Clinical trial NCT03764449
Conditions: Healthy Volunteers
Sponsor: Hoffmann-La Roche
Start date: 2019-01-10; Completion date: 2019-03-15
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was a non-randomized, open-label, parallel group, two-treatment study in healthy volunteers to investigate the absolute oral bioavailability of balovaptan. The study was conducted at 1 site in the Netherlands.

Detailed description:

Arms: arm 1: Participants received the study drug at dose level A in 2 periods. There was a minimum of a 14-day wash out period between Day 1 of Period 1 and Day 1 of Period 2. arm 2: Participants received the study drug at dose level B in 2 periods. There was a minimum of a 14-day wash out period between Day 1 of Period 1 and Day 1 of Period 2.
Interventions: intervention 1: Oral Balovaptan intervention 2: IV Balovaptan
Intervention descriptions: intervention 1: In Period 1, balovaptan was administered as a single oral dose.

In Period 2, balovaptan was administered as an oral dose once daily on Day 1 to Day 14. intervention 2: In Period 1, IV infusion of balovaptan was administered after the balovaptan oral dose.

In Period 2, IV infusion of balovaptan was administered after the final oral dose of balovaptan.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
PARALLEL GROUP, TWO-TREATMENT STUDY INVESTIGATING 
THE ABSOLUTE ORAL BIOAVAILABILITY OF BALOVAPTAN 
AFTER SINGLE AND MULTIPLE DAILY ORAL DOSES OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS 
NCT Number: 
NCT03764449 
Document Date:  Protocol Version 1: 22-October-2018 
 
 
 
 


FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Balovaptan—F. Hoffmann-La Roche Ltd 
Protocol WP40607, Final Version 1.0 
PROTOCOL 
TITLE: 
A SINGLE-CENTER, NON-RANDOMIZED, 
OPEN-LABEL, PARALLEL GROUP, TWO-
TREATMENT STUDY INVESTIGATING THE 
ABSOLUTE ORAL BIOAVAILABILITY OF 
BALOVAPTAN AFTER SINGLE AND MULTIPLE 
DAILY ORAL DOSES OF BALOVAPTAN IN 
HEALTHY VOLUNTEERS 
PROTOCOL NUMBER: WP40607 
VERSION NUMBER: 
1.0 
EUDRACT NUMBER: 
2018-003634-32 
IND NUMBER: 
NA 
TEST PRODUCT: 
Balovaptan (RO5285119) 
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 
 
22-Oct-2018 08:55:39
Title
Approver's Name
Company Signatory
Date and Time (UTC)


 
Balovaptan—F. Hoffmann-La Roche Ltd 
2/Protocol WP40607, Final Version 1.0 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1. 
BACKGROUND .......................................................................................... 19 
1.1 
Autism Spectrum Disorder ..................................................... 19 
 
 20 
1.2.1 
Previous and Ongoing Clinical Studies .................................. 22 
1.2.1.1 
Clinical Pharmacology ........................................................... 22 
 
 23 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 24 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 25 
3. 
STUDY DESIGN ......................................................................................... 26 
3.1 
Description of the Study ......................................................... 26 
3.2 
End of Study and Length of Study ......................................... 27 
3.3 
Rationale for Study Design .................................................... 28 
3.3.1 
Rationale for Open-Label Design .......................................... 28 
3.3.2 
Rationale for Balovaptan Dose and Schedule ....................... 28 
 
 29 
 
 29 
3.3.5 
Rationale for Genomics Assessments ................................... 29 
4. 
MATERIALS AND METHODS .................................................................... 30 
4.1 
Subjects ................................................................................. 30 
4.1.1 
Inclusion Criteria .................................................................... 30 
4.1.2 
Exclusion Criteria ................................................................... 31 
4.2 
Method of Treatment Assignment and Blinding ..................... 34 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 34 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 35 
4.3.1.1 
Balovaptan ............................................................................. 35 
4.3.1.2 
[13C]-Labeled Balovaptan ...................................................... 35 


 
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4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 35 
4.3.2.1 
Balovaptan (Oral Administration) ........................................... 35 
4.3.2.2 
[13C]-Labeled Balovaptan ...................................................... 35 
4.3.3 
Investigational Medicinal Product Accountability ................... 36 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 36 
4.4.1 
Permitted Therapy ................................................................. 36 
4.4.2 
Prohibited Therapy ................................................................ 36 
4.4.3 
Prohibited Food ..................................................................... 37 
4.4.4 
Additional Restrictions/Considerations .................................. 37 
4.5 
Study Assessments ............................................................... 38 
4.5.1 
Informed Consent Forms and Screening Log ........................ 38 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 39 
4.5.3 
Physical Examinations ........................................................... 39 
4.5.4 
Vital Signs .............................................................................. 39 
4.5.5 
Laboratory, Pharmacokinetic, and Other 
Biological Samples ................................................................ 39 
4.5.5.1 
Laboratory Samples .............................................................. 40 
4.5.5.2 
Pharmacokinetic Blood Samples ........................................... 40 
 
 41 
4.5.5.4 
Clinical Genotyping Samples ................................................. 41 
4.5.6 
Electrocardiograms ................................................................ 41 
4.5.7 
Columbia-Suicide Severity Rating Scale ............................... 42 
4.5.8 
Drug and Metabolite Concentration 
Measurements ....................................................................... 42 
4.5.9 
Timing of Study Assessments ............................................... 42 
4.6 
Treatment, Subject, Study, and Site 
Discontinuation ...................................................................... 42 
4.6.1 
Study Treatment Discontinuation ........................................... 42 
4.6.2 
Subject Discontinuation from Study ....................................... 43 
4.6.3 
Study Discontinuation ............................................................ 43 
4.6.4 
Site Discontinuation ............................................................... 44 




 
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5.3.5.5 
Abnormal Laboratory Values ................................................. 55 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 56 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 56 
5.3.5.8 
Deaths ................................................................................... 57 
5.3.5.9 
Preexisting Medical Conditions .............................................. 57 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 57 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 58 
5.4.1 
Emergency Medical Contacts ................................................ 58 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 59 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 59 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 59 
5.4.3 
Reporting Requirements for Pregnancies .............................. 59 
5.4.3.1 
Pregnancies in Female Subjects ........................................... 59 
5.4.3.2 
Pregnancies in Female Partners of Male 
Subjects ................................................................................. 60 
5.4.3.3 
Abortions ............................................................................... 60 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 60 
5.4.4 
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error ................................................ 60 
5.5 
Follow-Up of Subjects After Adverse Events ......................... 61 
5.5.1 
Investigator Follow-Up ........................................................... 61 
5.5.2 
Sponsor Follow-Up ................................................................ 62 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 62 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 62 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 63 
6.1 
Determination of Sample Size ............................................... 63 
6.2 
Summaries of Conduct of Study ............................................ 63 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 64 
6.4 
Efficacy Analyses .................................................................. 64 


 
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6.5 
Safety Analyses ..................................................................... 64 
6.6 
Pharmacokinetic Analyses ..................................................... 64 
6.7 
Genotyping Analyses ............................................................. 65 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 66 
7.1 
Data Quality Assurance ......................................................... 66 
7.2 
Electronic Case Report Forms ............................................... 66 
7.3 
Source Data Documentation .................................................. 66 
7.4 
Use of Computerized Systems .............................................. 67 
7.5 
Retention of Records ............................................................. 67 
8. 
ETHICAL CONSIDERATIONS .................................................................... 68 
8.1 
Compliance with Laws and Regulations ................................ 68 
8.2 
Informed Consent .................................................................. 68 
8.3 
Institutional Review Board or Ethics Committee .................... 69 
8.4 
Confidentiality ........................................................................ 69 
8.5 
Financial Disclosure .............................................................. 70 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 70 
9.1 
Study Documentation ............................................................ 70 
9.2 
Protocol Deviations ................................................................ 70 
9.3 
Site Inspections ..................................................................... 70 
9.4 
Administrative Structure ......................................................... 70 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 71 
9.6 
Protocol Amendments ........................................................... 72 
10. REFERENCES ........................................................................................... 73 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 25 
Table 2 
Adverse Event Severity Grading Scale ....................................... 53 
Table 3 
Causal Attribution Guidance ....................................................... 53 
Table 4 
Precision Factor Estimates ......................................................... 63 
 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 27 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ................................................................. 74 
Appendix 2 
 Schedule of Pharmacokinetic Blood 
 Samples ............ 76 




 
Balovaptan—F. Hoffmann-La Roche Ltd 
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PROTOCOL SYNOPSIS 
TITLE: 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
PARALLEL GROUP, TWO-TREATMENT STUDY INVESTIGATING 
THE ABSOLUTE ORAL BIOAVAILABILITY OF BALOVAPTAN 
AFTER SINGLE AND MULTIPLE DAILY ORAL DOSES OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS 
PROTOCOL NUMBER: 
WP40607 
VERSION NUMBER: 
1.0 
EUDRACT NUMBER: 
2018-003634-32 
IND NUMBER: 
NA 
TEST PRODUCT: 
Balovaptan (RO5285119) 
PHASE: 
I 
INDICATION: 
Not applicable 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
 
Objectives and Endpoints 
This study will evaluate the PK of balovaptan. Specific objectives and corresponding endpoints 
for the study are outlined below. 
 
 


 
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Primary Objective 
Corresponding Endpoint 
• To determine the absolute oral 
bioavailability of a single dose of 10 mg 
balovaptan.  
• Absolute bioavailability (F) for balovaptan at the 
indicated dose level. 
Secondary Objectives 
Corresponding Endpoints 
• To determine the absolute oral 
bioavailability of a single dose of 50 mg 
balovaptan. 
• To determine the absolute oral 
bioavailability of balovaptan after once 
daily doses of 10 mg or 50 mg for 14 days. 
• Absolute bioavailability (F) for balovaptan at the 
indicated dose level. 
 
• To characterize the dose- and 
time-dependency of the PK of oral 
balovaptan.  
• To determine plasma concentrations of 
[13C]-labeled balovaptan, balovaptan, and 
its metabolites M2, and M3, following a 
single oral dose of balovaptan 10 mg or 
50 mg together with a slow IV infusion of a 
microdose of [13C]-labeled balovaptan.  
• To determine plasma concentrations of 
[13C]-labeled balovaptan, balovaptan, and 
its metabolites M2, and M3, following once 
daily oral dosing of 10 mg or 50 mg QD for 
14 days together with a slow IV infusion of 
a microdose of [13C]-labeled balovaptan 
after the last oral dose. 
• Plasma concentrations and associated PK 
parameters for [13C]-labeled balovaptan, balovaptan, 
and its metabolites M2, and M3, including but not 
limited to Cmax, tmax, t1/2, AUClast, AUCinf, AUC0-24, 
Clast, tlast, λz, and (for [13C]-parent only) CL on Day 1 
and Day 14 and Vss on Day 1 and Day 14. 
• To evaluate the safety and tolerability of 
balovaptan 10 mg QD and 50 mg QD 
• Adverse events (AEs), clinical laboratory values, 
vital signs, electrocardiogram (ECG), and physical 
examination 
Exploratory Objectives 
Corresponding Endpoints 
• To determine whether genes relating to 
drug-metabolizing enzymes and/or drug 
transporter enzymes affect the PK and/or 
the safety profile of balovaptan.  
• The pharmacogeneticsa of metabolizing enzymes, 
transferases, transporters, etc., possibly involved in 
the absorption, distribution, metabolism and 
excretion of balovaptan and its major metabolites 
(e.g., CYP3A and P-glycoprotein). 
• 
 
 
 
• 
 
AE = adverse events; 
; CYP = cytochrome P450; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; F = bioavailability; IV = intravenous; 
PK = pharmacokinetic; QD = once daily 
a Results may be pooled with data from other studies of balovaptan and will be reported 
separately. 
 




 
Balovaptan—F. Hoffmann-La Roche Ltd 
12/Protocol WP40607, Final Version 1.0 
Number of Subjects 
A total of 8 subjects per cohort will be enrolled with the target of at least 6 subjects available for 
the primary PK analysis.  
Target Population 
The target population will be healthy male (at least 4 male subjects enrolled per cohort) and 
female subjects, aged 18 to 65 years, inclusive, at screening. At least 4 subjects enrolled per 
cohort should be aged 18 to 50 years, inclusive, at screening.  
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
1. Healthy male or female subject, aged 18 to 65 years, inclusive, at screening. Healthy status 
is defined by absence of evidence of any active or chronic disease following a detailed 
medical and surgical history, a complete physical examination including vital signs, 12-lead 
ECG, hematology, blood chemistry, urinalysis, and serology. 
2. Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive, at screening. 
3. For women of childbearing potential: agreement to use at least 2 acceptable contraceptive 
methods during the treatment period and for 90 days after the last dose of study drug. Also, 
total abstinence, in accordance with the lifestyle of the subject, is acceptable. 
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
• The following are acceptable contraceptive methods: bilateral tubal ligation; male 
sterilization; hormonal contraceptives; hormone-releasing intrauterine devices (IUD); 
copper IUD; male or female condom with or without spermicide (male and female 
condom must not be used simultaneously); and cap, diaphragm, or sponge with 
spermicide. 
• Hormonal contraceptive methods must be supplemented by a barrier method. 
4. For men: agreement to use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below: 
• With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for 90 days after the 
last dose of study drug to avoid exposing the embryo. Men must refrain from donating 
sperm during this same period. 
5. Able to participate and willing to give written informed consent and to comply with the study 
restrictions. 
6. Fluent in English or Dutch. 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. Female subjects who are pregnant or lactating. 
2. If female of childbearing potential, a positive serum pregnancy test at screening or at 
admission to the CRU (Day -1 of each period). 
3. Any condition or disease detected during the medical interview/physical examination that 
would render the subject unsuitable for the study, place the subject at undue risk or 
interfere with the ability of the subject to complete the study in the opinion of the 
Investigator. 
4. In the opinion of the Investigator, any major illness within one month before the screening 
examination or any febrile illness within one week prior to screening and up to first study 
drug administration. 
5. History of any clinically significant gastrointestinal, renal, hepatic, broncho pulmonary, 
neurological, psychiatric, cardiovascular, endocrinological, hematological, lymphatic, 


 
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musculoskeletal, genitourinary, immunological, dermatological, connective tissue or allergic 
disease, metabolic disorder, or cancer.  
6. Signs and symptoms potentially indicative of peripheral neuropathy. 
7. History or evidence of any medical condition potentially altering the absorption, metabolism, 
or elimination of drugs. Surgical history of the gastrointestinal tract affecting gastric motility 
or altering the gastrointestinal tract, with the exception of uncomplicated appendectomy, 
which is allowed. 
8. A history of clinically significant hypersensitivity (e.g., to drugs, including balovaptan, and 
excipients) or allergic reactions. 
9. Known personal or family history of congenital long QT syndrome or sudden death. 
10. History or presence of clinically significant ECG abnormalities before study drug 
administration. 
11. Subjects with screening or predose baseline mean QT interval corrected using Fridericia’s 
formula (QTcF) >450 milliseconds [msec] or <300 msec (using the same upper QTcF limit 
in both males and females). 
12. Notable resting bradycardia (mean heart rate [HR] <40 beats per minute [bpm]) on 
screening or predose baseline ECG. Notable resting tachycardia  on screening (mean 
HR > 90 bpm) or predose (mean HR > 100 bpm) baseline ECG. 
13. Screening or baseline ECGs with QRS and/or T-wave judged to be unfavorable for a 
consistently accurate QT measurement (i.e., neuromuscular artifact that cannot be readily 
eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T- and 
U-waves, prominent U-waves, etc.). 
14. Screening or baseline ECG with evidence of clinically relevant abnormalities, e.g. atrial 
fibrillation, atrial flutter, complete bundle branch block, Wolf-Parkinson-White Syndrome, or 
cardiac pacemaker. 
15. Systolic blood pressure greater than 139 or less than 90 mmHg, or diastolic blood pressure 
greater than 89 or less than 45 mmHg, based on the average of ≥ 3 consecutive 
measurements. 
16. Clinically significant abnormalities in laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel, coagulation parameters, and urinalysis). In 
the case of uncertain or questionable results, tests performed during screening may be 
repeated on Day -1 of Period 1 to confirm eligibility. 
17. History of coagulopathies, bleeding disorders, or blood dyscrasias. 
18. Subjects who have smoked within 3 months prior to first dose administration. 
19. Any clinically relevant history or any suspicion of alcohol and/or other substance abuse or 
addiction. Past alcohol and/or other substance abuse or addiction is also not allowed. 
20. Alcohol consumption of >24 units per week for males and females. One unit of alcohol 
equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of 
spirits.  
21. Positive urine alcohol test or urine drug screen at screening or each admission (Day -1 of 
each period) (barbiturates, benzodiazepines, methadone, amphetamines [including ecstasy], 
methamphetamines, opiates, cocaine, and cannabinoids). 
22. Positive result on human immunodeficiency virus (HIV)-1, HIV-2 antibodies, hepatitis C 
virus (HCV) antibody, hepatitis B virus surface antigen (HBsAg), or hepatitis B core (HepBc) 
antibody screen. 
23. Participation in an investigational drug or device study within 90 days prior to first dosing, or 
within 5 months prior to first dosing in case of a study with a biological, as calculated from 
the day of follow-up from the previous study. 
24. Any donation of blood or plasma or significant blood loss within 3 months prior to screening. 
25. Dietary restrictions that would prohibit the consumption of standardized meals. 
26. Use of any prohibited medications OR food before study start OR subjects who do not 
agree to refrain from consuming prohibited medications or food during the study. 




 
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Investigational Medicinal Products 
Balovaptan 
RO5285119/F17 10 mg dispersible film-coated tablets will be supplied by the Sponsor in high 
density polyethylene bottles. For information on the formulation and handling of balovaptan, see 
the Investigational Medicinal Product Dossier. 
 
[13C]-Labeled Balovaptan  
The [13C]-labeled balovaptan drug substance will be supplied by the Sponsor. RO5285119/F40 
[13C]-labeled balovaptan solution (20 µg/ml)  for IV infusion will be prepared by the site. For 
information on the formulation and handling of [13C]-labeled balovaptan, see the Investigational 
Medicinal Product Dossier. 
 
Statistical Methods 
Primary Analysis 
The primary PK parameter is absolute bioavailability (F) for balovaptan following a single 10 mg 
dose.  
 
Determination of Sample Size  
This is an exploratory study for which no formal statistical hypothesis will be tested, and 
therefore the sample size is chosen to estimate the absolute bioavailability of the 10 mg single 
dose with sufficient precision. 
A total of 8 subjects per cohort are to be enrolled with the target of at least 6 subjects available 
for the primary PK analysis (i.e., having taken a single dose of 10 mg on Day 1 and completed 
all PK assessment up to Day 10). If the number of subjects providing PK data from the multiple 
dose parts of the study is lower than 6 for either cohort more subjects may be enrolled. 
Assuming a within-subject variability of around 35% it can be estimated that with 6 subjects the 
half-width of the 90% confidence interval (CI) for the ratio of geometric means of the microdose 
IV kinetics with that from the oral dose (i.e. CL versus CL/F) would be obtained by 
dividing/multiplying the ratio estimate by a factor of 1.50. 
The within-subject variability value of around 35% has been identified as a reasonable 
assumption: it is smaller than the observed 42% between-subject variability for the apparent 
clearance of distribution (CL/F) from a single oral 10 mg dose in study WP40038, and it 
considers that the reference will be obtained from IV kinetics, which is expected to be less 
variable than oral kinetics.  
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated thromboplastin time 
ASD 
autism spectrum disorder 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve over the 
dosing interval at steady state 
AUC0-120h 
area under the plasma concentration vs time curve from 
time zero to 120 hours 
AUCinf 
area under the plasma concentration-time curve form 
time zero extrapolated to infinity  
AUClast 
area under the plasma concentration-time curve from 
time zero to the last measurable plasma concentration 
time point  
BMI 
body mass index 
bpm 
beats per minute 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CI 
confidence interval 
CL 
total body clearance 
Clast 
last measurable plasma concentration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CRU 
clinical research unit 
 
 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 


 
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EDC 
electronic data capture 
EU 
European Union 
F 
absolute bioavailability 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HepBc 
hepatitis B core 
hERG 
human ether-à-go-go related gene 
HR 
heart rate 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IC20 
20% inhibition 
IMP 
investigational medicinal product 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
λz 
terminal elimination rate constant 
LC/MS/MS 
liquid chromatography-tandem mass spectrometry 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond(s) 
NOEL 
no observed effect level 
NOAEL 
no observed adverse effect level 
NCI 
National Cancer Institute 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PND 
postnatal day 
PRA 
PRA Health Sciences 


 
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QD 
once daily 
QTcF 
QT interval corrected through use of Fridericia’s formula 
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SOP 
standard operating procedure 
t1/2 
apparent terminal half-life 
tlast 
time of last measurable plasma concentration 
tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
US 
United States 
V1a 
vasopressin receptor 1A 
Vss 
volume of distribution  
WBC 
white blood cell 
 


 
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1. 
BACKGROUND 
1.1 
AUTISM SPECTRUM DISORDER  
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder 
characterized by 2 core domains: impairments in social interaction and communication 
and presence of repetitive or restricted behaviors, interests, or activities (America  n 
Psychiatric Association, 2013). The Autism and Developmental Disabilities Monitoring 
Network recently reported, based on children’s records, that the estimated prevalence of 
ASD in the United States (US) for the year 2010 was 14.7 per 1000 (one in 68) children 
aged 8 years (Autism and Developmental Disabilities Monitoring Network Surveillance 
Year 2010 Principal Investigators, 2014). Core symptoms of ASD affecting domains of 
socialization, communication, and repetitive behavior are usually observed by 3 years of 
age, although typical language development might delay identification of symptoms. 
Deficits in socialization manifest themselves as impaired use of non-verbal 
communication, delayed and reduced interactions with peers, absent sharing of 
enjoyable experiences and interest with peers, and lack of social judgment. 
Abnormalities in communication include a delay in verbal language development, 
impaired expressive language, deficient language pragmatics, as well as stereotyped, 
repetitive, or idiosyncratic use of language. Stereotyped and repetitive behavior 
manifests as a preoccupation with stereotyped or restricted interests, adherence to 
routines, rigidity, and perseverative and stereotyped behavior, motor mannerisms, and 
preoccupation or fascination with parts of items, and unusual visual exploration (Levy et 
al., 2009). In addition to these core deficits, patients with ASD suffer from a range of 
comorbid conditions, including irritability, depression or anxiety, attention deficits, 
obsessive compulsive symptoms, seizures, and sleep disruption. Functional and 
structural deficits in the brain network subserving the processing of social cues (such as 
faces and speech) and social affiliative behavior have been implicated in the core 
symptom of abnormal socialization associated with ASD. Abnormalities have been found 
in key areas including structures in the superior temporal lobe, fusiform gyrus, amygdala, 
and prefrontal cortex. At present, no pharmacological treatment exists for the core 
deficits of ASD, and currently available treatments address only associated behavioral 
problems. Non-pharmacological treatments have been developed to address the core 
symptoms; however, efficacy has not been proven in large clinical trials 
(Meyer-Lindenberg et al., 2009). Accordingly, there is a large unmet medical need for 
pharmacological treatments that target and modify these key deficits. 
The etiology of ASD is highly genetic, although environmental factors also contribute to 
the overall risk. Heritability estimates from family and twin studies suggest that about 
90% of variance can be attributed to genetic factors, making ASD the neuropsychiatric 
disorder most affected by genetic factors. The vasopressin system has been implicated 
in autism by studies of the arginine vasopressin receptor 1A (V1a) gene, which encodes 
V1a and is located on chromosome 12q (Meyer-Lindenberg et al., 2009). Both over- and 
under-transmission of specific but different alleles of this gene have been reported in 


 
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autistic individuals and are associated with specific traits. One of these risk alleles has 
been found to increase activation of the amygdala during face processing and is 
associated with increased V1a receptor messenger ribonucleic acid (RNA) levels in the 
human hippocampus post-mortem. In particular, both nonclinical and clinical research 
support a specific role for vasopressin in affiliative behavior. 
In healthy subjects, intranasal vasopressin administration has been shown to increase 
the perception of ambiguous social stimuli as threatening and to impair emotion 
recognition in males. In non-human mammals, vasopressin receptors are distributed in 
various brain regions associated with central nervous system (CNS) control of stress 
and anxiety and, more importantly in this context, with social behavior, including parental 
care, pair-bonding, social memory, and social aggression. Specifically, vasopressin has 
been implicated more in male-typical social behaviors, including aggression, pair-bond 
formation, scent marking, and courtship. Recently, vasopressin was found to affect 
social recognition and interaction in rodents via its modulatory effect on olfaction 
(Tobin et al., 2010) – a sensory modality that may also be impaired in autism (May et al., 
2011). 
In summary, evidence from both human and animal studies strongly implicates the V1a 
receptor in mediating and modulating key social behaviors that are deficient in ASD. 
Given the known negative effects of intranasal administration of vasopressin on 
emotional cognition, a V1a receptor antagonist may provide a novel and first approach to 
treat the deficits at the core of these disorders. 
Balovaptan (RO5285119) is a potent and selective human V1a receptor antagonist that 
blocks the activation of the V1a G protein-coupled receptor. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
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1.2.1 
Previous and Ongoing Clinical Studies 
To date, balovaptan has been investigated in 6 completed Phase 1 studies including a 
proof-of-mechanism study in healthy volunteers (Study BP29412). Two Phase 1 studies 
(Study WP40608, drug-drug interaction [DDI] study with rifampicin and Study WP40609, 
DDI study with itraconazole) are ongoing.  
A Phase 2 study in adult male ASD patients has been completed (Study BP28420, also 
referred to as VANILLA). A Phase 2 study in pediatric ASD patients (Study BP30153, 
also referred to as AV1ATION) and a Phase 3 study in adult ASD patients 
(Study WN39434, also known as V1aduct) are ongoing in both male and female patients. 
1.2.1.1 
Clinical Pharmacology 
Plasma exposure of balovaptan increased in a greater than dose-proportional manner 
following single doses of 0.5 to 76 mg, whereas an approximately linear increase in 
exposure was observed after repeated dosing with 12 to 52 mg once daily (QD) for 
14 days.  
Balovaptan was rapidly absorbed with a median time to maximum observed plasma 
concentration (tmax) between 1 and 4.5 hours after administration of single doses in 
fasted state and between 3 and 4 hours following multiple dosing in fed state. Steady 
state was achieved after approximately 7 days, with an accumulation of approximately 
4-fold after 12 mg QD and 2-fold after 52 mg QD; the mean apparent elimination half-life 
after the last dose (Day 14) was approximately 46 hours. Food had no relevant effect on 
the overall plasma area under the plasma concentration-time curve (AUC) of balovaptan. 
In the human mass balance study (Study BP29279), an almost complete absorption of 
the study drug was observed within the first 72 hours following administration. 
In plasma, steady state exposure to the 
 metabolite M3 was similar to or 
slightly higher than that of balovaptan and exposure to the 
 metabolite M2 
was lower than that of parent. M3 and M2 qualify as major metabolites in plasma. 
 
 
 
 
Hepatic metabolism was found to be the major pathway of elimination with the primary 
route of excretion via urine (approximately 53% of the material recovered, mostly 


 
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composed of metabolites). A further 30% of the administered dose was recovered in 
feces. The majority of excretion occurred within the first 7 days. 
There was no clinically/statistically relevant PK interaction with the P-gp substrate 
risperidone, one of only 2 approved medications for ASD symptoms in the US, and 
fluoxetine, a weak CYP3A4 inhibitor often used to treat associated symptoms of ASD. 
Administration of a single dose of balovaptan 12 mg in combination with itraconazole, a 
strong CYP3A4 inhibitor, resulted in an increase in the exposure of balovaptan by 36% 
for maximum observed plasma concentration (Cmax) and an approximately 3.1-fold 
increase for area under the concentration curve from time 0 to 120 hours (AUC0-120h). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The study will be performed in healthy subjects who will not receive any health benefit 
from participating in this study. The study is necessary for the further development of 
balovaptan and may be of benefit for future patients. The primary objective in this study 
is to assess the absolute oral bioavailability of a single dose of 10 mg balovaptan. (see 
also Section 3.3). In addition, as the PK of balovaptan may be time and dose-dependent, 
the bioavailability will be tested at steady state and at a higher dose level (50 mg). 
To date, balovaptan has been dosed to 209 healthy subjects in 6 completed Phase 1 
studies (Studies BP25694, BP28318, BP28977, BP29279, BP29412, and WP40038). 
Additionally, balovaptan was dosed to 148 adult male patients with ASD in the 
completed Phase 2 study BP28420 (“VANILLA”), about 30 of whom received 10 mg QD 
for 12 weeks. 
 
 
 
 
 
 
 
 
 
 
 
In this study WP40607, multiple doses of 10 mg or 50 mg QD balovaptan will be 
administered to healthy volunteers for no longer than 14 days. While planned dosing of 
subjects in this study has been shown to be safe and well tolerated in previous Clinical 
Pharmacology trials, diligent safety monitoring and in-house stays are included in this 
study during dosing. Subjects will be asked to report any events of feeling “not well” to 
study staff immediately.  
 
 
 
 
 
 
The safety plan is detailed in Section 5.1. 


 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the PK of balovaptan. Table 1 presents objectives and endpoints. 
Table 1 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
• To determine the absolute oral 
bioavailability of a single dose of 10 mg 
balovaptan.  
• Absolute bioavailability (F) for balovaptan at the 
indicated dose level. 
Secondary Objectives 
Corresponding Endpoints 
• To determine the absolute oral 
bioavailability of a single dose of 50 mg 
balovaptan. 
• To determine the absolute oral 
bioavailability of balovaptan after once 
daily doses of 10 mg or 50 mg for 14 days. 
• Absolute bioavailability (F) for balovaptan at the 
indicated dose level. 
 
• To characterize the dose- and 
time-dependency of the PK of oral 
balovaptan.  
• To determine plasma concentrations of 
[13C]-labeled balovaptan, balovaptan, and 
its metabolites M2, and M3, following a 
single oral dose of balovaptan 10 mg or 
50 mg together with a slow IV infusion of a 
microdose of [13C]-labeled balovaptan.  
• To determine plasma concentrations of 
[13C]-labeled balovaptan, balovaptan, and 
its metabolites M2, and M3, following once 
daily oral dosing of 10 mg or 50 mg QD for 
14 days together with a slow IV infusion of 
a microdose of [13C]-labeled balovaptan 
after the last oral dose. 
• Plasma concentrations and associated PK 
parameters for [13C]-labeled balovaptan, balovaptan, 
and its metabolites M2, and M3, including but not 
limited to Cmax, tmax, t1/2, AUClast, AUCinf, AUC0-24, 
Clast, tlast, λz, and (for [13C]-parent only) CL on Day 1 
and Day 14 and Vss on Day 1 and Day 14. 
• To evaluate the safety and tolerability of 
balovaptan 10 mg QD and 50 mg QD 
• Adverse events (AEs), clinical laboratory values, 
vital signs, electrocardiogram (ECG), and physical 
examination 
Exploratory Objectives 
Corresponding Endpoints 
• To determine whether genes relating to 
drug-metabolizing enzymes and/or drug 
transporter enzymes affect the PK and/or 
the safety profile of balovaptan.  
• The pharmacogeneticsa of metabolizing enzymes, 
transferases, transporters, etc., possibly involved in 
the absorption, distribution, metabolism and 
excretion of balovaptan and its major metabolites 
(e.g., CYP3A and P-glycoprotein). 
• 
 
 
 
• 
 
AE = adverse events; 
; CYP = cytochrome P450; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; F = bioavailability; IV = intravenous; 
PK = pharmacokinetic; QD = once daily 
a Results may be pooled with data from other studies of balovaptan and will be reported 
separately. 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This study will be a non-randomized, open-label, parallel group, two-treatment study in 
healthy volunteers to investigate the absolute oral bioavailability of balovaptan. The 
study will be conducted at 1 site in the Netherlands. 
Screening 
Screening will be conducted up to 28 days prior to admission to the clinical research 
unit (CRU).  
In-Clinic Confinement 
Subjects will be in the CRU for 2 study periods. In both periods, subjects will be 
admitted on Day -1 (the day before dosing begins). Day 1 will be the first day of dosing. 
In Period 1, subjects will be discharged on Day 10 after all assessments have been 
completed. There will be a wash-out period of 14 days between Day 1 of Period 1 and 
Day 1 of Period 2.  
Subjects will be readmitted to the CRU for a second in-house period on Day 14 of 
Period 1 (Day -1 of Period 2) to begin Period 2. Day 1 will be the first day of dosing. In 
Period 2, subjects will be discharged in the morning of Day 19.  
During the in-house stays and screening and follow-up visits, subjects will undergo 
assessments as outlined in the schedule of activities (Appendix 1), including 
assessments of AEs and concomitant medications, vital signs, electrocardiograms 
(ECGs), clinical laboratory evaluations, and blood sampling for PK evaluations. 
 
 
  
Dosing 
Two cohorts of 8 subjects each will be included in the study. The 2 cohorts will receive 
the following treatment regimens: 
Cohort 1 
Period 1: 
• Day 1: a single oral dose of 10 mg balovaptan after at least 10 hours of fasting, 
followed 1.25 hours later by a 15-minute intravenous (IV) infusion of [13C]-labeled 
balovaptan 0.1 mg. 
Period 2: 
• Day 1 to Day 14: oral doses of 10 mg balovaptan QD; on Day 7 and Day 14 study 
drug administration will take place after at least 10 hours of fasting. 
• Day 14: the final oral dosing will be followed 1.25 hours later by a 15-minute IV 
infusion of [13C]-labeled balovaptan 0.1 mg. 


 
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Cohort 2 
Period 1: 
• Day 1: a single oral dose of 50 mg balovaptan after at least 10 hours of fasting, 
followed 1.25 hours later by a 15-minute IV infusion of [13C]-labeled balovaptan 0.1 
mg. 
Period 2: 
• Day 1 to Day 14: oral doses of 50 mg balovaptan QD; on Day 7 and Day 14 study 
drug administration will take place after at least 10 hours of fasting. 
• Day 14: the final oral dosing will be followed 1.25 hours later by a 15-minute IV 
infusion of [13C]-labeled balovaptan 0.1 mg. 
Follow-up 
Subjects will return for a follow-up visit between 14 and 21 days after the last dose. 
Follow-up visit will include a physical examination (excluding height), routine safety 
laboratory tests, 12-lead ECG (single) and vital signs (systolic and diastolic blood 
pressure and pulse rate). 
Figure 1 presents an overview of the study design. A schedule of activities is provided 
in Appendix 1. 
Figure 1 Study Schema 
 
 
Period 1:  
Day -1 to Day 14a 
 
Period 2:  
Day -1a to Day 19 
 
 
Screening 
(Day -28 to 
Day -2) 
Day 1: single dose 
of 10 mg (Cohort 1) 
or 50 mg (Cohort 2) 
balovaptan, followed 
1.25 hours later by 
15-minute IV 
infusion of 
[13C]-labeled 
balovaptan 0.1 mg 
 
Day 1 to Day 14: oral 
doses of 10 mg (Cohort 1) 
or 50 mg (Cohort 2) 
balovaptan QD; on 
Day 14 the final oral dose 
will be followed 
1.25 hours later by a 
15-minute IV infusion of 
[13C]-labeled balovaptan 
0.1 mg 
 
Follow-up (14 to 
21 days after 
last dose) 
IV = intravenous; QD = once daily 
a Day 14 of Period 1 is Day -1 of Period 2 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last subject, last visit occurs, or 
safety follow-up is received from the last subject, whichever occurs later. The end of the 


 
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study is expected to occur approximately 12 weeks after the last subject is enrolled, but 
this may be longer if, for example, subjects need to be replaced. 
The total length of the study, from screening of the first subject to the end of the study, is 
expected to be approximately 15 weeks. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Open-Label Design 
The primary objective in this study is to assess the absolute oral bioavailability of a 
single dose of 10 mg balovaptan. The secondary objectives are also PK objectives. 
Drug concentrations in plasma are assumed to be objective measurements, which 
cannot be affected by volunteer or staff behavior. This is different for tolerability 
reporting, for which it is conceivable that knowing what treatment is being 
administered may affect reporting or causality interpretation. Therefore, it is generally 
accepted to conduct bioavailability studies with an open-label design, without placebo 
treatments, and since evaluation of safety and tolerability is not a primary objective of 
this study, an open-label design was deemed appropriate. 
3.3.2 
Rationale for Balovaptan Dose and Schedule 
A dose of 10 mg balovaptan has shown statistically significant changes in efficacy 
parameters in patients with ASD and is the current recommended Phase 3 dose.  
In addition, a dose of 50 mg balovaptan will be studied as well to investigate any 
dose-dependent changes in oral bioavailability. In the MAD part of study BP25694, 
multiple doses of 52 mg QD in healthy subjects were well tolerated and resulted in a 
Cmax of 484 ng/mL, 
. Thus, a dose of 
50 mg balovaptan QD is considered suitable to study dose-dependent changes in oral 
bioavailability. 
Balovaptan is being developed for use in ASD, so it is expected that patients will need to 
take it for prolonged periods of time, likely for years or for life. Hence multiple dose 
testing is relevant from a clinical point of view. The multiple dose PK of balovaptan with 
14 days of dosing was previously characterized in humans and was found to be 
time-dependent. Accumulation was observed with multiple dosing, and steady state of 
balovaptan was observed after approximately 7 days of dosing and after 10 days for M3. 
The plasma PK time course of M2 has not been closely studied but steady state has 
been demonstrated after 2 weeks of QD dosing with balovaptan 10 mg. Based on these 
observations, a dosing period of 14 days has been selected to ensure steady state 
plasma levels of balovaptan and its major metabolites M2 and M3 are reached and to 
maximize the possibility to observe any time-dependent changes in PK. 
The microdose of [13C]-labeled balovaptan has been set to 0.1 mg; 0.1 mg is the 
maximum allowed IV microdose that can be administered without IV toxicity studies. 
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data. The tmax following oral dosing in the fasted state is expected to be approximately 
1.5 hours postdose after a single dose and approximately 3 hours after multiple doses. 
To have the end of the infusion and the tmax of [13C]-labeled balovaptan coincide with the 
tmax of the orally administered unlabeled balovaptan after a single dose, the 15-minute 
infusion of the microdose of [13C]-labeled balovaptan will be started at 1.25 hours. For 
consistency the time of infusion is similar after the (last) multiple oral dose when due to 
accumulation plasma levels of balovaptan are predicted to not be lower than at tmax after 
the single dose. 
3.3.3 
Rationale for Study Population 
Healthy male or female volunteers aged 18 to 65 years inclusive have been chosen as 
the study population due to the low risk of clinically significant toxicity at anticipated 
exposure levels. Moreover, use of healthy subjects, as opposed to patients, will allow a 
clearer interpretation of the study results, as there will be no confounding factors that 
result from changes in disease state and/or concomitant medication use. 
Although volunteers aged 18 to 65 years inclusive may be included in the study, a 
minimum of 4 subjects per cohort have to be aged 18 to 50 years inclusive. This is 
considered desirable because the observation of dose-dependency of PK was made in 
previous studies enrolling volunteers aged 18 to 50 years inclusive, and is expected to 
ensure comparability of this study WP40607 to previous studies. In addition, a minimum 
of 4 subjects per cohort will be male, as ASD male patients will be the main target 
population for balovaptan.  
 
 
 
 
 
 
 
 
 
 
3.3.5 
Rationale for Genomics Assessments 
A blood sample for DNA extraction will be taken from every participant on Day -1 of 
Period 1. The DNA will be used to evaluate if genes relating to drug-metabolizing 
enzymes and/or drug transporter enzymes affect the PK and/or the safety profile of 
balovaptan.  


 
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Data may be analyzed in the context of this study but will also be explored in aggregate 
with data from other studies. 
4. 
MATERIALS AND METHODS  
4.1 
SUBJECTS 
The target population will be healthy male (at least 4 male subjects enrolled per cohort) 
and female subjects, aged 18 to 65 years, inclusive, at screening. At least 4 subjects 
enrolled per cohort should be aged 18 to 50 years, inclusive, at screening.  
A total of 8 subjects per cohort will be enrolled with the target of at least 6 subjects 
available for the primary PK analysis (i.e., having taken a single dose of balovaptan on 
Day 1 and completed all PK assessments up to Day 10). If the number of subjects 
providing PK data from the single or multiple dose parts of the study is lower than 6 for 
either cohort, more subjects may be enrolled. Enrolled subjects who withdraw from the 
study may be replaced at the discretion of the Investigator and Sponsor to ensure 
adequate numbers of evaluable subjects. 
4.1.1 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
1. 
Healthy male or female subject, aged 18 to 65 years, inclusive, at screening. 
Healthy status is defined by absence of evidence of any active or chronic 
disease following a detailed medical and surgical history, a complete physical 
examination including vital signs, 12-lead ECG, hematology, blood chemistry, 
urinalysis, and serology. 
2. 
Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive, at screening. 
3. 
For women of childbearing potential: agreement to use at least 2 acceptable 
contraceptive methods during the treatment period and for 90 days after the last 
dose of study drug. Also, total abstinence, in accordance with the lifestyle of the 
subject, is acceptable. 
• 
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state 
(≥ 12 continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal 
of ovaries and/or uterus). 
• 
The following are acceptable contraceptive methods: bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing 
intrauterine devices (IUD); copper IUD; male or female condom with or 
without spermicide (male and female condom must not be used 
simultaneously); and cap, diaphragm, or sponge with spermicide. 
• 
Hormonal contraceptive methods must be supplemented by a barrier 
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4. 
For men: agreement to use contraceptive measures, and agreement to refrain 
from donating sperm, as defined below: 
• 
With female partners of childbearing potential or pregnant female 
partners, men must remain abstinent or use a condom during the 
treatment period and for 90 days after the last dose of study drug to 
avoid exposing the embryo. Men must refrain from donating sperm 
during this same period. 
5. 
Able to participate and willing to give written informed consent and to comply 
with the study restrictions. 
6. 
Fluent in English or Dutch. 
 
4.1.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. 
Female subjects who are pregnant or lactating. 
2. 
If female of childbearing potential, a positive serum pregnancy test at screening 
or at admission to the CRU (Day -1 of each period). 
3. 
Any condition or disease detected during the medical interview/physical 
examination that would render the subject unsuitable for the study, place the 
subject at undue risk or interfere with the ability of the subject to complete the 
study in the opinion of the Investigator. 
4. 
In the opinion of the Investigator, any major illness within one month before the 
screening examination or any febrile illness within one week prior to screening 
and up to first study drug administration. 
5. 
History of any clinically significant gastrointestinal, renal, hepatic, 
broncho-pulmonary, neurological, psychiatric, cardiovascular, endocrinological, 
hematological, lymphatic, musculoskeletal, genitourinary, immunological, 
dermatological, connective tissue or allergic disease, metabolic disorder, or 
cancer.  
6. 
Signs and symptoms potentially indicative of peripheral neuropathy. 
7. 
History or evidence of any medical condition potentially altering the absorption, 
metabolism, or elimination of drugs. Surgical history of the gastrointestinal tract 
affecting gastric motility or altering the gastrointestinal tract, with the exception of 
uncomplicated appendectomy, which is allowed. 
8. 
A history of clinically significant hypersensitivity (e.g., to drugs, including 
balovaptan, and excipients) or allergic reactions. 
9. 
Known personal or family history of congenital long QT syndrome or sudden 
death. 
10. History or presence of clinically significant ECG abnormalities before study drug 
administration. 


 
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11. Subjects with screening or predose baseline mean QT interval corrected using 
Fridericia’s formula (QTcF) >450 milliseconds [msec] or <300 msec (using the 
same upper QTcF limit in both males and females). 
12. Notable resting bradycardia (mean HR <40 beats per minute [bpm]) on 
screening or predose baseline ECG. Notable resting tachycardia  on screening 
(mean HR > 90 bpm) or predose (mean HR > 100 bpm) baseline ECG. 
13. Screening or baseline ECGs with QRS and/or T-wave judged to be unfavorable 
for a consistently accurate QT measurement (i.e., neuromuscular artifact that 
cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude 
T-wave, merged T- and U-waves, prominent U-waves, etc.). 
14. Screening or baseline ECG with evidence of clinically relevant abnormalities, 
e.g. atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-Parkinson-
White Syndrome, or cardiac pacemaker. 
15. Systolic blood pressure greater than 139 or less than 90 mmHg, or diastolic 
blood pressure greater than 89 or less than 45 mmHg, based on the average of 
≥ 3 consecutive measurements. 
16. Clinically significant abnormalities in laboratory test results (including hepatic and 
renal panels, complete blood count, chemistry panel, coagulation parameters, 
and urinalysis). In the case of uncertain or questionable results, tests performed 
during screening may be repeated on Day -1 of Period 1 to confirm eligibility. 
17. History of coagulopathies, bleeding disorders, or blood dyscrasias. 
18. Subjects who have smoked within 3 months prior to first dose administration. 
19. Any clinically relevant history or any suspicion of alcohol and/or other substance 
abuse or addiction. Past alcohol and/or other substance abuse or addiction is 
also not allowed. 
20. Alcohol consumption of >24 units per week for males and females. One unit of 
alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 
1/6 gill (25 mL) of spirits.  
21. Positive urine alcohol test or urine drug screen at screening or each admission 
(Day -1 of each period) (barbiturates, benzodiazepines, methadone, 
amphetamines [including ecstasy], methamphetamines, opiates, cocaine, and 
cannabinoids). 
22. Positive result on human immunodeficiency virus (HIV)-1, HIV-2 antibodies, 
hepatitis C virus (HCV) antibody, hepatitis B virus surface antigen (HBsAg), or 
hepatitis B core (HepBc) antibody screen. 
23. Participation in an investigational drug or device study within 90 days prior to first 
dosing, or within 5 months prior to first dosing in case of a study with a biological, 
as calculated from the day of follow-up from the previous study. 
24. Any donation of blood or plasma or significant blood loss within 3 months prior to 
screening. 


 
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25. Dietary restrictions that would prohibit the consumption of standardized meals. 
26. Use of any prohibited medications OR food before study start OR subjects who 
do not agree to refrain from consuming prohibited medications or food during the 
study (see Section 4.4). 
27. Subjects likely to need concomitant medication during the study (including for 
dental conditions). 
28. Subjects who have received any prescribed systemic or topical medication within 
4 weeks (or within 5 times the elimination half-life of the medication, whichever is 
longer) of the first dose administration, unless in the opinion of the Investigator 
the medication will not interfere with the study procedures or compromise safety, 
and subjects who have received slow release medicinal formulations considered 
to still be active within 4 weeks (or within 5 times the elimination half-life of the 
medication, whichever is longer) of the first dose administration will also be 
excluded unless in the opinion of the Investigator the medication will not interfere 
with the study procedures or compromise safety. 
29. Used the following within 7 days before the first study drug administration, unless 
in the opinion of the Investigator the medication will not interfere with the study 
procedures or compromise safety: 
• 
any non-prescribed systemic or topical medication 
• 
herbal remedies. 
Paracetamol (up to 4 g within 7 days before study drug administration and 
2 g/day within 48 hours before study drug administration), dietary supplements, 
vitamins and minerals, hormonal contraceptives and hormone replacement 
therapy are allowed. 
30. Received any medications known to chronically alter drug absorption or 
elimination processes within 4 weeks before the first study drug administration, 
unless in the opinion of the Investigator the medication will not interfere with the 
study procedures or compromise safety. 
31. Use of any drugs or substances, including herbal treatments such as St John’s 
Wort, that are known to be substrates, inducers, or inhibitors of CYP3A4 within 
4 weeks before the first study drug administration. 
32. Subjects under judicial supervision, guardianship or curatorship. 
33. Poor venous access for blood sampling.  
34. Subjects who have previously taken part in or withdrawn from this study. 
35. Subjects who are unwilling to practice safe sex (use male or female condom) for 
the duration of the study. 


 
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36. 
 
  
• 
 
 
  
• 
 
 
 
• 
 
37. Significant risk for suicidal behavior, in the opinion of the Investigator. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This study will be a non-randomized, single-center, open-label, parallel group, 
2-treatment study. Each subject will receive 1 treatment, depending on the cohort in 
which they participate. 
Subjects who have met all eligibility criteria will receive a subject number upon inclusion 
in the study (subject numbers: 01 - 16; 01 to 08 for Group 1 and 09 to 16 for Group 2). 
Subject numbers will be allocated sequentially in the order in which the subjects are 
enrolled. The subject number will ensure identification throughout the study. 
Replacement subjects (if needed) will receive the number of the subject to be replaced, 
increased by 100 (e.g., 101 replacement number for subject number 01), and will be 
administered the same treatments in the same order. 
Subjects who drop out or withdraw for any reason without completing all screening 
evaluations successfully, will be considered “screening failures”. Such subjects will not 
receive a subject number. The Investigator will keep a screening log of all subjects 
screened in order to assess the numbers and characteristics of the excluded subjects, 
and the reasons for their exclusion. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are balovaptan (unlabeled; 
for oral administration) and [13C]-labeled balovaptan (for IV infusion). 


 
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4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Balovaptan 
RO5285119/F17 10 mg dispersible film-coated tablets will be supplied by the Sponsor in 
high-density polyethylene bottles. For information on the formulation and handling of 
balovaptan, see the Investigational Medicinal Product Dossier. 
4.3.1.2 
[13C]-Labeled Balovaptan  
The [13C]-labeled balovaptan drug substance will be supplied by the Sponsor. 
RO5285119/F40 [13C]-labeled balovaptan solution (20 µg/ml)  for IV infusion will be 
prepared by the site. For information on the formulation and handling of [13C]-labeled 
balovaptan, see the Investigational Medicinal Product Dossier.  
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF). Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF. 
Guidelines for treatment interruption or discontinuation for subjects who experience AEs 
are provided in Section 5.1. 
4.3.2.1 
Balovaptan (Oral Administration)  
An oral dose of balovaptan 10 mg (Cohort 1) or 50 mg (Cohort 2) will be administered in 
the morning of Day 1 of Period 1 and each morning of Days 1 to 14 of Period 2. On Days 
1 of Period 1 and Days 7 and 14 of Period 2, study drug administration will be after an 
overnight fast of at least 10 hours, followed by another 4 hours of fasting until lunch. On 
the other dosing days, study drug administration will take place at least 30 minutes 
before breakfast. Water will be allowed ad libitum until 1 hour prior to dosing and from 
1 hour post dosing, and a maximum of 3 liters a day. 
Study drug will be swallowed whole with 240 mL of still water. 
4.3.2.2 
[13C]-Labeled Balovaptan 
On Day 1 of Period 1 and on Day 14 of Period 2, a single microdose of [13C]-labeled 
balovaptan 0.1 mg will be administered by a 15-minute constant IV infusion. The IV 
infusion will start 1.25 hours after administration of the oral dose of unlabeled balovaptan 
on Day 1 of Period 1 and Day 14 of Period 2.  
Details on study drug preparation by the PRA Health Sciences (PRA) pharmacy will be 
described in the Manufacturing Batch Record, which will be prepared by the PRA 
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4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (balovaptan tablets and the [13C]-labeled 
balovaptan drug substance for IV infusion) will be provided by the Sponsor where 
required by local health authority regulations. The study site will acknowledge receipt of 
IMPs supplied by the Sponsor by returning the appropriate documentation form to 
confirm the shipment condition and content. Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or be returned to the Sponsor (if supplied by the 
Sponsor) with the appropriate documentation. The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor. The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Accountability Form and Drug Dispensing 
Form. 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a subject in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the study completion/ discontinuation visit. All such 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications eCRF.  
4.4.1 
Permitted Therapy  
Existing hormonal contraceptives and hormone replacement therapy regimens must 
remain unchanged during the conduct of the study. However, women of childbearing 
potential must agree to combine hormonal contraceptive methods with a barrier method 
for 90 days after the last dose of study drug. Also, total abstinence, in accordance with 
the lifestyle of the subject, is acceptable. 
Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours 
prior to dosing and during the in-house portion of the study, but total should not exceed 
4 g total during the week prior to dosing. Subjects will be instructed not to exceed these 
limits. 
4.4.2 
Prohibited Therapy 
Any prescribed systemic or topical medication within 4 weeks (or within 5 times the 
elimination half-life of the medication, whichever is longer) prior to the first study drug 
administration through the follow-up visit, or any slow release medicinal formulations 
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the medication, whichever is longer) prior to the first study drug administration are 
prohibited through the follow-up visit, unless in the opinion of the Investigator the 
medication will not interfere with the study procedures or compromise safety.  
Any non-prescribed systemic or topical medication or herbal remedies are prohibited 
for 7 days prior to the first study drug administration through follow-up.  
This is with the exception of medications to treat AEs, unless the rationale for the 
exception is discussed and clearly documented between the Investigator, the medical 
and safety monitor and the Roche clinical pharmacologist, and with the exception of 
permitted therapies per Section 4.4.1. All medication administered to manage AEs 
should be recorded on the Adverse Event Report Form. 
The following concomitant medications in particular are prohibited, unless an exception 
has been agreed to as mentioned above: 
• 
Any inhibitor of CYP3A taken within 4 weeks (or within 5 half-lives, whichever is 
longer) prior to study drug administration, including but not limited to the 
following drugs: ketoconazole, miconazole, itraconazole, fluconazole, 
erythromycin, clarithromycin, ranitidine, and cimetidine, until follow-up. 
• 
Any inducer of CYP3A taken within 4 weeks (or within 5 half-lives, whichever is 
longer) prior to study drug administration, including but not limited to the 
following drugs: rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, 
phenobarbital, and St. John’s wort, until follow-up. 
• 
Investigational drug or medical device therapy (other than protocol-mandated 
study treatment) is prohibited 90 days prior to first dosing, or within 5 months 
prior to first dosing in case of a study with a biological, as calculated from the 
day of follow-up from the previous study of study treatment and during study 
treatment. 
 
4.4.3 
Prohibited Food 
Use of the following foods is prohibited as described below: 
• 
Consumption of methylxanthine-containing products (e.g., coffee, tea, cola, 
chocolate) will be forbidden from 24 hours prior to balovaptan dosing and during the 
stays in the CRU. 
• 
It is not permitted to take any nutrients known to modulate cytochrome CYP3A 
activity (e.g., grapefruit or grapefruit juice; Seville orange) within 2 weeks prior to 
first dosing until discharge from the CRU in Period 2. 
• 
Subjects should refrain from consumption of any foods containing poppy seeds 
within 48 hours (2 days) prior to screening and each admission to the CRU to avoid 
false positive drug screen results. 
 
4.4.4 
Additional Restrictions/Considerations 
• 
Subjects should have fasted for at least 4 hours prior to the screening visit, each 
admission to the CRU, and the follow-up visit. 


 
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• 
Water will be allowed ad libitum except for 1 hour before and 1 hour after oral 
dosing on Day 1 of Period 1 and Days 7 and 14 of Period 2. The excessive 
consumption of fluids (greater than 3 liters per day) should be avoided. 
• 
On Day 1 of Period 1 and Days 7 and 14 of Period 2, oral balovaptan will be 
administered after an overnight fast of at least 10 hours. In addition, fasting will be 
continued until at least 4 hours post oral dose. On these days, standardized meals 
will be served to all subjects at the times noted in Appendix 1. On these days a 
standardized lunch, afternoon snack, dinner, and evening snack will be served at 
similar times of the day, and subjects will be required to complete the meal.  
 
On dosing days other than Day 1 of Period 1 and Days 7 and 14 of Period 2, oral 
balovaptan will be administered at least 30 minutes prior to breakfast. On these 
dosing days, meals will not be standardized.  
 
During the remainder of the in-house periods, breakfast, lunch, dinner, and 
afternoon/evening snacks will be provided according to PRA standards. 
• 
Between the screening visit and follow-up, alcohol must be restricted to no more 
than 2 units per day (1 unit of alcohol equals ½ pint (285 mL) of beer or lager, 
1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits). Alcohol consumption will not 
be allowed 48 hours before balovaptan dosing and while staying in the CRU. 
Random alcohol/drugs of abuse testing may be employed throughout the study to 
verify compliance. 
• 
Subjects should refrain from strenuous exercise for at least 96 hours prior to first 
dosing until follow-up. Light ambulatory activities will be permitted, with the level of 
activities kept as similar as possible on all days in the CRU. 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities must be performed and documented for each subject.  
Subjects will be closely monitored for safety and tolerability throughout the study.  
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Informed 
Consent Forms (ICFs) for enrolled subjects and for subjects who are not subsequently 
enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that subjects meet 
all eligibility criteria before enrollment. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


 
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4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, 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. In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the subject within 14 days prior 
to initiation of study treatment will be recorded. At follow-up, any changes in medications 
and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and at follow-up visits, should 
include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; 
complaint-driven genitourinary examination may be performed. Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in subject notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the Adverse Event eCRF. 
Height, weight and BMI will be determined at screening. Weight measurements will be 
repeated on the days indicated in Appendix 1. 
4.5.4 
Vital Signs 
Body temperature (tympanic), blood pressure, and pulse rate measurements will be 
collected on the days indicated in Appendix 1. Blood pressure and pulse rate 
measurements will be performed after the subject has rested in a supine position for at 
least 5 minutes. 
4.5.5 
Laboratory, Pharmacokinetic, and Other Biological Samples 
For sampling and sample processing procedures, storage conditions, and shipment 
instructions, see the laboratory manual. 
Biological samples will be destroyed when the final clinical study report (CSR) has been 
issued, except where specified otherwise. 
When a subject withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the subject specifically requests that the 
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samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.5.1 
Laboratory Samples 
Laboratory samples will be collected at the time points indicated in Appendix 1. 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor subject safety. 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
• 
Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, absolute 
and percent differential WBC count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes). 
• 
Coagulation: prothrombin time (International Normalized Ratio [INR]) and activated 
thromboplastin time (aPTT). 
• 
Blood chemistry panel: sodium, potassium, chloride, bicarbonate, glucose 
(fasting), urea, creatinine, total protein, albumin, phosphate, calcium, total and 
conjugated bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), CPK, 
lactate dehydrogenase (LDH). 
• 
Urinalysis: A midstream, clean-catch urine specimen will be collected for dipstick 
analysis of pH, glucose, leukocytes, nitrites, protein and blood. Microscopy will be 
performed if abnormalities are observed and if deemed necessary by the 
Investigator or designee, in particular when blood or protein is positive or strong 
positive. If there is an explanation for the positive dipstick result, it should be 
recorded, and there is no need to perform laboratory for microscopy and culture. 
• 
Drugs of abuse (including cannabinoids, amphetamines [including ecstasy], 
methamphetamines, opiates, methadone, cocaine, benzodiazepines, and 
barbiturates), alcohol and cotinine will be measured in urine at screening and each 
admission to the CRU (Day -1 and Day 14). 
• 
Viral serology: HIV-1 and HIV-2 antibodies, HBsAg, HepBc-antibody and HCV 
antibody at screening only. 
• 
Pregnancy test: follicle-stimulating hormone (FSH) and beta-human chorionic 
gonadotropin (serum pregnancy test) will be performed at screening in all females. 
At other time points, a serum pregnancy test will be performed in all females. 
4.5.5.2 
Pharmacokinetic Blood Samples 
Pharmacokinetic samples will be taken via an indwelling catheter or by direct 
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Plasma samples for PK analysis will be shipped to designated bioanalytical laboratories 
for analysis. 
Plasma samples collected for PK analysis will be destroyed 6 months after the final CSR 
has been issued. 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.5.4 
Clinical Genotyping Samples 
A mandatory whole blood sample will be taken for DNA extraction from every subject 
during the study on Day -1 of Period 1. The DNA may be used to determine whether 
genes relating to drug-metabolizing enzymes and/or drug transporter enzymes affect the 
PK and/or the safety profile of balovaptan. Genotyping samples will be sent to the 
Sponsor or a designee for analysis. This specimen will be destroyed no later than 2 
years after the final CSR has been issued. 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This number is used 
to code the samples. Subject names are not included in samples that are sent for 
analysis. 
4.5.6 
Electrocardiograms 
Triplicate ECGs will be collected at the time points indicated in Appendix 1. 
Electrocardiograms will be collected after the subject has rested in a supine position for 
at least 5 minutes. 
Time of the assessments will be recorded directly in the eCRF. The ECG will be judged 
by the Investigator and the judgment documented directly on the ECG printout, which 
will be kept as a source document and added to the study record. The following ECG 
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(Fridericia's), T-wave and U-wave, and the interpretation of the ECG profile by the 
Investigator. 
4.5.7 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinical tool used to assess 
the lifetime suicidality of a subject (C-SSRS lifetime version) as well as any new 
instances of suicidality (C-SSRS since last visit). 
The structured interview prompts recollection of suicidal ideation, including the intensity 
of the ideation, behavior, and attempts with actual/potential lethality. 
The C-SSRS assessments will be completed by the Investigator or Research Physician 
at the time points as specified in Appendix 1. 
4.5.8 
Drug and Metabolite Concentration Measurements 
Plasma 
 concentrations of balovaptan and its metabolites M2 
, 
and M3 
 will be measured using separate specific and validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) methods.  
Plasma concentrations of [13C]-labeled balovaptan will be measured using another 
specific and validated LC-MS/MS method. 
4.5.9 
Timing of Study Assessments 
If performed at the same timepoint, assessments should be prioritized as follows, while 
ensuring PK blood sampling is conducted at the scheduled time: 
• 
12-lead ECGs 
• 
Vital signs measurements 
• 
 
• 
PK blood sampling 
• 
Laboratory safety tests, clinical genotyping sample and urine collection 
• 
Study drug administration 
• 
Provide standard meal 
4.6 
TREATMENT, SUBJECT, STUDY, AND SITE 
DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Subjects must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the subject’s safety if he or she continues to receive study treatment (see 


 
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Section 5.1.2 for additional guidance on the management of toxicities and of 
subjects who experience AEs) 
• 
Investigator or Sponsor determines it is in the best interest of the subject 
• 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Subjects who discontinue study treatment prematurely may be 
replaced. 
Subjects will return to the CRU for a follow-up visit 14 to 21 days after the last dose of 
study drug (see Appendix 1 for additional details). 
4.6.2 
Subject Discontinuation from Study 
Subjects will return to the CRU for a follow-up visit 14 to 21 days after the last dose of 
study drug. 
Subjects have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the Investigator has the right to withdraw a subject from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Subject withdrawal of consent 
• 
Study termination or site closure 
• 
Subject non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator or Sponsor 
Every effort should be made to obtain information on subjects who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents. Subjects who withdraw from the study 
may be replaced. The decision regarding the replacement of subjects will be 
documented. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
• 
Subject enrollment is unsatisfactory 
 
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4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice (GCP) 
• 
No study activity (i.e., all subjects have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Balovaptan is not approved, and clinical development is ongoing. The safety plan for 
subjects in this study is based on clinical experience with balovaptan in completed and 
ongoing studies. Potential safety risks for balovaptan are outlined below. Please refer to 
the RO5285119 (balovaptan) IB for a complete summary of safety information. 
Several measures will be taken to ensure the safety of subjects participating in this study. 
Eligibility criteria have been designed to exclude subjects at higher risk for toxicities. 
Subjects will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of AEs. In addition, guidelines for managing AEs, 
including criteria for treatment interruption or discontinuation, are provided below. 
Treatment will be discontinued in any subject with a medical condition that the 
Investigator or Sponsor determines may jeopardize the subject’s safety if he or she 
continues to receive study treatment. 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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5.1.2 
Management of Toxicities and of Subjects Who Experience 
Adverse Events 
5.1.2.1 
Management Guidelines 
In general, any emerging AEs must diligently be watched, treated as medically indicated 
according to common medical practice and documented in terms of onset-date, intensity, 
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No specific treatment guidance to any potentially emerging AEs in balovaptan clinical 
trials exist and treatment should be according to the common medical practice for the 
given AE. 
The Investigator should also consider discontinuation of treatment with balovaptan, in 
particular in case an AE is of severe intensity and considered to be possibly related to 
balovaptan. 
Temporary dosing interruptions must be discussed with the Sponsor’s Medical Monitor in 
the sense that temporary interruptions will have to be very limited in order to not 
jeopardize the trial’s PK objectives. Dose modifications because of an AE are not 
allowed in this study. 
 
 
 
 
  
 
 
 
 
 
 
 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AEs of special interest, performing protocol-specified safety laboratory assessments, 
measuring protocol-specified vital signs, and conducting other protocol-specified tests 
that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of 
causal attribution. An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 for more 
information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death) 
This does not include any AE that, had it occurred in a more severe form or was 
allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 




 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6. 
For each AE recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each subject contact. All AEs, whether 
reported by the subject or noted by study personnel, will be recorded in the subject’s 
medical record and on the Adverse Event eCRF (and Form, if appropriate). 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported (see Section 5.4.2 for instructions for 
reporting SAEs). 
After initiation of study drug, all AEs will be reported until up to 21 days after the last 
dose of study drug. 
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject evaluation timepoints. Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 2 provides guidance for assessing AE severity. 


 
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Table 2 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly. 
The following guidance should be taken into consideration (see also Table 3): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 3 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
(RELATED) 
There is a plausible temporal relationship between the onset of the adverse 
event and administration of the study drug, and the adverse event cannot be 
readily explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies; and/or the adverse event follows a known pattern of 
response to the study drug; and/or the adverse event abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, 
reappears upon re-challenge. 
NO (NOT 
RELATED) 
An adverse event will be considered related, unless it fulfills the criteria 
specified below.  
Evidence exists that the adverse event has an etiology other than the study 
drug (e.g., preexisting medical condition, underlying disease, intercurrent 
illness, or concomitant medication); and/or the adverse event has no 
plausible temporal relationship to administration of the study drug (e.g., 
cancer diagnosed 2 days after first dose of study drug). 


 
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For subjects receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction). 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For AEs other than infusion-related reactions (see Section 5.3.5.1), 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 AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, AEs 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 AE 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 3 events should be reported 
separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 


 
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All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation timepoints. Such events should only be recorded once on the Adverse Event 
eCRF (and Form, if appropriate). The initial severity (intensity or grade) of the event will 
be recorded at the time the event is first reported. If a persistent AE becomes more 
severe, the most extreme severity should also be recorded on the Adverse Event eCRF 
(and Form, if appropriate). If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions). The Adverse Event eCRF if already 
completed 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 SAEs. 
A recurrent AE is one that resolves between subject evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF (and Form if appropriate). 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the Investigator’s judgment  
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF (and Form if 
appropriate). 
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 (and Form if 
appropriate), 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 


 
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the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, an elevated 
serum potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent AEs). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the Investigator’s judgment  
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF (and Form if appropriate). 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent AEs). 
5.3.5.7 
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 AE the occurrence of 
either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a SAE or an AE of special interest (see Section 5.4.2). 


 
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5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the AE reporting period should be reported as described in 
Section 5.6. 
5.3.5.9 
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 AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE 
in Section 5.2.2), except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or an SAE: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The subject has not experienced an AE 


 
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An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead: 
• 
Hospitalization that was necessary because of subject requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs (defined in Section 5.2.2; see Section 5.4.2 for details on reporting 
requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
• 
Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements) 
 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and Institutional Review Board (IRB)/Ethics Committee (EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information: 
Medical Monitor: 
, M.D. (Primary) 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Medical
 
Monitor:
 
, M.D.
 
(Secondary)
 
Telephone No.: 
 
Mobile Telephone No.: 
 


 
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To ensure the safety of study subjects, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the Investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls. The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week. Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible contact information, will be distributed to all 
Investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported. The paper Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
Investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
Investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, SAEs and AEs of special interest will be reported until 
21 days after the last dose of study drug. Investigators should record all case details that 
can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form provided to investigators and submitting the report, either by faxing or by scanning 
and emailing the form using the fax number or email address provided to investigators. 
Instructions for reporting SAEs that occur > 21 days after the last dose of study treatment 
are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Subjects 
Female subjects of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 90 days after the last 
dose of study drug. A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to Investigators. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel
 
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possible effects on the fetus. Monitoring of the subject should continue until conclusion 
of the pregnancy. Any SAEs associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF. In addition, the 
Investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
5.4.3.2 
Pregnancies in Female Partners of Male Subjects 
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant during the study or within 90 days after the last dose of 
study drug. A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to Investigators. Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male subject exposed to study drug. When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy. If the authorization has been signed, 
the Investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. An 
Investigator who is contacted by the male subject or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see  
Section 5.4.2).  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female subject exposed to study 
drug or the female partner of a male subject exposed to study drug should be classified 
as a SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
• 
Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose 


 
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• 
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. 
 
Special situations are not in themselves AEs, but may result in AEs. All special situations 
associated with balovaptan, regardless of whether they result in an AE, should be 
recorded on the Adverse Event eCRF (and Form if appropriate) and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). Special 
situations should be recorded as described below: 
• 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
• 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details. 
Each AE associated with a special situation should be recorded separately on the 
Adverse Event eCRF. If the associated AE fulfills seriousness criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 ). For balovaptan, adverse events associated with special 
situations should be recorded as described below for each situation: 
• 
Accidental overdose: Enter the AE term. Check the "Accidental overdose" and 
"Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the AE term. Check the 
"Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the AE term. Check the 
"Accidental overdose" and "Medication error" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require the 
completion of 2 Adverse Event eCRF pages (and Forms if appropriate), one to report the 
accidental overdose and one to report the headache. The "Accidental overdose" and 
"Medication error" boxes would need to be checked on both eCRF pages. 
5.5 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the subject is lost to follow-up, 


 
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or the subject withdraws consent. Every effort should be made to follow all SAEs 
considered to be related to study drug or trial-related procedures until a final outcome can 
be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the subject’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For SAEs, AEs of special interest, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, email, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g., from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the Investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 21 days after the last dose of 
study drug), if the event is believed to be related to prior study drug treatment. The 
Investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to Investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and AEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document: 
• 
RO5285119 (Balovaptan) IB. 
 
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. 


 
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Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
A statistical analysis plan will be generated by the biostatistics department of PRA and 
will be finalized prior to database lock. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This is an exploratory study for which no formal statistical hypothesis will be tested, and 
therefore the sample size is chosen to estimate the absolute bioavailability of the 10 mg 
single dose with sufficient precision. 
A total of 8 subjects per cohort are to be enrolled with the target of at least 6 subjects 
available for the primary PK analysis (i.e., having taken a single dose of 10 mg on Day 1 
and completed all PK assessment up to Day 10). If the number of subjects providing PK 
data from the multiple dose parts of the study is lower than 6 for either cohort more 
subjects may be enrolled. 
Assuming a within-subject variability of around 35% it can be estimated that with 
6 subjects the half-width of the 90% confidence interval (CI) for the ratio of geometric 
means of the microdose IV kinetics with that from the oral dose (i.e. CL versus CL/F) 
would be obtained by dividing/multiplying the ratio estimate by a factor of 1.50. 
The within-subject variability value of around 35% has been identified as a reasonable 
assumption: it is smaller than the observed 42% between-subject variability for the 
apparent clearance of distribution (CL/F) from a single oral 10 mg dose in study 
WP40038, and it considers that the reference will be obtained from IV kinetics, which is 
expected to be less variable than oral kinetics.  
Table 4 
Precision Factor Estimates 
Number of Subjects  
Variability 
Precision Factor 
6 
30% 
1.42 
 
35% 
1.50 
 
40% 
1.59 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of subjects who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study withdrawal will be listed and summarized. 
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results. 


 
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6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate. Summaries will be presented overall and by cohort. 
6.4 
EFFICACY ANALYSES 
Not applicable. 
6.5 
SAFETY ANALYSES 
All subjects who have received at least one dose of balovaptan, whether prematurely 
withdrawn from the study or not, will be included in the safety analysis. 
The safety data, including AEs, laboratory data, and vital signs, will be listed and 
summarized by treatment. Reasons for withdrawal from study will be listed and 
summarized. Concomitant medications, 12-lead ECG data and clinically significant 
neurological examinations will be listed. For laboratory and 12-lead ECG data, subject 
listings will be presented with abnormalities flagged. 
Adverse events will be listed and summarized by treatment, body system and preferred 
term using the Medical Dictionary for Regulatory Activities (MedDRA). All verbatim AE 
terms will be mapped to MedDRA thesaurus terms, and AE severity will be graded 
according to Table 2. 
6.6 
PHARMACOKINETIC ANALYSES 
Subjects will be excluded from the PK analysis population if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from the protocol, or if data are 
unavailable or incomplete. Excluded cases will be documented together with the reason 
for exclusion. All decisions on exclusions from the analysis will be made prior to 
database closure. 
Individual plasma 
 concentrations at each sampling time point for balovaptan, 
M2, and M3, and individual plasma [13C]-labeled balovaptan concentrations will be 
presented by listings and descriptive summary statistics by treatment, including means, 
geometric means, ranges, standard deviations and coefficients of variation. Individual 
and mean concentration versus time will be plotted on semi-logarithmic scales. 
The primary PK parameter is absolute bioavailability (F) for balovaptan following a single 
10 mg dose.  
The following plasma PK parameters will be estimated for balovaptan, M2, M3, and 
[13C]-labeled balovaptan: 
• 
Cmax: 
Maximum observed plasma concentration 


 
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• 
tmax: 
Time to maximum observed plasma concentration 
• 
t1/2: 
Apparent terminal half-life 
• 
AUClast: Area under the plasma concentration-time curve from time zero to the last 
measurable plasma concentration time point (following a single oral dose) 
• 
AUCinf: Area under the plasma concentration-time curve form time zero 
extrapolated to infinity (following a single dose) 
• 
AUC0-24: Area under the plasma concentration-time curve over the dosing interval at 
steady state 
• 
Clast: 
Last measurable plasma concentration 
• 
Ctrough: 
Concentration measured at the end of the dosing interval 
• 
tlast: 
Time of last measurable plasma concentration 
• 
λz: 
Terminal elimination rate constant 
• 
RAUC:  
Accumulation ratio for AUCτ (Day 14 AUC0-τ / Day 1AUC0-τ) 
• 
RCmax:  
 Accumulation ratio for Cmax (Day 14 Cmax / Day 1Cmax) 
• 
RCtrough:  Accumulation ratio for Ctrough (Day 14 Ctrough / Day 1 Ctrough) 
 
The following plasma PK parameters will be estimated for the parent compound 
balovaptan: 
• 
F: 
Absolute bioavailability 
• 
CL: 
Total body clearance (IV administration only) 
• 
Vss:  
Volume of distribution 
 
plasma concentration ratios will be calculated for balovaptan, M2, and M3, as 
applicable. 
Additional PK parameters may be derived if deemed necessary. 
All PK parameters will be presented by individual listings and summary statistics by 
treatment including arithmetic means, geometric means, medians, ranges, standard 
deviations and coefficients of variation.  
6.7 
Genotyping ANALYSES 
The relationship between CYP3A4 genotype and steady state balovaptan exposure will 
be evaluated. Other isoforms may also be analyzed. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study. The contract research 
organization (CRO), PRA, will be responsible for data management of this study, 
including quality checking of the data. Data entered manually will be collected via 
electronic data capture (EDC) through use of eCRFs. Sites will be responsible for data 
entry into the EDC system. In the event of discrepant data, PRA will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system. 
PRA will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. Central laboratory data will be sent directly to the PRA, using the 
PRA’s standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the PRA’s data management plans and specifications. Data will be 
periodically transferred electronically from PRA to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.  
Electronic CRFs and correction documentation will be maintained in the EDC system’s 
audit trail. System backups for data stored at the CRO and records retention for the 
study data will be consistent with the CRO’s standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS  
The eCRF design will be performed with the computer program Oracle Clinical (Oracle, 
Redwood Shores, Redwood City, CA, USA) by the Database Programming Department 
of PRA. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which subject data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subject-reported outcomes, 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
67/Protocol WP40607, Final Version 1.0 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
subject files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the Investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review. The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper subject-reported data (if applicable), ICFs, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer. After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
68/Protocol WP40607, Final Version 1.0 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting). Studies 
conducted in the US or under a US Investigational New Drug (IND) application will 
comply with US Food and Drug Administration (FDA) regulations and applicable local, 
state, and federal laws. Studies conducted in the European Union (EU) or European 
Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs such as a Child’s Informed 
Assent Form or Mobile Nursing ICF, if applicable) will be provided to each site. If 
applicable, it will be provided in a certified translation of the local language. The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 
sample ICFs or any alternate consent forms proposed by the site (collectively, the 
"Consent Forms") before IRB/EC submission. The final IRB/EC−approved Consent 
Forms must be provided to the Sponsor for health authority submission purposes 
according to local requirements. 
If applicable, the ICF will contain separate sections for any optional procedures. The 
Investigator or authorized designee will explain to each subject the objectives, methods, 
and potential risks associated with each optional procedure. Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any 
reason. A separate, specific signature will be required to document a subject's 
agreement to participate in optional procedures. Subjects who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes. 
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 


 
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69/Protocol WP40607, Final Version 1.0 
Consent Forms, the case history or clinical records for each subject shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the subject or the subject’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the subject, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated. In addition, any 
subject recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that 
subject names are not included in data sets that are transmitted to any Sponsor location. 
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the subject, unless permitted or 
required by law. 
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study Investigators or 
subjects unless required by law. The aggregate results of any conducted research will 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
70/Protocol WP40607, Final Version 1.0 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. In 
addition, at the end of the study, the Investigator will receive the subject data, including 
an audit trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The Investigator should document and explain any protocol deviations. The Investigator 
should promptly report any deviations that might have an impact on subject safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities. As per the Sponsor's SOPs, prospective requests to deviate from the 
protocol, including requests to waive protocol eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs. The Investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor has contracted PRA, 
who will be delegated responsibility for various aspects of this clinical trial. 


 
Balovaptan—F. Hoffmann-La Roche Ltd 
71/Protocol WP40607, Final Version 1.0 
One site will participate to enroll 16 subjects. 
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests and PK analyses), as specified in Section 4.5. Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR. In addition, for all clinical trials in subjects involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation. This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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72/Protocol WP40607, Final Version 1.0 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by PRA. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes to the study conduct, except for 
changes necessary to eliminate an immediate hazard to subjects or changes that involve 
logistical or administrative aspects only (e.g., change in Medical Monitor or contact 
information). 


 
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73/Protocol WP40607, Final Version 1.0 
10. 
REFERENCES 
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 
5th ed. Washington, DC: American Psychiatric Association, 2013. 
Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 
Principal Investigators; Centers for Disease Control and Prevention (CDC). 
Prevalence of autism spectrum disorder among children aged 8 years – Autism 
and Developmental Disabilities Monitoring Network, 11 sites, United States, 2010. 
MMWR Surveill Summ. 2014;63(2):1-21. 
Levy SE, Mandell DS, Schultz RT: Autism. Lancet. 2009;374:1627–38. 
May T, Brewer WJ, Rinehart NJ, et al. Differential olfactory identification in children with 
autism and Asperger’s disorder: a comparative and longitudinal study. J Autism 
Dev Disord. 2011;41(7):837–47. 
Meyer-Lindenberg A, Kolachana B, Gold B, et al. Genetic variants in AVPR1A linked to 
autism predict amygdala activation and personality traits in healthy humans. Mol 
Psychiatry. 2009;14(10):968–75. 
Tobin VA, Hashimoto H, Wacker DW, et al. An intrinsic vasopressin system in the 
olfactory bulb is involved in social recognition. Nature. 2010;464(18):413-9. 


Balovaptan—F. Hoffmann-La Roche Ltd
74/Protocol WP40607, Final Version 1.0
Appendix 1
Schedule of Activities
Assessments
Screening
Period 1
(Single Dose)
Period 2
(Multiple Doses)
Follow-up
Day
-28 to -2
-1
1
2 to 10
-1
1 to 14
15 to 19
28 to 35
Resident at study centera
X
X
Written informed consent
X
Inclusion and exclusion criteria
X
Demographics
X
Medical history
X
Medication history
X
Blood sampling for CG
X
Study drug: oral administration 
X
X
Study drug: IV administrationb
X
X
Standardized mealsc
X
X
PK samplingd
X
X
X
X
Physical examination and 
measurement of body weight
Xf
X
X
X (D11)
X (D18)
X
C-SSRS
X
X
X (D18)
12-lead ECGg
X
X
Xg
X
X (D6, D11)
X (D18)
X
Vital signsh
X
X
X
X (D2, D5)
X
X (D1, D7, 
D14)
X (D18)
X
Urine drug screen including alcohol
X
X
X
Serology
X
Pregnancy testi
X
X
X
X
Hematologyj
X
X
X
X (D6, D11)
X (D18)
X
Biochemistryk
X
X
X
X (D11)
X (D18)
X
Urinalysis
X
X
X
X
Coagulationl
X
X (D11)l
X (D18)l
X
AE monitoring
Review concomitant medications


Appendix 1  
Schedule of Activities (cont.) 
Balovaptan—F. Hoffmann-La Roche Ltd 
75/Protocol WP40607, Final Version 1.0 
AE = adverse event; BMI = body mass index; CG = clinical genotyping; CRU = clinical research unit; 
; C-SSRS = 
Columbia-Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; FSH = follicle-stimulating hormone; IV = intravenous; PK = 
pharmacokinetic. 
 
a Subjects will be admitted to the CRU on Day -1 and will be allowed to leave when all assessments on Day 10 have been completed. Subjects 
will return in the afternoon of Day 14 of Period 1 (which is also Day -1 of Period 2) and will be allowed to leave when all assessments on Day 19 
have been completed. 
b The IV infusion of the microdose will start 1.25 hours after the oral study drug administration on Day 1 of Period 1 and Day 14 of Period 2. 
c On Day 1 of Period 1, and Days 7 and 14 of Period 2, subjects are fasted for at least 10 hours prior to dosing. Water will be allowed ad libitum 
until 1 hour prior to dosing and from 1 hour after dosing. No food is allowed for at least 4 hours postdose. Standardized lunch and dinner are 
provided 4 and 10 hours postdose, respectively, on Day 1 of Period 1, and Days 7 and 14 of Period 2. Standardized afternoon and evening 
snacks will be provided as well on these days.  
On the other dosing days in the multiple dosing period, subjects will be dosed at least 30 minutes prior to breakfast. On these dosing days, 
meals will not be standardized. 
d All PK sampling times are relative to oral dosing (see also Appendix 2). 
 
f Includes measurement of height and BMI. 
g Triplicate ECGs will be collected at screening and Day -1 of Period 1 only. At all other time points a single ECG will be collected (Period 1: 
Day 10; Period 2: Day -1 of Period 2; predose on Days 6 and 11; Day 18 (96 hours after last dosing); follow-up). 
h Vital signs will be measured at screening (in triplicate), and in Period 1: on Day -1 (in triplicate), Day 1 at 3 hours postdose, Day 2, Day 5; in 
Period 2: on Day -1, predose on Days 1, 7 and 14; on Day 18 (96 hours after last dosing); follow-up. At screening and on Day -1 of Period 1, 
vital signs will be measured in triplicate; at other time-points, vital signs will be single measurements.  
i For females only: FSH and serum pregnancy test at screening, and serum pregnancy test only at all other time points. 
j Hematology samples will be collected at screening, Day -1 of Period 1, Day -1 of Period 2; predose on Days 6 and 11 of Period 2; Day 18; 
follow-up. 
k Biochemistry samples will be collected at screening, Day -1 of Period 1, Day -1 of Period 2; predose on Day 11 of Period 2; Day 18; follow-up. 
 
  
 





SAP_001.pdf: 
Official Title: 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
PARALLEL GROUP, TWO-TREATMENT STUDY 
INVESTIGATING THE ABSOLUTE ORAL BIOAVAILABILITY OF 
BALOVAPTAN AFTER SINGLE AND MULTIPLE DAILY ORAL 
DOSES OF BALOVAPTAN IN HEALTHY VOLUNTEERS 
NCT Number: 
NCT03764449 
Document Date:  SAP Version 1: 27-February-2019 




Statistical Analysis Plan 
RPU014EC-180141 
Protocol: WP40607 
Version Date 25-Feb-2019  
EDSREP 009 T 01 G 
Page 2 of 26 
 
2.0 Table of Contents 
1.0 Approvals ................................................................................................................................................ 1 
2.0 Table of Contents .................................................................................................................................... 2 
3.0 Introduction ............................................................................................................................................. 4 
4.0 Changes from Previous Version of Approved SAP ................................................................................ 4 
5.0 Study Objectives ..................................................................................................................................... 4 
5.1 Primary Objective ................................................................................................................................ 4 
5.1.1 Primary Endpoints ........................................................................................................................ 4 
5.2 Secondary Objectives ......................................................................................................................... 4 
5.2.1 Secondary Endpoints ................................................................................................................... 4 
5.3 Tertiary/Exploratory Objectives ........................................................................................................... 5 
5.3.1 Tertiary/Exploratory Endpoints ..................................................................................................... 5 
6.0 Study Design ........................................................................................................................................... 5 
6.1 Sample Size Considerations ............................................................................................................... 6 
6.2 Randomization .................................................................................................................................... 6 
7.0 Overview of Planned Analysis ................................................................................................................ 6 
7.1 Changes from Protocol ....................................................................................................................... 6 
7.2 Interim Analysis and Key Results ....................................................................................................... 6 
7.3 Final Analysis ...................................................................................................................................... 7 
8.0 Data Review ............................................................................................................................................ 7 
8.1 Data Management ............................................................................................................................... 7 
8.2 Acceptance of Data for Summarization .............................................................................................. 7 
9.0 Definitions and General Analysis Methods ............................................................................................. 7 
9.1 Analysis Data Presentation ................................................................................................................. 7 
9.1.1 Rounding ...................................................................................................................................... 7 
9.1.2 Imputation .................................................................................................................................... 7 
9.1.3 Descriptive Statistics .................................................................................................................... 8 
9.1.4 Pooling ......................................................................................................................................... 8 
9.1.5 Unscheduled Measurements ....................................................................................................... 8 
9.2 Analysis Data Definitions .................................................................................................................... 8 
9.2.1 Baseline Definition ....................................................................................................................... 8 
9.2.2 Treatment Grouping ..................................................................................................................... 8 
9.2.3 Common Variable Derivations ..................................................................................................... 9 
9.2.4 QC ................................................................................................................................................ 9 
9.2.5 ADaM Datasets and Metadata ..................................................................................................... 9 
9.3 Software .............................................................................................................................................. 9 
9.4 Statistical Methods ............................................................................................................................ 10 
9.4.1 Statistical Outlier Determination ................................................................................................. 10 
9.4.2 Predetermined Covariates and Prognostic Factors ................................................................... 10 
9.4.3 Hypothesis Testing ..................................................................................................................... 10 
9.5 TFL Layout ........................................................................................................................................ 10 
10.0 Analysis Populations ........................................................................................................................... 11 
10.1 Safety Analysis Population ............................................................................................................. 11 
10.2 Pharmacokinetic Analysis Population ............................................................................................. 11 
11.0 Subject Disposition .............................................................................................................................. 11 
12.0 Protocol Deviations and Violations ..................................................................................................... 11 
13.0 Demographic and Baseline Characteristics ........................................................................................ 11 
13.1 Demographics ................................................................................................................................. 11 
13.2 Medical History ................................................................................................................................ 12 
13.3 Other Baseline Characteristics ....................................................................................................... 12 
14.0 Concomitant Medications .................................................................................................................... 12 
15.0 Treatment Compliance and Exposure ................................................................................................ 12 
16.0 Pharmacokinetic Analyses .................................................................................................................. 12 
16.1 Pharmacokinetic Variables.............................................................................................................. 12 
Page 1207 of 2325


Statistical Analysis Plan 
RPU014EC-180141 
Protocol: WP40607 
Version Date 25-Feb-2019  
EDSREP 009 T 01 G 
Page 3 of 26 
 
16.1.1 Concentrations ......................................................................................................................... 12 
16.1.2 Parameters ............................................................................................................................... 12 
16.2 Pharmacokinetic Summaries .......................................................................................................... 14 
16.2.1 Pharmacokinetic Concentrations ............................................................................................. 14 
16.2.2 Pharmacokinetic Parameters ................................................................................................... 15 
17.0 Safety Analyses .................................................................................................................................. 15 
17.1 Safety Variables .............................................................................................................................. 15 
17.1.1 Adverse Events ........................................................................................................................ 16 
17.1.2 Deaths and Serious Adverse Events ....................................................................................... 17 
17.1.3 Laboratory Data ....................................................................................................................... 17 
17.1.4 Vital Signs ................................................................................................................................ 17 
17.1.5 Electrocardiograms .................................................................................................................. 17 
17.1.6 Columbia Suicide Severity Rating Scale .................................................................................. 18 
18.0 References .......................................................................................................................................... 18 
Appendix 1: Glossary of Abbreviations ....................................................................................................... 18 
Appendix 2: Schedule of Assessments ....................................................................................................... 20 
Appendix 3: Schedule of Pharmacokinetic Blood
 Samples ......................................................... 22 
Appendix 4: List of End of Text Outputs ..................................................................................................... 23 
Document History ........................................................................................................................................ 26 
 
Page 1208 of 2325


Statistical Analysis Plan 
RPU014EC-180141 
Protocol: WP40607 
Version Date 25-Feb-2019  
EDSREP 009 T 01 G 
Page 4 of 26 
 
3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under F. Hoffmann-La Roche Ltd Protocol WP40607. 
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the plan has been developed using the protocol dated 22-Oct-2018 (including all 
amendments up to this protocol date) and the final eCRF(s) dated 08-Jan-2019. 
An approved and signed SAP is a requirement for database lock.  
This SAP only covers the results that will be processed by the PRA Early Development Services (EDS) 
Biostatistics Department. 
PRA EDS will perform the pharmacokinetic (PK) and safety and tolerability evaluation.  
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR) but not included in this SAP, will be clearly identified in Section 9.8.2 of the CSR. Changes to planned 
analyses do not require an updated SAP but should be included in the CSR if significant. 
4.0 Changes from Previous Version of Approved SAP 
This is the first version of the SAP. 
5.0 Study Objectives 
This study will evaluate the PK of balovaptan. 
5.1 Primary Objective 
• 
To determine the absolute oral bioavailability of a single dose of 10 mg balovaptan.  
5.1.1 Primary Endpoints 
• 
Absolute bioavailability (F) for balovaptan at the indicated dose level.  
5.2 Secondary Objectives 
• 
To determine the absolute oral bioavailability of a single dose of 50 mg balovaptan.  
• 
To determine the absolute oral bioavailability of balovaptan after once daily doses of 10 mg or 
50 mg for 14 days.  
• 
To characterize the dose- and time-dependency of the PK of oral balovaptan.  
• 
To determine plasma concentrations of [13C]-labeled balovaptan, balovaptan, and its metabolites 
M2, and M3, following a single oral dose of balovaptan 10 mg or 50 mg together with a slow 
intravenous (IV) infusion of a microdose of [13C]-labeled balovaptan.  
• 
To determine plasma concentrations of [13C]-labeled balovaptan, balovaptan, and its metabolites 
M2, and M3, following once daily oral dosing of 10 mg or 50 mg once daily (QD) for 14 days together 
with a slow IV infusion of a microdose of [13C]-labeled balovaptan after the last oral dose.  
• 
To evaluate the safety and tolerability of balovaptan 10 mg QD and 50 mg QD.  
5.2.1 Secondary Endpoints 
• 
Absolute bioavailability (F) for balovaptan at the indicated dose level.  
Page 1209 of 2325




Statistical Analysis Plan 
RPU014EC-180141 
Protocol: WP40607 
Version Date 25-Feb-2019  
EDSREP 009 T 01 G 
Page 6 of 26 
 
Figure 1 presents an overview of the study design. 
 
Figure 1: Study Schema 
 
Period 
1: 
Day -1 to Day 14a 
Period 
2: 
Day -1a to Day 19 
Screening 
(Day -28 to 
Day -2) 
 Day 1: single dose 
of 10 mg (Cohort 1) 
or 50 mg (Cohort 2) 
balovaptan, followed 
1.25 hours later by 
15-minute 
IV 
infusion of 
[13C]-labeled 
balovaptan 0.1 mg 
 Day 1 to Day 14: oral 
doses of 10 mg (Cohort 1) 
or 50 mg (Cohort 2) 
balovaptan QD; on 
Day 14 the final oral dose 
will be followed 
1.25 hours later by a 15-
minute IV infusion of 
[13C]-labeled balovaptan 
0.1 mg 
 Follow-up (14 to 
21 days after 
last dose) 
IV = intravenous; QD = once daily 
a Day 14 of Period 1 is Day -1 of Period 2 
6.1 Sample Size Considerations 
This is an exploratory study for which no formal statistical hypothesis will be tested, and therefore the 
sample size is chosen to estimate the absolute bioavailability of the 10 mg single dose with sufficient 
precision. A total of 8 subjects per cohort are to be enrolled with the target of at least 6 subjects available 
for the primary PK analysis (i.e., having taken a single dose of 10 mg on Day 1 and completed all PK 
assessment up to Day 10). If the number of subjects providing PK data from the multiple dose parts of the 
study is lower than 6 for either cohort more subjects may be enrolled.  
 
Assuming a within-subject variability of around 35% it can be estimated that with 6 subjects the half-width 
of the 90% confidence interval (CI) for the ratio of geometric means of the microdose IV kinetics with that 
from the oral dose (i.e. CL versus CL/F) would be obtained by dividing/multiplying the ratio estimate by a 
factor of 1.50. The within-subject variability value of around 35% has been identified as a reasonable 
assumption: it is smaller than the observed 42% between-subject variability for the apparent clearance of 
distribution (CL/F) from a single oral 10 mg dose in study WP40038, and it considers that the reference will 
be obtained from IV kinetics, which is expected to be less variable than oral kinetics. 
6.2 Randomization 
Not applicable, this is a non-randomized study.  
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
There are no changes from the protocol. 
7.2 Interim Analysis and Key Results 
No interim reporting is planned for this study.  
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7.3 Final Analysis 
Draft Tables, Figures and Listings (TFLs) will be provided with the draft CSR. After Sponsor comments 
have been incorporated, the TFLs will be finalized and incorporated in the final CSR. 
8.0 Data Review 
8.1 Data Management 
Data handling, transfer and coding will take place under the PRA Data Management Plan for the study. 
8.2 Acceptance of Data for Summarization 
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) after 
database lock. Only quality assured (QA’d) results released by the Safety Laboratory, Bioanalytical 
Laboratory, or other external data source will be used for the programming of analysis datasets and TFLs 
for the final report. Any data values requiring investigation or corrections that are identified while 
programming the analysis datasets and TFLs will be sent to the project Data Manager. If the issue affects 
the TFLs the Programmer or Statistician who identified the issue will follow it to resolution. 
9.0 Definitions and General Analysis Methods 
9.1 Analysis Data Presentation 
9.1.1 Rounding 
In listings, all data (except the PK data) will be presented with the same precision as the original data. 
Derived data will be rounded for presentation purposes.  
For descriptive statistics of safety data, range values will be presented with the same precision (number of 
decimals or significant digits) as the data they are calculated from, median, arithmetic mean values with 1 
more decimal digit, standard deviation (SD) with 2 more decimal digits. Percentages will be rounded to 
integers. 
For the rounding of derived PK parameters Appendix 2 of the Roche Clinical Pharmacology Guideline will 
be followed [3]. For all PK parameters except tmax, tlast and t1/2; individual subject data, range values, median, 
arithmetic mean, geometric mean and SD will be presented with a precision of 3 significant digits. The 
coefficients of variation (CV) with 1 decimal digit.  
All individual data and descriptive statistics for tmax, tlast and t1/2 will be reported with 2 decimals, except for 
the CVs, which will be presented with 1 decimal digit. 
9.1.2 Imputation 
Except for the substitution of any PK concentrations below the lower limit of quantification (LLOQ) (see 
Section 16.2) and missing start or end date/times of AEs for the calculation of onset and duration (see 
Section 17.1.1), any missing data will not be imputed. 
 
 
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9.4 Statistical Methods 
9.4.1 Statistical Outlier Determination 
No statistical outlier analysis is planned. 
9.4.2 Predetermined Covariates and Prognostic Factors 
CYP3A4 genotype will be investigated as a factor in this study. PK tables will be presented by CYP3A4 
genotype. 
The pharmacogenetics of other isoforms, metabolizing enzymes, transferases, transporters, etc, possibly 
involved in the absorption, distribution, metabolism and excretion of balovaptan and its major metabolites 
(e.g., CYP3A and P-glycoprotein) may be investigated additionally (e.g. CYP3A5 genotype). Beside 
CYP3A, transporters that will be investigated (others may follow) are: P-glycoprotein 
(ABCB1), OCT2 (SLC22A2), OATP2B1 (SLCO2B1), AOT3 (SLC22A8). The results may be pooled with 
data from other studies of balovaptan and will be reported separately.  
9.4.3 Hypothesis Testing 
No formal hypothesis testing will be done.  
9.5 TFL Layout 
Report layout will be according to the PRA EDS – ICH E3 compliant – CSR Template. The layout of TFLs 
will be according to the PRA EDS standards. 
No table shells will be provided. The TFLs will be provided in Adobe PDF format. 
Format: 
• 
Page size: A4 
• 
Data in listings will be sorted by subject number and time point. 
• 
Data in tables will be sorted by treatment and time point. 
• 
Column titles will be in title case letters. 
• 
All tables and listings will be in landscape format. 
• 
The treatment labels will be as outlined in Section 9.2.2 Treatment/Subject Grouping Definition. 
 
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13.2 Medical History 
Medical history will be listed including the coding according to the Medical Dictionary for Regulatory 
Activities (MedDRA; latest version). 
13.3 Other Baseline Characteristics 
• 
Drug and alcohol screen: The results of urine drug screen (barbiturates, benzodiazepines, 
methadone, amphetamines [including ecstasy], methamphetamines, opiates, cocaine, and 
cannabinoids and urine alcohol test will be listed.  
• 
Serology: The results of serology (human immunodeficiency virus (HIV)-1 and HIV-2, hepatitis B 
virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody) at screening will be listed.  
• 
Pregnancy test (females only): Serum pregnancy test results (beta-human chorionic gonadotropin) 
and follicle-stimulating hormone (FSH) test results will be listed for each female subject at 
screening. All other timepoints for serum pregnancy test will be listed as well.  
• 
Non-compliance to inclusion or exclusion criteria (if any) will be listed.  
14.0 Concomitant Medications 
Concomitant medications, categorized by medication group and subgroup according to GNE Drug 
dictionary, will be summarized. The number and percentage of subjects using each medication will be 
displayed with the number and percentage of subjects using at least one medication within each medication 
group and subgroup, by treatment. 
Concomitant medication will be listed. Medications with an end date prior to the first dose of study drug will 
be considered prior medications and will be noted in the listing. If a partial date allows a medication to be 
considered concomitant it will be categorized as such. 
15.0 Treatment Compliance and Exposure 
Exposure data will be listed by subject.  
The number of subjects receiving each dose of study drug will be summarized.  
16.0 Pharmacokinetic Analyses  
PK concentrations will be collected in plasma. 
16.1 Pharmacokinetic Variables 
16.1.1 Concentrations 
• 
Plasma concentration of balovaptan 
• 
Plasma concentration of [13C]-balovaptan 
• 
Plasma concentration of metabolites (M2, M3) 
• 
 
• 
 
16.1.2 Parameters 
• 
PK Parameters for balovaptan, [13C]-balovaptan, M2 and M3 as defined in Table 1 and Table 2. 
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Linear and semi-logarithmic plots of the geometric mean plasma concentration by scheduled sampling time 
will be provided by analyte, cohort, treatment and analysis day. Separate plots will be created by analyte 
and cohort (dose level), with the analysis days (SD and QD treatment) displayed in the same plot. These 
plots will show time in hours. The plots will match the summary table results and will not have an observation 
at a given time point if more than half of the subjects have values BQL. Geometric mean trough balovaptan, 
M2 and M3 concentrations (Period 2) will be plotted separately. 
Combined individual (spaghetti) plots of the individual plasma balovaptan, [13C]-balovaptan, M2 and M3 
concentration versus actual sampling time will be provided by treatment and day. These plots will show 
time in hours. 
Separate plots will be created for the individual plasma balovaptan, [13C]-balovaptan, M2 and M3 profiles 
by treatment. These plots will show period 1 (single dose), day 1 and period 2 (multiple dose), day 14 per 
subject in the same plot. Individual plots will use the BQL handling procedure described below for 
“Pharmacokinetic Parameters”. 
Individual plasma concentration data will be presented together with descriptive statistics by analyte and 
treatment. 
 concentration data will be listed only.  
16.2.2 Pharmacokinetic Parameters 
Plasma PK parameters for balovaptan, [13C]-balovaptan, M2 and M3, will be estimated using non-
compartmental methods with WinNonlin®. 
The plasma PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters, BQL values will be set to zero for the pre-dose PK sample, as well as for all other samples 
being BLQ and occurring before tmax. For subsequent time points, the result will be set to missing. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving sampling 
times. If the actual time or dose time is missing, the scheduled time may be substituted in order to calculate 
the PK parameter. 
Descriptive statistics (number of subjects, arithmetic mean, geometric mean, SD, geometric and arithmetic 
CV, median, min, and max) will be used to summarize the calculated PK parameters by treatment, day and 
analyte. For tmax, only median, min and max will be presented. 
The points to be included in the λz range will be determined by the pharmacokineticist after inspection of 
the semi-log concentration-time profiles. At least 3 points will be required to be used and the range should 
ideally be spread over a time interval representing at least 2 half-lives. The Cmax data point will not be 
included. 
 
Parameters based on R2 below 0.70 or %AUCextra above 20% will be flagged and excluded from descriptive 
statistics. 
The ratio of geometric means from the microdose IV kinetics with that from the oral dose will be estimated 
using an analysis of variance (ANOVA) of the natural logarithm transformed clearance (CL and CL/F). A 
mixed model will be used, separately for the 2 cohorts with the 2 doses of 10mg and 50mg, and will include 
fixed effects for route (oral or iv) and for day (1 and 14) and a random effect for subject. From this model 
the least-squares means (LSMeans) for clearance (CL) of [13C]-balovaptan iv and for CL/F of oral 
balovaptan will be presented. The ratios of the LSMeans for the comparison of CL to CL/F (IV/Oral) will be 
obtained by exponentiating the difference of the LSMeans on the log scale. A 90% confidence interval for 
the ratios of the treatment means will be calculated. 
17.0 Safety Analyses  
17.1 Safety Variables 
Physical examination and body weight (including BMI) will be listed according to scheme times.  
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The following safety variables will be summarized: 
• 
AEs 
• 
Vital Signs 
o 
Supine Blood Pressure  
 
Systolic Blood Pressure (SBP) 
 
Diastolic Blood Pressure (DBP) 
o 
Pulse rate 
o 
Body temperature (tympanic) 
o 
Respiratory rate 
• 
Electrocardiograms (ECG) 
o 
Heart Rate 
o 
PR Interval 
o 
QRS-Duration 
o 
QT Interval 
o 
QTc (Fridericia) Interval 
o 
T-Wave 
o 
U-Wave 
• 
Clinical Laboratory Evaluations 
o 
Serum Chemistry  
o 
Hematology 
o 
Urinalysis 
o 
Coagulation 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
o 
Suicidal ideation  
o 
Suicidal behavior  
17.1.1 Adverse Events 
All AEs will be coded to the current version of Medical Dictionary for Regulatory Activities (MedDRA, the 
latest version) by F. Hoffmann-La Roche, Ltd.  
All AE summaries will include only treatment emergent adverse events (TEAEs). Treatment-emergent 
adverse events are those which occur after the first dose of study drug. AEs starting prior to medication 
dosing in the first period will be regarded as pre-dose AEs (i.e. non-TEAEs).  
TEAEs occurring following dosing in a specific analysis period but before dosing in the next analysis period 
will be attributed to that specific analysis period, thus to the last received treatment. If the time is missing 
for an AE on a dosing day then the AE will be attributed to the treatment given on that day.  
All AEs (including non-TEAEs) recorded on the eCRF will be listed (including analysis period and treatment 
information). Pre-dose AEs will be presented in a separate listing. In addition, a separate listing of AEs 
leading to withdrawal from study will be provided.  
TEAEs will be tabulated by system organ class and preferred term: one table with all TEAEs (number and 
percentage of subjects) overall and by treatment; one table with related TEAEs (number and percentage 
of subjects) overall and by treatment; one table with all TEAEs (number and percentage of subjects) by 
treatment and relationship to study drug; one table with TEAEs (number and percentage of subjects) by 
treatment and severity.  
Subjects are counted once, per preferred term per treatment, for the most severe of multiple occurrences 
(in case of severity) or most drug-related event (in case of relationship) of a specific MedDRA term. AEs 
whose causal relationship was characterized as ‘Yes’/’No’ will be regarded as being related/not related to 
the study medication. 
The following missing data will be imputed as defined (for calculations only / will not be presented): 
• 
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times 
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• 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
• 
Missing AE start times for the determination of treatment emergence will be assumed to occur after 
treatment unless partial date documents the AE as happening prior to treatment 
• 
Missing AE start times for the determination of treatment assignment will be assumed to occur after 
treatment on the recorded date one minute after dosing 
• 
Missing AE start date will be attributed to the treatment from analysis period 1 unless the AE end 
date occurs before first IMP administration 
17.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other serious adverse events (SAE) will be provided by subject. 
17.1.3 Laboratory Data 
Clinical laboratory data will be presented using units from the study data tabulation model (SDTM) 
Controlled Terminology. 
All laboratory data will be listed, including laboratory variables not listed in the protocol. A separate listing, 
including out-of-range values will also be provided. Normal ranges will be used directly from the clinical 
laboratory. 
Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
urinalysis (observed and derived changes from baseline) by treatment and scheduled time will be provided.  
Additionally, for CPK (chemistry) a frequency table for the following ranges will be added: 
• 
≤ 2 times upper limit of normal (ULN) 
• 
> 2 and ≤5 times ULN 
• 
> 5 and ≤10 times ULN 
• 
≥10 times ULN 
For categorical urinalysis parameters frequency tables, showing the number of subjects in a category (n) 
and the percentage of the total number of subjects per treatment (N), will be provided. Sporadic urinalysis 
tests that were performed when abnormalities were observed (i.e. microscopy/sediment) will only be listed.  
17.1.4 Vital Signs 
All vital signs data including derived changes from baseline will be listed. For timepoints with triplicate 
measurements the mean of the triplicate measurements and the change from baseline of the mean triplicate 
measurements will be listed by subject additionally. 
Descriptive statistics will be provided to summarize vital signs including changes from baseline by treatment 
and scheduled time. 
17.1.5 Electrocardiograms 
All ECG parameters (including changes from baseline) and the corresponding abnormalities and 
physician’s conclusions will be listed by subject. 
The observed measurements for all ECG parameters (including T-wave, U-wave) and the corresponding 
abnormalities will be listed for all time points. The means of triplicate measurements for continuous 
parameters and the change from baseline of the mean triplicate measurements at each scheduled time 
point will be listed by subject. 
Descriptive statistics will be provided to summarize mean continuous ECG parameters (observed and 
changes from baseline) by treatment and scheduled time. A frequency table will be provided as well to 
summarize the ECG parameters by physicians conclusion (normal, abnormal not clinically significant, 
abnormal clinically significant). Additionally a frequency table for the following pre-specified QTcF ranges 
(for the rounded values) will be added: 
 
 
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DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDS 
Early Development Services 
FSH 
Follicle-stimulating hormone 
HBsAg  
Hepatitis B virus surface antigen  
HCV  
Hepatitis C virus  
HIV  
Human immunodeficiency virus  
ICH 
The International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IV 
Intravenous  
LLOQ 
Lower limit of quantification 
M2, M3 
Metabolites 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
QA’d 
Quality assured 
QC’d 
Quality controlled 
QD 
Once daily 
SAP 
Statistical analysis plan 
SAE 
Serious adverse event 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
TEAE 
Treatment-emergent adverse event 
TFL(s) 
Tables, figures and listings 
ULN 
Upper limit of normal 
WNL 
WinNonlin 
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Appendix 2: Schedule of Assessments 
 
Assessments 
Screening 
Period 
1 
(Single Dose) 
Period 
2 
(Multiple Doses) 
Follow-up 
Day 
-28 to -2 
-1 
1 
2 to 10 
-1 
1 to 14 
15 to 19 
28 to 35 
Resident at study centera 
X 
X 
Written informed consent 
X 
Inclusion and exclusion criteria 
X 
Demographics 
X 
Medical history 
X 
Medication history 
X 
Blood sampling for CG 
X 
Study drug: oral administration 
X 
X 
Study drug: IV administrationb 
X 
X 
Standardized mealsc 
X 
X 
PK sampling 
X 
X 
X 
X 
 
 
Physical examination and 
measurement of body weight 
Xf 
X 
X 
X (D11) 
X (D18) 
X 
C-SSRS 
X 
X 
X (D18) 
12-lead ECGg 
X 
X 
Xg 
X 
X (D6, D11) 
X (D18) 
X 
Vital signsh 
X 
X 
X 
X (D2, D5) 
X 
X (D1, D7, 
D14) 
X (D18) 
X 
Urine drug screen including alcohol X 
X 
X 
Serology 
X 
Pregnancy testi 
X 
X 
X 
X 
Hematologyj 
X 
X 
X 
X (D6, D11) 
X (D18) 
X 
Biochemistryk 
X 
X 
X 
X (D11) 
X (D18) 
X 
Urinalysis 
X 
X 
X 
X 
Coagulationl 
X 
X (D11)l 
X (D18)l 
X 
AE monitoring 
 
Review concomitant medications 
 
AE = adverse event; BMI = body mass index; CG = clinical genotyping; CRU = clinical research unit; 
; C-SSRS = Columbia-
Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; FSH = follicle-stimulating hormone; IV = intravenous; PK = pharmacokinetic.  
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Section 16.2.2 – Protocol Deviations 
 
Not part of TFL – Reserved for protocol deviations in CSR 
Section 16.2.3 – Excluded Subjects 
Listing 16.2.3.1 
Analysis Sets 
Section 16.2.4 – Demographics and Baseline Characteristics 
Listing 16.2.4.1 
Subject Demographics (including genotype) 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Prior and Concomitant Medications 
Listing 16.2.4.4 
Drug and Alcohol Screen 
Listing 16.2.4.5 
Serology Test Results  
Listing 16.2.4.6 
Pregnancy and Serum FSH Test Results  
Listing 16.2.4.7 
Genotyping Results 
Section 16.2.5 – Compliance and Drug Concentration Data 
Listing 16.2.5.1 
Study Dates 
Listing 16.2.5.2 
Study Drug Administration 
Listing 16.2.5.3 
Deviations from Inclusion/Exclusion criteria 
Listing 16.2.5.4 
PK Blood Sampling Time Deviations and Comments  
Listing 16.2.5.5 
Food Intake  
Section 16.2.7 – Adverse Events Data 
Listing 16.2.7.1 
Adverse Events 
Listing 16.2.7.2 
Adverse Events Leading to Withdrawal 
Section 16.2.8 – Laboratory Data 
Listing 16.2.8.1 
Clinical Laboratory Results – Hematology 
Listing 16.2.8.2 
Clinical Laboratory Results – Chemistry 
Listing 16.2.8.3 
Clinical Laboratory Results – Urinalysis 
Listing 16.2.8.4 
Clinical Laboratory Results – Coagulation 
Section 16.2.9 – Other Safety Data 
Listing 16.2.9.1 
Vital Sign Results 
Listing 16.2.9.2 
12-Lead Electrocardiogram Results 
Listing 16.2.9.3 
Abnormalities 
and 
Changes 
in 
Findings 
at the 
Physical 
Examinations 
Listing 16.2.9.4 
Columbia-Suicide Severity Rating Scale 
Listing 16.2.9.5 
Weight and BMI 
 
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