Clinical trial NCT05401565
Conditions: Stress Disorders, Post-Traumatic
Sponsor: Hoffmann-La Roche
Start date: 2022-08-02; Completion date: 2023-10-05
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of 10 mg of oral administration balovaptan once a day (QD) compared with matching placebo in adults with PTSD.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Balovaptan intervention 2: Placebo
Intervention descriptions: intervention 1: Intervention of oral administration of 10mg balovaptan QD for 12 weeks followed by two weeks of follow-up period intervention 2: Matching placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase II, Randomized, Double-Blind, Placebo-Controlled, Two-
Arm, Parallel-Group, Multicenter Study to Evaluate the Efficacy and 
Safety of Balovaptan in Adults With Post-Traumatic Stress Disorder 
NCT Number: 
NCT05401565 
Document Date: 
Protocol Version 3: 09-January-2023 
 
 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 BN43546, Version 3 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, TWO-ARM, 
PARALLEL-GROUP, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
BALOVAPTAN IN ADULTS WITH 
POST-TRAUMATIC STRESS DISORDER
PROTOCOL NUMBER: BN43546 
VERSION NUMBER: 
3 
ROCHE COMPOUND: 
Balovaptan (RO5285119) 
STUDY PHASE: 
Phase II 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
158940 
NCT NUMBER: 
NCT05401565 
SPONSOR NAME AND 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 


Balovaptan—F. Hoffmann-La Roche Ltd 
2/Protocol BN43546, Version 3 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
3 
See electronic date stamp on the 
final page of this document 
2 
23 February 2022 
1 
22 December 2021 


Balovaptan—F. Hoffmann-La Roche Ltd 
3/Protocol BN43546, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol BN43546 has been primarily amended to include Sponsor-initiated 
modifications including the reduction of the sample size, an update to the QT interval 
corrected through use of Fridericia's formula (QTcF) monitoring, and the removal of the 
planned interim analysis.  Changes to the protocol, along with a rationale for each 
change, are summarized below: 
• 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitor has been removed from the protocol (Protocol title page, protocol 
acceptance form, and Section 8.3.8).  Medical Monitor contact information has been 
replaced with a sentence indicating that this information will be provided separately 
to sites. 
• 
The protocol synopsis has been simplified to align with Clinical Trial Regulation and 
other guidelines (Section 1.1). 
• 
The sample size has been reduced from 252 participants to 30 participants to 
investigate the objectives of the study with a reduced scope (Sections 1.2, 4.1.2, 5, 
and 9.2; Appendix A1−5) and the following changes have been made as a result:  
– 
The objectives of this study have been revised from "evaluate" to "investigate" 
as the reduced sample size precludes formal comparisons (Section 3). 
– 
The description of the primary estimand, statistical hypothesis, and primary, 
secondary, and exploratory analysis methodologies have been removed as all 
analyses will be conducted using descriptive statistics (Section 3, 9.1, 9.4.2, 
9.4.3.1, and 9.4.4). 
– 
The estimated time to complete enrollment has been updated from 
approximately 13 or 15 months to 9 months (Sections 4.1 and 4.4). 
– 
The planned and optional interim analyses have been removed (Sections 4.1, 
9.4, 9.5.1, and 9.5.2). 
– 
The total length of the study has been updated from approximately 18 months 
to 13 months (Section 4.4). 
– 
The number of sites has been reduced from 25 to 12 (Appendix A1−5). 
• 
Guidance has been added to clarify that if a participant cannot be reached during 
the telephone visits, at least 3 documented attempts to contact the participant must 
occur (Section 1.3). 
• 
To align with the protocol text, the footnote for measurement of vital signs in the 
schedule of activities has been updated to include guidance that three consecutive 
blood pressure readings will be recorded at intervals of at least 1 minute and the 
average of the three blood pressure readings will be recorded on the eCRF 
(Section 1.3). 
• 
Guidance has been added to provide instructions for participants who need to take 
their daily dose at a different time of the day and for missed doses (Sections 1.3 and 
6.1). 


Balovaptan—F. Hoffmann-La Roche Ltd 
4/Protocol BN43546, Version 3 
• 
The exclusion criterion for ECG abnormality has been updated to clarify that the two 
consecutive measurements of the ECGs during screening should be taken 
approximately 30 minutes apart and the second measurement is only taken if it is 
necessary to confirm initial ECG abnormality.  The exclusion criterion has also been 
updated to include a separate QTcF threshold of ≥ 470 ms for female participants to 
better reflect current standard of care QTcF thresholds (Section 5.2). 
• 
Text has been added to specify that tobacco use is permitted during the study and 
to provide examples of nicotine and tobacco use (Section 5.3.2). 
• 
As all analysis will now be conducted by the Sponsor instead of external partners, 
text has been added to specify that some individuals from the Sponsor may have 
access to unblinded data as needed for ongoing analysis but the core study team 
with direct site contact will remain blinded throughout the conduct of the study.  
Additionally, text regarding access to blinded data through a secure data sharing 
platform by the external partner has been removed (Section 6.3.2). 
• 
The responsibilities of the investigator and the role of the Medical Monitor during 
study conduct have been clarified (Sections 6.8, 6.8.2.1, and 8.2.5; 
Appendix A6−2.2). 
• 
It has been clarified that there is no preclinical or clinical evidence that balovaptan 
administration is associated with an increase in abnormal liver tests (Section 7.1.1). 
• 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 8.11.2.6). 
• 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Appendix A1−4). 
• 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Appendix A1−6). 
• 
The Sponsor record retention policy has been clarified (Appendix A1−7).  
• 
The descriptions of potential risks associated with balovaptan has been updated to 
include a clinical study in pediatric participants (Study BP30153) at 10 mg or an 
equivalent dose based on predicted exposure of balovaptan (Appendices A6−1.2 
and A6−1.5). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


Balovaptan—F. Hoffmann-La Roche Ltd 
5/Protocol BN43546, Version 3 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM  ......................................... 11 
1.
PROTOCOL SUMMARY ............................................................... 12
1.1
Synopsis .................................................................................. 12
1.2
Study Schema ......................................................................... 15
1.3
Schedule of Activities ............................................................... 16
2.
INTRODUCTION ........................................................................... 22
2.1
Study Rationale ....................................................................... 22
2.2
Background.............................................................................. 22
2.3
Benefit–Risk Assessment ........................................................ 25
3.
OBJECTIVES, ENDPOINTS AND ESTIMANDS........................... 26
4.
STUDY DESIGN ........................................................................... 28
4.1
Overall Design ......................................................................... 28
4.1.1
Screening Period ..................................................................... 29
4.1.2
Blinded Treatment Period ........................................................ 29
4.1.3
Follow-Up Period ..................................................................... 30
4.2
Rationale for Study Design ...................................................... 30
4.2.1
Rationale for Study Population ................................................ 30
4.2.2
Rationale for Use of Placebo ................................................... 31
4.2.3
Rationale for Biomarker Assessments ..................................... 31
4.2.4
Rationale for Use of Clinician-Administered PTSD Scale 
for DSM-5 (CAPS-5) ................................................................ 32
4.3
Justification for Dose and Schedule ......................................... 32
4.4
End of Study Definition ............................................................ 33
4.5
Duration of Participation .......................................................... 33
5.
STUDY POPULATION .................................................................. 33
5.1
Inclusion Criteria ...................................................................... 34
5.2
Exclusion Criteria ..................................................................... 35
5.3
Lifestyle Considerations ........................................................... 37
5.3.1
Meals and Dietary Restrictions ................................................ 37
5.3.2
Alcohol, Tobacco, and Cannabis ............................................. 37


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5.3.3 
Activity ..................................................................................... 37 
5.3.4 
Contraception Requirements ................................................... 37 
5.4 
Screen Failures ........................................................................ 37 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY ........ 38 
6.1 
Study Treatments Administered ............................................... 38 
6.2 
Preparation, Handling, Storage, and Accountability ................. 39 
6.3 
Treatment Assignment and Blinding ........................................ 40 
6.3.1 
Treatment Assignment ............................................................. 40 
6.3.2 
Blinding .................................................................................... 40 
6.4 
Study Treatment Compliance .................................................. 41 
6.5 
Dose Modification .................................................................... 42 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 42 
6.7 
Treatment of Overdose ............................................................ 42 
6.8 
Concomitant Therapy .............................................................. 42 
6.8.1 
Permitted Therapy ................................................................... 43 
6.8.2 
Cautionary Therapy ................................................................. 44 
6.8.2.1 
Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes ................................................ 44 
6.8.2.2 
Herbal Therapies ..................................................................... 44 
6.8.3 
Prohibited Therapy .................................................................. 44 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............ 45 
7.1 
Discontinuation of Study Treatment ......................................... 45 
7.1.1 
Liver Chemistry Stopping Criteria ............................................ 46 
7.1.2 
QTc Stopping Criteria .............................................................. 47 
7.1.3 
Hematological Toxicity Criteria ................................................ 47 
7.1.4 
Cardiac Toxicity ....................................................................... 47 
7.1.5 
Peripheral Neuropathy ............................................................. 48 
7.2 
Participant Discontinuation or Withdrawal from the Study ....... 49 
7.3 
Participants Lost to Follow-Up ................................................. 49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 50 
8.1 
Efficacy Assessments .............................................................. 51 


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7/Protocol BN43546, Version 3 
8.1.1 
Clinical Outcome Assessments ............................................... 51 
8.1.1.1 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) ....... 51 
8.1.1.2 
Clinician-Global Impression of Severity (CGI-S) and 
Change (CGI-C) ....................................................................... 52 
8.1.1.3 
Patient Health Questionnaire-9 (PHQ-9) ................................. 52 
8.1.1.4 
Life Events Checklist for DSM-5 (LEC-5) ................................. 53 
8.1.1.5 
PTSD Checklist for DSM-5 (PCL-5) ......................................... 53 
8.1.1.6 
Structured-Clinical Interview for DSM-5 (SCID-5) .................... 54 
8.1.1.7 
Beck Anxiety Inventory (BAI) ................................................... 54 
8.1.1.8 
Pittsburgh Sleep Quality Index (PSQI) ..................................... 54 
8.1.1.9 
Sheehan Disability Scale (SDS) .............................................. 55 
8.1.1.10 
Cognitive and Physical Functioning Questionnaire (CPFQ) .... 55 
8.1.1.11 
Patient-Global Impression of Severity (PGI-S) and Change 
(PGI-C) .................................................................................... 55 
8.1.1.12 
Computerized Cognitive Battery .............................................. 55 
8.2 
Safety Assessments ................................................................ 56 
8.2.1 
Physical Examinations ............................................................. 56 
8.2.2 
Vital Signs ................................................................................ 56 
8.2.3 
Neurological Examination ........................................................ 56 
8.2.4 
Electrocardiograms .................................................................. 57 
8.2.5 
Clinical Safety Laboratory Assessments .................................. 58 
8.2.6 
Pregnancy Testing ................................................................... 58 
8.2.7 
Monitoring for Suicidal Ideation and Behavior.......................... 59 
8.3 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 59 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 60 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 60 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 60 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 61 
8.3.5 
Pregnancy................................................................................ 61 
8.3.6 
Death Events ........................................................................... 62 
8.3.7 
Adverse Events of Special Interest .......................................... 62 


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8/Protocol BN43546, Version 3 
8.3.8 
Medical Monitors and Emergency Medical Contacts ............... 63 
8.4 
Pharmacokinetics .................................................................... 63 
8.5 
Pharmacodynamics ................................................................. 63 
8.6 
Genetics .................................................................................. 64 
8.7 
Biomarker Assessments .......................................................... 64 
8.8 
Immunogenicity Assessments ................................................. 65 
8.9 
Health Economics and Medical Resource Utilization ............... 65 
8.10 
Clinical Outcome Assessments ............................................... 65 
8.10.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 65 
8.10.2 
Description of Clinical Outcome Assessment Instruments ....... 66 
8.11 
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ........................................................ 66 
8.11.1 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Participants at Participating Sites) .......... 66 
8.11.2 
Samples for Research Biosample Repository (Participants 
Providing Separate Consent at Participating Sites) ................. 68 
8.11.2.1 
Overview of the Research Biosample Repository .................... 68 
8.11.2.2 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 68 
8.11.2.3 
Sample Collection .................................................................... 68 
8.11.2.4 
Confidentiality .......................................................................... 69 
8.11.2.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 69 
8.11.2.6 
Withdrawal from the Research Biosample Repository ............. 70 
8.11.2.7 
Monitoring and Oversight ......................................................... 70 
9. 
STATISTICAL CONSIDERATIONS .............................................. 71 
9.1 
Statistical Hypotheses ............................................................. 71 
9.2 
Sample Size Determination ..................................................... 71 
9.3 
Analysis Sets ........................................................................... 71 
9.4 
Statistical Analyses .................................................................. 71 
9.4.1 
General Considerations ........................................................... 71 
9.4.2 
Primary Endpoint ..................................................................... 72 
9.4.3 
Secondary Endpoints ............................................................... 72 


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9/Protocol BN43546, Version 3 
9.4.3.1 
Clinician-Global Impression of Severity (CGI-S) ...................... 72 
9.4.3.2 
Patient Health Questionnaire-9 (PHQ-9) ................................. 72 
9.4.4 
Exploratory Endpoints .............................................................. 73 
9.4.5 
Safety Analyses ....................................................................... 73 
9.4.6 
Other Analyses ........................................................................ 73 
9.4.6.1 
Summaries of Conduct of Study .............................................. 73 
9.4.6.2 
Summaries of Treatment Group Comparability ........................ 74 
9.4.6.3 
Pharmacokinetic Analyses ....................................................... 74 
9.5 
Interim Analyses ...................................................................... 74 
9.6 
Internal Monitoring Committee ................................................. 74 
10. 
REFERENCES.............................................................................. 74 
 
 
LIST OF TABLES 
Table 1 
Schedule of Activities .................................................................. 16 
Table 2 
Objectives and Corresponding Endpoints ................................... 26 
Table 3 
Study Treatment Description ....................................................... 38 
Table 4 
Management Guidelines for Cardiac Events ............................... 48 
Table 5 
Patient Health Questionnaire-9 (PHQ-9) Score and  
Corresponding Categories .......................................................... 72 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 15 
 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........... 80 
Appendix 2 
Clinical Safety Laboratory Tests ................................................. 87 
Appendix 3 
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................... 89 
Appendix 4 
Contraceptive and Barrier Guidance ......................................... 105 
Appendix 5 
Genetics:  Use and Analysis of DNA ......................................... 108 
Appendix 6 
Safety Plan:  Management of Identified and Potential Risks ..... 109 
Appendix 7 
Structured Brief Interview and Examination for Peripheral 
Neuropathy ............................................................................... 122 
Appendix 8 
ChildPugh Classification ......................................................... 128 


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10/Protocol BN43546, Version 3 
Appendix 9 
Questionnaire to Evaluate for Signs and Symptoms 
Indicative of Infections .............................................................. 129 
Appendix 10 
Examples of Cytochrome P450 3A4 Inducers and Inhibitors .... 130 
Appendix 11 
Clinical Outcome Assessment Instruments ............................... 132 
Appendix 12 
Abbreviations ............................................................................ 213 
Appendix 13 
Protocol Amendment History .................................................... 215 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
11/Protocol BN43546, Version 3 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, TWO-ARM, 
PARALLEL-GROUP, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
BALOVAPTAN IN ADULTS WITH 
POST-TRAUMATIC STRESS DISORDER  
PROTOCOL NUMBER: BN43546 
VERSION NUMBER: 
3 
ROCHE COMPOUND: 
Balovaptan (RO5285119) 
SPONSOR NAME: 
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 retain the signed original of this form for your study files. Please return a copy of 
the signed form as instructed by your local study monitor. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
12/Protocol BN43546, Version 3 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
 
PROTOCOL TITLE: 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, TWO-ARM, PARALLEL-GROUP, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF BALOVAPTAN IN ADULTS WITH 
POST-TRAUMATIC STRESS DISORDER 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  158940 
EudraCT Number:  Not applicable 
NCT Number:  NCT05401565  
  
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of balovaptan, a vasopressin 1a 
(V1a) receptor antagonist, in participants with post-traumatic stress disorder (PTSD).  Treatment 
options for PTSD include trauma-focused (TF) psychological interventions, such as cognitive 
behavioral therapy (CBT) and pharmacological treatments, including antidepressants (selective 
serotonin reuptake inhibitors [SSRIs] and serotonin and norepinephrine reuptake inhibitors 
[SNRIs]).  The overall response rate with these interventions is limited, and there continues to be 
a need for treatments with better benefit-risk profiles that target the core symptoms of PTSD.   
OBJECTIVES AND ENDPOINTS AND ESTIMANDS 
This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg once a day (QD) 
balovaptan compared with placebo in participants with PTSD.  Specific primary and secondary 
objectives and corresponding endpoints for the study are outlined below. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
13/Protocol BN43546, Version 3 
Primary Objective 
Efficacy Objective 
Corresponding Endpoint 
• To investigate the efficacy of 
balovaptan compared with 
placebo 
• Change from baseline at Week 12 in the CAPS-5 total 
symptom severity score 
Secondary Objectives 
Efficacy Objectives 
Corresponding Endpoints 
• To investigate the efficacy of 
balovaptan compared with 
placebo 
• Change from baseline in symptom  severity as 
measured by CGI-S after 12 weeks of treatment 
• To investigate the efficacy of 
balovaptan compared with 
placebo in depression 
• Change from baseline at Week 12 in the PHQ-9 total 
score 
Safety Objective 
Corresponding Endpoints 
• To investigate the safety of 
balovaptan compared with 
placebo 
Safety will be assessed through the following: 
• Incidence and severity of adverse events, with severity 
determined according to a mild/moderate/severe 
grading scale  
• Physical and neurologic examinations, vital signs, 
hematology, blood chemistry, including urinalysis 
• ECGs and Doppler echocardiograms (the latter 
performed only in case of confirmed cardiac biomarker 
elevation) 
• C-SSRS 
Pharmacokinetic Objectives 
Corresponding Endpoints 
• To investigate the plasma 
pharmacokinetics of balovaptan 
• Concentration per timepoint for balovaptan a 
• PK parameters as appropriate 
CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CGI-S = Clinician-Global Impression of 
Severity; M2 = metabolite 2; M3 = metabolite 3; PHQ-9 = Patient Health Questionnaire-9; 
PK = pharmacokinetic; PTSD = post-traumatic stress disorder. 
a Concentration of M2 and M3 may be measured if indicated (e.g., safety concern). 
 
OVERALL DESIGN 
Study BN43546 is a Phase II, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group, multicenter study to evaluate the efficacy and safety of 10 mg of oral balovaptan 
QD in adults with PTSD.   


 
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14/Protocol BN43546, Version 3 
Several key aspects of the study design and study population are summarized below. 
 
Phase: 
Phase II 
Population Type: 
Adult patients 
Control Method: 
Placebo 
Population Diagnosis 
or Condition: 
Post-traumatic stress 
disorder 
Interventional 
Model: 
Parallel 
Population Age: 
18-60 years, inclusive 
Test Compound: 
Balovaptan 
Site Distribution: 
Multi-site 
Active Comparator: Not applicable 
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 30 
 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is balovaptan and placebo. 
One tablet of study drug (10 mg of balovaptan or placebo) should be taken orally QD at home at 
the same time each day, preferably in the morning, with or without food.  The tablet should be 
swallowed whole with something to drink.  
Participants who need to take their study drug at a time of day outside of their usual routine 
may do so (e.g., participant typically takes their study drug in the morning, but due to an 
unforeseen scheduling conflict cannot take their medication until the afternoon), but only one 
dose may be taken each day.  If a dose is missed, the participant should make a note to report 
this missed dose to the site at their next contact.  A missed dose of study treatment must not 
be made up the next day. 
The first dose of the study drug will be administered on Day 1 after all pre-dose assessments 
have been conducted.  At subsequent visits at Weeks 2 and 12 (except for the Week 6 visit), the 
study drug will be administered after all protocol-mandated study assessments have been 
completed.  
Modification of the balovaptan or placebo dose is not permitted. 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to be approximately 
18 weeks. 
 
COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee 


 
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15/Protocol BN43546, Version 3 
1.2 
STUDY SCHEMA 
Figure 1 Study Schema 
 
BL = baseline; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; DSM-5 = Diagnostic 
and Statistical Manual of Mental Disorders, Version 5; PTSD = post-traumatic stress disorder; 
QD = once a day; W = week. 
 








Table 1  
Schedule of Activities (cont.)  
Balovaptan—F. Hoffmann-La Roche Ltd 
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CAPS-5=Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Version 5; CGI-C=Clinician Global 
Impression of Change; CGI-S=Clinician-Global Impression of Severity; CPK=creatine phosphokinase; CK-MB=creatine kinase-MB; 
CPFQ=Cognitive and Physical Functioning Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale; cTnI=cardiac troponin; 
DSM-5=Diagnostic and Statistical Manual of Mental Disorders, Version 5; eCRF=electronic Case Report Form; EEG=electroencephalogram; 
HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HDL = high-density lipoprotein; 
hs-cTnT=high−sensitivity-cardiac troponin T; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LEC-5=Life Events Checklist for DSM-5; 
PCL-5=PTSD Checklist for DSM-5; PCP=phencyclidine; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of 
Severity; PHQ-9=Patient Health Questionnaire-9; PK=pharmacokinetic; PTSD=post-traumatic stress disorder; QTc=corrected QT interval; 
Pre-Rand=randomization; SCID-5=Structured-Clinical Interview for DSM-5; SDS=Sheehan Disability Scale; RBR=Research Biosample Repository; 
UV=unscheduled visit; ULN=upper limit of normal; WGS=whole genome sequencing. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
The visit window is ± 3 days, and all assessments should be completed within the visit window.  Following any visit that may occur outside of 
allowable visit window, participants should return to the initial planned schedule (per randomization as Day 1) for all subsequent visits.  For 
participants who terminate early, assessments listed under the early discontinuation visit should be completed.  For safety follow up, the visit 
window is −3/+7 days and all safety assessments should be completed within the visit window. 
Unscheduled visits may be performed if clinically indicated.  The following assessments should be performed at a minimum: concomitant 
medications, adverse events, and vital signs.  Additional safety assessments may be performed as clinically indicated, per investigator discretion. 
a A safety follow-up visit must occur for all participants at 2 weeks following their last study treatment dose. 
b To be conducted if a participant discontinues from the study or study-drug treatment prematurely.  
c All participants who withdraw or discontinue from the study treatment early will be asked to return as soon as possible (and within 2 weeks after 
the last dose of study drug) for an early discontinuation visit, unless the withdrawal occurs within 2 weeks of the Week 12 visit.  
d Participants will be called by the site personnel to monitor safety and tolerability when not attending the clinic. In the event that the participant 
cannot be reached, at least 3 documented attempts to contact the participant for these visits must occur. 
e Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
f Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, use of alcohol and drugs of abuse, and all 
medications (e.g., prescription drugs, over‑the‑counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
participant within 24 weeks prior to the screening visit as well as details of psychosocial or non‑pharmacological interventions used during the 
previous 24 weeks.  Demographic data will include age, sex, and self‑reported race/ethnicity.  Participants will also be asked about their 
residential setting, school, or employment status, level of education, participation in educational or day programs, and any non-medical 
hospitalizations. 
g EEG:  Two runs each of resting eyes open and eyes closed. 


Table 1  
Schedule of Activities (cont.)  
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h These assessments should be completed no more than 7 days prior to the baseline visit and will be considered the baseline measure.   
i EEG to be conducted if a participant discontinues study treatment before Week 6. 
j Urinalysis will be performed at the site by dipstick for blood, protein, glucose, ketones, specific gravity, and pH.  Microscopic examination 
performed at the central laboratory if blood and/or protein results are positive or strongly positive.  If there is an explanation for the positive 
dipstick results (e.g., menses), it should be recorded and there is no need to perform microscopy and culture. 
k Urine samples will be analyzed for the presence of drugs such as:  alcohol, cannabinoids, opiates, cocaine, barbiturates, methadone, and PCP.  
Results will be used to verify participant eligibility pertaining to drugs of abuse.  Inconclusive results may be repeated once during the screening 
period.  Investigators should use their best clinical judgment in cases where results may be erroneous (e.g., permitted use of opiates or ingestion 
of food or food supplements). 
l Viral serology includes HIV (specific tests for HIV-1 antibody, HIV-1 and -2 antibodies, and HIV-2 antibody), HBsAg, HBcAb, and HCV antibody. 
m Coagulation assessments include INR, aPTT, and PT. 
n Females of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening and must have a 
urine pregnancy test performed at the site prior to each dose administration at the specified visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents. 
o Vital signs include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated 
position, and body temperature.  Vital sign assessments should be performed just prior to study drug administration.  All vital signs should be 
recorded on the eCRF.  Three consecutive blood pressure readings will be recorded at intervals of at least 1 minute.  The average of the 
three blood pressure readings will be recorded on the eCRF.  
p PK samples should be obtained just prior to study drug administration, if possible.  At Week 6, two PK samples will be taken (pre- and 
post-dose).  Following the pre-dose sample, at the start of the study visit, the participant will receive study drug.  A post-dose sample can be 
taken at any time between 3 hours after study drug administration and the end of the study visit.  Accurate recording of the time of study drug 
administration and sample collection is critical. 
q Can be collected on any study visit if not collected at baseline visit. 
r Not applicable for a site that has not been granted approval for WGS. 
s Not applicable for a site that has not been granted approval for RBR sampling.  Perform only for participants at participating sites who have 
provided written informed consent to participate. 
t Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems.  Complete physical examinations will not include pelvic, rectal, or breast examinations.  Record 
abnormalities observed at screening on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.  Limited, symptom-directed physical examinations should be 
performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 


Table 1  
Schedule of Activities (cont.)  
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u Site personnel will check for any emergence of clinical signs and symptoms of infection according to semi-structured questionnaire (Appendix 9).  
This will occur either by telephone call or in person site visits at Weeks 4, 6, 9, and 12. 
v Twelve-lead ECGs are to be performed after the participant has been in a supine position for 5 minutes.  ECGs for each participant should be 
obtained from the same machine whenever possible and performed prior to any blood draws.  ECGs obtained at baseline will be in triplicate.  All 
others will be single recordings.  In the event of prolongation of the QTc interval, an unscheduled PK sample should be obtained. 
w Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells). 
x Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, CPK, total protein, albumin, phosphorus, 
calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, LDH, cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, including hs-cTnT.  
If CPK value exceeds 2×ULN at baseline, CPK, creatinine, and potassium levels should be monitored at Week 2. 
y The C-SSRS Baseline/Screening version should be used at the first screening visit; subsequent visits should use the C-SSRS Since Last Visit 
version.   
z Wearable device to be distributed and data collected 7 days prior to randomization (Day 1). 
aa Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, approved dietary and herbal supplements, 
nutritional supplements, and any non medicinal interventions, such as individual psychotherapy, smoking cessation therapy, and rehabilitative 
therapy) used by a participant 24 weeks prior to screening until the follow-up visit. 
bb After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  The investigator is not required to actively monitor participants for adverse events after the end of the adverse 
event reporting period (defined as 2 weeks after the final dose of study drug).  However, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that occurs after the end of the adverse event reporting period if the event is believed to be related 
to prior study drug treatment.  Every effort should be made to follow all serious adverse events considered to be related to study drug or 
trial-related procedures until a final outcome can be reported. 
cc Participants should be instructed to take their medication at home at the same time each day, preferably in the morning.  At study visits, they 
should take the study drug once all assessments are completed, except for Week 6.  Study drug dispensation can take place at any time during 
the visit.  Participants who need to take their medication at a time of day outside of their normal routine may do so, but only one dose may be 
taken each day.  If a dose is missed for that day, the participant should make a note to report this missed dose to the site at their next 
telephone or site visit. 


 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of balovaptan, a 
vasopressin 1a (V1a) receptor antagonist, in participants with post-traumatic stress 
disorder (PTSD).  Treatment options for PTSD include trauma-focused (TF) 
psychological interventions, such as cognitive-behavioral therapy (CBT) and 
pharmacological treatments, including antidepressants (selective serotonin reuptake 
inhibitors [SSRIs] and serotonin and norepinephrine reuptake inhibitors [SNRIs]).  The 
overall response rate with these interventions is limited, and there continues to be a 
need for treatments with better benefit−risk profiles that target the core symptoms of 
PTSD.  Patients with PTSD suffer from a cluster of debilitating symptoms that have a 
profound effect on many aspects of their lives. 
2.2 
BACKGROUND  
PTSD is a chronic impairment disorder that occurs after exposure to severe stressors 
(e.g., combat, natural disaster, or other traumatic events) (Miao et al. 2018).  It is 
characterized by re-experiencing, avoidance, and hyperarousal symptoms, as well as 
negative alterations in cognition and arousal.  These symptoms can lead to disturbances 
to the individual and their family, as well as significant medical, financial, and social 
problems. 
Re-experiencing symptoms manifest as one of the following:  recurrent, distressing 
recollections in the form of thoughts, perceptions, or dreams; feeling as if the traumatic 
event is happening again accompanied by illusions, hallucinations, and dissociative 
flashbacks; or intense psychological distress or physiological reactivity when exposed to 
internal or external cues reminiscent of the traumatic event(s) (American Psychiatric 
Association [APA] 2013; Jellestad et al. 2021).  Avoidance symptoms are characterized 
by efforts to avoid thoughts, feelings, conversation, activities, places, or things that 
remind the individual of the traumatic event(s), as well as marked decrease in affect.  
Individuals with PTSD demonstrate negative alterations in mood and elevated levels of 
arousal, including problems initiating and maintaining sleep, increased irritability, 
hypervigilance, and hyperactive startle response, as well as difficulty concentrating. 
These symptoms can often lead to clinically significant distress and significant 
impairments in daily functioning. 
A diagnosis, per Diagnostic and Statistical Manual of Mental Disorders, Version 5 
(DSM-5) criteria, includes exposure to trauma and this trauma is persistently 
experienced through unwanted memory intrusions, nightmares, flashbacks, and 
emotional distress following an exposure to traumatic reminders (APA 2013).  In 
addition, individuals avoid trauma-related stimuli and demonstrate negative alterations in 
cognition and mood, which may include overly negative thoughts about oneself and 
exaggerated blame of self or others for causing the trauma or negative affect.   


 
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According to the DSM-5, some individuals may receive a diagnosis of acute stress 
disorder in the first month following exposure to trauma (Bryant et al. 2016).  In order to 
meet the criteria, an individual must present with at least nine symptoms from the 
categories of intrusion, negative mood, dissociation, avoidance, and arousal.  These 
symptoms present at the beginning of the traumatic event or if these symptoms are 
pre-existing, then they worsen after the traumatic event.  The duration of the disturbance 
is 3 days to 1 month following a trauma exposure.  Although acute stress disorder and 
PTSD share similar requirements for diagnosis, there is a clear differentiation such that 
PTSD diagnosis requires meeting a certain number of symptoms within established 
clusters.  This includes non−fear-based symptoms and a dissociative subtype, and the 
symptoms persist for longer than 1 month.   
PTSD is generally associated with co-occurring psychiatric disorders and approximately 
80% of patients with PTSD meet criteria for at least one other psychiatric condition 
(Brady 1997).  The most common comorbidities are depression, alcohol and substance 
use disorders, anxiety disorders, physical health problems, and cognitive impairment 
(Kessler et al. 1995; Qureshi et al. 2011; Paccella et al. 2013).  Common psychiatric 
comorbidities exacerbate PTSD symptoms and increase functional impairment 
(Ikin et al. 2010; Drapkin et al. 2011). 
The National Comorbidity Survey Replication (NCS-R), which was conducted between 
2001 and 2003, estimated the lifetime prevalence of PTSD among adult Americans to be 
6.8% (NCS-R 2007a, 2007b).  The lifetime prevalence of PTSD among men was 3.6% 
and among women was 9.7%.  The reported prevalence of PTSD ranges from 5.4% to 
16.8% among military service members and veterans, which is higher than among the 
general population (Miao et al. 2018).  Genetic and epigenetic factors may account for 
up to 70% of the individual differences in PTSD development, with PTSD heritability 
estimated at 30%. 
Most guidelines strongly recommend TF-psychological interventions as treatment 
options for PTSD, including CBT, cognitive-processing therapy (CPT), cognitive therapy 
(CT), cognitive restructuring (CR), coping skills therapy (including stress inoculation 
therapy), exposure-based therapies, eye movement desensitization and reprocessing 
(EMDR), hypnosis and hypnotherapy, and brief eclectic psychotherapy (APA 2017).  
Individual TF-CBT and EMDR have shown to be effective in reducing PTSD symptom 
severity (Bisson et al. 2013; Coventry et al. 2020).  However, the quality of evidence 
showing superiority of TF-CBT and EMDR over waitlist and/or usual care comparison is 
low (Bisson et al. 2013).  Furthermore, although psychological interventions have shown 
success in alleviating symptoms, there is no evidence for a significant improvement in 
affect dysregulation (Coventry et al. 2020).  Additionally, psychological interventions, 
such as TF-CBT, EMDR, and mindfulness, do not show a maintenance of treatment 
effects at the 6-month follow up in veterans (Coventry et al. 2020).  Various 
psychological interventions also show high dropout rates, with one review finding up to 
54% (Schottenbauer et al. 2008) and another up to 65% (Lewis et  al. 2020).  


 
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Furthermore, TF-therapies having a significantly higher dropout rate compared with 
non-TF therapies (Lewis et al. 2020).  This could be reflective of patients’ psychological 
preparedness to confront their trauma.   
Pharmacological treatments for PTSD include antidepressants, such as SSRIs, SNRIs, 
and monoamine oxidase (MAO) inhibitors, sympatholytic drugs such as alpha-blockers, 
antipsychotics, anticonvulsants, and benzodiazepines (Coventry et al. 2020; Hoskins et 
al. 2015; Stein et al. 2006;  Davidson et al. 2006a; Davidson et al. 2006b).  The (U.S.) 
Food and Drug Administration (FDA) has approved two SSRIs for the treatment of 
PTSD:  sertraline and paroxetine.  These SSRIs primarily act upon the serotonin 
neurotransmitter system and have the strongest empirical evidence.  Overall response 
rates with the use of SSRIs rarely exceed 60% in patients with PTSD and less than 
20%−30% of patients achieve complete remission (Stein et al. 2002; Zohar et al. 2002).  
Other medications which are not approved for treatment of PTSD, such as fluoxetine, 
topiramate, risperidone, and venlafaxine, are also used in clinical practice.  Maintenance 
of effect is also only observed through continued treatment, which suggests that the 
medication is addressing symptoms rather than the underlying source of the disorder 
(Asnis et al. 2004).  Beyond SSRIs, a number of different research avenues have been 
explored, including prazosin and d-cycloserine but although some positive signals in 
small studies have been observed, these have typically not translated into larger 
confirmatory outcomes (de Kleine et al. 2012; Germain et al. 2012; Raskind et al. 2018).  
Patients with PTSD often receive treatment with multiple agents that often lack evidence 
of benefit, including diverse antidepressants, anxiolytics, mood stabilizers and 
antipsychotics (Davidson and Connor 1999; Keane et al. 2006; Miao et al. 2018). 
Balovaptan is a brain penetrant, potent, and highly selective human V1a receptor 
antagonist that blocks the activation of the V1a G protein−coupled receptor. 
In vitro, balovaptan exhibited an inhibition constant of 0.7 nM for the human V1a receptor 
with at least 1000-fold binding selectivity over 118 other receptors, enzymes, and ion 
channels, including human vasopressin 2 (V2) receptor, vasopressin 1b (V1b) receptor, 
and human oxytocin receptors. 
Previous clinical studies of balovaptan have been conducted in healthy volunteers and 
participants with autism spectrum disorder (ASD) using the same dose (10 mg) as 
proposed for this study.  In those trials, an estimated 448 subjects with ASD have 
received 10 mg once a day (QD) of balovaptan for at least 12 weeks, of whom 
approximately 326 subjects received 10 mg QD of balovaptan for at least 24 weeks.  
Balovaptan was found to be safe and well tolerated. 
Detailed information on balovaptan is provided in the Balovaptan Investigator's 
Brochure. 


 
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2.3 
BENEFIT–RISK ASSESSMENT 
This study will assess the efficacy and safety of balovaptan in adults with 
moderate-to-severe PTSD.  Currently, the first-line therapy for PTSD is individual 
TF-psychological interventions.  However, these psychological interventions have not 
shown a significant improvement in affect dysregulation or maintenance of treatment 
effects at 6 month follow up in veterans (Coventry et al. 2020).   
Areas in the brain that are rich in vasopressin receptors have been implicated in PTSD 
suggesting that arginine vasopressin (AVP) may be able to influence behavior that is 
relevant to PTSD (Torok et al. 2019).  Nonclinical studies have shown that AVP agonists 
result in PTSD-like behavior in rodents (Sipos et al. 2020).  In AVP-deficient Brattleboro 
rats, which have significant reduction of AVP signaling in the brain, demonstrated 
improved behavioral parameters that can be linked to PTSD symptoms.  Furthermore, 
serum AVP concentrations have been observed to be higher in veterans with PTSD 
compared with those without (de Kloet et al. 2008).  These findings imply that treatment 
with a V1a antagonist, such as balovaptan, may offer a means to alleviate symptoms of 
PTSD. 
Across previous clinical trials of balovaptan, it has been found to be safe and well 
tolerated.  This includes studies in healthy volunteers and in individuals with ASD 
(children, adolescents, and adults).  No pattern of adverse events possibly characteristic 
for the use of balovaptan in humans has emerged to date.   
The following are hypothetical or potential risks for balovaptan, based on its mechanism 
of action and available nonclinical data:  seizure risk (animal studies), hematological 
toxicity (animal studies; mainly peripheral decrease in neutrophils), risk of bleeding 
(hypothetical relative to the mechanism of action), skeletal muscle toxicity (animal 
studies), cardiac toxicity (animal studies and interpreted to be stress related), blood 
pressure changes (hypothetical risk relative to the mechanism of action), and risk of 
peripheral neuropathy (animal studies) (for further details see Appendix 6).  However, 
dedicated safety monitoring across clinical trials in healthy volunteers and in subjects 
with ASD have not revealed a safety signal with regard to the mechanism of action of 
balovaptan and animal-related potential safety risks. 
The dose planned in this study is 10 mg QD, and this dose is the same as the highest 
dose administered in the ASD clinical trials which had a treatment duration of 12 weeks 
or longer.  The safety monitoring planned in this study will continue to cover these 
hypothetical and animal-related safety considerations and is considered sufficient to 
ensure participant safety. 
Refer to Appendix 6 for information on potential risks for balovaptan and risk mitigation 
measures, including guidelines for managing adverse events.  


 
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More detailed information about the known and expected benefits and risks and 
reasonably expected events of balovaptan may be found in the Balovaptan Investigator's 
Brochure.  
With the data thus far, the Sponsor believes the benefit−risk profile of balovaptan for 
participants in this study is favorable. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg QD 
balovaptan compared with placebo in participants with PTSD.  Specific objectives and 
corresponding endpoints for the study are outlined in Table 2. 
Table 2 
Objectives and Corresponding Endpoints 
Primary Objective 
Efficacy Objective 
Corresponding Endpoint 
• To investigate the efficacy of 
balovaptan compared with 
placebo 
• Change from baseline at Week 12 in the CAPS-5 total 
symptom severity score 
Secondary Objectives 
Efficacy Objectives 
Corresponding Endpoints 
• To investigate the efficacy of 
balovaptan compared with 
placebo 
• Change from baseline in symptom severity as 
measured by CGI-S after 12 weeks of treatment 
• To investigate the efficacy of 
balovaptan compared with 
placebo in depression 
• Change from baseline at Week 12 in the PHQ-9 total 
score 
Safety Objective 
Corresponding Endpoints 
• To investigate the safety of 
balovaptan compared with 
placebo 
Safety will be assessed through the following: 
• Incidence and severity of adverse events, with severity 
determined according to a mild/moderate/severe 
grading scale  
• Physical and neurologic examinations, vital signs, 
hematology, blood chemistry, including urinalysis 
• ECGs and Doppler echocardiograms (the latter 
performed only in case of confirmed cardiac biomarker 
elevation) 
• C-SSRS 
Pharmacokinetic Objectives 
Corresponding Endpoints 
• To investigate the plasma 
pharmacokinetics of balovaptan 
• Concentration per timepoint for balovaptan a 
• PK parameters as appropriate 
 


 
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Table 2 
Objectives and Corresponding Endpoints (cont.) 
Exploratory Objectives 
Exploratory Biomarker Objective 
Corresponding Endpoints 
• To identify and/or investigate 
biomarkers that are predictive of 
response to balovaptan (i.e., 
predictive biomarkers) or are early 
signs of efficacy 
• 
Relationship between biomarkers (e.g., EEG, 
genomics, digital biomarkers, computerized cognitive 
battery) and efficacy, safety, PK, or other biomarker 
endpoints (see Section 8.7) 
Exploratory Efficacy Objectives 
Corresponding Endpoints 
• To investigate the efficacy of 
balovaptan compared with 
placebo 
• Change from baseline at Week 12 on the CAPS-5 
symptom cluster scores 
• Proportion of participants with no symptoms, very mild, 
mild, moderate, severe, very severe in the PGI-S at 
each scheduled visit  
• Proportion of participants with no change, 
improvement or worsening in the CGI-C and PGI-C at 
Weeks 6 and 12 
• Change from baseline at Week 6 on the CAPS-5 total 
symptom severity score 
• To investigate the efficacy of 
balovaptan compared with 
placebo in PTSD symptoms, 
anxiety, sleep, functioning, and 
cognition 
• Change from baseline at Weeks 6 and 12 on the 
following: 
− 
PCL-5 total score 
− 
BAI total score 
− 
PSQI total and domain scores 
− 
CPFQ total score and domain scores 
− 
SDS global score 
− 
Computerized cognitive battery 
BAI=Beck Anxiety Inventory; CAPS-5=Clinician-Administered PTSD Scale for DSM-5; 
CGI-C=Clinician-Global Impression of Change; CGI-S=Clinician-Global Impression of Severity; 
CPFQ=Cognitive and Physical Functioning Questionnaire; C-SSRS=Columbia-Suicide Severity 
Rating Scale; DSM-5=Diagnostic and Statistical Manual of Mental Disorders, Version 5; 
EEG=electroencephalogram; M2=Metabolite 2; M3=Metabolite 3; PCL-5=PTSD Checklist for 
DSM 5; PGI-C=Patient-Global Impression of Change; PGI-S=Patient-Global Impression of 
Severity; PHQ-9=Patient Health Questionnaire-9; PK=pharmacokinetic; PSQI=Pittsburgh Sleep 
Quality Index; PTSD=Post-traumatic stress disorder; SDS=Sheehan Disability Scale. 
a Concentration of M2 and M3 may be measured if indicated (e.g., safety concern). 
  
The clinical question of interest is to assess the study treatment effect of 10 mg QD 
balovaptan compared with placebo in terms of the change from baseline at Week 12 in 
the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) irrespective of adherence 
to randomized treatment.  


 
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4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN  
Study BN43546 is a Phase II, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group, multicenter study to evaluate the efficacy and safety of 10 mg of oral 
balovaptan QD in adults with PTSD.  The study will comprise a 28-day screening period, 
12-week blinded treatment period, and a 2-week follow-up period.  A study schema is 
provided in Section 1.2 (see Figure 1). 
Participants providing informed consent will undergo screening up to 4 weeks prior to the 
first double-blind study drug (balovaptan or placebo) administration.  Eligible participants 
will be randomized in a 1:1 ratio in a blinded fashion to either 10 mg of balovaptan or 
matching oral placebo QD.  The primary efficacy endpoint is the change from baseline at 
Week 12 in the CAPS-5. 
For participants completing the full study, the approximate length of the study will be 
18 weeks or approximately 4 months (screening [up to 4 weeks], blinded treatment 
[12 weeks] and a safety follow-up visit 2 weeks after a participant’s Week 12 visit or 
2 weeks following last study treatment dose). 
Participants will be recruited from sites within the United States.  It is estimated that it will 
take approximately 9 months to reach full enrollment.  Participants who prematurely 
discontinue from study treatment or from the study will not be replaced.   
Randomization will be stratified by sex (male vs. female), type of trauma (veteran vs. 
civilian), and concurrent medication use (no concurrent antidepressant treatment vs. 
antidepressant treatment [SSRI or SNRI]; see Section 5.1).  The main analysis of the 
primary and secondary efficacy endpoints will occur once the final data from all visits of 
the follow-up period have been collected and cleaned and the database is locked.  
An Internal Monitoring Committee (IMC), consisting of a selected subset of internal 
Roche representatives who are not in direct contact with the sites, will review relevant 
safety data on a regular basis or on an ad-hoc basis, if deemed necessary, as described 
in the IMC Charter.  The IMC Charter provides further details about the roles and 
responsibility of the members, defining the timing of meetings and communication of 
meeting’s discussion points. 
Secondary and exploratory endpoints will examine core and associated symptoms of 
PTSD, impact on health-related quality of life, as well as the ability to identify predictive 
or prognostic biomarkers.  Safety will be examined via adverse events, clinical laboratory 
values, ECGs, physical and neurologic examinations, and safety outcome assessments 
such as suicidality. 


 
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Individuals who do not meet the criteria for participation in this study (screen failure) may 
be re-screened one additional time (Section 5.4).  Re-screening will not be allowed if a 
participant does not meet the disease-specific inclusion criteria (e.g., PTSD diagnosis as 
per DSM-5 and Structured-Clinical Interview for DSM-5 [SCID-5], PTSD Checklist for 
DSM-5 [PCL-5] score).  The investigator will record reasons for screen failure in the 
screening log. 
4.1.1 
Screening Period 
Consenting participants will enter a screening period of up to 28 days in length to be 
evaluated for eligibility.  Procedures at screening are listed in the schedule of activities in 
Section 1.3 (see Table 1).  Participants must meet all of the eligibility criteria in order to 
qualify for the study (see the inclusion and exclusion criteria [see Sections 5.1 and 5.2, 
respectively]).  
To enter the double-blind period, there must be: 
• 
No significant new or worsening psychiatric or medical illness since screening that in 
the opinion of the Investigator would interfere with the participant’s ability to 
participate in the study. 
• 
No change in medications or psychotherapy since screening except as allowed in 
the Concomitant Medication section (see Section 6.8.1) 
 
4.1.2 
Blinded Treatment Period 
The study will enroll approximately 30 participants with moderate-to-severe PTSD (as 
measured by PCL-5).  All participants will undergo 12 weeks of double-blind treatment 
consisting of four in-clinic visits.  
At the baseline visit (Day 1), participants will undergo a series of assessments outlined 
in the schedule of activities (see Section 1.3).  Breaks should be allowed between tests 
when necessary.  Study drug (balovaptan or placebo) must be administered only after all 
protocol-mandated assessments are completed. 
As a rule, the test sequence for all assessments should remain the same for a given 
participant as established at screening and baseline.  At all visits, patient-reported 
outcome (PRO) assessments should be completed prior to any other assessments or 
procedures.  All assessments must be performed before administration of study drug.  
If Columbia-Suicide Severity Rating Scale (C-SSRS) assessments at pre-randomization 
or Study Day 1 reveal score/category of 4 or greater, treatment must not be started and 
the participant should be discontinued from the study and referred to psychiatrist.  
Interim telephone calls will occur at Weeks 4 and 9.  Participants will be called by site 
personnel to monitor safety and tolerability when not attending the clinic.  Assessments 
will include adverse event collection, concomitant medication review, and dose 
accountability. 


 
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4.1.3 
Follow-Up Period 
A safety follow-up visit will take place 2 weeks after the participant’s Week 12 visit or 
2 weeks after last dose to assess whether any adverse events have occurred following 
the end of treatment.   
A study schema is provided in Section 1.2 (see Figure 1).  A schedule of activities is 
provided in Section 1.3 (see Table 1). 
4.2 
RATIONALE FOR STUDY DESIGN  
4.2.1 
Rationale for Study Population  
A key component of PTSD vulnerability, development and treatment seems to involve 
the hypothalamic-pituitary adrenocortical (HPA) axis (Yehuda, 2002).  Arginine 
vasopressin (AVP) is an important co-stimulator of the HPA axis, modulating 
glucocorticoid release synergistically with corticotrophin-releasing hormone (CRH) 
(Engelmann et al. 2004; Rotzinger et al. 2010).  In PTSD, three main brain areas have 
been shown to be implicated:  the prefrontal cortex (PFC), the hippocampus, and the 
basolateral amygdala (Torok et al. 2019).  These brain areas are not rich in 
AVP-producing cells but contain vasopressin receptors at high density.  This suggests 
that AVP is able to influence behavior that is also relevant to PTSD by either directly 
innervating these areas as a neurotransmitter or released in remote areas such as the 
hypothalamus and traveling via the extracellular space as a neuromodulator.  
In mouse models, the V1a receptor is highly expressed in the bed nucleus of the stria 
terminalis, a region of the amygdala implicated in stress response (Bielsky et al. 2004). 
V1a receptor knockout and inhibition have anxiolytic effects in mice while elevating 
levels of vasopressin has an anxiogenic effect. 
A study of veterans with PTSD and veterans, without PTSD who witnessed or 
experienced traumatic events, found that serum AVP levels were higher in veterans with 
PTSD than other cohorts (de Kloet et al. 2008).  No difference in AVP levels were found 
between veterans without PTSD and non-military healthy controls.  A strong correlation 
was found between avoidance symptoms as determined by using the 
Clinical-Administered PTSD Scale (CAPS) and AVP serum concentrations in patients 
with PTSD.  
These findings may imply that treatment with AVP antagonists might offer a way to 
alleviate symptoms in patients with PTSD.   
Study BN43546 will include both males and females.  The lifetime prevalence of PTSD 
among adult Americans has been reported to be 6.8%, with females being affected 
approximately twice as much as males (NCS-R 2007a, 2007b).  Furthermore, the 
reported prevalence among military service members and veterans is higher than among 
the general population (Miao et al. 2018).  To investigate potential differences in these 
populations, the study will include veterans and civilians. 


 
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To limit the impact of diagnostic heterogeneity, eligible participants must meet DSM-5 
criteria for PTSD, which will be confirmed using the PCL-5 and the Structured-Clinical 
Interview for DSM-5 (SCID-5) (APA 2013).  The PCL-5 is a 20-item, self-reported 
measure that assesses 20 DSM-5 symptoms of PTSD (Weathers et al. 2013c; Blevins 
et al. 2015).  The SCID-5 is a semi-structured interview guide for making the major 
DSM-5 diagnoses (First 2014).  It is administered by a clinician or trained mental health 
professional who is familiar with the DSM-5 classification and diagnostic criteria.  
For pharmacological interventions of PTSD, SSRIs (sertraline, paroxetine, and 
fluoxetine) and SNRI (venlafaxine XR) are recommended as monotherapy (APA 2017).  
Participants in this study will include individuals who are on a stable dose of an 
antidepressant treatment and have not reached full therapeutic effect or those who are 
not taking any antidepressants because of intolerance or treatment failure at baseline.  
This will be assessed by the treating physician. 
4.2.2 
Rationale for Use of Placebo 
Two SSRIs (sertraline and paroxetine) have been approved by the FDA for the treatment 
of PTSD.  Overall response rates with SSRIs rarely exceed 60% in patients with PTSD 
and less than 20%−30% of patients achieve complete remission (Stein et al. 2002; 
Zohar et al. 2002).   
Vasopressin signaling is involved in the body’s stress response, and has been 
implicated in affective illnesses, including PTSD.  Plasma levels of vasopressin have 
been noted to be increased in PTSD (de Kloet et al. 2008).  Balovaptan is an antagonist 
at the V1a receptor, and thus may ameliorate symptoms related to elevated 
stress-related and vasopressin-mediated signaling.  
This study will only enroll individuals who are either on a stable dose of a single 
antidepressant for management of PTSD or have demonstrated prior lack of tolerability 
or lack of efficacy (see Section 5.1).  Given the limited pharmacotherapies available for 
the treatment of PTSD and limitations in therapeutic effect, a placebo-controlled trial is 
acceptable, provided that appropriate participant consent and safeguards are instituted 
to minimize the risk of serious or irreversible harm resulting from exposure to placebo. 
4.2.3 
Rationale for Biomarker Assessments 
In a Phase I study of healthy volunteers (Study BP29412), 10 mg of balovaptan was 
found to elicit a decrease in power envelope connectivity within the α power band of a 
resting-state electroencephalogram (EEG) taken with eyes closed (1111327 [available 
on request]).  The predominant source of this change in connectivity was localized to the 
vicinity of the left anterior insula and the left intraparietal cortex.  Retrospective analyses 
of open-label study data indicated that broadly similar patterns of α-band power 
envelope connectivity change may predict clinical improvement following a change in 
pharmacological treatment among patients with a PTSD diagnosis.  Changes in α-band 
connectivity have also been implicated in subsequent clinical improvement in patients 


 
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with a PTSD diagnosis following the administration of repetitive-transcranial magnetic 
stimulation (rTMS), and the topography of these effects could be consistent with the 
insular and parietal sources described above (Zandvakili et al. 2019).  Thus, 
pharmacodynamic EEG activity elicited by balovaptan bears some similarity, both in 
frequency and in spatial topography, with EEG changes associated with clinical 
improvement in patients with PTSD receiving rTMS.   
However, PTSD is a heterogeneous disorder, hence participants in this study may not all 
respond similarly to treatment with balovaptan.  Therefore, an objective of this study is to 
define which patients with PTSD may be most likely to benefit from balovaptan using 
one or more biomarkers acquired prior to treatment and to relate the strength of any 
response to balovaptan with change in clinical measures.  In addition to EEG, 
biosamples will be collected for identifying variants in the arginine vasopressin receptor 
1A (AVPR1A) gene that may be associated with response to balovaptan.  For this 
purpose, a mandatory predose whole blood sample will be obtained for DNA extraction 
from every participant on Day 1.  
Additionally, digital biomarkers will be derived from a wearable device (e.g., OURA 
Ring).  The following wearable sensor data will be recorded:  heart rate, movement, and 
sleep.  These measures will be recorded to enable the derivation of exploratory 
biomarkers related to autonomic function and arousal, movement kinematics and 
behavior, and sleep.  Finally, established cognitive assessments will be performed and 
completed as a battery by the participant, and cognitive data obtained (Qureshi et al. 
2011).  On the basis of these data, cognitive biomarkers may be derived from different 
levels of cognitive functioning as well as exploring the relationship of these biomarkers to 
outcomes. 
4.2.4 
Rationale for Use of Clinician-Administered PTSD Scale for 
DSM-5 (CAPS-5) 
The Clinician-Administered PTSD Scale (CAPS) is a validated and widely used 
structured diagnostic interview, considered as the gold standard to assess symptoms 
associated with PTSD (Weathers et al. 2001).  It has been used in multiple studies on 
PTSD as either a primary diagnostic or outcome measure.  
The CAPS has been revised to correspond with PTSD criteria in the fifth edition of the 
Diagnostic and Statistical Manual of Mental Disorders (DSM–5; APA 2013).  A 
description of the scale is provided in Section 8.1. 
4.3 
JUSTIFICATION FOR DOSE AND SCHEDULE  
Balovaptan is a brain penetrant, potent, and highly selective human V1a receptor 
antagonist that blocks the activation of the V1a G protein−coupled receptor.  In vitro, 
balovaptan exhibited an inhibition constant of 0.7 nM for the human V1a receptor with at 
least 1000-fold binding selectivity over 118 other receptors, enzymes, and ion channels, 
including human V2, V1b, and human oxytocin receptors (1042558 [available on 


 
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request]).  Furthermore, the predicted brain occupancy of the V1a receptor reaches near 
maximal saturation (average of approximately 89% at trough) with the 10 mg dose of 
balovaptan.  This predicted receptor occupancy was calculated according to a model 
which used an ex-vivo functional assay that measured the inhibition of V1a mediated 
and vasopressin induced platelet aggregation in human whole blood, and based on 
trough concentrations observed in Study BP28420 (“VANILLA”) (1056966 [available on 
request] and 1106698 [available on request]).  
Across previous clinical studies of balovaptan in healthy volunteers and in individuals 
with ASD (children, adolescents, and adults), a dose of 10 mg QD for at least 12 weeks 
has been found to be well-tolerated and without an emerging adverse event pattern 
considered to be related to balovaptan.  Potential risks for balovaptan based on its 
mechanism of action and nonclinical data have not been confirmed in humans.  The 
dose selected for this study, 10 mg QD, is the same as the highest dose administered in 
the ASD clinical trials.  Together with the exclusion criteria and the safety monitoring 
scheduled for this study, balovaptan is expected to be well-tolerated by participants to be 
enrolled in this trial.  Please see Appendix 6 for more details. 
See the Balovaptan Investigator's Brochure for details about nonclinical and 
clinical studies. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all 
phases of the study, including the last visit shown in the schedule of activities (see 
Section 1.3). 
The end of this study is defined as the date of the last visit of the last participant in the 
study or the date at which the last data point required for statistical analysis or safety 
follow-up is received from the last participant, whichever occurs later.  It is anticipated 
that it may take approximately 9 months to recruit all participants for the study; hence, 
the total length of the study is estimated to be approximately 13 months. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.5 
DURATION OF PARTICIPATION  
The total duration of study participation for each individual is expected to be 
approximately 18 weeks. 
5. 
STUDY POPULATION  
Approximately 30 adult participants with PTSD will be enrolled in this study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


 
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5.1 
INCLUSION CRITERIA 
Potential participants are eligible to be included in the study only if all of the following 
criteria apply: 
• 
Capable of giving signed informed consent as described in Appendix 1 (see Section 
A1–3), which includes compliance with the requirements and restrictions listed in the 
Informed Consent Form and in this protocol and able to comply with the study 
protocol 
• 
Age ≥18 and ≤60 years at the time of signing Informed Consent Form 
• 
Current diagnosis of PTSD as per DSM-5 criteria and confirmed by the SCID-5 
conducted during screening 
• 
Moderate-to-severe PTSD, as assessed by a score of ≥33 on the PCL-5 completed 
during screening 
• 
The index trauma event must have occurred in adulthood, i.e., when the participant 
was ≥18 years old 
• 
The index trauma event must have occurred at least 6 months prior to screening 
and no more than 10 years prior to screening 
• 
Participants who, at baseline, are: 
– 
Either taking a stable dose of a single antidepressant (SSRI or SNRI) for 
management of PTSD and have been on that medication for ≥6 weeks at that 
stable dosage and demonstrating residual symptoms of PTSD 
or 
– 
Prior demonstrated lack of tolerability or lack of efficacy (treatment failure, 
defined as trial of at least two antidepressant medications (SSRI or SNRI) with 
lack of efficacy for management of PTSD) and not taking an antidepressant 
medication at baseline for ≥6 weeks 
• 
Treatment with permitted medications and/or non-pharmacological interventions 
should be at a stable dose/regiment for 6 weeks prior to screening, with the intent 
that such treatments remain stable throughout the study, with no expected changes 
before the Week 12 visit 
• 
Fluent in English 
• 
For female participants of childbearing potential:  agree to remain abstinent (refrain 
from heterosexual intercourse) or use contraception method, as defined below: 
Female participants must remain abstinent or use contraceptive methods with a 
failure rate of <1% per year during the treatment period and for at least 14 days 
after the final dose of study drug. 
A female participant is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (≥12 continuous 
months of amenorrhea with no identified cause other than menopause), and is 
not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 


 
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(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of <1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
• 
Note:  No specific contraception methods for males are required.  The Sponsor does 
not require male contraception because of the minimal seminal dose transmitted via 
sexual intercourse (Banholzer et al. 2012). 
 
5.2 
EXCLUSION CRITERIA 
Potential participants are excluded from the study if any of the following criteria apply: 
• 
Ongoing exposure to traumatic events within 3 months of screening 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 14 days after the final dose of study drug 
• 
Concurrent use of any of the prohibited medications and food products listed in 
Section 6.8.3 
• 
Any clinically significant psychiatric and/or neurological conditions, which may 
interfere with the assessment of safety or efficacy endpoints.  This includes: 
– 
Any contraindications to EEG (e.g., requiring high concentration oxygen) 
– 
Significant risk for suicidal behavior, as assessed by the investigator, or a 
score of  4 or 5 on the C-SSRS in the past 6 months or category 6 or greater on 
the C-SSRS in the past 12 months (for C-SSRS categories and score 
see Section 8.2.7) 
– 
Diagnosis of schizophrenia, bipolar disorder, other psychotic disorder, or 
cognitive disorder, as defined by DSM-5 
– 
Epilepsy or seizure disorder considered not well controlled within the past 
6 months or changes in anticonvulsive therapy within the last 6 months 
– 
Clinical diagnosis of peripheral neuropathy or signs and symptoms indicative of 
peripheral neuropathy 
– 
Substance use disorders (including alcohol or substance abuse or dependence 
disorder) during the last 12 months, as defined using the DSM-5 criteria 
– 
Diagnosis of traumatic brain injury  


 
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• 
Any cardiovascular disorders such as: 
– 
Uncontrolled hypertension (e.g., blood pressure repeatedly >160 mmHg systolic 
or >95 mmHg diastolic) 
– 
Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, or New York Heart Association 
Class II or higher cardiac failure) 
– 
Confirmed (e.g., on two consecutive measurements taken approximately 
30 minutes apart during screening; the second measurement is only taken if it 
is necessary to confirm initial ECG abnormality) clinically significant 
abnormality on ECG at screening, including, but not limited to, a QT interval 
corrected through the use of Fridericia’s formula (QTcF) of ≥450 ms in male 
participants and ≥470 ms in female participants, absence of dominating sinus 
rhythm, or second- or third-degree atrioventricular block 
– 
Confirmed elevation above upper limit of normal (ULN) of high-sensitivity 
cardiac troponin T (hs-cTnT) 
– 
Unexplained syncopal episode within the last 12 months 
• 
Participants who meet any of the following criteria related to other organ systems 
will be excluded from the study: 
– 
Positive serology results for hepatitis B surface antigen (HBsAg), hepatitis B 
core antibody (HBcAb), hepatitis C virus (HCV) antibody, or HIV-1 or HIV-2 
All participants must have a negative HBsAg result and negative hepatitis C 
antibody screening tests prior to enrollment.  If total HBcAb is positive at 
screening, hepatitis B virus (HBV) DNA measured by polymerase chain 
reaction must be negative to be eligible.   
– 
Moderate or severe hepatic impairment defined as Child-Pugh class B 
(7−9 points) and class C (10−15 points), respectively (see Appendix 8) 
– 
Moderate or severe renal impairment defined as estimated glomerular filtration 
rate (eGFR) based on serum creatinine value of: < 60 mL/min/1.73m2  
– 
Evidence of current or past gastrointestinal (GI) disease that could potentially 
limit the absorption of study drug or pose unacceptable risks in the opinion of 
the investigator (e.g., GI bleeding, active stomach ulcer) 
– 
History of coagulopathies, bleeding disorders, blood dyscrasias, hematological 
malignancies, myelosuppression (including iatrogenic) 
– 
Concomitant disease or condition that could interfere with, or treatment of which 
might interfere with, the conduct of the study, or what would, in the opinion of 
the investigator, poses an unacceptable risk to the participant in this study 
– 
Confirmed clinically significant abnormality in parameters of hematology (e.g., a 
neutrophil count of <1500/µL; in case of assumed "benign ethnic neutropenia," 
a count of <1300/µL constitutes exclusion) 
– 
Confirmed clinically significant abnormality in parameters of clinical chemistry, 
coagulation, or urinalysis 


 
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– 
Medical history of malignancy, if not considered cured 
 
• 
Participants who meet any of the following exclusion criteria will be excluded from 
the study: 
– 
Participants who have received treatment with investigational therapy within 
8 weeks prior to randomization  
– 
Known hypersensitivity to balovaptan, its components, or any of the excipients 
used in the formulation 
– 
Any other condition and/or situation that the Investigator believes may interfere 
with the safety of the participant, study conduct, or interpretation of study data 
(safety or efficacy endpoints) 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
This study has the following meal and dietary restrictions: 
• 
Refrain from consumption of grapefruit or grapefruit juice, grapefruit hybrids from 
2 weeks before the start of study treatment until after the final dose. 
 
5.3.2 
Alcohol, Tobacco, and Cannabis 
This study has the following alcohol, tobacco, and cannabis restrictions: 
• 
Alcohol consumption is permitted as per Centers for Disease Control (CDC) and 
Prevention guidelines (2 drinks or less in a day for males and 1 drink or less in a day 
for females; one alcoholic drink equivalent is defined as containing 14 grams [0.6 fl 
oz] of pure alcohol) (U.S. Department of Agriculture and U.S. Department of Health 
and Human Services 2020). 
Participants will abstain from alcohol for 24 hours prior to study visits. 
• 
Nicotine and tobacco use is permitted, including the use of nicotine patches, 
cigarettes (traditional or electronic/vaping), and chewing tobacco; the type and 
amount used should be recorded in the electronic Case Report Form (eCRF). 
• 
Occasional cannabis use is permitted and should not exceed 2 times per week.  
Participants will abstain from cannabis use for 24 hours prior to study visits. 
 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, female participants must use contraception or take other precautions 
as described in Section 5.1. 
5.4 
SCREEN FAILURES  
Individuals who do not meet the criteria for participation in this study (screen failure), 
unrelated to symptom severity, may qualify for 1 re-screening opportunity (for a total of 


 
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2 screenings per individual) at the investigator's discretion.  Re-screening will not be 
allowed if a participant does not meet the disease-specific inclusion criteria (e.g., PTSD 
diagnosis as per DSM-5 and SCID-5, PCL-5 score).  Individuals must re-sign the 
consent form prior to re-screening.  The investigator will record reasons for screen 
failure in the screening log (see Section 8). 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY  
Study treatment is defined as any investigational treatment, marketed product, placebo, 
or medical device intended to be administered to a study participant according to the 
study protocol. 
The investigational medicinal products (IMPs) for this study are balovaptan and placebo.   
6.1 
STUDY TREATMENTS ADMINISTERED 
Table 3 provides a description of assigned study treatments for this study. 
Table 3 
Study Treatment Description 
 
Balovaptan  
Placebo 
Use 
Experimental 
Placebo comparator 
Type of medicinal 
product 
IMP 
IMP 
Drug form 
Tablet 
Tablet 
Unit dose 
strength 
10 mg/tablet 
Not applicable 
Formulation 
Refer to 
Balovaptan Investigator's Brochure. 
Refer to 
Balovaptan Investigator's Brochure.  
Packaging 
50 tablets per one high-density 
polyethylene bottle 
50 tablets per one high-density 
polyethylene bottle 
Labeling 
Per local requirements 
Route of 
administration 
Oral 
Oral 
Source 
Sponsor 
Sponsor 
IMP = investigational medicinal product. 
  
Guidelines for treatment interruption or discontinuation for participants who experience 
adverse events are provided in Appendix 6 (see Sections A6–2.1 and A6–2.2). 
The total daily doses will be administered as one tablet containing either 10 mg 
balovaptan or placebo. 


 
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One tablet of study drug (balovaptan or placebo) should be taken orally QD at home at 
the same time each day, preferably in the morning, with or without food.  The tablet 
should be swallowed whole with something to drink. 
Participants who need to take their study drug at a time of day outside of their usual 
routine may do so (e.g., participant typically takes their study drug in the morning, but 
due to an unforeseen scheduling conflict cannot take their medication until the 
afternoon), but only one dose may be taken each day.  If a dose is missed, the 
participant should make a note to report this missed dose to the site at their next 
contact.  A missed dose of study treatment must not be made up the next day. 
The first dose of the study drug will be administered on Day 1 after all pre-dose 
assessments have been conducted.  At subsequent visits (except for the Week 6 visit), 
the study drug will be administered after all protocol-mandated study assessments have 
been completed.  
6.2 
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel e.g., pharmacist) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each participant, and disposition or return of unused IMP, thus enabling reconciliation of 
all IMP received, and for ensuring that participants are provided with doses specified by 
the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using an interactive 
voice or web-based response system (IxRS) to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  The investigator or designee must 
confirm that appropriate temperature conditions have been maintained during transit, 
either by time monitoring (shipment arrival date and time) or temperature monitoring, for 
all IMPs received and that any discrepancies have been reported and resolved before 
use of the IMPs.  All IMPs must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 


 
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any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the Balovaptan Investigator's Brochure for 
information on IMP preparation, storage, handling, and accountability.  
6.3 
TREATMENT ASSIGNMENT AND BLINDING  
6.3.1 
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a participant, the study site will obtain the participant's 
identification number and treatment assignment from an IxRS. 
Participants will be randomly assigned to one of two treatment arms:  balovaptan 10 mg 
QD or placebo.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method.  To ensure a balanced assignment to each treatment arm, the 
randomization will be stratified by sex (male vs. female), type of trauma (veteran vs. 
civilian), and concurrent medication use (no concurrent antidepressant treatment vs. 
antidepressant treatment [SSRI or SNRI]) (see Section 4.1 for details). 
6.3.2 
Blinding 
Study site personnel and participants will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to participant treatment assignments to fulfill 
their job roles during a clinical trial.  For example, some individuals from the Sponsor 
may have access to unblinded data as needed for ongoing analysis, including EEG, 
clinical, cognitive, genetic, and digital biomarker data.  The core study team with direct 
site contact will remain blinded throughout the conduct of the study. 
While PK samples must be collected from participants assigned to the placebo arm to 
maintain the blinding of treatment assignment, PK results for such participants are 
generally not needed for the safe conduct or proper interpretation of the study data.  
Laboratories responsible for performing study drug PK assays will be unblinded to 
participant treatment assignments to identify appropriate samples for analysis.  PK 
samples from participants assigned to the placebo arm will not be analyzed for study 
drug PK concentration except by request (e.g., to evaluate a possible error in dosing). 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which participant management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The treatment code should not be broken except in emergency 


 
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situations.  The investigator is not required to contact the Medical Monitor prior to 
breaking the treatment code.  However, the investigator should inform the Medical 
Monitor that the treatment code has been broken. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  Unblinding 
may be permitted if an investigator is deciding whether a participant should withdraw 
from the study and initiate treatment with a proven therapy.  However, unblinding will not 
be permitted if an investigator is deciding whether a participant should withdraw from the 
study and initiate treatment with an unproven therapy. 
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to participant unblinding, the investigator will 
be able to break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 8.3.4) that are considered by the investigator or Sponsor to be related to an 
IMP (defined in Section 6).  The participant may continue to receive treatment, and the 
investigator, participant, and Sponsor personnel, with the exception of the Drug Safety 
representative and personnel who must have access to participant treatment 
assignments to fulfill their roles (as defined above), will remain blinded to treatment 
assignment. 
6.4 
STUDY TREATMENT COMPLIANCE  
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic as well as the time of administration of the preceding 
dose (at home) will be recorded in the source documents and recorded on the Study 
Drug Administration eCRF.  The dose of study treatment and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study treatment. 
When participants self-administer study treatment at home, compliance with study 
treatment will be assessed.  Compliance regarding administration of study drug at home 
will be monitored by the maintenance of adequate drug dispensing logs and return 
records. 
Study drug accountability will be performed at every site visit to monitor dose adherence.  
Interim telephone calls will occur at Weeks 4 and 9.  Participants will be called by the 
site personnel to monitor safety and tolerability when not attending the clinic.  
Assessments will include adverse event, concomitant medication review, and dose 
accountability (querying adherence, missed doses, etc). 


 
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Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration eCRF.  Cases of accidental overdose 
or medication error, along with any associated adverse events, should be reported as 
described in Appendix 3 and Section 6.7. 
6.5 
DOSE MODIFICATION 
Modification of the balovaptan or placebo dose is not permitted. 
6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
Currently, the Sponsor does not have any plans to provide balovaptan or any other study 
treatments to participants who have completed the study.  The Sponsor may evaluate 
whether to continue providing balovaptan in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following 
website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
6.7 
TREATMENT OF OVERDOSE 
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose.  There is no known antidote for treating an overdose with balovaptan.  Cases of 
overdose, along with any associated adverse events, should be reported as described in 
Appendix 3. 
In the event of an overdose, the investigator should take the following steps: 
1. 
Contact the Medical Monitor immediately. 
2. 
Closely monitor the participant for any adverse event or serious adverse event, and 
laboratory abnormalities. 
3. 
Obtain a plasma sample for PK analysis within 7 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis). 
 
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor on the basis of clinical evaluation of the participant. 
6.8 
CONCOMITANT THERAPY 
Any medication and/or vaccine, including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements used by a participant in addition to 
protocol−mandated treatment from 12 weeks prior to initiation of study treatment to the 
follow-up visit must be recorded on the Concomitant Medications eCRF along with the 
following information: 
• 
Reason for use 
• 
Dates of administration, including start and end dates 


 
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• 
Dosage information, including dose and frequency 
 
Based on hypothetical on-target considerations, results from Good Laboratory Practice 
(GLP) toxicology animal studies and clinical trial experience, there is no indication of 
immune-suppressant effects of balovaptan.  The existing safety monitoring and 
management guidelines, as well as the risk minimization measures outlined in the 
clinical protocol, are considered appropriate to support vaccinations including COVID-19 
vaccines concomitant to the treatment with balovaptan. 
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 
6.8.1 
Permitted Therapy 
In general, investigators may manage a participant's care (including preexisting 
conditions) as clinically indicated and per local standard practice, with the exception of 
prohibited therapies defined in Section 6.8.3 and taking into account cautionary 
therapies defined in Section 6.8.2. 
It is also common for individuals with PTSD to be engaged in a variety of 
non-pharmacological interventions, including individual and group based behavioral 
and/or cognitive psychotherapies.  Stable (6 weeks prior to screening) 
non-pharmacological intervention is permitted.  The frequency of sessions cannot 
exceed more than twice monthly.  Neither initiation of new psychotherapy nor a change 
to the frequency of existing psychotherapy is permitted during the course of the study. 
Use of the following concomitant therapies is permitted as described below: 
• 
SSRIs (sertraline, paroxetine, and fluoxetine) or SNRI (venlafaxine XR):  stable 
dose (see Section 5.1) 
• 
Non-narcotic analgesics (i.e., non-steroidal anti-inflammatory drugs [NSAIDs], 
acetaminophen/paracetamol)  
• 
Prescribed opioids:  no more than 2 times per week but not for 24 hours before 
study visits  
• 
Trazadone:  PRN up to 3 times per week  
• 
Sedating antihistamines (e.g., alimemazine, chlorphenamine, diphenhydramine, 
clemastine, cyproheptadine, hydroxyzine, ketotifen, or promethazine):  allowed up to 
3 times per week but not for 24 hours before study visit 
• 
Benzodiazepines:  up to 3 times per week but not for 24 hours before study visits 
• 
Other anxiolytics (buspirone, gabapentin, hydroxyzine, propranolol, atenolol, 
guanfacine, clonidine, pregabalin, prazosin) 
• 
Muscle relaxants:  up to 3 times per week but not for 24 hours before study visit 
• 
Sedatives/hypnotics:  allowed up to 3 times per week but not for 24 hours before 
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• 
Stimulants:  up to 3 times per week but not for 24 hours before study visit 
• 
Melatonin 
• 
Anti-epileptic drugs used for treatment of epilepsy given at stable dosage for at least 
6 months prior to screening 
• 
Drugs with known risk of neutropenia per Warnings and Precaution section of U.S. 
Prescribing Information while not requiring tight controls as mandated for clozapine, 
are allowed as long as the following criteria are met: 
– No hematological side effects have been noted with such drugs prior to study 
enrollment. 
– In this case hematological controls as often as every 2 weeks during study 
treatment should be considered by the investigator. 
 
6.8.2 
Cautionary Therapy 
6.8.2.1 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
Balovaptan is metabolized by cytochrome P450 3A4 (CYP3A4) and medications that are 
strong or moderate inhibitors or inducers of this enzyme will affect the PK of balovaptan.  
Therefore, the CYP3A4 inducers and inhibitors included in Appendix 10 should be 
avoided.  If use of one of these medications is deemed necessary by the investigator, the 
Medical Monitor should be consulted regarding benefits and risks prior to concomitant 
administration with balovaptan. 
Moderate inhibitors of CYP3A4 (e.g., erythromycin, ciprofloxacin, diltiazem) may be 
allowed for a treatment duration of no more than approximately 10 days (e.g., in the 
context of an adverse event). 
These lists of medications are not necessarily comprehensive.  The investigator should 
consult the prescribing information when determining whether a concomitant medication 
can be safely administered with study treatment.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
6.8.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions are generally 
unknown.  However, herbal therapies may be used during the study at the discretion of 
the investigator. 
6.8.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below and must be 
stopped 2 weeks prior to screening to ensure washout of medication: 
• 
Moderate or strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, 
erythromycin, ciprofloxacin, diltiazem, and grapefruit juice)  


 
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• 
Moderate or strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, St. John’s 
wort) 
• 
Quinidine 
• 
All other clinically relevant substrates of P-gp:  An interaction cannot be ruled out 
and caution is advised in particular for those medications that have a narrow 
therapeutic window (e.g., loperamide or paliperidone) or chronic adrenocorticoid or 
glucocorticoid use, in particular prednisolone.  However, when balovaptan is 
administered 5 or more hours prior to such a P-gp substrate, the risk of PK 
interaction is predicted to be small. 
• 
Oxytocin 
• 
DDAVP(desmopressin) 
• 
Bumetanide 
• 
Agents inhibiting vasopressin receptors (e.g., tolvaptan, conivaptan) 
• 
Tricyclic antidepressants:  TCAs, MAO inhibitors, or mirtazapine 
• 
Agents that have been associated with significant and/or irreversible hematological 
toxicity and therefore require frequent hematologic monitoring (e.g., clozapine) 
• 
Use of any concomitant medication known to potentially cause peripheral 
neuropathy per the Warnings and Precautions section of the U.S. Prescribing 
Information. 
• 
Antipsychotic medications or mood stabilizers 
 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
An excessive rate of withdrawals (either because of participant discontinuing study drug 
or withdrawal from the study) can render the study non-interpretable.  Therefore, 
unnecessary withdrawal of participants should be avoided and all efforts should be taken 
to motivate participants to comply with all the study specific procedures and to be 
followed until the end of the 12-week treatment period. 
Before permanently discontinuing study drug (either initiated by the participant or the 
investigator), an interruption should be considered (see Appendix 6, Section A6–2.2 for 
further details).  Participants, who temporarily discontinue study drug for any reason, 
should restart as soon as medically justified in the opinion of the investigator. 
The investigator should show due diligence and explore all possible options to reach a 
participant who fails to return to a visit.  The site must document all attempts to try to 
contact the participant in the source documents.  
7.1 
DISCONTINUATION OF STUDY TREATMENT 
It may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment.  If study treatment is definitively discontinued, the 


 
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participant will remain in the study for additional assessments.  Refer to the schedule of 
activities (see Section 1.3) for data to be collected at the time of discontinuation of study 
treatment and for any further follow-up evaluations that need to be completed. 
Participants must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
• 
Pregnancy 
• 
Inability of participant to continue to comply with study requirements 
• 
Suicidal ideation score of 4 or 5 or category 6 or greater on the C-SSRS 
• 
Specific events that are described in Sections 7.1.1, 7.1.2, 7.1.3, and 7.1.4 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
All participants who withdraw or discontinue from the study treatment early will be asked 
to return as soon as possible (and within 2 weeks after the last dose of study drug) for 
an early discontinuation visit and complete the assessments as per the schedule of 
activities in Section 1.3 (see Table 1).  Participants will also be asked to return for 
assessments of the primary and secondary efficacy outcomes at the end of the 12-week 
planned visit, regardless of their adherence to treatment.  If the time between the early 
discontinuation visit and the 12-week planned visit is fewer than 2 weeks, then 
participants are exempted from the 12-week planned visit.  If the time between the early 
discontinuation visit and the previous visit is fewer than 2 weeks, then participants are 
exempted from completing again all the primary and secondary assessments at the early 
discontinuation visit. 
Refer to the schedule of activities in Section 1.3 (see Table 1) for details on follow-up 
assessments to be performed for participants who permanently discontinue study 
treatment.  If a participant requests to be withdrawn from treatment or follow-up 
assessments, this request must be documented in the source documents and signed by 
the investigator. 
7.1.1 
Liver Chemistry Stopping Criteria 
There is no preclinical or clinical evidence that balovaptan administration is associated 
with an increase in abnormal liver tests. 
Discontinuation of study treatment is required by the investigator when a study 
participant meets abnormal liver tests as outlined Appendix 3 (see Section A3–7.6), or if 


 
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the investigator believes that it is in best interest of the participant when abnormal liver 
chemistries not meeting protocol-specified stopping rules. 
Discontinuation of study treatment is also required if the participant experiences 
moderate or severe hepatic impairment, defined as Child-Pugh class B (7−9 points) and 
class C (10−15 points), respectively.  Please see Appendix 8 for Child-Pugh 
classification. 
7.1.2 
QTc Stopping Criteria 
There is no preclinical or clinical evidence that balovaptan administration may be 
associated with an increase in the corrected QT interval (QTc). 
Nevertheless, treatment should be discontinued in case of the following: 
• 
Sustained (at least two ECG measurements >30 minutes apart) QTcF that is 
>500 ms and/or >60 ms longer than the baseline value 
Treatment with balovaptan should be discontinued in participants who develop changes 
in QT interval, as described in Appendix 6.  ECG assessment should be conducted as 
outlined in Section 8.2.4. 
7.1.3 
Hematological Toxicity Criteria 
Treatment discontinuation is suggested for participants who meet the following criterion 
for decreased absolute neutrophil count (ANC): 
If the ANC falls <800/µL and the low ANC is confirmed in a second sample to be 
obtained within about 3 working days.  If the ANC is <800/µL for the second sample, 
the investigator should consider treatment discontinuation. 
In cases of ANC related−treatment discontinuation, additional laboratory parameters 
should be considered by the Investigator, including fibrinogen, high-sensitivity C-reactive 
protein (hs-CRP), and check for anti-neutrophil cytoplasmic antibody (ANCA).  
7.1.4 
Cardiac Toxicity 
Management guidelines and treatment discontinuation for cardiac events are provided in 
Table 4. 


 
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Table 4 
Management Guidelines for Cardiac Events 
Cardiac Biomarker 
Result 
Actions 
hs-cTnT elevated above 
ULN 
• If increased to more than 50 pg/mL, permanently stop treatment 
and manage as cardiac emergency 
• If increased to above ULN and by more than 50% compared with 
baseline:  
− 
Check for cardio-vascular adverse events as soon as 
possible.  
– 
Perform 12-lead ECG as soon as possible. 
– 
Repeat cardiac biomarker testing, including troponin T, 
NT-proBN,  and troponin I panel within 3 days of availability 
of results. 
− 
If repeat sample cannot be obtained within 3 days, treatment 
must be interrupted until repeat test results are available. 
• If increased to above ULN and by less than 50% compared with 
baseline: 
− 
Repeat cardiac biomarker testing, including troponin T, 
NT-proBNP, and troponin I panel, within 1 week of availability 
of results. 
− 
Perform 12-lead ECG within 1 week of availability of results. 
− 
If repeat sample cannot be obtained within 1 week, treatment 
must be interrupted until repeat test results are available. 
Repeat blood sample  
• If hs-cTnT has further increased or stays above ULN with 50% 
increase relative to baseline: 
− 
Permanently discontinue treatment. 
− 
Perform 12-lead ECG. 
− 
Refer participant to local cardiologist consultant and 
cardiologist consult should include Doppler echocardiogram, 
including assessment of systolic and diastolic ventricular wall 
function. 
• If hs-cTnT is above ULN but has not further increased plus 
hs-cTnT value is less than baseline value plus 50% of baseline 
value:  
− 
Interrupt study treatment. 
− 
Perform 12-lead ECG. 
− 
Refer participant to cardiologist consultant and cardiologist 
consult should include Doppler echocardiogram, including 
assessment of systolic and diastolic ventricular wall function. 
− 
Consider-restart of treatment with tight hs-cTnT monitoring 
with local cardiologist consult. 
• If hs-cTnT has returned below ULN, no further activity is needed 
and treatment can continue.   
hs-cTnT=high-sensitivity cardiac troponin T; NT-proBNP=N-terminal prohormone of brain 
natriuretic peptide; ULN=upper limit of normal. 
  
7.1.5 
Peripheral Neuropathy 
Signs and symptoms suggestive of peripheral neuropathy should promptly be 
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other than study treatment.  Follow-up activities may include electro-physiological 
examinations, temporary treatment hold, and a consultancy by an expert to diagnose 
peripheral neuropathy in humans.   
Should the suspicion of peripheral neuropathy be verified and no alternative explanation 
known, study treatment should be discontinued permanently.  
7.2 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM 
THE STUDY 
A participant may withdraw from the study at any time at his or her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a participant requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the schedule of activities (see Section 1.3).  Refer to 
the schedule of activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study treatment and from 
the study at that time. 
If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent.  Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) or local laws require 
destruction of the samples.  However, if samples have been tested prior to withdrawal, 
results from those tests will remain as part of the overall research data.  
7.3 
PARTICIPANTS LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule.  If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic, and determine if there are ways to support participant 
participation.  


 
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• 
Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, three 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods).  These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up and will be withdrawn from the study.  
 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled individuals and for individuals who are not subsequently 
enrolled will be maintained at the study site. 
Study procedures and their timing are summarized in the schedule of activities (see 
Section 1.3).  Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure as applicable. 
Medical history and baseline conditions, including clinically significant diseases, 
surgeries history and baseline conditions, including clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and use of alcohol and drugs of abuse will be recorded at 
baseline.  Any medication and/or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) used by the participant within 24 weeks 
prior to the screening visit will be recorded at baseline.  Demographic data, including 
age, sex, and self-reported race/ethnicity, will also be recorded.  At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 


 
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Participants will be closely monitored for safety throughout the study.  For in-clinic visits, 
participants should be assessed for toxicity prior to each dose; treatment will be 
administered only if the clinical assessment and local laboratory test values are 
acceptable.  Urgent safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Clinical Outcome Assessments 
Participant-reported outcomes (PRO), clinician-reported outcomes (ClinRO) and 
performance outcome (PerfO) instruments will be completed to assess the treatment 
benefit of balovaptan.   
PRO data will be collected through use of the following instruments:  Life Events 
Checklist for DSM-5 (LEC-5), PCL-5, Patient Health Questionnaire-9 (PHQ-9), Beck 
Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Sheehan Disability Scale 
(SDS), Cognitive and Physical Functioning Questionnaire (CPFQ), Patient-Global 
Impression of Severity (PGI-S), and Patient-Global Impression of Change (PGI-C).  
ClinRO data will be collected through use of the following instruments:  SCID-5, CAPS-5, 
Clinician-Global Impression of Severity (CGI-S), and Clinician-Global Impression of 
Change (CGI-C).   
PCL-5 and LEC-5 are the PROs completed at screening, as well as the SCID-5 
(ClinRO).  The recommended order for administration is:  PCL-5, SCID-5, and LEC-5.  
For all other visits, PROs must be completed before the ClinROs in the following order:  
PHQ-9, PCL-5, PSQI, BAI, CPFQ, SDS, PGI-S, PGI-C.  ClinROs should be completed, 
starting with the CAPS-5, CGI-S, followed by the CGI-C. 
Clinician-Administered PTSD scale for DSM-5 (CAPS-5) is the clinical outcome 
assessment that will be used to determine the primary endpoint (see Table 2 and 
Section 9.4.2).  CGI-S and PHQ-9 are the clinical outcome assessments that will be 
used to determine the secondary endpoints (see Table 2 and Section 9.4.3).  For any 
individual patient, the CGI-S/C should be completed by the same rater throughout the 
study.  
PerfO data will be collected through the use of a computerized cognitive battery. 
8.1.1.1 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
The CAPS-5 is a 30-item structured interview that can be used to make current (past 
month) diagnosis of PTSD, make lifetime diagnosis of PTSD, or assess PTSD 
symptoms over the past week (Weathers et al. 2013a, 2018; see Appendix 11).  For this 
study the past week version of the CAPS-5 will be used and will be administered by 
central rater.  Items are scored using a 5-point scale, rated from 0 (absent) to 


 
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4 (extreme/incapacitating), with a higher overall score indicating a worse outcome.  In 
addition to assessing the 20 DSM-5 PTSD symptoms, questions asked target the onset 
and duration of symptoms, subjective distress, impact of symptoms on social and 
occupational functioning, improvement in symptoms since a previous CAPS 
administration, overall response validity, overall PTSD severity, and specifications for the 
dissociative subtype (depersonalization and derealization).  Responses will be collected 
by means of free text to understand intensity and frequency of symptoms, which are 
then used to select a response on a 5-point Likert scale, ranging from 0 (absent) to 
4 (extreme/incapacitating).  A total score is calculated by summing severity scores for 
items 1−20, where a higher score corresponds to greater severity of PTSD or presence 
of PTSD.  Symptom cluster severity scores can also be derived by summing the 
individual item severity scores for symptoms corresponding to a given DSM-5 cluster:  
Criterion B (items 1−5); Criterion C (items 6−7); Criterion D (items 8−14); and, Criterion E 
(items 15−20).  For each symptom, standardized questions and probes are provided.  
Administration requires identification of an index traumatic event to serve as the basis for 
symptom inquiry via the Life Events Checklist for DSM-5 (LEC-5; see Section 8.1.1.4 for 
more detail).  The LEC-5 will be administered prior to the CAPS-5 at screening only.  
The CAPS was designed to be administered by clinicians and clinical researchers who 
have a working knowledge of PTSD but can also be administered by appropriately 
trained paraprofessionals. 
The full interview takes 45−60 minutes to administer.  In this study, the past week 
version of the CAPS-5 will be administered remotely by a central assessor.  This first 
CAPS-5 assessment will be administered no more than 7 days prior to the baseline and 
at Week 6 and Week 12.  
8.1.1.2 
Clinician-Global Impression of Severity (CGI-S) and Change 
(CGI-C) 
The CGI-S and CGI-C are single items rated by the clinician (Guy 1976; see 
Appendix 11).  The CGI-S is used to assess the overall severity of PTSD symptoms over 
the past 7 days, whereas the CGI-C is used to assess change in overall PTSD 
symptoms from baseline.  Each item is rated on a 7-point scale, ranging from 1 (no 
symptoms/very much improved) to 7 (very severe/very much worse) for the CGI-S and 
CGI-C, respectively.  Clinicians should make a judgment on severity and any changes 
from baseline based on the totality of information available to them (e.g., insights from 
the patient captured during the completion of other trial assessments).  The 
assessments will take up to 5 minutes to complete in their entirety.  The CGI-S will be 
collected at baseline, Week 6, and Week 12.  The CGI-C will be collected at Week 6 and 
Week 12. 
8.1.1.3 
Patient Health Questionnaire-9 (PHQ-9) 
The PHQ-9 is a 9-item PRO used to assess severity of depression over the last 
2 weeks.  It was developed using each of the 9 DSM-IV criteria.  On the basis of these 
criteria, the diagnosis of depressive disorders is made (Kroenke et al. 2001; see 


 
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Appendix 11).  Responses are rated based on frequency of symptoms on a 4-point 
Likert scale, ranging from 0 (not at all) to 3 (nearly every day).  Reponses are reported 
using a recall of the last 2 weeks.  A total PHQ-9 total score ranging from 0 to 27 can be 
calculated by summing the nine items, of which a higher score corresponds to more 
severe depression.  Scores of 5, 10, 15, and 20 represent cutpoints for mild, moderate, 
moderately severe, and severe depression, respectively.  It takes approximately 
90 seconds to 3 minutes to complete.  The PHQ-9 will be administered at baseline, 
Week 6, and Week 12. 
8.1.1.4 
Life Events Checklist for DSM-5 (LEC-5) 
The LEC-5 standard version is a 17-item PRO designed to screen for potentially 
traumatic events in an individual’s lifetime (Gray et al. 2004; Weathers et al. 2013b; see 
Appendix 11).  The LEC-5 is intended to gather information about the potentially 
traumatic experiences a person has experienced.  It assesses exposure to 16 events 
known to potentially result in PTSD or distress and one additional item assessing any 
other extraordinarily stressful event not captured in the first 16 items.  Responses are 
reported on a 6-point nominal scale of which one or more responses can be made based 
on whether the event:  happened to the individual personally; they witnessed it happen 
to someone else; they learned about it happening to a close family member or close 
friend; they were exposed to it as part of their job (e.g., first responders); they are not 
sure if it fits; it does not apply.  There is no formal scoring protocol or interpretation 
per se, other than identifying whether a person has experienced one or more of the 
events listed.  
The purpose of the LEC-5 generally and in this study is to inform other measures 
(e.g., CAPS-5) to establish exposure to a PTSD Criterion A traumatic event.  It takes 
approximately 4−8 minutes to complete.  The LEC-5 must be completed at the screening 
visit. 
8.1.1.5 
PTSD Checklist for DSM-5 (PCL-5) 
The PCL-5 is a 20-item PRO used to assess the 20 DSM-5 symptoms of PTSD 
(Weathers et al. 2013c; Blevins et al. 2015; see Appendix 11).  Reponses are reported 
on a 5-point Likert scale, ranging from 0 (not at all) to 4 (extremely).  A recall period of 
one month has been validated.  However, the PCL-5 manual acknowledges a recall 
period of less than one month may make more sense in some cases, but to be aware 
that the psychometric properties may differ to those published using the one-month 
recall (National Center for PTSD 2013).  In this study, the one-month recall will be used 
at screening for diagnostic purposes and a one week recall version will be used 
thereafter for efficacy.  This is to allow for more frequent PCL-5 administrations without 
overlapping recalls.  A total severity score, ranging from 0 to 80, can be calculated by 
summing all items, of which a higher score corresponds to more severe symptoms.  The 
PCL-5 can be used to determine a provisional diagnosis in two ways; either using a 
cutpoint score of 31 to 33, or alternatively, by treating each item rated as 2 (moderately) 
or higher as a symptom endorsed and then following the DSM-5 diagnostic rule, which 


 
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requires at least:  1 Criterion B item (Questions 1−5), 1 Criterion C item (Questions 6−7), 
2 Criterion D items (Questions 8−14), and 2 Criterion E items (Questions 15−20).  If a 
patient meets a provisional diagnosis using either of the methods above, then he or she 
needs further assessment (e.g., CAPS-5 or SCID-5) to confirm a diagnosis of PTSD.  It 
takes approximately 5−10 minutes to complete.  The PCL-5 will be administered at 
screening, baseline, Week 2, Week 6, and Week 12. 
8.1.1.6 
Structured-Clinical Interview for DSM-5 (SCID-5)  
The SCID-5 is a structured diagnostic instrument for assessing DSM-5 disorders (First 
2014; Appendix 11).  The instrument is designed to be administered by a clinician or 
trained mental health professional.  The SCID-5 is organized into diagnostic modules 
corresponding to categories of diagnoses.  Most sections begin with an entry question 
that would allow the interviewer to skip the associated questions if not met.  For all 
diagnoses, symptoms are coded as present, subthreshold, or absent.  The SCID-5 will 
be used only at screening for the diagnosis of PTSD. 
8.1.1.7 
Beck Anxiety Inventory (BAI) 
The BAI is a 21-item PRO used to assess severity of anxiety in psychiatric populations 
(Beck et al. 1988; see Appendix 11).  BAI is a self-reported measure of clinical anxiety.  
BAI was designed to specifically assess the physiological and cognitive symptoms of 
anxiety and is independent of depression.  Responses are reported using a recall of 
1  week on the basis of how much an individual has been bothered by each symptom 
and then recorded using a 4-point Likert scale, ranging from 0 (not at all) to 
3 (severelyit bothered me a lot).  A total score, ranging from 0 to 63, can be calculated 
by summing the 21 items, for which a higher score corresponds to more severe anxiety.  
Scores of 0 to 21, 22 to 35, and 36 and above represent cutpoints for low, moderate, 
and concerning levels of anxiety.  It takes approximately 2−4 minutes to complete.  The 
BAI will be administered at baseline, Week 6, and Week 12. 
8.1.1.8 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI is a 19-item PRO used to assess sleep quality over the past month (Buysse et 
al. 1989; see Appendix 11).  It contains 7 domains, consisting of subjective sleep quality 
(1 item), sleep latency (2 items), sleep duration (1 item), habitual sleep efficiency 
(3 items), sleep disturbances (9 items), use of sleep medication (1 item), and daytime 
dysfunction (2 items).  It is rated by entering numeric values or on a 4-point Likert scale 
with a range of response options from 0 (corresponding to better outcomes) to 
3 (corresponding to worse outcomes).  Reponses are reported using a recall of the past 
month.  The PSQI can be scored as a total score ranging from 0 to 21 by summing all 
items or by domain (mentioned above), for which higher scores correspond to worse 
sleep quality.  A global score of 5 represents poor sleep quality.  It takes approximately 
5−10 minutes to complete.  The PSQI will be administered at baseline, Week 6, and 
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8.1.1.9 
Sheehan Disability Scale (SDS) 
The SDS is a 5-item PRO used to assess health-related quality of life and social 
functioning (Sheehan 1983, Sheehan and Sheehan 2008; see Appendix 11).  It consists 
of 3 core items that are related to disruption at work, social life, and family life, as well as 
2 optional items stating the number of days lost or underproductive due to symptoms.  
Using a recall period of the past week, items are rated on a 10-point numerical rating 
scale, ranging from 0 (unimpaired) to 10 (highly impaired).  The measure can be scored 
either by item as a percentage or as a global score from 0 to 30, for which higher scores 
correspond to greater impairment.  There are no referenced cutoff scores for this 
measure.  It takes approximately 1−2 minutes to complete.  The SDS will be 
administered at baseline, Week 6 and Week 12.   
8.1.1.10 
Cognitive and Physical Functioning Questionnaire (CPFQ) 
CPFQ is a 7-item PRO used to assess physical and psychological functioning in mood 
and anxiety disorders (Fava et al. 2009; see Appendix 11).  The participant is asked to 
report how affected he or she has been over the past month by seven of the most 
common complaints of depressed individuals.  Responses are made using a 6-point 
Likert scale from 1 (greater than normal) to 6 (totally absent).  Scoring can be calculated 
as a total score, ranging from 7 to 42 or by domain (cognitive, 4 items; physical, 3 items) 
by summing items and a higher score corresponds to poorer functioning.  It takes 
approximately 60−90 seconds to complete.  The CPFQ will be administered at baseline, 
Week 6, and Week 12. 
8.1.1.11 
Patient-Global Impression of Severity (PGI-S) and Change 
(PGI-C) 
The PGI-S and PGI-C are single items rated by the participant that is used to assess the 
overall severity over the past 7 days or change of PTSD symptoms relative to baseline 
(see Appendix 11).  Each item is rated on a 7-point scale, ranging from 1 (no 
symptoms/very much improved) to 7 (very severe/very much worse) for PGI-S and 
PGI-C, respectively.  The assessments will each take approximately 30 seconds to 
complete.  The PGI-S will be collected at baseline, Week 6, and Week 12.  The PGI-C 
will be collected at Week 6 and Week 12. 
8.1.1.12 
Computerized Cognitive Battery 
A computerized cognitive battery will be administered and completed by participants to 
assess domains such as psychomotor functioning (e.g., simple and choice-reaction time 
tasks), non-verbal receptive communication (e.g., facial-emotion recognition task), verbal 
memory, and executive function (including set-shifting and/or reversal learning).  The 
data will be used mainly to derive cognitive biomarkers (see Section 8.7) and may also 
be used for exploratory efficacy endpoints.  The assessments will take approximately 
30 minutes to complete and will be administered at the pre-randomization visit, Week 2, 
Week 6, and Week 12. 


 
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8.2 
SAFETY ASSESSMENTS 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
A brief or limited physical examination should be symptom-directed and will include, at a 
minimum, assessments of the skin, lungs, and the cardiovascular and neurologic 
systems.   
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  Changes from baseline abnormalities should be recorded in participant notes.  
New or worsened clinically significant abnormalities beyond what is expected in the 
clinical situation should be recorded as adverse events on the Adverse Event eCRF. 
8.2.2 
Vital Signs 
Temperature (tympanic), pulse rate, respiratory rate, and blood pressure will be 
assessed. 
Blood pressure and pulse measurements will be assessed while the participant is in a 
seated position with a completely automated device.  Manual techniques will be used 
only if an automated device is not available.   
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs (to be taken before any blood collection) will consist of one pulse and three 
blood pressure measurements (three consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute).  The average of the three blood pressure 
readings will be recorded on the eCRF. 
Abnormalities observed at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, new or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
8.2.3 
Neurological Examination 
Neurologic examinations of the upper and lower limbs will be completed as per the 
schedule of activities in Section 1.3 (see  Table 1)and conducted as per the instructions 
provided in in Appendix 7. 


 
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8.2.4 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the schedule of activities (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR interval, QRS interval, QT interval, and QTcF.  Refer to Appendix 6 for 
prolonged QTc management criteria and any additional QTc readings that may be 
necessary. 
For the baseline ECG at which triplicate ECGs are required, three individual ECG 
tracings should be obtained as closely as possible in succession, approximately 
1−2 minutes apart.   
All ECG recordings must be performed through use of a standard high-quality, 
high-fidelity digital electrocardiograph machine.  Lead placement should be as consistent 
as possible.  ECG recordings must be performed after the participant has been resting in 
a supine position for at least 5 minutes.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre−ECG resting period and during ECG 
recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
reports.  Paper copies of ECG tracings will be kept as part of the participant's permanent 
study file at the site.  Digital recordings will be stored at the site as part of the medical 
record and the central ECG laboratory.  The following parameters will be provided as 
non-eCRF data:  heart rate, RR interval, QRS interval, PR duration (beginning of P wave 
to first part of QRS complex), uncorrected QT interval, and QTcF based on machine 
readings of the individual ECG tracings.  Any concerning morphologic waveform 
changes or other ECG abnormalities that lead to change in management or increased 
monitoring must be documented on the eCRF as an adverse event.  
If at a particular postdose timepoint the mean QTcF is > 500 ms and/or > 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
30 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted at the investigator's discretion.  If a PK sample is not scheduled for that 
timepoint, one should be obtained.  A decision on study drug discontinuation should be 
made, as described in Appendix 6 (see Section A6–2.7).  The investigator should also 
evaluate the participant for potential concurrent risk factors (e.g., electrolyte 
abnormalities, concomitant medications known to prolong the QT interval, severe 
bradycardia). 


 
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8.2.5 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
schedule of activities (see Section 1.3) for the timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the Adverse Event eCRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  A laboratory test result must be reported as an adverse event if it 
meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days of the final dose of study treatment should be 
repeated until the values return to normal or baseline or are considered to be stable and 
no longer considered clinically significant by the investigator.  If such values do not 
return to normal or baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the schedule of activities 
(Section 1.3). 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event or 
adverse event or dose modification), the results must be recorded on the eCRF. 
Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final CSR. 
8.2.6 
Pregnancy Testing 
The schedule for pregnancy testing for enrolled female participants is outlined in 
Section 1.3 and will be conducted as outlined in Appendix 2. 


 
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8.2.7 
Monitoring for Suicidal Ideation and Behavior 
The assessment for suicidality in clinical trials is a requirement for CNS-active molecules 
requested by health authorities. 
The C-SSRS is a clinician-rated tool recommended by health authorities, including the 
FDA, to assess previous suicidality of a subject (C-SSRS Baseline/Screening version) 
as well as any new instances of suicidality during this study (C-SSRS Since Last Visit 
version to be used at subsequent visits) (Posner et al. 2009a, Posner et al. 2009a) 
(Appendix 11).  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. 
The C-SSRS is made up of ten categories, all of which maintain binary responses 
(yes/no) to indicate a presence or absence of the behavior.  The ten categories included 
in the C-SSRS are as follows:  Category 1-Wish to be Dead; Category 2-Non-specific 
Active Suicidal Thoughts; Category 3-Active Suicidal Ideation with Any Methods 
(Not Plan) without Intent to Act; Category 4-Active Suicidal Ideation with Some Intent to 
Act, without Specific Plan; Category 5-Active Suicidal Ideation with Specific Plan and 
Intent; Category 6-Preparatory Acts or Behavior; Category 7-Aborted Attempt; 
Category 8-Interrupted Attempt; Category 9-Actual Attempt (non-fatal); 
Category 10-Completed Suicide.  A yes or no binary response is also utilized in 
assessing self-injurious behavior without suicidal intent.  The outcome of the C-SSRS is 
a numerical score obtained from the aforementioned categories.  The maximum suicidal 
ideation category (1−5 on the C-SSRS) will determine the suicidal ideation score for the 
participant.  A score of 0 represents no ideation.  
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior.  Consideration should be given 
to discontinuing the study drug in participants who experience signs of suicidal ideation 
or behavior, following a risk assessment.  If the investigator concludes there is a risk of 
suicidality for a participant, the investigator must further evaluate the risk, which may 
involve local experts in the field of suicidality. 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
The definitions of adverse event and serious adverse event can be found in  (see 
Sections A3–1 and A3–2). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are 


 
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considered related to the study treatment or study procedures, or caused the participant 
to discontinue the study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  All 
other medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the General Medical History and 
Baseline Conditions eCRF, not the Adverse Event eCRF. 
All adverse events will be reported from the start of treatment until 14 days after final 
study drug or until the last follow-up visit at the timepoints specified in the schedule of 
activities (see Section 1.3). 
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation.  However, if the investigator learns of 
any serious adverse event, including a death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify the 
Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about adverse event occurrences. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts.  All 


 
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adverse events will be followed until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the participant is lost to follow-up (as 
defined in Section 7.3), or the participant withdraws consent.  Further information on 
follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the investigator to the Sponsor of a serious adverse event is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory authorities about the safety of a study treatment under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards or 
Ethics Committees (IRBs/ECs), and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the balovaptan Investigator’s Brochure. 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 
events) from the Sponsor will review and then file it along with the Investigator’s 
Brochure and will notify the IRB/EC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 14 days after the final dose of balovaptan. 


 
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If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Appendix 4.  The Sponsor or a designee may follow up by telephone, fax, email, and/or 
a monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
8.3.6 
Death Events 
Information on reporting deaths is provided in Appendix 3 (see Section A3–7.7) 
8.3.7 
Adverse Events of Special Interest  
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 the investigator becomes aware 
of the event; see Section A3–5 for reporting instructions).  Adverse events of special 
interest for this study are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section A3–7.6) 
• 
Suspected transmission of an infectious agent by a study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies 
only when a contamination of the study treatment is suspected. 
• 
ANC values <800/µL and confirmed in a second sample. 
• 
Creatine phosphokinase (CPK) values triggering a change in monitoring schedule 
and also when: 
– 
CPK values exceed 10×ULN for several days without trend of normalization 
according to CPK half-life in plasma 
– 
CPK increases associated with a relevant decrease in kidney function and no 
alternative explanation exists 
– 
CPK values increase again to similar values as noted before when treatment 
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• 
Cases of neurological abnormalities emerging from adverse event reporting or 
neurological examination (see Section 8.2.3) that are potentially indicative of 
dysfunction of peripheral nerves or otherwise represent a neurological deficit and for 
which no other explanation is apparent (see Safety Plan: Management of Identified 
and Potential Risks in Appendix 6, Section A6–2.9 for further details on when a 
measurement of the nerve conduction velocity (NCV) may be needed).  
 
8.3.8 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately.  An Emergency 
Medical Call Center will be available 24 hours per day, 7 days per week, in case the 
above-listed contacts cannot be reached.  The Emergency Medical Call Center will 
connect the investigator with an Emergency Medical Contact, provide medical translation 
service if necessary, and track all calls.  Contact information, including toll-free numbers 
for the Emergency Medical Call Center, will be distributed to investigators.  
8.4 
PHARMACOKINETICS 
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of balovaptan using a specific and validated liquid chromatography 
coupled to tandem mass spectrometry (LC-MS/MS) assay as specified in the schedule 
of activities in Section 1.3 (see Table 1).  Concentration of metabolite 2 (M2) and 
metabolite 3 (M3) may be measured if indicated (e.g., safety concern). 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples will be used to evaluate the pharmacokinetics of balovaptan.  Samples 
collected for analyses of balovaptan plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on these plasma samples unless consent for this 
was included in the Informed Consent Form.  Participant confidentiality will be 
maintained.  At visits during which blood samples for the determination of multiple 
aspects of balovaptan will be taken, one sample of sufficient volume can be used. 
PK samples will be destroyed no later than 5 years after the final CSR has been 
completed to allow for assay development and validation (if needed). 
Information on unblinding of personnel responsible for performing PK assays is provided 
in Section 6.3. 
8.5 
PHARMACODYNAMICS 
Refer to Section 8.7 for information on pharmacodynamic biomarkers. 


 
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8.6 
GENETICS 
Refer to Section 8.7 and Appendix 5 for information on genetic biomarkers. 
8.7 
BIOMARKER ASSESSMENTS 
The following biomarker assessments will be collected, as applicable, from participants 
at all sites: 
• 
EEG assessments.  Resting-state EEG will be acquired at 1000 Hz from 
64 locations following the extended 10−20 system electrode montage.  This 
assessment will follow the recommendations of the International Pharmaco-EEG 
Society (Jobert et al. 2012) in 4-minute blocks as follows:  eyes closed (recording 
eyes closed [REC] 1), eyes open (recording eyes open [REO] 1), eyes closed 
(REC2), and eyes open (REO2), amounting to a total of 16 minutes, while 
participants sit relaxed looking at a fixating cross during eyes-open conditions.  
Raw, unfiltered EEG data along with impedances (targeting < 15 kOhm for each 
channel in each run) will be recorded.  Resting state data will be processed offline to 
assess electrical brain activity including, but not limited to power at frequency bands 
and connectivity. 
• 
Computerized cognitive assessments.  A battery of cognitive assessments will be 
administered, using an electronic display and with manual responses controlled by 
participants using their left and/or right hands on a mouse, keyboard, or tablet as 
appropriate for the task.  The neurocognitive assessments to be administered will 
include assessments of psychomotor functioning (simple and choice-reaction time 
tasks), non-verbal receptive communication, verbal memory, and executive function. 
• 
Digital biomarkers.  These will be derived from a wearable device (e.g., OURA 
Ring).  The following wearable sensor data will be recorded:  heart rate, movement, 
and sleep.  These measures will be recorded to enable the derivation of exploratory 
biomarkers related to autonomic function and arousal, movement kinematics and 
behavior, and sleep.  The wearable will be worn starting during screening about 
1 week prior to randomization and worn throughout the study.  Staff will instruct the 
participant on how to wear and care for the wearable, and on the importance of 
sleep hygiene. 
 
The following biomarker samples will be collected, as applicable, from participants at all 
sites: 
• 
Blood samples for exploratory research on biomarkers and biomarker assay 
development 
 
Biomarker samples collected at participating sites and biomarker samples 
requiring separate consent are described in Section 8.11. 
Exploratory biomarker research may include, but will not be limited to, analysis of 
biomarkers relevant to balovaptan (e.g., AVPR1A gene), PTSD and related disorders, 
and drug safety.  Research may involve extraction of DNA, cell-free DNA, or RNA; 
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genomic profiling through use of next-generation sequencing (NGS) of a comprehensive 
panel of genes.  Genomic research will be aimed at exploring inherited characteristics.  
NGS methods may include whole genome sequencing (WGS) or whole exome 
sequencing (WES) of blood samples, but only at participating sites (see Section 8.11.1). 
Biomarker samples will be collected according to the schedule outlined in Section 1.3 
(see Table 1).  Biomarker samples will be sent to one or several central laboratories or 
to the Sponsor or a designee.  Instructions for the collection and handling of biomarker 
samples, including sampling procedures, storage conditions, and shipment instructions, 
are provided in the laboratory manual. 
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.11), biomarker samples will be 
destroyed no later than 5 years after the final CSR has been completed.  
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
8.8 
IMMUNOGENICITY ASSESSMENTS 
Immunogenicity assessments will not be performed in this study. 
8.9 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economics and medical resource utilization assessments will not be performed in 
this study. 
8.10 
CLINICAL OUTCOME ASSESSMENTS 
8.10.1 
Data Collection Methods for Clinical Outcome Assessments 
For the description of the clinical outcome assessment used in the study see 
Section 8.1.1.  
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see the schedule of activities in Section 1.3).  At the clinic, instruments will be 
administered before the participant receives any information on disease status, prior to 
the performance of non-PRO assessments, and prior to the administration of study drug. 
PRO instruments will be completed through use of an electronic device provided by the 
Sponsor.  The device will be pre-programmed to enable the appropriate instruments to 
be administered in the correct order at each specified timepoint.  The electronic device 
and instructions for completing the instruments electronically will be provided by the site 


 
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staff.  The data will be transmitted to a centralized database maintained by the electronic 
device vendor.  The data will be available for access by appropriate study personnel. 
During clinic visits, PRO instruments should be administered as outlined below: 
• 
Participants' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for participants to complete the instruments, 
estimated to be approximately 15−30 minutes at baseline, Week 6, and Week 12. 
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Participants should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers. 
• 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
• 
Participants should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
ClinRO instruments will be completed at the clinic at specified timepoints during the 
study (see schedule of activities in Section 1.3).  ClinRO instruments will be 
administered prior to the administration of study drug.  The instruments will be 
completed through use of an electronic device provided by the Sponsor.  Clinicians must 
complete the official version of each ClinRO instrument, as provided by the Sponsor.  
Instruments must not be copied from the protocol.  The data will be transmitted to a 
centralized database maintained by the electronic device vendor. 
8.10.2 
Description of Clinical Outcome Assessment Instruments 
For the description of the clinical outcome assessment used in the study see 
Section 8.1.1.  
8.11 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
8.11.1 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Participants at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants (inherited characteristics) that are predictive of response to 
study treatment, are associated with progression to a more severe disease state, are 
associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety. 


 
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Research will be aimed at exploring inherited characteristics. 
The samples may be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 8.11.1) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC−approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual basis.  Thus, there will be no identification and 
reporting of incidental findings to investigators or participants. 
If permitted by local law, a participant may request access to uninterpreted WGS or 
WES data derived from analysis of his or her blood sample.  If a participant wishes to 
access these data, the investigator must inform the Sponsor, using the following email 
address:  global.return-genomics-results@roche.com.  The Sponsor will provide 
available data to the investigator in the form of a raw genomic sequencing data file, but 
will not provide any interpretation of the data.  The investigator should not include the 
data file in the participant’s medical record.  Samples may be stored and analyzed in the 
future, and some samples may never be analyzed.  Thus, data may not be available at 
the time of the request or may never be available. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication (see Appendix 1). 


 
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8.11.2 
Samples for Research Biosample Repository (Participants 
Providing Separate Consent at Participating Sites)  
8.11.2.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
• 
To increase knowledge and understanding of disease biology and drug safety 
• 
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 
 
8.11.2.2 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 8.11) will 
not be applicable at that site. 
8.11.2.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to balovaptan, PTSD, or 
drug safety: 
• 
Leftover PK samples (see Section 8.4)  
• 
Leftover blood for DNA sample collected at baseline (Day 1) 
• 
Additional whole-blood sample for RBR at the timepoints specified in the schedule 
of activities in Section 1.3 (see Table 1). 
 
The above samples may be sent to one or more laboratories for analysis including, but 
not limited to, the analysis of germline or somatic variants via WGS, WES, or other 
analysis methods.  Genomics is increasingly informing researcher's understanding of 


 
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disease pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or that may be predictive of which patients 
are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  RBR samples are to be stored until they are no longer needed or 
until they are exhausted.  However, the RBR storage period will be in accordance with 
the IRB/EC−approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
8.11.2.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique participant identification 
number. 
Participant medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
8.11.2.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to choose not to provide optional RBR samples and may 


 
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withdraw their consent at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a participant's agreement to 
provide optional RBR samples.  Participants who choose not to provide optional RBR 
samples will not provide a separate signature.  The investigator should document 
whether or not the participant has given consent to provide optional RBR samples and (if 
applicable) the date(s) of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
8.11.2.6 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If a 
participant wishes to withdraw consent to the testing of his or her RBR samples during 
the study, the investigator must inform the Medical Monitor in writing of the participant's 
wishes through use of the appropriate RBR Subject Withdrawal Form and must enter the 
date of withdrawal on the Sample Informed Consent/Withdrawal eCRF.  If a participant 
wishes to withdraw consent to the testing of his or her RBR samples after closure of the 
site, the investigator must inform the Sponsor by emailing the study number and 
participant number to the following email address: 
global.rcr-withdrawal@roche.com 
A participant's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a participant's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study. 
8.11.2.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to an individual's participation in the RBR for the purposes of 
verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 


 
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9. 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
No formal statistical hypotheses will be tested for this study.  All analyses will be 
conducted using descriptive statistics. 
9.2 
SAMPLE SIZE DETERMINATION  
Approximately 30 participants will be randomly assigned to study treatment (15 in 
balovaptan arm and 15 in placebo arm) to perform the final analysis with reduced 
scope. 
9.3 
ANALYSIS SETS  
The following populations are defined: 
Participant Analysis Set 
Description 
Intent to treat  
All participants randomly assigned to study drug.  Participants will 
be analyzed according to the treatment to which they were 
assigned. 
Safety evaluable  
All participants randomly assigned to study drug and who receive 
at least one dose of study drug.  Participants will be analyzed 
according to the treatment they actually receive. 
PK evaluable 
The PK-evaluable population will include all participants who 
receive at least one dose of balovaptan and have sufficient 
evaluable concentrations to determine the overall exposure to 
balovaptan. 
Participants may be excluded from the PK-evaluable population if 
they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or if data are unavailable or 
incomplete.  Excluded cases will be documented together with 
the reason for exclusion.  All decisions about exclusions from the 
analysis will be made prior to database lock. 
PK = pharmacokinetic. 
  
9.4 
STATISTICAL ANALYSES  
The intent-to-treat (ITT) analysis set, as defined in 9.3, will be used for efficacy analyses.  
The safety analysis set, as defined in 9.3, will be used for safety analyses.  
Final database lock to enable the analysis of the primary and secondary endpoints will 
occur once all patients have either completed their follow-up assessment or withdrawn 
from the study early, and all data required for analysis have been cleaned and verified. 
9.4.1 
General Considerations  
For all endpoints, baseline will be defined as the last assessment made up to and 
including the day of first study drug intake. 


 
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In general, descriptive statistics will be used to summarize continuous endpoints and 
counts and percentages will be used to summarize categorical endpoints. 
Missing values will not be replaced.   
9.4.2 
Primary Endpoint 
The primary endpoint is the change in CAPS-5 total symptom severity score from 
baseline at Week 12, as defined in Section 3 (see Table 2).  The change from baseline 
in CAPS-5 total symptom severity score at Week 12 will be calculated as the score at 
Week 12 minus the score at baseline.  A negative change from baseline in CAPS-5 total 
symptom severity score indicates improvement.  
Every effort will be made to minimize missing data.  Participants who discontinue early 
from study treatment will be asked to return for collection of safety and limited efficacy 
data (i.e., the primary and secondary efficacy endpoints) at the scheduled visits. 
9.4.3 
Secondary Endpoints 
The secondary endpoints are the changes from baseline at Week 12 in the CGI-S and 
PHQ-9, as defined in Section 3 (see Table 2). 
9.4.3.1 
Clinician-Global Impression of Severity (CGI-S) 
The change from baseline in CGI-S will be calculated as the CGI-S score at Week 12 
minus the CGI-S score at baseline.  A negative change from baseline in CGI-S indicates 
improvement. 
The count and percentages for each value of CGI-S changes will be evaluated. 
9.4.3.2 
Patient Health Questionnaire-9 (PHQ-9) 
The PHQ-9 is a 9-question instrument to assess presence and severity of depression 
(see Section 8.1.1.3 for details).  The total sum of responses score ranges from 0 to 27 
and will be summarized using descriptive statistics at each assessment timepoint for 
absolute values as well as change from baseline.  Additionally, the score will be 
categorized as shown in Table 5, and a shift table will be provided to examine changes 
in depression severity categories from baseline to worst post-baseline depression 
severity. 
Table 5 
Patient Health Questionnaire-9 (PHQ-9) Score and  
Corresponding Categories 
PHQ-9 Score 
Depression Severity 
04 
None-minimal 
59 
Mild 
1014 
Moderate 
1519 
Moderately severe 
2027 
Severe 
PHQ-9Patient Health Questionnaire-9  
  


 
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9.4.4 
Exploratory Endpoints 
Exploratory endpoints as defined in Section 3, Table 2, will be analyzed descriptively by 
treatment arm.  Descriptive statistics (mean, standard deviation, median, and range) will 
be presented for continuous variables and counts and percentages will be presented for 
categorical variables. 
The relationship between biomarkers (see Section 8.7) and efficacy, safety, PK, or other 
biomarker endpoints may be explored to identify biomarkers that are predictive of 
response to balovaptan or are early signs of efficacy.   
9.4.5 
Safety Analyses 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, physical and neurologic examinations, urine drug screens, changes in laboratory 
test results, changes in vital signs, ECGs and Doppler echocardiograms (where 
applicable), and C-SSRS. 
Study treatment exposure (such as treatment duration and treatment compliance) will be 
summarized with descriptive statistics. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to mild, 
moderate, or severe scale (see Adverse Events Severity Grading Scale; Appendix 3, 
Table 1).  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, 
and temperature), and ECG data will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum post-baseline severity grade.  Changes in vital 
signs and ECGs will be summarized.  
9.4.6 
Other Analyses  
9.4.6.1 
Summaries of Conduct of Study 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study treatment discontinuation will also 
be tabulated.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm. 


 
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9.4.6.2 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, type of trauma 
[veteran/armed forces service-related or civilian], concurrent antidepressant use, time 
since triggering event, and time since PTSD diagnosis) will be summarized by treatment 
arm.  Baseline data are the last data obtained prior to initiation of study treatment.  
Descriptive statistics (mean, standard deviation, median, and range) will be presented 
for continuous variables and counts and percentages will be presented for categorical 
variables. 
9.4.6.3 
Pharmacokinetic Analyses  
Individual and mean plasma concentrations of balovaptan at each sampling timepoint 
will be presented by listings and descriptive summary statistics, including means, 
medians, geometric means, ranges, standard deviations, and coefficients of variation.  If 
warranted by the observed data, empirical Bayes estimates for individual balovaptan PK 
parameters and exposure may be derived using a previously developed population PK 
model (1101622 [available upon request]).  Concentration of M2 and M3 may be 
measured if indicated (e.g., safety concern) and presented in listings and descriptive 
summary statistics. 
Graphical exploration of the relationship between balovaptan exposure and outcome 
measures and biomarkers as well as safety parameters may be performed.  If indicated 
by such exploration, more formal analyses of PK to pharmacodynamic (PD), safety or 
efficacy measures of interest may be undertaken. 
Results of population PK or PK/PD modelbased analyses may be reported in a 
separate study summary. 
9.5 
INTERIM ANALYSES 
There are no planned interim analyses for this study.  
9.6 
INTERNAL MONITORING COMMITTEE 
Refer to Section 4.1 for information on the IMC for this study. 


 
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10. 
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Regulatory, Ethical, and Study Oversight Considerations 
TABLE OF CONTENTS 
A1–1 
Regulatory and Ethical Considerations .................................... 81 
A1–2 
Financial Disclosure ................................................................. 81 
A1–3 
Informed Consent Process ...................................................... 82 
A1–4 
Data Protection ........................................................................ 82 
A1–5 
Administrative Structure ........................................................... 83 
A1–6 
Dissemination of Clinical Study Data ....................................... 83 
A1–7 
Data Quality Assurance ........................................................... 84 
A1–8 
Source Documents .................................................................. 85 
A1–9 
Study and Site Closure ............................................................ 85 
A1–10 
Publication Policy ..................................................................... 86 
A1–11 
Protocol Deviations .................................................................. 86 
 
 


Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
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A1–1 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
• 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
• 
Applicable laws and regulations 
 
The protocol, Informed Consent Form, Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board or 
Ethics Committee (IRB/EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• 
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 
• 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
• 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Clinical Trials Directive (2001/20/EC) or Clinical Trials 
Regulation 536/2014 (EEA sites only), and all other applicable local regulations 
 
A1–2 
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 
study and for 1 year after completion of the study (see definition of end of study in 
Section 4.4). 


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A1–3 
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study to the 
participant or his or her legally authorized representative and answer all questions 
regarding the study. 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a participant's willingness to continue in the 
study, the participant or the participant's legally authorized representative must 
re-consent by signing the most current version of the Informed Consent Form or the 
addendum, in accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. 
Participants who are re-screened are required to sign a new Informed Consent Form. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each participant the objectives of the exploratory 
research.  Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period.  A 
separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research.  Participants who decline to 
participate in this optional research will not provide this separate signature. 
A1–4 
DATA PROTECTION 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 


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Participants will be assigned a unique identifier by the Sponsor.  Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; the 
participant's name or any information that would make the participant identifiable will not 
be transferred. 
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the Informed Consent Form. 
Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A1–5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.  
The Sponsor has contracted IQVIA, who will be delegated responsibility for various 
aspects of this clinical trial. 
Approximately 12 sites located in the United States will participate to enroll 
approximately 30 participants.  Enrollment will occur through an interactive voice or 
web-based response system.  
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and pharmacokinetic analyses), as specified 
in Section 8 and Appendix 2. 
A1–6 
DISSEMINATION OF CLINICAL STUDY DATA 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and/or other summaries of clinical study 
results may be available in health authority databases for public access, as required by 
local regulation, and will be provided upon request.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Roche policy on study data publication. 
A1–7 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed or electronic Case 
Report Form (CRFs) unless transmitted to the Sponsor or designee electronically (e.g., 
laboratory data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered on the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site 
monitoring), are provided prior to study initiation, in the various functional 
monitoring plans (including, but not limited to, Quality Tolerance Limit Management Plan 
and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered on the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, the ICH Guideline 
for Good Clinical Practice, and all applicable regulatory requirements. 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 


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approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
A1–8 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the electronic Case Report Form (eCRF) that 
are transcribed from source documents must be consistent with the source documents, 
or the discrepancies must be explained.  The investigator may need to request previous 
medical records or transfer records, depending on the study.  Also, current medical 
records must be available. 
Definition of what constitutes source data can be found in the Trial Monitoring Plan. 
A1–9 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The Investigator shall promptly 


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inform the participants and should ensure appropriate participant therapy and/or 
follow-up. 
A1–10 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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. 
A1–11 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
 


 
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Clinical Safety Laboratory Tests  
The tests detailed in Table A2-1 will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for study treatment administration and/or response evaluation.  
If a local sample is required, it is important that a sample for central analysis be obtained 
at the same time.  Additionally, if the local laboratory results are used to make either a 
study treatment decision or a response evaluation, the results together with the normal 
range of the parameters measured must be entered on the electronic Case Report 
Form.  
Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Section 5. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 


Appendix 2:  Clinical Safety Laboratory Tests 
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Table A2-1 Protocol-Required Safety Laboratory Assessments 
Central Laboratory Tests 
• Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and other cells) 
• Chemistry panel (serum):  bicarbonate, sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, CPK, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, uric acid, and LDH   
If CPK value exceeds 2× ULN at baseline, creatinine and potassium levels should be 
monitored at Week 2 
• Lipids:  total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides   
• Cardiac biomarkers:  hs-cTnT (troponin T) 
• Coagulation:  INR, aPTT, and PT 
• HIV serology:  HIV-1 antibody, HIV-1/2 antibody, and HIV-2 antibody 
• HBV serology:  HBsAg and total HBcAb for all individuals; HBV DNA for individuals with 
negative HBsAg tests and a positive total HBcAb test  
• HCV serology:  HCV antibody for all individuals  
• Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
• Quantitative immunoglobulins:  IgA, IgG, IgM, and IgE 
• Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
• Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and blood).  
Microscopic examination performed at the central laboratory if blood and/or protein results are 
positive or strongly positive.  If there is an explanation for the positive dipstick results (e.g., 
menses), it should be recorded and there is no need to perform microscopy and culture. 
HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HDL=high-density lipoprotein; hs-cTnT=high-sensitivity cardiac 
troponin T; LDL=low-density lipoprotein. 
  
Investigators must document their review of each laboratory safety report.  


 
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Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting  
TABLE OF CONTENTS 
A3–1 
Definition of Adverse Event...................................................... 90 
A3–2 
Definition of Serious Adverse Event ........................................ 91 
A3–3 
Recording and Follow-Up of Adverse Events and/or 
Serious Adverse Events .......................................................... 92 
A3–3.1 
Adverse Event and Serious Adverse Event Recording ............ 92 
A3–3.2 
Assessment of Severity ........................................................... 93 
A3–3.3 
Assessment of Causality ......................................................... 93 
A3–3.4 
Follow-up of Adverse Events and Serious Adverse Events ..... 94 
A3–3.4.1 
Investigator Follow-Up ............................................................. 94 
A3–3.4.2 
Sponsor Follow-Up .................................................................. 95 
A3–4 
Reporting of Serious Adverse Events ...................................... 95 
A3–4.1 
Serious Adverse Event Reporting to The Sponsor via an 
Electronic Collection Tool ........................................................ 95 
A3–4.2 
Serious Adverse Event Reporting to The Sponsor via 
Paper CRF ............................................................................... 96 
A3–5 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 96 
A3–5.1 
Events That Occur prior to Study Treatment Initiation ............. 96 
A3–5.2 
Events That Occur after Study Treatment Initiation ................. 96 
A3–6 
Reporting Adverse Events That Occur after the Adverse 
Event Reporting Period ............................................................ 97 
A3–7 
Procedures for Recording Adverse Events .............................. 97 
A3–7.1 
Diagnosis Versus Signs And Symptoms .................................. 97 
A3–7.2 
Adverse Events that are Secondary to Other Events ............... 98 
A3–7.3 
Persistent of Recurrent Adverse Events .................................. 98 
A3–7.4 
Abnormal Laboratory Values ................................................... 99 
A3–7.5 
Abnormal Vital Sign Values ..................................................... 99 
A3–7.6 
Abnormal Liver Function Tests .............................................. 100 
A3–7.7 
Deaths ................................................................................... 100 
A3–7.8 
Preexisting Medical Conditions .............................................. 101 
A3–7.9 
Lack of Efficacy or Worsening of Post-traumatic Stress 
Disorder (PTSD) .................................................................... 101 
A3–7.10 
Hospitalization or Prolonged Hospitalization .......................... 101 
A3–7.11 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 102 
A3–7.12 
Participant-Reported Outcome Data ...................................... 104 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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A3–1 
DEFINITION OF ADVERSE EVENT  
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
participant temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease) 
• 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
• 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
• 
Signs, symptoms, or clinical sequelae of a suspected drug−drug interaction 
• 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
• 
Overdose per se will not be reported as an adverse event or serious adverse event 
unless it is an intentional overdose taken with possible suicidal or self-harming 
intent.  Such overdoses should be reported regardless of sequelae. 
• 
Lack of efficacy will not be reported as an adverse event or serious adverse event.  
Such instances will be captured in the efficacy assessments.  However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
an adverse event or serious adverse event if they fulfill the definition of an adverse 
event or serious adverse event. 
 
Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 


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• 
The disease or disorder being studied or expected progression, signs, or symptoms 
of the disease or disorder being studied, unless more severe than expected for the 
participant’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 
• 
The condition that leads to the procedure is the adverse event. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen 
 
A3–2 
DEFINITION OF SERIOUS ADVERSE EVENT  
If an event is not an adverse event per the definition in Section A3–1, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose: 
• 
Results in death 
• 
Is life threatening 
The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event. 
• 
Results in persistent disability or incapacity 
The term "disability" means a substantial disruption of a person’s ability to 
conduct normal life functions. 


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This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly or birth defect 
• 
Other situations: 
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]; 
see Section A3–2); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the electronic Case Report Form (eCRF). 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event) (see Section A3–5 for reporting instructions). 
A3–3 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS 
AND/OR SERIOUS ADVERSE EVENTS 
A3–3.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 


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It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A3–3.2 
ASSESSMENT OF SEVERITY 
The investigator will make an assessment of the severity of each adverse event and 
serious adverse event during the study and assign it to one of the categories in 
Table A3-1. 
Table A3-1 Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities 
Moderate 
An event that causes sufficient discomfort and interferes with normal 
everyday activities 
Severe 
An event that prevents normal everyday activities 
An adverse event that is assessed as severe should not be confused 
with a serious adverse event.  Severe is a category utilized for rating 
the severity of an event, and both adverse events and serious 
adverse events can be assessed as severe. 
An event is defined as "serious" when it meets at least one of the 
predefined outcomes as described in the definition of a serious 
adverse event, NOT when it is rated as severe. 
 
A3–3.3 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 


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The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or prescribing 
information (for marketed products) in his or her assessment. 
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A3–3.4 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
A3–3.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor with a copy of any post-mortem findings, 
including histopathology.  
New or updated information will be recorded in the originally completed CRF. 


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New or updated information should be recorded on the originally completed Adverse 
Event eCRF.  For serious adverse events and adverse events of special interest, the 
investigator must report new significant follow-up information to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes 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 
 
During the adverse event reporting period (defined in Section 8.3.1), resolution of 
adverse events (with dates) should be documented on the Adverse Event eCRF and in 
the participant's medical record to facilitate source data verification. 
A3–3.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
A3–4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A3–4.1 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA AN ELECTRONIC COLLECTION TOOL 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A3–5.  
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations Form, as described in Section A3–5, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off line to prevent the entry of new data or changes to existing data. 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
96/Protocol BN43546, Version 3 
If a site receives a report of a new serious adverse event from a study participant or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken off line, the site can report this information 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A3–5.  
A3–4.2 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA PAPER CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations Form, as 
described in Section A3–5. 
A3–5 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A3–5.1 
EVENTS THAT OCCUR PRIOR TO STUDY TREATMENT 
INITIATION 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., biopsy, 
discontinuation of medications) should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators. 
A3–5.2 
EVENTS THAT OCCUR AFTER STUDY TREATMENT 
INITIATION 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 14 days after the final dose of study treatment.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after the investigator becomes aware of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
97/Protocol BN43546, Version 3 
Instructions for reporting serious adverse events that occur more than 14 days after the 
final dose of study treatment are provided in Section A3–6. 
A3–6 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
14 days after the final dose of study treatment), if the event is believed to be related to 
prior exposure to study treatment.  These events should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Special Situations Form, 
using the fax number or email address provided to investigators. 
A3–7 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the participant's medical records to the Medical Monitor in lieu of 
completion of the eCRF.  Investigators should use correct medical terminology and 
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 of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
A3–7.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
98/Protocol BN43546, Version 3 
A3–7.2 
ADVERSE EVENTS THAT ARE SECONDARY TO OTHER 
EVENTS 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
A3–7.3 
PERSISTENT OF RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware that the event became 
serious; see Section A3–5 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from "non-serious" to "serious," providing the date 
that the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between participant evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
99/Protocol BN43546, Version 3 
A3–7.4 
ABNORMAL LABORATORY VALUES 
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 
laboratory value abnormality that is not associated with the underlying disease must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.  Please see Section 8.3.7 for 
details on adverse events of special interest and associated reporting requirements. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 × upper limit of normal (ULN) associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A3–7.3 for 
details on recording persistent adverse events). 
A3–7.5 
ABNORMAL VITAL SIGN VALUES 
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
100/Protocol BN43546, Version 3 
vital sign abnormality that is not associated with the underlying disease must be reported 
as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., hypertension) should be recorded 
on the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A3–7.3 for 
details on recording persistent adverse events). 
A3–7.6 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × upper limit of normal (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 A3–7.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A3–5). 
A3–7.7 
DEATHS 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 8.3.1), regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section A3–5).  


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
101/Protocol BN43546, Version 3 
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"). 
A3–7.8 
PREEXISTING MEDICAL CONDITIONS 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
A3–7.9 
LACK OF EFFICACY OR WORSENING OF POST-TRAUMATIC 
STRESS DISORDER (PTSD)  
Medical occurrences or symptoms of deterioration that are anticipated as part of 
post-traumatic stress disorder (PTSD) should not be recorded as adverse events.  
However, deterioration that is judged by the investigator to have unexpectedly worsened 
in severity or frequency or changed in nature at any time during the study should be 
recorded as an adverse event.  When recording an unanticipated worsening of PTSD on 
the Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated worsening of 
post-traumatic stress disorder"). 
A3–7.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section A3–2), except as outlined 
below.  


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
102/Protocol BN43546, Version 3 
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 a preexisting condition, provided that all of the following criteria 
are met: 
– 
The participant was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when treatment 
became necessary because of the expected normal progression of the 
condition 
– 
The participant has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of participant requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
A3–7.11 
CASES OF OVERDOSE, MEDICATION ERROR, DRUG ABUSE, 
OR DRUG MISUSE 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse} 
(hereafter collectively referred to as "special situations") are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
• 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm} 
• 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the participant. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
103/Protocol BN43546, Version 3 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event; see Section A3–5).  For balovaptan or 
matching placebo, adverse events associated with special situations should be recorded 
as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
• 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
• 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with balovaptan / matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
• 
Accidental overdose:  Enter balovaptan and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter balovaptan 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 balovaptan 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. 


Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Balovaptan—F. Hoffmann-La Roche Ltd 
104/Protocol BN43546, Version 3 
• 
Intercepted medication error:  Enter balovaptan 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 balovaptan and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter balovaptan 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 balovaptan and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter balovaptan and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the participant:  Enter balovaptan and 
"participant supplied drug to third party" as the event term.  Check the "Drug 
misuse" box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
A3–7.12 
PARTICIPANT-REPORTED OUTCOME DATA 
Adverse event reports will not be derived from (participant-reported outcome) PRO data 
by the Sponsor.  Sites are not expected to review the PRO data for adverse events. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
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Contraceptive and Barrier Guidance 
TABLE OF CONTENTS 
 
A4–1 
Pregnancies in Female Participants ...................................... 106 
A4–2 
Abortions................................................................................ 106 
A4–3 
Abnormal Pregnancy Outcomes ............................................ 107 
 
 


Appendix 4:  Contraceptive and Barrier Guidance 
 
Balovaptan—F. Hoffmann-La Roche Ltd 
106/Protocol BN43546, Version 3 
A4–1 
PREGNANCIES IN FEMALE PARTICIPANTS 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 14 days after the final dose of balovaptan.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after the investigator becomes aware 
of the pregnancy), either by faxing or by scanning and emailing the form, using the fax 
number or email address provided to investigators.  Pregnancy should not be recorded 
on the Adverse Event electronic Case Report Form (eCRF).  The investigator should 
discontinue study treatment and counsel the participant, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the participant should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly or birth defect in the child) should be reported on 
the Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A4–2 
ABORTIONS 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event; see Section A3–5). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware of the event; see 
Section A3–5).  A therapeutic or elective abortion performed for reasons other than an 
underlying maternal or embryofetal toxicity is not considered an adverse event. 


Appendix 4:  Contraceptive and Barrier Guidance 
 
Balovaptan—F. Hoffmann-La Roche Ltd 
107/Protocol BN43546, Version 3 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
A4–3 
ABNORMAL PREGNANCY OUTCOMES  
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after the investigator becomes aware of the event; see Section A3–5). 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
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Genetics:  Use and Analysis of DNA 
Genetic variation may impact a participant’s response to study treatment and 
susceptibility to, and severity and progression of, disease.  Variable response to study 
treatment may be due to genetic determinants that impact drug absorption, distribution, 
metabolism, and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated.  Therefore, where local regulations and 
the Institutional Review Board or Ethics Committee allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
DNA samples will be used for research related to balovaptan in post-traumatic stress 
disorder (PTSD) and related diseases.  They may also be used to develop tests or 
assays, including diagnostic tests related to balovaptan and PTSD.  Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome (as appropriate).  
DNA samples will be analyzed for genetic variation that may be associated with disease 
trajectory, diagnosis, or treatment response.  Additional analyses may be conducted if it 
is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to balovaptan or study treatments of this class to understand 
PTSD or related conditions. 
The results of genetic analyses may be reported in the Clinical Study Report or in a 
separate study summary. 
The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
The samples will be retained while research on balovaptan or PTSD continues but no 
longer than 15 years or other period as per local requirements. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
109/Protocol BN43546, Version 3 
  
Safety Plan:  Management of Identified and Potential Risks  
TABLE OF CONTENTS 
 
A6–1 
Potential Risks Associated with Balovaptan .......................... 110 
A6–1.1 
Potential Seizure Risk Based on Data from Animal Studies .. 110 
A6–1.2 
Potential Risk of Neutropenia Based on Data from Animal 
Studies ................................................................................... 111 
A6–1.3 
Potential Risk of Skeletal Muscle Toxicity .............................. 112 
A6–1.4 
Potential Risk of Cardiac Toxicity .......................................... 113 
A6–1.5 
Potential Risk of Peripheral Neuropathy ................................ 113 
A6–1.6 
Potential Risk of Bleeding ..................................................... 115 
A6–1.7 
Potential Risk of Blood Pressure Changes ............................ 115 
A6–2 
Management of Participants Who Experience Adverse 
Events .................................................................................... 116 
A6–2.1 
Dose Modifications ................................................................ 116 
A6–2.2 
Treatment Interruption ........................................................... 116 
A6–2.3 
Management of Seizures ....................................................... 116 
A6–2.4 
Management of Neutropenia ................................................. 117 
A6–2.5 
Management of Bleeding ....................................................... 117 
A6–2.6 
Management of Skeletal Muscle Toxicity ............................... 117 
A6–2.7 
Management of Cardiac Adverse Events .............................. 118 
A6–2.8 
Management of Blood Pressure Changes ............................. 119 
A6–2.9 
Management of Neurological Toxicity/Peripheral 
Neuropathy ............................................................................ 120 


Appendix 6: Safety Plan:  Management of Identified and Potential Risks  
 
Balovaptan—F. Hoffmann-La Roche Ltd 
110/Protocol BN43546, Version 3 
Balovaptan is not approved for clinical use in any country for any indication.  However, 
clinical trials in healthy volunteers and participants with autism spectrum disorder (ASD) 
have not revealed adverse drug reactions considered causally related to the 
administration of balovaptan.  The safety plan for participants in this study is based on 
potential safety risks related to toxicities observed in animals and hypothetical risks 
related to the mechanism of action of balovaptan.  Please refer to the Balovaptan 
Investigator's Brochure for a complete summary of safety information. 
Several measures will be taken to ensure the safety of study participants and minimize 
hypothetical risks.  Eligibility criteria have been designed to exclude individuals at higher 
risk for toxicities.  Participants will undergo comprehensive safety monitoring during the 
study, including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided in the following section. 
A6–1 
POTENTIAL RISKS ASSOCIATED WITH BALOVAPTAN  
A6–1.1 
POTENTIAL SEIZURE RISK BASED ON DATA FROM ANIMAL 
STUDIES  
In-life convulsion and epileptiform abnormalities were observed in dogs.  At 
no-observed-adverse-effect level (NOAEL) the balovaptan maximum concentration 
(Cmax) based safety margin for electroencephalogram (EEG) effects is approximately 
36-fold to the Cmax for a 10 mg oral dose at steady state.  
No convulsions have been noted in rats. 
Mechanistically, the blockade of the vasopressin 1a (V1a) receptor may rather not 
possess pro-convulsive effects given that seizure threshold lowering effects of low-dose 
vasopressin were reversed by the V1a receptor SR49059 in the pentylenetetrazole 
paradigm in mice (Javadian et al. 2016).  
In clinical trials, EEG recordings from healthy volunteers in Study BP29412, receiving 
the 50-mg once a day (QD) treatment regimen for 6 days, did not reveal 
treatment-emergent epileptiform abnormalities. 
In clinical trials involving participants with ASD, two adverse events of seizure and one 
adverse event of abnormal EEG were reported in 2 children and 1 adult.  With seizures 
being a known co-morbidity in ASD, 2 of the subjects were receiving ongoing 
anti-epileptic treatment and were thought to have subtherapeutic levels of anti-epileptic 
medication.  Please refer to the Balovaptan Investigator's Brochure for further details. 
In conclusion, the risk of balovaptan to lower the seizure threshold is considered 
minimal.  Participants with a history of seizures who are well controlled within the 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
111/Protocol BN43546, Version 3 
previous 6 months to screening and have not had any changes in anti-convulsive 
therapy, may be enrolled in this study. 
A6–1.2 
POTENTIAL RISK OF NEUTROPENIA BASED ON DATA FROM 
ANIMAL STUDIES  
In 13-week toxicology studies in dogs, balovaptan-related hematologic changes were 
observed starting approximately 4 weeks after the first dose.  Analysis of hematologic 
results in peripheral blood demonstrated a decrease in RBCs, WBCs, platelets, and 
neutrophils, with the most pronounced changes observed in peripheral neutrophils.  The 
bone marrow of affected dogs, however, did not show hypocellularity but rather 
normocellularity to hypercellularity.  The hematologic abnormalities were reversible after 
drug discontinuation. 
The area under the concentration−time curve (AUC) at the NOAEL for the observed 
hematological toxicity in the dog provides a margin relative to a 10-mg QD dose in 
human adults of about 21-fold for the parent molecule, about 4.5-fold for the metabolite 3 
(M3), and of about 3.5-fold for the metabolite 2 (M2).  M2 is not a major metabolite in 
dogs and is not considered relevant for this effect.   
No hematotoxicity was observed in toxicology studies in rats.  
Across clinical trials, 1 subject (Study WP40734) developed a decrease in absolute 
neutrophil count (ANC) (from approximately 1300/µL at pre-treatment to 500−700/µL) at 
a dose of 10 mg balovaptan QD for 2 weeks that rapidly recovered after conclusion of 
the 2-week treatment period.  There were no signs of infection and no adverse event 
relief actions were undertaken, however, the subject was withdrawn from the trial.  
Six pediatric participants taking 10 mg or an equivalent dose based on predicted 
exposure (Study BP30153) experienced events of neutropenia (4 events in 
4 participants) and neutrophil count decreased (2 events in 2 participants), of which 
4 were moderate and 2 were mild.  One participant had neutropenia that was ongoing 
at the end of the study, however, this was in the context of acute lymphocytic leukemia 
and Epstein Barr virus infection and was not considered to be associated with 
balovaptan.  One participant recovered despite continuing balovaptan and the 
remaining 4 recovered after dose interruption or withdrawal.  All events occurred after 
20 weeks of study therapy and the majority were temporally associated with an 
infection.  Neutropenia is relatively frequent in children, and an association with virus 
infection is recognized (Callejas Caballero et al. 2021).  When the events reported in the 
other dose groups are considered, a difference in frequency was not seen with 
comparison to the placebo group (10 mg balovaptan equivalent dose [eq] 2 participants 
[1.7%], 4 mg balovaptan eq 2 participants [1.2%], placebo 2 participants [1.9%], open-
label extension 10 mg balovaptan eq 4 participants [2.0%]).  


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
112/Protocol BN43546, Version 3 
There were no events of neutropenia or leukopenia in adult patients with ASD taking 
10 mg in Study BP30153. 
Please refer to the Balovaptan Investigator's Brochure for further details.  
Overall, the available clinical safety database does not suggest a causal neutropenia risk 
due to balovaptan administration.  However, participants receiving concomitant 
treatment with clozapine will be excluded due to relatively high risk of agranulocytosis.  
Patients with clinically significant hematologic abnormalities or history of blood 
dyscrasias, hematologic malignancies, or myelosuppression (including iatrogenic) will be 
excluded from the study.  Safety surveillance in Study BN43546 includes hematological 
monitoring and check for clinical signs and symptoms of infection. 
A6–1.3 
POTENTIAL RISK OF SKELETAL MUSCLE TOXICITY  
Skeletal muscle degeneration associated with increases in creatine phosphokinase 
(CPK) was noted after treatment with a high dose of balovaptan in male rats.  
After treatment completion, these effects promptly reversed.  The mechanism of 
balovaptan effects on skeletal muscle in rats is unclear.  In vitro experiments indicate 
that M3 may play a major role.  This is consistent with this finding only being observed in 
male rats that have higher M3 exposures than female rats.  No mitochondrial toxicity or 
cytotoxicity due to cell-cycle inhibition was demonstrated.  Based on AUC values 
measured at NOAEL, the margins relative to anticipated AUC after 10 mg QD 
balovaptan in adult humans are approximately 8-fold with regard to parent and 
approximately 10-fold with regard to M3.  
In the literature, the involvement of the V1a receptor to regain muscle integrity after 
tumor necrosis factor-α exposure has been suggested based on V1a receptor gene 
delivery experiments in mice (Costa et al. 2014).  No skeletal muscle effects of 
balovaptan have been observed in dogs. 
In humans, a severe adverse event of rhabdomyolysis was reported in a patient with 
ASD treated with 1.5 mg QD balovaptan, and occasional CPK elevations were noted in 
clinical trials.  Nevertheless, the totality of clinical data available to date (including 
analysis of CPK values and musculoskeletal adverse events) does not indicate a safety 
alert for skeletal muscle toxicity due to balovaptan.  This conclusion is based on the 
observations that CPK elevations were also measured in placebo-treated subjects with 
ASD and that treatment-emergent CPK elevations decreased when treatment was 
continued.  CPK levels will be monitored during the study drug treatment period and with 
a defined CPK-related adverse event of special interest.   
Please refer to the Balovaptan Investigator's Brochure for additional details. 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
113/Protocol BN43546, Version 3 
Overall, the risk of skeletal muscle toxicity for this study is considered minimal given the 
safety margin relative to NOAEL noted in rats, the absence of skeletal muscle toxicity in 
dogs, and the clinical trial experience not indicating skeletal muscle toxicity.  
In addition to adverse event monitoring, CPK levels will be used to monitor for possible 
occurrences of skeletal muscle toxicity.  
A6–1.4 
POTENTIAL RISK OF CARDIAC TOXICITY  
In rats dosed from post-natal day (PND) 14 (juvenile to adult), an increase in heart 
weight was observed at the highest dose tested.  The increase in heart weight was 
considered non-adverse based on the lack of associated creatine phosphokinase (CPK) 
changes or a histopathological correlate.  In the 26-week Good Laboratory Practice 
(GLP) toxicology study in adult rats, an increased incidence of spontaneous 
cardiomyopathy changes was observed, but these changes were considered to be 
non-adverse exacerbations due to stress.  Cardiac pathologies were not observed when 
balovaptan was administered to dogs in GLP toxicology studies.  
Intense exploration of interference with cardiac ion channels for balovaptan and its M3 
and M2, did not reveal a pre-clinical safety alert for QTc prolongation.  
In clinical trials, treatment with balovaptan (10 mg QD) for more than 12 weeks did not 
produce a cardiac toxicity alert based on clinical adverse event reporting and monitoring 
with cardiac biomarkers (troponin and N-terminal prohormone of brain natriuretic peptide 
[NT-proBNP]).  Results from a thorough QT study are available (Study WP40734) and 
confirmed absence of corrected QT interval (QTc) prolonging effects after administration 
of balovaptan at 10 mg and 50 mg QD dosing regimens.  
The risk of cardiac toxicity in Study BN43546 is considered minimal because of the lack 
of cardiac toxicity in dogs, the delayed onset of cardiac effects in rats (which were 
considered stress-related rather than direct cardiac effects, and in particular the absence 
of a safety alert from dedicated cardiac monitoring in clinical trials.  
Safety monitoring in Study BN43546 will include ECG, adverse event monitoring and 
assessment of high-sensitivity cardiac troponin T (hs-cTnT) in conjunction with a 
follow-up plan if elevated hs-cTnT levels are measured.   
A6–1.5 
POTENTIAL RISK OF PERIPHERAL NEUROPATHY  
In the 26-week toxicity study in rats and in two subsequent supplementary 26-week 
toxicology studies in adult and juvenile rats, test article−related microscopic effects were 
observed in multiple peripheral nerves (degeneration of the perineurium with edema and 
cellular infiltrates).  The onset of peripheral nerve histopathology effects was seen as 
early as 13 weeks of treatment, and further progression noted after 26 weeks of 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
114/Protocol BN43546, Version 3 
treatment.  Changes in peripheral nerve histology were found to be associated with and 
preceded by electrophysiological abnormalities (i.e., a reduction in nerve conduction 
velocity (NCV) noted at Week 6, no relevant changes to amplitude in line with 
dominating pathology of perineurium and myelin sheath rather than axonal loss).  The 
electrophysiogical abnormalities were recorded for sensory and mixed nerves and not 
for motoric nerves.  The histopathologic changes did not fully recover within the 13-week 
recovery period included in the 26-week GLP toxicology study while the 
electrophysiological changes did.  Of note, across sexes, the emergence of peripheral 
nerve toxicities does not correlate with parent plasma levels but with the plasma levels of 
M3.  It is unproven whether the peripheral nerve effects seen in rats are caused by the 
parent or M3 moiety; however, the incidence of the effects are better correlated with M3 
levels than with the parent.  The M2 is not considered to be the causative agent because 
of low plasma levels.  The margins between the plasma levels at the NOAEL and those 
after 10-mg QD dose in humans are about 10-fold with regard to parent and about 
20-fold lower with regard to M3 for the 10 mg  QD balovaptan dose.  In addition to the 
effects on peripheral nerves, perivascular inflammation in certain regions of the brain 
was observed in rats; however, the respective safety margins are about 2-fold higher.   
No such neurohistopathologies were seen in dogs.   
In clinical trials, neurological monitoring (including quantitative vibration testing) did not 
reveal a signal of treatment-emergent peripheral neuropathy or other neurologic 
abnormalities.  In 1 subject with ASD whose sense of vibration was lost during treatment 
with 10 mg QD balovaptan, subsequent nerve conduction examinations showed a 
severe peripheral neuropathy dominated by a decrease in electrostimulus provoked 
amplitude and a mildly decreased NCV.  This signature contrasts with the findings from 
electrophysiological monitoring of peripheral nerve in rats that showed a slowing in NCV 
and a maintained amplitude in line with perineurial myelin sheath damage rather than 
axonal loss histopathologically.  Post hoc, this subject reported occasional tingling in the 
feet that was indicative of preexisting peripheral neuropathy; however, no specific cause 
for peripheral neuropathy could be identified.  
The risk of study treatment linked peripheral neuropathy for participants in this study is 
considered to be minimal because of the safety margins relative to the NOAEL in rats, 
no neurohistopathologies have been noted in dogs, and the results from neurological 
monitoring in clinical trials have not generated a signal for balovaptan caused peripheral 
neuropathy.  
This study excludes participants with signs and symptoms of peripheral neuropathy.  
Neurologic examinations focusing on the lower limbs (longer nerves being more 
susceptible to neuropathy) will be completed during the study (see the schedule of 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
115/Protocol BN43546, Version 3 
activities in Section 1.3, Table 1).  The neurological examination must be conducted as 
outlined in Appendix 7.  
Please refer to the Balovaptan Investigator's Brochure for additional details. 
A6–1.6 
POTENTIAL RISK OF BLEEDING 
Theoretically, due to expression of V1a receptors on platelets, antagonism could impact 
platelet aggregation.  Neither animal studies nor clinical studies of balovaptan up to 
50 mg for 2 weeks have shown a bleeding risk.  
Selective serotonin reuptake inhibitors (SSRIs) have been shown to possess a bleeding 
risk, even though fairly small (Dalton et al. 2006; Serebruany 2006).  In the ASD clinical 
trials 156 subjects were receiving concomitant SSRI medications.  No bleeding risk 
events were reported. 
Patients with a history of coagulopathies or other bleeding disorders or current clinically 
relevant bleeding event will be excluded from the study.  
Treatment with study drug should be stopped about 1 week prior to surgeries and 
invasive procedures anticipated to be associated with major blood losses or bleedings in 
sensitive organs (e.g., eye, brain, and spinal cord). 
A6–1.7 
POTENTIAL RISK OF BLOOD PRESSURE CHANGES  
Given the vasoconstrictive effects on systemic resistance blood vessels of vasopressin 
mediated through the V1a receptor, blockade of this receptor by balovaptan may lead to 
reductions in blood pressure.  However, in a cardiovascular safety pharmacology study 
conducted in telemetered dogs, an increase in blood pressure was observed with an 
approximately 19-fold margin between the NOAEL Cmax for the dog (1917 ng/mL) and 
the predicted highest average Cmax for participants in Study BN43546 (103 ng/mL).  The 
physiology behind the blood pressure increase seen in dogs is unknown. 
Ambulatory blood pressure monitoring of healthy volunteers was included in clinical 
Study WP40734 (a thorough QT study), which evaluated both a 10 mg QD and a 50 mg 
QD treatment regimen over 2 weeks.  No significant blood pressure changes emerged; in 
particular, no decrease in blood pressure measurements was observed.   
The absence of a decrease in blood pressure may be explained by blood concentrations 
of vasopressin being too low to meaningfully activate the V1a receptor and/or by the 
multifactorial blood pressure regulation system in the sense that blockade of the V1a 
receptor is compensated by alternative regulator pathways. 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
116/Protocol BN43546, Version 3 
Nevertheless, participants should be instructed to avoid rapid movements when moving 
from supine to sitting to standing position.  Blood pressure will be monitored at regular 
intervals during the treatment period. 
A6–2 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS 
A6–2.1 
DOSE MODIFICATIONS 
No dose modifications will be allowed in this study. 
A6–2.2 
TREATMENT INTERRUPTION 
Balovaptan may be withheld in participants who experience toxicity considered to be 
related to study drug.  If balovaptan has been withheld for >10 days because of toxicity, 
the participant should be discontinued from study drug, unless resumption of treatment 
is approved by the investigator following consultation with the Medical Monitor.  
Balovaptan may be withheld for reasons other than toxicity (e.g., surgical procedures) at 
the investigator's discretion following consultation with the Medical Monitor.  The 
investigator may consult the Medical Monitor to determine the acceptable length of 
treatment interruption. 
A6–2.3 
MANAGEMENT OF SEIZURES 
While the risk of seizure/convulsive events due to balovaptan is considered minimal, 
local treatment guidelines should be followed to manage such events should they occur.  
Participants experiencing an adverse event of convulsion should be seen by the relevant 
physician immediately and as soon as possible, they should be referred to a clinical 
expert in the area of epilepsy to define diagnostic steps.  These may include 24-hour 
dedicated video EEG monitoring.  Collection of blood and urine samples is 
recommended to measure, as applicable, levels of balovaptan, any anti-eplieptic drugs, 
drugs of abuse, glucose, and electrolytes (sodium, potassium, chloride, magnesium).  If 
possible, a blood sample for prolactin should be taken within 1 hour since seizure onset.  
Psychogenic non-epileptic seizures are reported to occur in patients with PTSD 
(Popkirov et al. 2019; Perez et al. 2016).  Vital signs should be monitored and a 12-lead 
ECG recorded as soon as possible.   
Depending on the nature and severity of the convulsive event, it may not result in 
permanent study treatment discontinuation.   
Adverse events of seizure/convulsion should be discussed with the Medical Monitor as 
soon as possible. 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
117/Protocol BN43546, Version 3 
A6–2.4 
MANAGEMENT OF NEUTROPENIA  
As outlined above, the risk of relevant neutropenia due to balovaptan is considered low. 
In case of emergent neutropenia, treatment discontinuation is suggested for participants 
who meet the following criterion for decreased ANC:  
• 
If the ANC falls <800/µL and the low ANC is confirmed in a second sample to be 
obtained within about 3 days, the investigator should consider treatment 
discontinuation.  In cases of ANC-related treatment discontinuation, additional 
laboratory parameters should be considered by the investigator, including 
fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and an assessment for 
anti−neutrophil cytoplasmic antibody (ANCA).  
• 
Follow-up management of participants who experience fever and/or infection in the 
context of reduced ANC should be discussed with the Medical Monitor and the 
participant may be referred to a specialist to decide on next steps.   
 
ANC values below 800/µL (confirmed), should be reported as an adverse event of 
special interest (see Appendix 3, Section A3–5). 
A6–2.5 
MANAGEMENT OF BLEEDING 
While the risk of bleeding events due to balovaptan is considered low, should such an 
event occur, a review of concomitant medications should be undertaken especially those 
that have known bleeding risks.  Based on the clinical significance of the bleeding, 
treatment with study drug should be interrupted and may be permanently discontinued if 
no alternative causative factors of the bleeding adverse event can be identified and 
removed. 
Blood samples to assess coagulation parameters (INR, PT, aPTT) as well as balovaptan 
blood levels should be taken.  
A6–2.6 
MANAGEMENT OF SKELETAL MUSCLE TOXICITY 
Elevated CPK levels at screening and baseline are not exclusions as long as serum 
creatinine and potassium values do not exceed the upper limit of normal (ULN).  In 
instances where CPK is increased more than 2×ULN at screening, additional CPK, 
creatinine, and potassium samples should also be obtained at Week 2 of treatment.  
Samples from screening, baseline, Week 2, and Week 6 can then indicate whether an 
elevated CPK level observed at screening is part of a fluctuation because of physical 
exercise, for example, or is indicative of inherently elevated CPK levels in an individual 
participants.  Participants are advised to abstain from intense physical exercise and to 
report musculoskeletal adverse events to the Investigator promptly.  


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
118/Protocol BN43546, Version 3 
In the event of reports matching the related adverse events of special interest definition 
(see Section 8.3.7), participants should be evaluated for use of any concomitant 
medication as well as occurrence of any recent accidents or physical exercise.  In the 
event that CPK values exceed 10×ULN, confirmatory samples should be obtained within 
3−5 days, depending on the actual CPK value and circumstances, for example, whether 
or not a possible alternative explanation like an accident or sports is present.  Serum 
creatinine and serum potassium levels should be measured at the same time.  An ECG 
recording may provide information about QRS complex changes and arrhythmias 
potentially related to changes in potassium. 
Hydration status should be assessed and intake of fluids is advised.  The need for 
hospitalization and intravenous administration of fluids, respectively, should be 
considered, depending on the CPK increase and a participant’s hydration status.  The 
investigator may decide to temporarily withdraw treatment if no alternative explanation 
exists and CPK values do not show a trend for normalization according to the half-life of 
CPK in plasma.  Treatment may be re-started once CPK values have shown a clear 
trend toward normalization and if CPK increases were not associated with relevant 
kidney dysfunction.  CPK levels should be monitored until they are below 2×ULN or in 
the range of screening and baseline values.   
CPK laboratory abnormality as per Section 8.3.7 must be reported as an adverse event 
of special interest. 
CPK values will be assessed at baseline, at Week 6 and Week 12 (see the schedule of 
activities in Section 1.3 [see Table 1]) as well as at the post-treatment follow-up visit. 
A6–2.7 
MANAGEMENT OF CARDIAC ADVERSE EVENTS 
Increases in the Corrected QT Interval (QTc) Interval 
There is no preclinical or clinical evidence that balovaptan administration may be 
associated with an increase in the QTc interval.  Nevertheless, treatment should be 
discontinued in case of the following:  
• 
Sustained (at least two ECG measurements >30 minutes apart) QT interval 
corrected through use of Fridericia's formula (QTcF) that is >500 ms and >60 ms 
longer than the baseline value.  In this instance, serum electrolytes, in particular, 
potassium, and magnesium, as well as use of any concomitant medications should 
be analyzed as a potential cause of the increase in the QTc interval.  
Management of participants with sustained QTc prolongation should include close 
monitoring, with ECGs repeated until two successive ECGs show resolution of the 
findings, correction of any electrolyte abnormalities, and possible discontinuation of other 
concomitant medications that are known to prolong the QTc interval.  Consultation with a 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
119/Protocol BN43546, Version 3 
cardiologist or an electrophysiologist is recommended to help in the management of 
such participants.  
Signs and Symptoms of Cardiac Toxicity 
As outlined above, the risk of cardiac toxicity to participants in this study is considered 
minimal. 
An algorithm relative to results from cardiac troponin T (cTnT) monitoring is provided in 
Section 7.1.4, Table 5 
In all cases of cardio-vascular adverse even reportings and where no clear non-cardiac 
alternative explanation is identified, a consultation with a cardiologist should be 
considered with urgency driven by the clinical adverse event and further diagnostics may 
include, but are not limited to, 24-hour ECG recordings and echocardiographic 
examinations.   
Control of vital signs and by ECG monitoring should be considered relative to clinical 
adverse event presentation. 
Blood samples for cardiac biomarker monitoring (hs-cTnT, troponin I, NT-proBNP) and 
to measure blood levels of balovaptan together with the information of the time interval 
since last intake of study medication should be obtained as soon as possible. 
A check of all concomitant medications should be performed and documented.  In 
addition, a urine drug screen should be performed. 
For further details see Section 7.1.4. 
A6–2.8 
MANAGEMENT OF BLOOD PRESSURE CHANGES 
To date, pre-clinical and clinical profiling for any balovaptan associated blood pressure 
changes have not issued an alert. 
Abnormal blood pressure values together with pulse heart rate should first be verified by 
repeat measurement ensuring technical conduct. 
Circumstances should be carefully evaluated; for example, rapid blood pressure 
decrease due to rapid body erection, dehydration situations, blood sample draw, or a 
blood pressure increase caused by hypertension.  It is advised to check for concomitant 
medications and conduct a urine drug screen. 
Vital sign monitoring should be supplemented by ECG monitoring. 


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
120/Protocol BN43546, Version 3 
Participants should be reminded to avoid situations of rapid fluid shift from the upper to 
the lower part of the body.  In context of blood pressure increases, ambulatory blood 
pressure monitoring (ABPM) may be considered. 
In case of persistent blood pressure changes, participants should be seen by a clinical 
expert in the field of blood pressure regulation. 
Depending on the magnitude and clinical relevance of the blood pressure observed, 
treatment with study drug may be interrupted or even permanently withdrawn.  In such 
situations, blood samples to measure balovaptan levels in blood should be considered. 
A6–2.9 
MANAGEMENT OF NEUROLOGICAL TOXICITY/PERIPHERAL 
NEUROPATHY 
This study excludes patients with signs and symptoms of peripheral neuropathy.  
Neurologic examinations (see Appendix 7) will be performed as per the schedule of 
activities (Section 1.3, Table 1).  
Adverse events of neurological abnormalities should be discussed with the Medical 
Monitor as soon as possible. 
Cases of neurological abnormalities emerging from adverse event reporting or 
neurological examination that are potentially indicative of dysfunction of peripheral 
nerves or otherwise represent a neurological deficit and for which no other explanation is 
apparent should be reported as an adverse event of special interest (see Section 8.3.7).  
For such cases, the investigator is encouraged to seek advice from and have the 
participant seen by an expert in the field of peripheral neuropathy (neurologist).  
Furthermore, a NCV exam may be recommended as a follow-up for these adverse 
events.  The investigator must inform the Sponsor immediately (i.e., no more than 
24 hours after the investigator becomes aware of the data) of all out of range NCV data. 
To define pathological values from the NCV examinations, the range of normal values of 
the investigating electrophysiological laboratory will be used.  Repeat measurements 
may be indicated to describe the NCV over a prolonged period of time, allowing 
interpretation of the case.   
Verified symptoms indicative of peripheral neuropathy should be considered to trigger 
permanent treatment discontinuation of the participant.  Participants are asked to report 
any signs and symptoms indicative of peripheral neuropathy (e.g., burning, pain, 
numbness, tingling, impaired motoric skills) to the investigator as soon as possible.  


Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Balovaptan—F. Hoffmann-La Roche Ltd 
121/Protocol BN43546, Version 3 
It is also recommended to take blood samples to measure blood levels of balovaptan. 
Also, biomarkers indicative for alternative causes of emerging neuropathy should be 
evaluated with neurologist. 
REFERENCES 
Callejas Caballero I, Illán Ramos M, Berzosa Sánchez A, et al. Autoimmune 
neutropenia associated with influenza virus infection in childhood: a case report. 
BMC Infect Dis 2021;21:830. 
Costa A, Toschi A, Murfuni I, et al. Local overexpression of V1a-vasopressin receptor 
enhances regeneration in tumor necrosis factor-induced muscle atrophy. J Biomed 
Biotech 2014;2014:235426. 
Dalton SO, Sørensen HT, Johansen C. SSRIs and upper gastrointestinal bleeding: what 
is known and how should it influence prescribing? CNS Drugs 2006;20:143−51.  
Javadian N, Rahimi N, Javadi-Paydar M, et al. The modulatory effect of nitric oxide in 
pro- and anti-convulsive effects of vasopressin in PTZ-induced seizures threshold 
in mice. Epilepsy Res 2016;126:134−40. 
Perez DL, LaFrance WC Jr. Nonepileptic seizures: an updated review. CNS Spectr. 
2016;21(3):239−46. 
Popkirov S, Asadi-Pooya AA, Duncan R, et al. The aetiology of psychogenic 
non-epileptic seizures: risk factors and comorbidities. Epileptic Disord. 
2019;21(6):529−47. 
Serebruany VL. Selective serotonin reuptake inhibitors and increased bleeding risk: are 
we missing something? Am J Med. 2006;119:113−6. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
122/Protocol BN43546, Version 3 
  
Structured Brief Interview and Examination for Peripheral 
Neuropathy 
As part of the general neurologic examination, a dedicated neurologic assessment of the 
lower limbs must be conducted as follows: 
Equipment needed: 
• 
Cotton swab or Q-tip® 
• 
Disposable neurological pin 
• 
Tendon hammer 
• 
Metal tuning fork 
 
Ask the study participant: 
“Do you have any new numbness, pain, tingling or unusual sensations anywhere on your 
body, e.g., in your arms, hands, feet, legs, lower back, or buttocks?” 
• 
If yes, ask about the onset, distribution, quality, intensity, and frequency and 
document on the electronic Case Report Form (eCRF). 
“Do you have new weakness in your arms, hands, legs or feet or any changes in how 
you are walking?” 
• 
If yes, document new symptoms on the eCRF. 
 
Guided examination of the upper limbs: Document any new abnormalities on the eCRF. 
Item 1: Sensation 
For each location indicated below and on the diagram (see Figure 1), ask the 
participant to close his or her eyes.  Use the top of the sternum as the reference 
point.  Ask the participant if the sensation feels the same, decreased, or 
increased. 
• 
Distal fifth digit dorsal (n ulnaris); part of dermatome C8 assessed 
• 
Distal third digit dorsal (n medianus): part of dermatome C7 assessed 
• 
Latero-distal thumb (n radialis); part of dermatome C6 assessed 
 
Light Touch 
• 
Touch the Q-tip/cotton swab to each indicated location on each hand.  
 
Pinprick  
• 
Touch the disposable neurologic pin to each indicated location on each hand.  
 
Cold  
• 
Touch the metal tuning fork to each indicated location- on each hand. 


Appendix 7:  Structured Brief Interview and Examination for Peripheral Neuropathy 
Balovaptan—F. Hoffmann-La Roche Ltd 
123/Protocol BN43546, Version 3 
 
Vibration 
• 
Hit the tuning fork and ask the participant if he or she can feel buzzing when it is 
placed on the sternum.   
• 
Then, hit the tuning fork again and place it on the indicated locations and ask the 
participant whether he or she can sense the vibration.  
  
Item 2: Power 
For each arm, check the power of the participant to perform the following maneuvers 
against resistance: 
• 
elbow flexion and extension 
• 
thumb abduction  
 
Instructions for elbow flexion: 
Myotomes assessed: C5/6 (musculocutaneous and radial nerve) and Muscles 
assessed:  biceps brachii, coracobrachialis, and brachialis 
• 
Ask the patient to flex their elbow: “Put your hands up like a boxer.” 
• 
Apply resistance by pulling the forearm whilst stabilizing the shoulder joint: “Don’t let 
me pull your arm away from you.” 
 
Instructions for elbow extension: 
Myotome assessed:  C7 (radial nerve) and muscles assessed: triceps brachii 
• 
With the patient’s elbows still in the flexed position, apply resistance by pushing the 
forearm towards the patient whilst stabilizing the shoulder joint: “Don’t let me push 
your arm towards you.” 
  
Instructions for thumb abduction: 
Myotome assessed: T1 (median nerve) and muscle assessed: abductor pollicis brevis 
• 
Ask the patient to turn their hand over so their palm is facing upwards and to 
position their thumb over the midline of the palm. Advise them to keep it in this 
position whilst you apply downward resistance with your own thumb: “Point your 
thumbs to the ceiling and don’t let me push them down.” 
  
Note any new onset weakness (i.e., power less than full strength with maximum effort 
against resistance). 
• 
Each movement is to be rated as per the scale proposed by the Medical Research 
Council by the Royal College of Physicians and Surgeons:  


Appendix 7:  Structured Brief Interview and Examination for Peripheral Neuropathy 
Balovaptan—F. Hoffmann-La Roche Ltd 
124/Protocol BN43546, Version 3 
0: no muscle function 
1: muscle activation without movement 
2: move with gravity 
3: move (“just”) against gravity 
4: good / against resistance, but not normal muscle 
power 
5: normal strength 
 
Guided physical examination of the lower limbs:  Document any new abnormalities on 
the eCRF. 
Expose both of the study participant’s legs from the upper thighs downward. 
Item 1: Gait 
• 
Observe the study participant’s natural gait.  
• 
Ask the study participant to walk on his or her tiptoes and then on the back of the 
heels.  This will elicit any compensated weakness or dystonia.  
• 
Ask the study participant to walk heel-to-toe in a straight line.  This will bring out any 
uncoordination due to sensory or motor neuropathy or cerebellar signs. 
 
Item 2: Tone and Deep Tendon Reflexes 
• 
Ask the study participant to lie on the examination couch and to relax his or her legs.  
• 
Observe any new signs of deformity, fasciculation, wasting, or atrophic skin 
changes. 
• 
Asking the participant to remain relaxed, gently roll each leg in laterally and 
medially.  Then support each knee in dorsiflexion with your palm.  Gently lift each 
leg and allow it to fall naturally.  
• 
Put each leg into dorsiflexion at the knee.  Use the tendon hammer to tap the 
patellar tendon to elicit the patellar reflex.  Then place the legs flat with the knee and 
ankle dorsiflexed.  Tap the Achilles tendon to elicit the ankle reflex.  
• 
Finally with the leg relaxed, take the plantar surface of each foot in turn and sharply 
dorsiflex the ankle to check for clonus (sustained clonus of >5 beats is abnormal).  
• 
Grade the reflex response as: No (“0”), little (“+”), moderate (“++”), or strong (“+++”) 
reaction (patellar and ankle reflexes) 
• 
Check for emerging clonus when plantar surface of foot is dorsiflexed sharply 
(plantar reflex). 
- Note: sustained clonus of >5 beats is abnorma 
Note any abnormalities of tone, hyporeflexia, hyperreflexia, or sustained clonus. 


Appendix 7:  Structured Brief Interview and Examination for Peripheral Neuropathy 
Balovaptan—F. Hoffmann-La Roche Ltd 
125/Protocol BN43546, Version 3 
Item 3: Power 
For each leg, check the power of the participant to perform the following maneuvers 
against resistance:  
• 
Hip flexion and extension  
• 
Knee flexion and extension  
• 
Ankle dorsiflexion and plantar flexion  
 
Note any new onset weakness (i.e., power less than full strength with maximum effort 
against resistance). 
• 
Each movement is to be rated as per the scale proposed by the Medical Research 
Council by the Royal College of Physicians and Surgeons: 
0: no muscle function 
1: muscle activation without movement 
2: move with gravity 
3: move (“just”) against gravity 
4: good / against resistance, but not normal muscle 
power 
5: normal strength 
  
Item 4: Sensation  
For each dermatome indicated on the diagram (see Figure 2: S1, S2, L2, L4, and L5), 
ask the participant to close his or her eyes.  Use the top of the sternum as the reference 
point.  Ask the participant if the sensation feels the same, decreased, or increased.  
Light Touch 
• 
Touch the Q-tip/cotton swab to the sternum and then each indicated dermatome 
(S1, S2, L2, L4, and L5) on each leg.  
 
Pinprick  
• 
Touch the disposable neurologic pin to the sternum and then each indicated 
dermatome (S1, S2, L2, L4, and L5) on each leg.  
 
Cold  
• 
Touch the metal tuning fork to the sternum and then each indicated dermatome (S1, 
S2, L2, L4, and L5) 
 


Appendix 7:  Structured Brief Interview and Examination for Peripheral Neuropathy 
Balovaptan—F. Hoffmann-La Roche Ltd 
126/Protocol BN43546, Version 3 
Vibration 
• 
Hit the tuning fork and ask the participant if he or she can feel buzzing when it is 
placed on the sternum.   
• 
Then, hit the tuning fork again and place it on the dorsum of the interphalangeal joint 
of the hallux (left/right) and ask the participant whether he can sense the vibration.  
• 
Repeat this on the medial malleolus of each ankle.  
 
Joint Position Sense  
• 
Ask the participant to keep his or her eyes closed.  Hold the big toe at its base.  Use 
your hand to move the toe up or down.  Ask the participant to tell you in which 
direction you are moving the toe.  Repeat on the other foot. 
 
Figure 1: Dermatomes of the Upper Limb 
 
Adapted from https://neurochirurgie.insel.ch/erkrankungen-
spezialgebiete/wirbelsaeule/bandscheibenvorfall/zervikaler-bandscheibenvorfall 
 


Appendix 7:  Structured Brief Interview and Examination for Peripheral Neuropathy 
Balovaptan—F. Hoffmann-La Roche Ltd 
127/Protocol BN43546, Version 3 
Figure 2: Dermatomes of the Lower Limb 
 
 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
128/Protocol BN43546, Version 3 
  
Child−Pugh Classification 
Hepatic impairment will be classified according to the Child-Pugh system (Table A8-1), 
and the parameters to determine Child-Pugh classification for each participant will be 
collected at Screening. 
Table A8-1 Child−Pugh Classification of Hepatic Function 
 
Points Scored for Observed Findings 
 
1 
2 
3 
Hepatic encephalopathy grade a 
0 
1 or 2 b 
3 or 4 b 
Ascites c 
Absent 
Slight 
Moderate 
Serum bilirubin, mg/dL (µmol/L) 
< 2 (< 34) 
2 to 3 (34 to 50) 
> 3 (> 50) 
Serum albumin, g/dL (g/L) 
> 3.5 (> 35) 
2.8 to 3.5 (28 to 35) 
< 2.8 (< 28) 
International normalized ratio 
< 1.7 
1.7 to 2.3 
> 2.8 
Note:  Chronic hepatic impairment is classified into Child-Pugh class A to C, employing the 
added score of the 5 parameters described above. 
Severe impairment (Child-Pugh class C):  10 to 15 points 
Moderate impairment (Child-Pugh class B):  7 to 9 points 
a In this study (BN43546), hepatic encephalopathy will be graded according to the following 
criteria: 
Grade 0:  normal consciousness, personality, neurological examination, or normal 
electroencephalogram. 
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, or 5 
cycles per second (cps) waves. 
Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, or slow triphasic 
waves. 
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, or slower 
waves. 
Grade 4:  unarousable coma, no personality/behavior, decerebrate, or slow 2 to 3 cps delta 
activity. 
b Subjects with hepatic encephalopathy Grade 2 or above will not be enrolled into the study. 
c Subjects with evidence of severe ascites will not be enrolled into the study.  Ascites will be 
graded according to the following criteria: 
Absent:  no ascites is detectable by manual examination or by ultrasound investigation (if 
performed). 
Slight:  ascites palpitation doubtful, but ascites measurable by ultrasound investigation (if 
performed). 
Moderate:  ascites detectable by palpitations and by ultrasound investigation (if 
performed). 
Severe:  necessity of paracentesis; does not respond to treatment. 
 
  


 
Balovaptan—F. Hoffmann-La Roche Ltd 
129/Protocol BN43546, Version 3 
  
Questionnaire to Evaluate for Signs and Symptoms Indicative of 
Infections 
The following questionnaire will be used to evaluate signs and symptoms indicative of 
infection in participants either by telephone interview or in-person between site 
personnel and the participant at Weeks 4, 6, 9, and 12.   
The objective of the questionnaire is to assess fever, infections of pharynx and the 
respiratory system, and skin given that these are the most prevalent sites of infections in 
context of agranulocytosis and to provide guidance using a semi-structured interview 
format. 
• 
Study staff: Introduce yourself and explain the purpose of the interview. 
 
Check for Infections  
• 
“Did you have any episodes of feeling like you were having a “fever” (e.g., fatigue, 
shivering, “feeling hot”)?  
• 
“Did you experience a runny nose, sore throat, or cough since we talked last time?”  
• 
“Did you experience any infections of your skin or in your mouth?”  
• 
“Did you suffer from diarrhea?”  
• 
If yes to any of the above: 
- 
“Can you describe in more detail the symptoms, when they started, and how 
long they lasted?” 
- 
“Did you measure your body temperature at the time of the symptoms and can 
you remember the date when done?”  
- 
“Did you visit a health care provider?”  
- 
“Have the symptoms resolved or are they improving?” 
- 
“Did you take any medicines (over the counter or prescription)?” 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
130/Protocol BN43546, Version 3 
  
Examples of Cytochrome P450 3A4 Inducers and Inhibitors 
 
Strong CYP3A4 Inducers 
Apalutamide 
Mitotane 
Avasimibe 
Phenobarbital 
Carbamazepine 
Phenytoin 
Enzalutamide 
Rifapentine 
Ivosidenib 
Rifampin 
Lumacaftor 
St. John’s Wort extract 
Moderate CYP3A4 Inducers 
Asunaprevir 
Lesinurad 
Beclabuvir  
Lorlatinib  
Bosentan 
Modafinil  
Cenobamate  
Nafcillin 
Dabrafenib  
Rifabutin 
Daclatasvir 
Semagacestat 
Efavirenz 
Talviraline 
Elagolix 
Telotristat ethyl 
Etravirine  
Thioridazine 
Lersivirine  
 
Strong CYP3A4 Inhibitors 
Boceprevir 
Nefazodone 
Ceritinib 
Nelfinavir 
Clarithromycin 
Posaconazole 
Cobicistat 
Ribociclib 
Conivaptan 
Ritonavir 
Danoprevir 
Saquinavir 
Elvitegravir 
Telaprevir 
Idelalisib 
Telithromycin 
Indinavir 
Tipranavir 
Itraconazole 
Troleandomycin 
Ketoconazole 
Tucatinib 
Lopinavir 
VIEKIRA PAK (dasabuvir, ombitasvir, 
paritaprevir, ritonavir) 
Mibefradil 
Voriconazole 
Mifepristone 
 


Appendix 10:  Examples of Cytochrome P450 3A4 Inducers and Inhibitors 
Balovaptan—F. Hoffmann-La Roche Ltd 
131/Protocol BN43546, Version 3 
Moderate CYP3A4 Inhibitors 
Amprenavir 
Fluconazole 
Aprepitant 
Grapefruit juice 
Atazanavir 
Imatinib 
Casopitant 
Isavuconazole 
Cimetidine 
Istradefylline 
Ciprofloxacin 
Lefamulin 
Crizotinib 
Letermovir 
Cyclosporine 
Magnolia vine (Schisandra sphenanthera) 
Darunavir 
Netupitant 
Diltiazem 
Nilotinib 
Dronedarone 
Ravuconazole 
Duvelisib 
Tofisopam 
Erythromycin 
Verapamil 
Faldaprevir 
Voxelotor 
Fedratinib 
 
CYP3A4 = cytochrome P450 3A4. 
Sourced from https://www.druginteractionsolutions.org/. 
 
REFERENCES 
Drug Interaction Solutions, University of Washington School of Pharmacy [resource on 
the internet].  2020.  Available from: https://www.druginteractionsolutions.org/. 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
132/Protocol BN43546, Version 3 
  
Clinical Outcome Assessment Instruments 
All assessments (except Structured-Clinical Interview for DSM-5 [SCID-5]) will be 
completed through use of an electronic device.  Please note, the assessments shown in 
this appendix may not be exactly the same as they appear on the electronic device. 
TABLE OF CONTENT  
A11–1 
Clinician-Administered PTSD Scale For DSM-5 (CAPS-5) .... 133 
A11–2 
Clinician-Global Impression of Severity (CGI-S) .................... 157 
A11–3 
Clinician-Global Impression of Change (CGI-C) .................... 158 
A11–4 
Patient-Health Questionnaire-9 (PHQ-9) ............................... 159 
A11–5 
Life-Events Checklist For DSM-5 (LEC-5) ............................. 160 
A11–6 
PTSD Checklist for DSM-5 (PCL-5) ....................................... 162 
A11–7 
Structured-Clinical Interview for DSM-5 (SCID-5) .................. 164 
A11–8 
Beck Anxiety Inventory (BAI) ................................................. 200 
A11–9 
Pittsburgh-Sleep Quality Index (PSQI) .................................. 201 
A11–10 
Sheehan Disability Scale (SDS) ............................................ 203 
A11–11 
Cognition And Physical Functioning Questionnaire (CPFQ) .. 204 
A11–12 
Patient-Global Impression of Severity (PGI-S) ....................... 205 
A11–13 
Patient-Global Impression Of Change (PGI-C) ...................... 206 
A11–14 
Columbia-Suicide Severity Rating Scale (C-SSRS), 
Baseline ................................................................................. 207 
A11–15 
Columbia-Suicide Severity Rating Scale (C-SSRS), Since 
Last Visit ................................................................................ 210 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
133/Protocol BN43546, Version 3 
A11–1 
CLINICIAN-ADMINISTERED PTSD SCALE FOR DSM-5 (CAPS-5) 
(Sample; Not to Be Used to Enter Subject Data) 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
134/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
135/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
136/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
137/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
138/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
139/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
140/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
141/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
142/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
143/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
144/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
145/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
146/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
147/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
148/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
149/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
150/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
151/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
152/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
153/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
154/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
155/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
156/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
157/Protocol BN43546, Version 3 
A11–2 
CLINICIAN-GLOBAL IMPRESSION OF SEVERITY (CGI-S) 
(Sample; Not to Be Used to Enter Subject Data) 
Taking into account all aspects of the individual’s PTSD symptoms, please rate how the 
individual’s symptom severity has been during the past 7 days?  Do not consider other 
conditions or comorbidities in your assessment. 
☐ 
No symptoms 
 
☐ 
Very mild 
 
☐ 
Mild 
 
☐ 
Moderate 
 
☐ 
Severe 
 
☐ 
Very severe 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
158/Protocol BN43546, Version 3 
A11–3 
CLINICIAN-GLOBAL IMPRESSION OF CHANGE (CGI-C) 
(Sample; Not to Be Used to Enter Subject Data) 
Taking into account all aspects of the individual’s PTSD symptoms, how much would 
you rate the change in clinical status since their admission to the study?  Do not 
consider other conditions or comorbidities in your assessment. 
☐ 
Very much improved 
 
☐ 
Much improved 
 
☐ 
Minimally improved 
 
☐ 
No change 
 
☐ 
Minimally worse 
 
☐ 
Much worse 
 
☐ 
Very much worse 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
159/Protocol BN43546, Version 3 
A11–4 
PATIENT-HEALTH QUESTIONNAIRE-9 (PHQ-9)   
(Sample; Not to Be Used to Enter Subject Data) 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
160/Protocol BN43546, Version 3 
A11–5 
LIFE-EVENTS CHECKLIST FOR DSM-5 (LEC-5)  
(Sample; Not to Be Used to Enter Subject Data) 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
161/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
162/Protocol BN43546, Version 3 
A11–6 
PTSD CHECKLIST FOR DSM-5 (PCL-5)  
(Sample; Not to Be Used to Enter Subject Data) 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
163/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
164/Protocol BN43546, Version 3 
A11–7 
STRUCTURED-CLINICAL INTERVIEW FOR DSM-5 (SCID-5)   
(Sample; Not to Be Used to Enter Subject Data) 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
165/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
166/Protocol BN43546, Version 3 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
167/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
168/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
169/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
170/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
171/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
172/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
173/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
174/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
175/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
176/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
177/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
178/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
179/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
180/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
181/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
182/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
183/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
184/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
185/Protocol BN43546, Version 3 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
186/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
187/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
188/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
189/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
190/Protocol BN43546, Version 3 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
191/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
192/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
193/Protocol BN43546, Version 3 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
194/Protocol BN43546, Version 3 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
195/Protocol BN43546, Version 3 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
196/Protocol BN43546, Version 3 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
197/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
198/Protocol BN43546, Version 3 
 
 
 
 
 
 
 
 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
199/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
200/Protocol BN43546, Version 3 
A11–8 
BECK ANXIETY INVENTORY (BAI) 
(Sample; Not to Be Used to Enter Subject Data) 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
201/Protocol BN43546, Version 3 
A11–9 
PITTSBURGH-SLEEP QUALITY INDEX (PSQI)  
(Sample; Not to Be Used to Enter Subject Data) 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
202/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
203/Protocol BN43546, Version 3 
A11–10 
SHEEHAN DISABILITY SCALE (SDS)  
(Sample; Not to Be Used to Enter Subject Data) 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
204/Protocol BN43546, Version 3 
A11–11 
COGNITION AND PHYSICAL FUNCTIONING QUESTIONNAIRE 
(CPFQ)  
(Sample; Not to Be Used to Enter Subject Data) 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
205/Protocol BN43546, Version 3 
A11–12 
PATIENT-GLOBAL IMPRESSION OF SEVERITY (PGI-S)  
(Sample; Not to Be Used to Enter Subject Data) 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
206/Protocol BN43546, Version 3 
A11–13 
PATIENT-GLOBAL IMPRESSION OF CHANGE (PGI-C)  
(Sample; Not to Be Used to Enter Subject Data) 
 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
207/Protocol BN43546, Version 3 
A11–14 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS), 
BASELINE 
(Sample; Not to Be Used to Enter Subject Data) 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
208/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
209/Protocol BN43546, Version 3 
 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
210/Protocol BN43546, Version 3 
A11–15 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS), 
SINCE LAST VISIT 
(Sample; Not to Be Used to Enter Subject Data) 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
211/Protocol BN43546, Version 3 
 


Appendix 11: Clinical Outcome Assessment Instruments 
Balovaptan—F. Hoffmann-La Roche Ltd 
212/Protocol BN43546, Version 3 
 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
213/Protocol BN43546, Version 3 
  
Abbreviations 
Abbreviation or Term 
Definition 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ASD 
autism spectrum disorder 
AVP 
(arginine) vasopressin 
BAI 
Beck Anxiety Inventory 
CBT 
cognitive-behavioral therapy 
CAPS-5 
Clinician-Administered PTSD scale for DSM-5  
CGI-C 
Clinician-Global Impression of Change 
CGI-S 
Clinician-Global Impression of Severity 
CI 
confidence interval 
ClinRO 
clinician-reported outcome  
COVID-19 
Coronavirus Disease 2019  
CPFQ 
Cognitive and Physical Functioning 
Questionnaire 
CPK 
creatine phosphokinase 
CSR 
Clinical Study Report  
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP3A4 
cytochrome P450 3A4  
DSM-5 
Diagnostic and Statistical Manual of Mental 
Disorders, Version 5 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EMDR 
eye movement desensitization and 
reprocessing 
HBcAb 
hepatitis B core antibody  
HBsAg 
hepatitis B surface antigen  
HPA 
hypothalamic-pituitary adrenocortical  
hs-cTnT 
high-sensitivity-cardiac troponin T 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
MAO 
monoamine oxidase 
M2 
metabolite 2 
M3 
metabolite 3 
NGS 
next-generation sequencing 


Appendix 12:  Abbreviations  
Balovaptan—F. Hoffmann-La Roche Ltd 
214/Protocol BN43546, Version 3 
Abbreviation or Term 
Definition 
NCS-R 
National Comorbidity Survey Replication  
PCL-5 
PTSD Checklist for DSM-5 
PerfO 
performance outcome 
PGI-C 
Patient-Global Impression of Change 
PGI-S 
Patient-Global Impression of Severity 
P-gp 
P-glycoprotein 
PHQ-9 
Patient Health Questionnaire-9 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PSQI 
Pittsburgh Sleep Quality Index 
PTSD 
post-traumatic stress disorder 
QD 
quaque die (once a day) 
QTc 
corrected QT interval 
QTcF 
QT interval corrected through use of 
Fridericia's formula 
RBR 
Research Biosample Repository 
REC 
recording eyes closed 
REO 
recording eyes open 
rTMS 
transcranial magnetic stimulation 
SCID-5 
Structured-Clinical Interview for DSM-5 
SDCR 
study drug or condition related  
SDS 
Sheehan Disability Scale 
SNRI 
serotonin and norepinephrine reuptake 
inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TCAs 
tricyclic antidepressants  
TF 
trauma-focused 
ULN 
upper limit of normal 
V1a 
vasopressin 1a 
V1b 
vasopressin 1b  
V2 
vasopressin 2  
WES 
whole exome sequencing 
WGS 
whole genome sequencing 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
215/Protocol BN43546, Version 3 
  
Protocol Amendment History 
A rationale for the current amendment precedes the Table of Contents. 
PROTOCOL AMENDMENT, VERSION 2:  23 FEBRUARY 2022 
Protocol BN43546 has been amended to reflect recent feedback from the U.S. Food and 
Drug Administration (FDA) after submission of the Investigational New Drug Application.  
In addition, Sponsor-initiated modifications have been incorporated including clarification 
of non-pharmacological interventions and the number of interim analyses to be 
performed.  Substantive changes to the protocol, along with a rationale for each change, 
are summarized below. 
• 
The exclusion criterion for moderate or severe hepatic and renal impairment was 
updated to include specific grading criteria; Child-Pugh classification, and eGFR, 
respectively (Section 5.2). 
• 
An exclusion criterion was added for participants with current or past gastrointestinal 
disease that could potentially limit the absorption of study drug.  Some reduction in 
gastrointestinal absorption is considered acceptable since the brain receptor 
occupancy is predicted to remain relatively high with even moderate reduction in 
absorption (Section 5.2). 
• 
The exclusion criterion for participants currently receiving trauma-based 
psychotherapy was removed (Section 5.2) and clarification language was added 
describing the types and frequency of non-pharmacological interventions for 
post-traumatic stress disorder that are permitted during the study (Section 6.8.1).   
• 
Language on screen failures was updated to more closely align with Roche Global 
Data Standards (Section 5.4). 
• 
Following FDA comment to include structured questions about general and upper 
extremity neuropathy symptoms and to include upper extremity testing as part of the 
neurological evaluation, the following sections in the protocol have been updated.  
Section 7.1.5 now has a section describing considerations for treatment 
discontinuation regarding emerging AE of peripheral neuropathy.  Text was updated 
to include both upper and lower limbs in neurological examinations (Section 8.2.3).  
In Appendix 7, details of the structured brief interview and examination for peripheral 
neuropathy were updated to include upper extremity sensory and motor testing.  
• 
The randomization ratio was updated from 3:1 to 1:1 (Sections 4.1, 6.3.1, and 9.2), 
which will allow for a more robust comparison between balovaptan and placebo 
arms based on the data collected in the study. 
• 
Text was added describing the rationale for the target number of enrolled 
participants, which is based on drop-out rates seen in similar clinical studies 
(Section 9.2). 
• 
Language has been revised to include only one interim analysis instead of two.  The 
information will be used for internal purposes and planning of future development of 
the compound; sample size re-estimation may be performed (Section 9.5.1).  


Appendix 13:  Protocol Amendment History 
Balovaptan—F. Hoffmann-La Roche Ltd 
216/Protocol BN43546, Version 3 
• 
Language was updated to clarify that electrocardiogram parameters will be provided 
as non-eCRF data (Section 8.2.4).  
• 
Language has been clarified in Appendix 1, Section A1-1 to indicate that any 
substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception 
of administrative changes or changes necessary to eliminate an immediate hazard 
to study participants. 
• 
Due to administrative changes “serious adverse event reporting form” has been 
updated to “Clinical Trial Adverse Event/Special Situations Form” and “Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form” has been 
updated to “Clinical Trial Adverse Event/Special Situations Form” throughout the 
protocol. 
 
 


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