploratory PK/PD analyses.  The PK/PD population 
consists of a subset of the Efficacy Global population and includes all subjects with at least 
one post-baseline efficacy measurement and an exposure estimate. For subjects assigned 
to Placebo, exposure will be assumed to be 0. In case of missing PK information for subjects 
assigned to a starting dose other than Placebo, the subject with missing PK information will 
be excluded from exposure-efficacy analyses. 
4.3 
ANALYSIS OF STUDY CONDUCT  
The number of subjects who enroll, discontinue or complete the study will be summarized for 
the Safety population/dataset by treatment group.  Reasons for premature withdrawal from 
the study and premature withdrawal from treatment will be listed and summarized.  
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY  
Demographic and baseline characteristics (including age, sex, WASI-II IQ score, SRS-2 total 
t-score, Vineland-II 2DC score) and clinically relevant disease characteristics (including 
background antipsychotics) will be summarized for the Safety population/dataset by 
treatment group using means, standard deviations, medians and ranges for continuous 
variables and proportions for categorical variables, as appropriate.   
4.5 
EFFICACY ANALYSES  
Summary tables and graphs will be provided both for the “Efficacy ITT Global” and for the 
“Efficacy ITT Inferential” populations, while listings of individual data will be provided for the 
“Efficacy ITT Global” population only, separately by subjects’ patterns (b, c, d). 
Inferential statistical analysis will be performed on pooled data from subjects taking 
balovaptan 10 mg equivalent dose compared with those from the concurrently randomized 
placebo in the corresponding randomization stage, as identified by the “Efficacy ITT 
Inferential” population.  Multiple endpoints will be analyzed however, due to the exploratory 
nature of the study, multiplicity will not be statistically adjusted for and the risk of false 
positive results will be taken into consideration during the interpretation of the results.  


16 
 
The primary efficacy endpoint, the change from baseline of VinelandTM-II 2-DC standard 
score, as well as the secondary endpoints expressed in terms of change from baseline on a 
continuous scale (namely, Vineland-II standard scores, PedsQL Scale factors, ABC factors 
and RBS-R factors) will be analyzed using Mixed Model Repeat Measurements (MMRM) on 
the overall population of adolescents and children.  The MMRM model will include treatment, 
sex and visit (week) as main effects, individual age and baseline score as covariates, and 
treatment-by-visit and baseline-by-visit as interaction terms.  Visit will be fitted as a repeated 
effect with an unstructured correlation structure across visits within each subject.  All main 
effects and interactions will be retained in the final model regardless of their statistical 
significance.   
The results of the analysis will be presented as point estimates, 90% confidence intervals 
and associated p-values for the adjusted mean differences between 10 mg eq balovaptan 
and placebo after 24 weeks of treatment as well as at intermediate visits.  
The main analysis outlined above will be done using a mixed effect model, which can handle 
missing data without any need to recur to imputation or discarding of data.  
The proportion of subjects with ≥6-point improvement in the Vineland™-II 2DC score 
(clinically meaningful response) will be analyzed using logistic regression.  A Generalised 
Estimating Equations (GEE) model will be fitted including treatment, sex and visit (week) as 
main effects, age as covariate, baseline-by-visit and treatment-by-visit interactions, with 
subject fitted as a repeated effect.  It will be based on the binomial distribution and thus the 
link function will be the ‘logit’.   
The odds ratio will be presented for descriptive purposes along with the corresponding 90% 
confidence interval and p-value for the comparisons between 10 mg eq balovaptan and 
placebo after 24 weeks of treatment as well as at intermediate visits. 
Change from baseline in severity of clinical impressions as measured by CGI-S  
The proportion of subjects with at least 1-point decrease (i.e. improvement) from baseline on 
CGI-S will be analyzed using logistic regression.  A GEE model will be fitted including 
treatment, sex and visit (week) as main effects, age and baseline CGI-S as covariates, 
baseline-by-visit and treatment-by-visit interactions, with subject fitted as a repeated effect.  
It will be based on the binomial distribution and thus the link function will be the ‘logit’.   
The odds ratio will be presented for descriptive purposes along with the corresponding 90% 
confidence interval and p-value for the comparisons between 10 mg eq balovaptan and 
placebo after 24 weeks of treatment as well as at intermediate visits. 
Improvements in clinical impressions, as measured by CGI-I scores  
The proportion of subjects with a value of at least 2 (i.e., “Much improved” or better) on CGI-I 
will be analyzed using logistic regression applying the same model above described for 
CGI-S. 
4.5.1 
Subgroup Analyses  
The results of the primary and secondary efficacy variables will be summarized within 
subgroups using descriptive statistics. The following categorization will be used to define the 
subgroups:  


17 
 
• 
Sex (male, female)  
• 
Age (adolescents 13-17yrs, children 5-12yrs)  
 
The statistical model for subgroup analyses of efficacy data will be performed using MMRM 
with subgroup, treatment-by-subgroup, subgroup-by-time and treatment-by-subgroup-by-
time interaction terms included along the independent effects described above.  
Estimates of treatment effect and associated 90% CIs will be presented in forest plots. 
Unadjusted p-values will also be presented for these analyses. 
4.5.2 
Interim Analysis  
The populations assessed at the Interim Analysis will be the “Safety Inferential” and the 
“Efficacy ITT Inferential” with all subjects randomized prior to 21FEB2019, which is the date 
of the last subject expected to provide 12 week data for the 10mg-Placebo comparison by 
16MAY19. 
The efficacy interim analysis will focus on the outcome measures derived from Vineland™-II 
and, only descriptively, from PedsQL v4.0 Generic Core Scale, CGI-I and CGI-S.   
Summary statistics will be provided for the overall population and for the adolescents/ 
children subgroups separately. 
4.5.3 
PK/PD Analyses  
An exploratory graphical analysis of the relationship between pharmacokinetic exposure and 
efficacy will be performed by Clinical Pharmacology. For the exploratory graphical exposure-
efficacy analyses, Cave will be used either as a continuous covariate or as grouping variable. 
Graphical displays will include (but are not limited to) efficacy outcome measure vs. 
exposure by visit, and efficacy outcome measure vs. time, with trend lines split by exposure 
category (e.g. placebo, Low, Medium and High Tertile of Cave). The effect of subpopulations 
will also be investigated.  
If warranted after review of initial graphical displays, a model based approach may be 
considered to quantify the exposure-effect relationship for Vineland™-II 2-DC. A model 
based exposure-efficacy analysis of other efficacy outcome measures might be considered 
upon agreement with the project team. 
Results from pharmacometric analyses may be reported in a document separate from the 
clinical study report. 
 
4.6 
SAFETY ANALYSES 
Summary tables and graphs will be provided both for the “Safety Global” and for the “Safety 
Inferential” populations, while listings of individual data will be provided for the “Safety 
Global” population only, separately by subjects’ patterns (a, b, c, d). 
As appropriate, listings, summary tables and graphs by treatment group will be provided for 
safety and tolerability assessments, including:  
• 
Incidence of adverse events (overall, by intensity, and by relationship to study 
medication).  




19 
 
represent a defined change from baseline will be considered marked laboratory 
abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a 
subject, the midpoint of the standard reference range will be used as the subject’s baseline 
value for the purposes of determining marked laboratory abnormalities. Marked laboratory 
abnormalities will be labeled in the subject listings as “HH” for very high or “LL” for very low.  
Vital Signs and ECG 
Vital signs and ECG will be presented by individual listings and summary tables by treatment 
group and time of raw values and change from baseline. 
Concomitant Medications 
Concomitant medications will be presented in summary tables and listings.  
 
5 
DERIVED ENDPOINTS 
• Aberrant Behavior Checklist (ABC) 
The ABC consists of 58 items subdivided in 5 subscales: Irritability, Lethargy and Social 
Withdrawal, Stereotypic Behavior, Hyperactivity/Non-Compliance and Inappropriate 
Speech.   
The total scores for each of the 5 subscales (but not the values of all 58 items) will be 
electronically transferred to Roche.  
• Pediatric Quality of Life Inventory (PedsQL ™ 4.0) Generic Core 
The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment 
consists of 23 items encompassing 4 core scale domains:  
― Physical Functioning (8 items) 
― Emotional Functioning (5 items) 
― Social Functioning (5 items) 
― School Functioning (5 items) 
summarised into: 
― Total Score (23 items) 
To create the scores for the above described 4 Functioning Scales and the Total Score a 
mean is computed as the sum of the items divided by the number of items answered 
(this accounts for missing data).  If more than 50% of the items in the scale are missing, 
the Scale Score is not computed [Viecili and Weiss, 2015].  
Additional Summary Scores will be derived as follows:  
― Psychosocial Health Summary Score, as the sum of the items divided by the 
number of items (15, in case of no missing values) answered in the Emotional, 
Social, and School Functioning Scales.   


20 
 
― Physical Health Summary Score, which is the same as the Physical Functioning 
Scale Score. 
― PedsQL Total Score, computed as the sum of all the items divided by the number 
of items (23, in case of no missing values) answered on all the Scales. 
If more than 50% of the items are missing, the Summary Score is not computed [Viecili 
and Weiss, 2015]. 
The above described Functioning Scales and Summary Scores will be derived by Roche 
Statistical Programmer.  
• Pediatric Quality of Life Cognitive Functioning Scale 
The PedsQL Cognitive Functioning Scale consists of 6 items.  
To create the Cognitive Functioning Total Score a mean is computed as the sum of the 
items divided by the number of items answered (this accounts for missing data).  If more 
than 50% of the items in the scale are missing, the Scale Score is not computed [Viecili 
and Weiss, 2015].  
• Pediatric Quality of Life Family Impact Scale 
The Pediatric Quality of Life Inventory (PedsQL™) Family Impact Module version 2 
consists of 36 items encompassing the following 6 scales  
― Physical Functioning (6 items)  
― Emotional Functioning (5 items)  
― Social Functioning (4 items)  
― Cognitive Functioning (5 items)  
― Communication (3 items) 
― Worry (5 items) 
and the 2 following scales measuring parent-reported family functioning  
― Daily Activities (3 items) 
― Family Relationships (5 items) 
The above described 6+2 scales are summarised by mean scores computed as the sum 
of the items scores divided by the number of items answered (this accounts for missing 
data).  If more than 50% of the items in the scale are missing, the Scale Score is not 
computed [Varni et al., 2004].   
Additional Summary Scores will be derived as follows: 
― Total Score, by averaging across all 36 items 
― Parent HRQoL Summary Score, by averaging the 20 items in Physical, 
Emotional, Social and Cognitive Functioning 
― Family Summary Score, by averaging the 8 items in Daily Activities and Family 
Relationships 


21 
 
The above described Functioning Scale and Summary Scores will be derived by Roche 
Statistical Programmer.  
• Repetitive Behavior Scale - Revised (RBS-R)  
The RBS-R is a 43-item informant-based questionnaire assessing the variety of 
restricted and repetitive behaviors observed in individuals with ASD.  The scale is 
grouped into 6 subscales: Stereotyped, Self-injurious, Compulsive, Ritualistic, 
Sameness, and Restricted Behaviors. 
The subscales score will be electronically transferred to Roche.  
• Vineland-II Adaptive Behaviour Scale (VABS)  
Values of Vineland-II Adaptive Behavior Composite Score (as Sum and Standard 
score), domains (as v-scale and standard score for each of the 3 domains, 
Communication, Daily Living Skills, Socialization), subdomains (as raw and v-scale for 
each of the subdomains) and age-equivalent values (years:months, for each subdomain) 
will be derived via computerized system and electronically transferred to Roche. 
The value for the primary endpoint, Vineland™-II Adaptive Behavior Scales 2-Domain 
Composite (2DC) Score, defined as the mean of the Communication domain standard 
score and the Socialization domain standard score, will be derived by Roche Statistical 
Programmer.  If any of the two individual domain standard scores is missing the 2DC 
score is not computed.