Clinical trial NCT04156646
Conditions: Autism Spectrum Disorder
Sponsor: Hoffmann-La Roche
Start date: 2019-11-19; Completion date: 2020-01-06
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will investigate the effect of food and the effect of esomeprazole on the pharmacokinetics (PK) of a single dose of balovaptan in healthy volunteers.

Detailed description:

Arms: arm 1: In Period 1 participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose arm 2: In Period 1 participants will receive 1 tablet of balovaptan after 10-hour fast. In Period 2, after 12 to 21 days wash-out, participants will receive 1 tablet of balovaptan after high-fat, high-calorie meal. In Period 3 participants will receive esomeprazole administered once daily for 6 days and with a single oral dose of balovaptan in the fasted state 1 hour after the fifth esomeprazole dose
Interventions: intervention 1: Balovaptan intervention 2: Esomeprazole
Intervention descriptions: intervention 1: Balovaptan will be administered after a high-fat, high-calorie meal (Treatment A), after a 10-hour fast (Treatment B), and after a 10-hour fast with esomeprazole 40 mg (Treatment C) intervention 2: Esomeprazole will be administered once daily for 6 days and with a single dose of balovaptan 1 hour after the fifth esomeprazole dose

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A SINGLE-CENTER, PART-RANDOMIZED, OPEN-LABEL, SINGLE-
DOSE, THREE-PERIOD, CROSSOVER STUDY TO INVESTIGATE 
THE EFFECT OF ESOMEPRAZOLE AND THE EFFECT OF FOOD 
ON THE PHARMACOKINETICS OF BALOVAPTAN IN HEALTHY 
VOLUNTEERS 
NCT Number: 
NCT04156646 
Document Date: 
Protocol Version 1: 26-September-2019 
 
 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 WP41047 v1.0
PROTOCOL
TITLE:
A SINGLE-CENTER, PART-RANDOMIZED, 
OPEN-LABEL, SINGLE-DOSE, THREE-PERIOD, 
CROSSOVER STUDY TO INVESTIGATE THE 
EFFECT OF ESOMEPRAZOLE AND THE EFFECT 
OF FOOD ON THE PHARMACOKINETICS OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
WP41047
VERSION NUMBER:
1.0
EUDRACT NUMBER:
NA
IND NUMBER:
116483
NCT NUMBER
To be determined
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, MD
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below
26-Sep-2019 13:26:27
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
2
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 7
PROTOCOL SYNOPSIS ...................................................................................... 8
1.
BACKGROUND .......................................................................................... 16
1.1
Autism Spectrum Disorder..................................................... 16
1.2
Preclinical Background on Balovaptan .................................. 16
1.2.1
Previous and Ongoing Clinical Studies.................................. 18
1.2.1.1
Clinical Pharmacology ........................................................... 19
1.2.1.2
Safety .................................................................................... 20
1.3
Study Rationale and Benefit-Risk Assessment...................... 21
2.
OBJECTIVES AND ENDPOINTS ............................................................... 22
3.
STUDY DESIGN......................................................................................... 23
3.1
Description of the Study......................................................... 23
3.2
End of Study and Length of Study......................................... 24
3.3
Rationale for Study Design.................................................... 25
3.3.1
Rationale for Balovaptan and Esomeprazole 
Dose ...................................................................................... 25
3.3.1.1
Balovaptan............................................................................. 25
3.3.1.2
Esomeprazole........................................................................ 25
3.3.2
Rationale for Study Population .............................................. 26
4.
MATERIALS AND METHODS .................................................................... 26
4.1
Subjects................................................................................. 26
4.1.1
Inclusion Criteria.................................................................... 26
4.1.2
Exclusion Criteria................................................................... 27
4.2
Method of Treatment Assignment and Blinding..................... 30
4.2.1
Blinding.................................................................................. 30
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 31
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 31
4.3.1.1
Balovaptan............................................................................. 31
4.3.1.2
Esomeprazole........................................................................ 31


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
3
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 31
4.3.2.1
Balovaptan............................................................................. 31
4.3.2.2
Esomeprazole........................................................................ 32
4.3.3
Investigational Medicinal Product Accountability ................... 32
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 32
4.4.1
Permitted Therapy................................................................. 32
4.4.2
Prohibited Therapy ................................................................ 33
4.4.3
Prohibited Food ..................................................................... 33
4.4.4
Additional Restrictions/Considerations .................................. 34
4.5
Study Assessments ............................................................... 34
4.5.1
Informed Consent Forms and Screening Log........................ 35
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 35
4.5.3
Physical Examinations........................................................... 35
4.5.4
Vital Signs.............................................................................. 35
4.5.4.1
Orthostatic Challenge Testing ............................................... 35
4.5.5
Clinical Laboratory Samples.................................................. 36
4.5.6
Pharmacokinetic Samples ..................................................... 37
4.5.7
Genotyping Samples ............................................................. 37
4.5.8
Electrocardiograms................................................................ 38
4.5.9
Drug and Metabolite Concentration 
Measurements....................................................................... 38
4.6
Treatment, Subject, Study, and Site 
Discontinuation...................................................................... 39
4.6.1
Study Treatment Discontinuation........................................... 39
4.6.2
Subject Discontinuation from the Study................................. 39
4.6.3
Study Discontinuation............................................................ 40
4.6.4
Site Discontinuation............................................................... 40
5.
ASSESSMENT OF SAFETY....................................................................... 40
5.1
Safety Plan ............................................................................ 40
5.1.1
Management of Subjects Who Experience 
Adverse Events ..................................................................... 41




Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
5
5.4.3.2
Pregnancies in Female Partners of Male 
Subjects................................................................................. 52
5.4.3.3
Abortions ............................................................................... 52
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 53
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 53
5.5
Follow-Up of Subjects after Adverse Events.......................... 54
5.5.1
Investigator Follow-Up........................................................... 54
5.5.2
Sponsor Follow-Up ................................................................ 54
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 54
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 55
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 55
6.1
Determination of Sample Size ............................................... 55
6.2
Summaries of Conduct of Study............................................ 55
6.3
Summaries of Demographic and baseline 
Characteristics....................................................................... 56
6.4
Efficacy Analyses .................................................................. 56
6.5
Safety Analyses..................................................................... 56
6.6
Pharmacokinetics Analyses................................................... 56
6.7
Other Analyses...................................................................... 58
6.7.1
Clinical Genotyping................................................................ 58
7.
DATA COLLECTION AND MANAGEMENT ............................................... 58
7.1
Data Quality Assurance......................................................... 58
7.2
Electronic Case Report Forms............................................... 59
7.3
Source Data Documentation.................................................. 59
7.4
Use of Computerized Systems .............................................. 59
7.5
Retention of Records............................................................. 60
8.
ETHICAL CONSIDERATIONS.................................................................... 60
8.1
Compliance with Laws and Regulations ................................ 60
8.2
Informed Consent.................................................................. 60
8.3
Institutional Review Board or Ethics Committee.................... 61




Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
7
PROTOCOL ACCEPTANCE FORM
TITLE:
A SINGLE-CENTER, PART-RANDOMIZED, OPEN-
LABEL, SINGLE-DOSE, THREE-PERIOD, 
CROSSOVER STUDY TO INVESTIGATE THE 
EFFECT OF ESOMEPRAZOLE AND THE EFFECT 
OF FOOD ON THE PHARMACOKINETICS  OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS.
PROTOCOL NUMBER:
WP41047
VERSION NUMBER:
1.0
EUDRACT NUMBER:
NA
IND NUMBER:
116483
NCT NUMBER
To be determined
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, MD
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy of 
the signed form by your local study monitor to the contact provided below.
Roche Products Limited
6 Falcon Way, Shire Park
Welwyn Garden City,
AL7 1TW, United Kingdom


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
8
PROTOCOL SYNOPSIS
TITLE:
A SINGLE-CENTER, PART-RANDOMIZED, OPEN-LABEL, 
SINGLE-DOSE, THREE-PERIOD, CROSSOVER STUDY TO 
INVESTIGATE THE EFFECT OF ESOMEPRAZOLE AND THE 
EFFECT OF FOOD ON THE PHARMACOKINETICS  OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS.
PROTOCOL NUMBER:
WP41047
VERSION NUMBER:
1.0
EUDRACT NUMBER:
NA
IND NUMBER:
116483
TEST PRODUCT:
Balovaptan (RO5285119)
PHASE:
Phase 1
INDICATION:
Not applicable
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will investigate the effect of food and the effect of esomeprazole on the 
pharmacokinetics (PK) of a single dose of balovaptan in healthy volunteers.
Objective
Endpoints
Primary Objectives

To investigate the effect of 
esomeprazole on the PK of 
balovaptan following a single oral dose 
of balovaptan in the fasted state

To investigate the effect of a high-fat 
meal compared to the fasted state on 
the PK of balovaptan following a single 
oral dose of balovaptan

Plasma concentrations of balovaptan

Derived plasma PK parameters for 
balovaptan
Secondary Objectives

To investigate the effect of 
esomeprazole on the PK of M2 (as 
appropriate) and M3 following a single
oral dose of balovaptan in the fasted 
state

To investigate the effect of a high-fat 
meal compared to the fasted state on 
the PK of M2 (as appropriate) and M3 
following a single oral dose of 
balovaptan

Plasma concentrations of M2 and M3

Derived plasma PK parameters for M2 
and M3

To measure the PK of esomeprazole 
following 5 once daily doses of 
esomeprazole 

Plasma concentrations of 
esomeprazole

Derived plasma PK parameters for 
esomeprazole


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
9

To investigate the safety and 
tolerability of a single 20 mg oral dose 
of balovaptan alone or in combination 
with esomeprazole in healthy subjects

Incidence and severity of AEs, 
incidence of SAEs, non-serious AESIs, 
and AEs leading to treatment 
withdrawal

Results of vital signs, 12-lead ECGs, 
physical examinations, and clinical 
laboratory tests
Exploratory Objectives

To explore the effect of genetic 
variations in genes associated with 
drug ADME, and transport on the PK 
and/or safety profile of balovaptan.

Genotyping data for study subjects. 
Data will be reported separately if 
analysis is conducted
Study Design
This will be a single-center, part-randomized, open-label, single-dose, 3-period crossover study 
to investigate the effect of food and of esomeprazole on the PK of balovaptan in healthy 
volunteers.
Screening will be conducted between Day -28 and Day -2. 
In Period 1, eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 (the 
day prior to balovaptan dosing on Day 1) and will remain confined in the CRU until discharge on 
the morning of Day 5.
In Period 2, subjects will be re-admitted to the CRU on Day -1 (the day prior to balovaptan 
dosing on Day 1) and will remain confined in the CRU until discharge on the morning of Day 5. 
In Period 3, subjects will return to the CRU for re-admission 5 days prior to administration of 
balovaptan (Day 9 of Period 2) to begin esomeprazole dosing. Esomeprazole will be dosed for 6 
days: for 4 days prior to co-administration with balovaptan on Day 1 of Period 3, plus an 
additional dose on Day 2. Subjects will be discharged on Day 5.
In each period, following discharge from the CRU on Day 5, subjects will return to the CRU on 
Day 7 and Day 9 for further PK sampling.
There will be a washout of at least 12 days and up to 21 days between administrations of 
balovaptan. Thus, re-admission for Period 2 may be between 3 to 12 days after Day 9 of 
Period 1, and readmission for Period 3 will be on Day 9 of Period 2.
Subjects will be randomized to 1 of 2 treatment sequences (ABC or BAC) on Day 1 of Period 1, 
with the treatments being as follows:

Treatment A: 20 mg balovaptan administered as a single oral dose following consumption 
of high-fat, high-calorie meal 

Treatment B: 20 mg balovaptan administered as a single oral dose after a ≥10-hour fast

Treatment C: 40 mg esomeprazole administered once daily for 6 days and with a single 
dose of balovaptan 20 mg 1 hour after the fifth esomeprazole dose in the fasted state
Subjects will return for a follow-up visit on Day 16 ± 2 of Period 3.
Number of Subjects
A total of approximately 16 healthy subjects is anticipated to be enrolled in this study to target 
12 evaluable subjects. An attempt will be made to have 50% male and 50% female participants, 
and at least 30% of each sex.
Target Population
Healthy male and female subjects between 18 to 65 years of age, inclusive.


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
10
Inclusion Criteria
Subjects must meet the following criteria for study entry:
1.
Healthy male and female subjects, aged 18 to 65 years, inclusive. 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 ECGs, hematology, blood chemistry, urinalysis, and serology.
2.
Body mass index (BMI) between 18 and 32 kg/m2 inclusive, at screening.
3.
For women of childbearing potential: if engaging in heterosexual activity, agreement to 
use at least two adequate forms of contraception during the entire study and for 90 days 
following the last dose of study drug. Contraceptive measures are not required for 
women with exclusively same-sex partners and for those for whom complete abstinence 
is their preferred and usual lifestyle.
a.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (> 12 continuous months of 
amenorrhea with no identified cause other than menopause, confirmed with 
follicle-stimulating hormone (FSH) ≥35 IU/L), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
b.
The following are adequate contraceptive methods: bilateral tubal ligation; 
sterilization of male ‘partner; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; Essure.
c.
Barrier methods alone are not considered an adequate form of contraception for 
this study and if utilized must be supplemented by one of the adequate methods 
described above. For this study barrier contraception methods are defined as: 
male or female condom with or without spermicide (male and female condom 
must not be used simultaneously); and cap, diaphragm, or sponge with 
spermicide.
d.
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:
a.
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during sexual activity for the entire 
study 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.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
Medical History
1.
Female subjects who are pregnant or lactating.
2.
If female, a positive serum pregnancy test at screening or at admission.
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 4 weeks prior to the screening 
examination or any febrile illness within 1 week prior to screening.
5.
History of any clinically significant, as determined by the investigator, gastrointestinal, renal, 
hepatic, broncho-pulmonary, neurological, psychiatric, cardiovascular, endocrinological, 
hematological, lymphatic, musculoskeletal, genitourinary, immunological, dermatological, or 
connective tissue or allergic disease, metabolic disorder, or cancer.
6.
Signs and symptoms potentially indicative of peripheral neuropathy.


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
11
7.
History or evidence of any medical condition potentially altering the absorption, distribution, 
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 in the opinion of the Investigator hypersensitivity (e.g., to 
drugs, including balovaptan or its excipients, esomeprazole or its ingredients, or other 
proton pump inhibitors, e.g., pantoprazole, lansoprazole, rabeprazole, omeprazole) or 
allergic reactions.
9.
History or presence of clinically significant ECG abnormalities before study drug 
administration.
10. Subjects with screening or predose baseline mean QT interval corrected using Fridericia’s 
formula (QTcF) >450 msec or <300 msec (using the same upper QTcF limit in both males 
and females).
11. Notable resting bradycardia (mean HR <40 bpm) on screening or predose baseline ECG. 
Notable resting tachycardia (mean HR >100 bpm) on screening or predose baseline ECG.
12. 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. Isolated first degree atrioventricular block or right bundle branch block 
will not be exclusionary.
13. Confirmed (based on the average of ≥3 consecutive measurements) systolic blood 
pressure greater than 139 or less than 90 mmHg, and diastolic blood pressure greater than 
89 or less than 45 mmHg.
14. Clinically significant abnormalities in laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel, and urinalysis). In the case of uncertain or 
questionable results, screening tests may be repeated to confirm eligibility. For ANC, any 
result below the lower limit of normal.
15. History of coagulopathies, bleeding disorders, or blood dyscrasias.
16. Current suicidal risk, in the opinion of the Investigator.
17. Subjects with unexplained syncope during the 6 months prior to screening or with 
presyncopal and/or syncopal symptoms during orthostatic challenge testing.
18. Current smoker or user of tobacco or nicotine-containing products or subjects who have 
smoked or used tobacco or nicotine-containing products within 3 months prior to first study 
drug administration.
19. Suspicion of or presence of a clinically relevant history of or current alcohol and/or other 
substance abuse or addiction. 
20. Alcohol consumption of >14 units per week for males and females. One unit of alcohol 
equals 12 ounces of regular beer, 5 ounces of wine or 1.5 ounces of 80-proof spirits within 
3 months of first dose of study drug.
21. Positive urine alcohol test or urine drug screen at screening or Day -1 of any treatment 
period (amphetamines [including ecstasy], barbiturates, benzodiazepines, cannabinoids, 
cocaine, cotinine, methadone, methamphetamines, and opiates).
22. Subjects on hormone replacement therapy if postmenopausal status cannot be ascertained 
from medical history or FSH levels.
23. Clinically relevant deviation from normal in the physical examination including vital signs, as 
determined by the investigator.
24. Positive result for HIV 1, HIV 2, hepatitis C virus antibody, or hepatitis B core (HBc) 
antibody. Subjects with positive antiHBc but negative hepatitis B virus surface antigen and 
negative hepatitis B viral DNA will be allowed.
25. Participation in an investigational drug or device study within 4 weeks or 5 times the 
elimination half-life, whichever is longer, prior to first dosing, or within 5 months prior to first 
administration of study drug in case of a study with a biological, as calculated from the day 
of Follow-up visit from the previous study.
26. Any donation of blood or plasma or significant blood loss within 3 months prior to screening.


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
12
27. Dietary restrictions that would prohibit the consumption of standardized meals or the high-
fat, high-calorie meal planned for this study.
28. 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.
29. Subjects likely to need concomitant medication during the study (including for dental 
conditions).
30. 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 
administration of study drug, 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 
administration of study drug will also be excluded unless in the opinion of the Investigator 
the medication will not interfere with the study procedures or compromise safety.
31. 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 nonprescribed systemic or topical medication

herbal remedies
Paracetamol (up to 4 g/day 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.
32. Received any medications known to chronically alter drug absorption or elimination 
processes within 4 weeks before the first administration of study drug, unless in the opinion 
of the Investigator the medication will not interfere with the study procedures or compromise 
safety.
33. 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 administration of study drug.
34. Use of any drugs or substances, including herbal treatments, such as fluoxetine, 
fluvoxamine, aspirin, norethisterone, rifampicin, etc that are known to be substrates, 
inducers, or inhibitors of CYP2C19 within 4 weeks before the first administration of study 
drug.
35. Subjects under judicial supervision, guardianship, or curatorship.
36. Poor venous access for blood sampling.
37. Subjects who are intolerant to sucrose. 
38. Previous exposure to balovaptan.
End of Study
The end of this study is defined as the date when the last subject, last observation occurs, or 
safety follow-up is received from the last subject, whichever occurs later.
Length of Study
The total length of the study, from screening of the first subject to the end of the study, is 
expected to be approximately 11 weeks.
Investigational Medicinal Products
Test Product (Investigational Drug)
Balovaptan 20-mg dispersible tablets (Ro 528-5119/F41), administered as a single oral dose 
after a high-fat, high-calorie meal (Treatment A), after a 10-hour fast (Treatment B), and after a 
10-hour fast with esomeprazole 40 mg (Treatment C).
Esomeprazole 40 mg capsule administered once daily for 6 days and with a single dose of 
balovaptan 20 mg 1 hour after the fifth esomeprazole dose.


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
13
Statistical Methods
Primary Analysis
Analysis of variance models will be applied to the logarithmically transformed PK parameters of 
balovaptan AUC0-inf and Cmax, to investigate 1) the relative bioavailability of balovaptan 20-mg
dispersible tablets administered following a high-fat, high-calorie meal vs in the fasted state, and 
2) the relative bioavailability of balovaptan 20-mg dispersible tablets administered in the fasted 
state either alone or in combination with esomeprazole.
Determination of Sample Size:
Sixteen subjects will be enrolled with the target of at least 12 subjects available for the final PK 
analysis. Considering the observed residual CV% for AUC0-inf from Study WP40038 of 
approximately 14%, with 12 subjects the 90% CI would be obtained by dividing/multiplying the 
ratio estimate by a factor of 1.11.
.


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ADME
absorption, distribution, metabolism, excretion
ALT
alanine transaminase 
ANC
absolute neutrophil count
ASD
autism spectrum disorder
AST
aspartate transaminase
AUC
area under the curve
BMI
body mass index
BP
blood pressure
Cmax
maximum observed plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
CRO
contract research organization
CRU
clinical research unit
CSF
cerebral spinal fluid
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
LLN
lower limit of normal
LS
least squares
MAD
multiple ascending dose
MATE
multidrug and toxin extrusion
mmHg
millimeters of mercury
NOEL
no observed effect level


Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
15
Abbreviation
Definition
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
P-gp
P-glycoprotein
PK
pharmacokinetic
PND
postnatal day
PRA
PRA Health Sciences
qd
once daily
SAD
single ascending dose
SAE
serious adverse event
SOA
schedule of activities
Tmax
time to reach Cmax
TQT
thorough QT
ULN
upper limit of normal
USPI
US package insert
WBC
white blood cells


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1.
BACKGROUND
1.1
AUTISM SPECTRUM DISORDER
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder
characterized by two core domains: impairments in social interaction and communication
and the presence of repetitive or restricted behaviors, interests, or activities (American
Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 2013). 
The Autism and Developmental Disabilities Monitoring Network recently reported, based 
on pediatric records, that the estimated prevalence of ASD in the US for the year 2010 
was 14.7 per 1000 (1 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.
Evidence from both human and animal studies strongly implicates the V1a receptor in 
mediating and modulating key social behaviors that are deficient in ASD. Together with 
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. More detailed information 
regarding ASD and balovaptan are presented in the Investigator’s Brochure.
1.2
PRECLINICAL BACKGROUND ON BALOVAPTAN
The in vitro metabolism of balovaptan was studied in hepatic preparations from human, 
rat, dog, minipig, cynomolgus monkey, mouse, and rabbit. In microsomes from all 
species tested, 
 
whereas further secondary metabolites including 
oxidations and desaturations were found at low amounts.
Balovaptan up to 20 mg has biopharmaceutics classification system class 1-like 
properties but has pH dependent solubility which may affect its absorption at values 
closer to neutral pH. 
 
 
 
 
 
 




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1.2.1
Previous and Ongoing Clinical Studies
The clinical development program of balovaptan started with the entry-into-human Study 
BP25694, which assessed the safety, tolerability, PK, and pharmacodynamics of 
escalating single and multiple doses of balovaptan. Subsequently, the excretion balance, 
PK, and metabolism of balovaptan were investigated in a mass balance study (Study 
BP29279). Four drug-drug interaction studies assessed the interaction of balovaptan as 
a P-gp inhibitor with the P-gp substrate risperidone (Study BP28318), the effect of the 
CYP3A4 inhibitors itraconazole and fluoxetine on the PK of a single dose of balovaptan 
(Study BP28977), and the effect of itraconazole and rifampicin on the PK of multiple 
doses of balovaptan (Studies WP40609 and WP40608, respectively). A study comparing 
the Phase 3 tablet formulation with formulations used in Phase 1 and 2 studies has been 
completed (Study WP40038). A proof-of-mechanism study (Study BP29412) to 
investigate the effect of balovaptan on vasopressin pathway activation in healthy male 
volunteers has also been completed. Additionally, a thorough QT (TQT) study 
(WP40734) and an absolute bioavailability study (WP40607) are clinically complete, with 
reporting ongoing at the time of protocol writing.


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A Phase 2 study investigating the efficacy and safety of balovaptan in male adults with 
ASD (Study BP28420) has been completed. In total 223 patients were enrolled into this 
study at 26 sites in the US. The patients were randomized 2:1 to balovaptan or placebo. 
In total, 192 patients completed 12 weeks of treatment; of these 192 patients, 25, 69, 
and 30 patients received 1.5 mg, 4 mg, and 10 mg balovaptan, respectively, and 67 
patients received placebo.
Balovaptan is currently being investigated in a Phase 2 pediatric study to assess the
efficacy, safety, and PK of balovaptan in adolescents (13 to 17 years of age) and 
children (5 to 12 years of age) with ASD (Study BP30153). Recruitment into this study 
started in November 2016 and was completed in September 2019 (339 enrolled). A 
Phase 3 study investigating the efficacy and safety of balovaptan in adults with ASD 
(Study WN39434) is underway. Recruitment into this study started in August 2018 and 
was ongoing at the time of protocol writing. A Phase 1b study investigating the 
pharmacokinetics, safety and tolerability in children (2-4 years of age) with ASD 
(WP40877) is also ongoing.
1.2.1.1
Clinical Pharmacology
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 in the fed state following multiple dosing. Steady state was 
achieved after approximately 7 days; the mean apparent elimination half-life after the 
last dose (Day 14) was approximately 46 hours. Food had no relevant effect on the 
overall exposure of balovaptan. The terminal half-lives after 14 once daily dosing of 
balovaptan 10 mg for balovaptan, 
, respectively 
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.
 
 
Mean cerebral spinal fluid (CSF)-to-plasma concentration ratios of balovaptan 
 
following 7 days of dosing of 10 and 52 mg qd balovaptan were independent of dose. 
 
 
 




Balovaptan—F. Hoffmann-La Roche Ltd
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Refer to the IB for more details on non-clinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This study will investigate the effect of esomeprazole and the effect of food on the PK of 
balovaptan in healthy volunteers. Balovaptan has shown pH dependent solubility, which 
may affect its absorption at values closer to neutral pH. The 20 mg tablet used in this 
study is the highest possible dose strength of the to-be-marketed formulation.
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.


Balovaptan—F. Hoffmann-La Roche Ltd
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The balovaptan dose planned for this study is 20 mg with a single tablet of the highest 
dose strength of the final formulation that may be used in pivotal studies. Plasma 
exposures with a single dose of balovaptan 20 mg are predicted to be approximately 
8-fold below the concentrations observed after the once daily balovaptan doses for 14 
days in Study BP25694 (52 mg qd) and Studies WP40607 and WP40734 (50 mg qd; 
both studies are clinically completed but have not yet reported). The SAD part in the 
entry-into-human study (BP25694) applied single doses up to 76 mg. No safety concern 
for the administration of a single dose of 20 mg have emerged from these trials or from 
any other clinical trial. 
Esomeprazole is an approved medication, and the dose planned for this study, 40 mg qd,
is the recommended dose for the treatment of duodenal and gastric ulcers. 
While planned study treatments in this study are expected to be well tolerated, routine
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.
2.
OBJECTIVES AND ENDPOINTS
This study will investigate the effect of esomeprazole and the effect of food on the 
pharmacokinetics of balovaptan in healthy volunteers. Study objectives are presented in 
Table 1.
Table 1
Objectives and Corresponding Endpoints
Objective
Endpoints
Primary Objectives

To investigate the effect of 
esomeprazole on the PK of balovaptan 
following a single oral dose of 
balovaptan in the fasted state

To investigate the effect of a high-fat 
meal compared to the fasted state on the 
PK of balovaptan following a single oral 
dose of balovaptan

Plasma concentrations of balovaptan

Derived plasma PK parameters for 
balovaptan
Secondary Objectives

To investigate the effect of 
esomeprazole on the PK of M2 (as 
appropriate) and M3 following a single
oral dose of balovaptan in the fasted 
state

To investigate the effect of a high-fat 
meal compared to the fasted state on 
the PK of M2 (as appropriate) and M3 
following a single oral dose of 
balovaptan

Plasma concentrations of M2 and M3

Derived plasma PK parameters for M2 
and M3

To measure the PK of esomeprazole 
following 5 once daily dosing of 
esomeprazole

Plasma concentrations of esomeprazole

Derived plasma PK parameters for 
esomeprazole


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Objective
Endpoints

To investigate the safety and tolerability 
of a single 20 mg oral dose of 
balovaptan alone or in combination with 
esomeprazole in healthy subjects

Incidence and severity of AEs, incidence 
of SAEs, nonserious AESIs, and AEs 
leading to treatment withdrawal

Results of vital signs, 12-lead ECGs, 
physical examinations, and clinical 
laboratory tests
Exploratory Objectives

To explore the effect of genetic 
variations in genes associated with drug 
ADME and transport on the PK and/or 
safety profile of balovaptan.

Genotyping data for study subjects. Data 
will be reported separately if analysis is 
conducted
ADME=absorption, distribution, metabolism, excretion; AE=adverse event; AESI=adverse event of special 
interest; ECG=electrocardiogram; PK=pharmacokinetics; SAE=serious adverse event;
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This will be a single-center, part-randomized, open-label, single-dose, 3-period 
crossover study to investigate the effect of food and of esomeprazole on the PK of 
balovaptan in healthy volunteers.
Screening will be conducted between Day -28 and Day -2. 
In Period 1, eligible subjects will be admitted to the clinical research unit (CRU) on 
Day -1 (the day prior to balovaptan dosing on Day 1) and will remain confined in the 
CRU until discharge on the morning of Day 5. 
In Period 2, subjects will be re-admitted to the CRU on Day -1 (the day prior to 
balovaptan dosing on Day 1) and will remain confined in the CRU until discharge on the 
morning of Day 5.
In Period 3, subjects will return to the CRU for re-admission 5 days prior to 
administration of balovaptan (Day 9 of Period 2) to begin esomeprazole dosing. 
Esomeprazole will be dosed for 6 days: for 4 days prior to co-administration with 
balovaptan on Day 1 of Period 3, plus an additional dose on Day 2. Subjects will be 
discharged on Day 5.
In each period, following discharge from the CRU on Day 5, subjects will return to the 
CRU on Day 7 and Day 9 for further PK sampling.
There will be a washout of at least 12 days and up to 21 days between administrations
of balovaptan. Thus, re-admission for Period 2 may be between 3 to 12 days after Day 9 
of Period 1, and re-admission for Period 3 will be on Day 9 of Period 2.


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Subjects will be randomized to 1 of 2 treatment sequences (ABC or BAC) on Day 1 of 
Period 1, with the treatments being as follows:

Treatment A: 20 mg balovaptan administered as a single oral dose following 
consumption of high-fat, high-calorie meal 

Treatment B: 20 mg balovaptan administered as a single oral dose following a 
≥10-hour fast

Treatment C: 40 mg esomeprazole administered once daily for 6 days and with a 
single oral dose of balovaptan 20 mg in the fasted state 1 hour after the fifth
esomeprazole dose 
During treatment periods 1 and 2, subjects will receive each of Treatment A or B, 
according to the randomization schedule. All subjects will receive Treatment C in 
Treatment Period 3.
Subjects will return for a follow-up visit on Day 16 ± 2 of Period 3. Assessments during 
the study will be conducted according to the schedule of assessments (Appendix 1 ).
Figure 1 presents an overview of the study design. 
Figure 1
Study Schema
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last subject, last observation 
occurs, or safety follow-up is received from the last subject, whichever occurs later.


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The total length of the study, from screening of the first subject to the end of the study, is
expected to be approximately 11 weeks. For each enrolled subject the duration of the 
study from screening to last subject observation will be approximately 6 to 11 weeks.

Screening: Approximately 4 weeks (Day -28 through Day -2)

Treatment periods: 
o
Treatment Period 1: up to 3 weeks (Day -1 – Day 13, 14, 15, 16, 17, 18, 
19, 20, or 21 [12 to 21 day washout between balovaptan administrations])
o
Treatment Period 2: 2 weeks (Day -1 – Day 13)
o
Treatment Period 3: 1.5 weeks (Day -1 – Day 9)

Follow-up: up to 5 days (Day 16 ± 2 of Period 3) (at least 14 days after the final
dose of balovaptan)
3.3
RATIONALE FOR STUDY DESIGN
This study is designed to evaluate the effect of food and modification of gastric pH by 
esomeprazole on the PK of balovaptan, with the highest dose strength of the final 
formulation of balovaptan that may be used in pivotal studies. The PK parameters of 
balovaptan administered fasted with or without administration of esomeprazole, a gastric 
pH modifier, or balovaptan administered following a high-fat, high-calorie meal, will be 
compared. A crossover design was chosen to allow for within-subject assessments, 
minimizing the impact of variability across subjects on the planned analyses. An open-
label study was considered appropriate because of the objective nature of the PK 
measures.
3.3.1
Rationale for Balovaptan and Esomeprazole Dose 
3.3.1.1
Balovaptan
A dose of 20 mg balovaptan is the highest daily dose that is currently foreseen to be 
used in further clinical development.
Based on previous clinical experience, single doses of balovaptan 20 mg are expected 
to be well tolerated. The effect of food on the plasma exposure of balovaptan has 
previously been shown to be small, with in particular, a reduction in Cmax; esomeprazole 
is expected to have either no effect on or to reduce the exposure of balovaptan.
3.3.1.2
Esomeprazole
The study will examine the effect of esomeprazole 40 mg on the PK of a single dose of 
20 mg balovaptan. Esomeprazole is an approved medication, and the dose planned for 
this study, 40 mg qd, is approved for the treatment of gastric and duodenal ulcers and 
has an acceptable safety profile. During repeated once-daily dosing with an 
enteric-coated granule capsule omeprazole formulation, inhibition of acid secretion 
increases initially, and stabilizes within about 4 days (Olbe, 1989). The mean percentage 
of time with intragastric pH > 4 increases significantly after 5 days of dosing compared to 
after a single dose with esomeprazole 40 mg (Röhss, 2002). Intragastric pH rises to 


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26
above 4 about 1 hour to 2 hours after the morning of Day 5 (Lind, 2000). In the current 
study, esomeprazole 40 mg will be dosed for 4 consecutive days prior to 
coadministration with a single dose of balovaptan on the fifth day of esomeprazole 
dosing (Day 1), followed by a further single dose of esomeprazole on Day 2, to ensure 
that during any recirculation of balovaptan in the first 48 hours after administration,
inhibition of acid production is maintained.
3.3.2
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 this study. 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.
4.
MATERIALS AND METHODS
4.1
SUBJECTS
The target population will be healthy male or female volunteers aged 18 to 65 years,
inclusive. An attempt will be made to have 50% male and 50% female participants, and 
at least 30% of each sex.
Approximately 16 subjects will be enrolled, with the goal of obtaining 12 evaluable 
subjects. Enrolled subjects who withdraw from the study may be replaced at the 
discretion of the Investigator (or designee) 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 and female subjects, aged 18 to 65 years, inclusive. 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 ECGs, hematology, blood chemistry, urinalysis, and serology.
2. Body mass index (BMI) between 18 and 32 kg/m2 inclusive, at screening.
3. For women of childbearing potential: if engaging in heterosexual activity, 
agreement to use at least two adequate forms of contraception during the entire 
study and for 90 days following the last dose of study drug. Contraceptive 
measures are not required for women with exclusively same-sex partners and for 
those for whom complete abstinence is their preferred and usual lifestyle.


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a. A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (> 12 
continuous months of amenorrhea with no identified cause other than 
menopause, confirmed with follicle-stimulating hormone (FSH) ≥35 IU/L), 
and has not undergone surgical sterilization (removal of ovaries and/or 
uterus).
b. The following are adequate contraceptive methods: bilateral tubal ligation; 
sterilization of male ‘partner; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; Essure.
c.
Barrier methods alone are not considered an adequate form of 
contraception for this study and if utilized must be supplemented by one 
of the adequate methods described above. For this study barrier 
contraception methods are defined as: male or female condom with or 
without spermicide (male and female condom must not be used 
simultaneously); and cap, diaphragm, or sponge with spermicide.
d. 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:
a. With female partners of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom during sexual activity for the 
entire study 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.
4.1.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
Medical History
1.
Female subjects who are pregnant or lactating.
2.
If female, a positive serum pregnancy test at screening or at admission.
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 4 weeks prior to the
screening examination or any febrile illness within 1 week prior to screening.


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5.
History of any clinically significant, as determined by the investigator,
gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, 
cardiovascular, endocrinological, hematological, lymphatic, musculoskeletal, 
genitourinary, immunological, dermatological, or 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, 
distribution, 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 in the opinion of the Investigator hypersensitivity 
(e.g., to drugs, including balovaptan or its excipients, esomeprazole or its 
ingredients, or other proton pump inhibitors, e.g., pantoprazole, lansoprazole, 
rabeprazole, omeprazole) or allergic reactions.
9.
History or presence of clinically significant ECG abnormalities before study drug 
administration.
10. Subjects with screening or predose baseline mean QT interval corrected using 
Fridericia’s formula (QTcF) >450 msec or <300 msec (using the same upper QTcF 
limit in both males and females).
11. Notable resting bradycardia (mean HR <40 bpm) on screening or predose baseline 
ECG. Notable resting tachycardia (mean HR >100 bpm) on screening or predose 
baseline ECG.
12. 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. Isolated first degree atrioventricular block or right 
bundle branch block will not be exclusionary.
13. Confirmed (based on the average of ≥3 consecutive measurements) systolic blood 
pressure greater than 139 or less than 90 mmHg, and diastolic blood pressure 
greater than 89 or less than 45 mmHg.
14. Clinically significant abnormalities in laboratory test results (including hepatic and 
renal panels, complete blood count, chemistry panel, and urinalysis). In the case of 
uncertain or questionable results, screening tests may be repeated to confirm 
eligibility. For ANC, any result below the lower limit of normal.
15. History of coagulopathies, bleeding disorders, or blood dyscrasias.
16. Current suicidal risk, in the opinion of the Investigator.
17. Subjects with unexplained syncope during the 6 months prior to screening or with 
presyncopal and/or syncopal symptoms during orthostatic challenge testing.
18. Current smoker or user of tobacco or nicotine-containing products or subjects who 
have smoked or used tobacco or nicotine-containing products within 3 months prior 
to first study drug administration.


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19. Suspicion of or presence of a clinically relevant history of or current alcohol and/or 
other substance abuse or addiction. 
20. Alcohol consumption of >14 units per week for males and females. One unit of 
alcohol equals 12 ounces of regular beer, 5 ounces of wine or 1.5 ounces of 
80-proof spirits within 3 months of first dose of study drug.
21. Positive urine alcohol test or urine drug screen at screening or Day -1 of any 
treatment period (amphetamines [including ecstasy], barbiturates, benzodiazepines, 
cannabinoids, cocaine, cotinine, methadone, methamphetamines, and opiates).
22. Subjects on hormone replacement therapy if postmenopausal status cannot be 
ascertained from medical history or FSH levels.
23. Clinically relevant deviation from normal in the physical examination including 
vital signs, as determined by the investigator.
24. Positive result for HIV 1, HIV 2, hepatitis C virus antibody, or hepatitis B core (HBc) 
antibody. Subjects with positive antiHBc but negative hepatitis B virus surface 
antigen and negative hepatitis B viral DNA will be allowed.
25. Participation in an investigational drug or device study within 4 weeks or 5 times the 
elimination half-life, whichever is longer, prior to first dosing, or within 5 months prior 
to first administration of study drug in case of a study with a biological, as calculated 
from the day of Follow-up visit from the previous study.
26. Any donation of blood or plasma or significant blood loss within 3 months prior to 
screening.
27. Dietary restrictions that would prohibit the consumption of standardized meals or the 
high-fat, high-calorie meal planned for this study.
28. 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.
29. Subjects likely to need concomitant medication during the study (including for dental 
conditions).
30. 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 administration of study drug, 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 administration
of study drug will also be excluded unless in the opinion of the Investigator the 
medication will not interfere with the study procedures or compromise safety.
31. 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 nonprescribed systemic or topical medication

herbal remedies


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Paracetamol (up to 4 g/day 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.
32. Received any medications known to chronically alter drug absorption or elimination 
processes within 4 weeks before the first administration of study drug, unless in the 
opinion of the Investigator the medication will not interfere with the study procedures 
or compromise safety.
33. 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 administration of study drug.
34. Use of any drugs or substances, including herbal treatments, such as fluoxetine, 
fluvoxamine, aspirin, norethisterone, rifampicin, etc that are known to be substrates, 
inducers, or inhibitors of CYP2C19 within 4 weeks before the first administration of 
study drug.
35. Subjects under judicial supervision, guardianship, or curatorship.
36. Poor venous access for blood sampling.
37. Subjects who are intolerant to sucrose.
38.
Previous exposure to balovaptan.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is a single-center, part-randomized, open-label, 3-treatment, 3-period crossover 
study. Subjects will be randomly assigned in equal proportions to one of the 2 treatment 
sequences according to a computer-generated randomization scheme.
After informed consent is obtained, subjects will be screened according to the inclusion
and exclusion criteria. Subjects who have met all eligibility criteria will receive a 
randomization number on Day 1 of the first treatment period and according to the 
randomization code generated by the Biostatistics Department of PRA Health Sciences 
(PRA). Replacement subjects will receive the randomization number of the subject to be 
replaced, increased by a fixed unit (e.g., 1901 replacement number for randomization
number 1001), and will be assigned to the same treatment sequence.
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 randomization number, and only applicable data will be entered in the 
electronic case report forms (eCRFs).
4.2.1
Blinding
Not applicable; this is an open-label study.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are balovaptan and 
esomeprazole.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Balovaptan
Balovaptan 20-mg dispersible tablets (Ro 528-5119/F41) will be supplied by the Sponsor 
in high-density polyethylene bottles. Balovaptan must be stored and handled according 
to the details specified on the product label. For additional details, refer to the 
balovaptan IB.
4.3.1.2
Esomeprazole
Esomeprazole 40-mg capsules will be obtained commercially by the site. Esomeprazole 
must be stored and handled according to the specifications in the US package insert
(USPI).
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1
Refer to the balovaptan Investigator Brochure or esomeprazole USPI for detailed 
instructions on drug preparation, storage, and administration.
Cases of accidental overdose or medication error along with any associated adverse 
events, should be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation of subjects who experience 
adverse events are provided in Section 5.1.
4.3.2.1
Balovaptan
Single oral doses of balovaptan 20 mg (1 × 20 mg tablet) will be administered following
consumption of a high-fat, high-calorie meal (Treatment A), after a ≥10 h fast 
(Treatment B), and following a ≥10 h fast and coadministered with esomeprazole 40 mg 
(Treatment C) in a fasted state. Balovaptan will be administered with approximately 
240 mL of water.
For the fed treatment, balovaptan will be administered within 30 minutes of the start of 
the meal and after all of the meal has been consumed.
For fasted treatments, subjects are to continue to fast for 4 hours following dosing and 
refrain from drinking for 1 hour prior to and 1 hour after balovaptan administration,
except for water provided to take study medication.


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4.3.2.2
Esomeprazole
Single doses of esomeprazole 40 mg will be administered alone for 4 days prior to 
coadministration with balovaptan 20 mg on Day 1 of Period 3, and administered alone 
on Day 2 of Period 3. When esomeprazole is coadministered with balovaptan, 
esomeprazole will be administered 1 hour prior to balovaptan in a fasted state.
Esomeprazole will be administered with approximately 240 mL of water.
4.3.3
Investigational Medicinal Product Accountability
Balovaptan will be provided by the Sponsor. Esomeprazole will be procured by the study 
site. The study site will acknowledge receipt of balovaptan by returning to the Sponsor 
the appropriate documentation form to confirm the shipment condition and content. 
Esomeprazole shipping documents will be filed at the site. Any damaged shipments will 
be replaced. 
Balovaptan will either be disposed of at the study site according to the study site’s 
institutional standard operating procedures (SOPs) or be returned to the Sponsor with 
the appropriate documentation. The site’s method of destroying Sponsor-supplied IMPs 
must be agreed to by the Sponsor. The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. Esomeprazole will be disposed of at the study site 
according to the study site’s institutional SOPs.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, or homeopathic remedies, nutritional supplements) 
used by a subject in addition to protocol-mandated treatment from 4 weeks prior to 
initiation of study drug to the study completion/ discontinuation visit. All such medications 
should be reported to the Investigator or designee and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Existing hormonal contraceptives and hormone replacement therapy regimens may 
remain unchanged during the conduct of the study. 
Acetaminophen/paracetamol is allowed up to a maximum dose of 4 g/day within 7 days 
before study drug administration and 2 g/day within 48 hours before study drug 
administration, but total should not exceed 4 g during the week prior to dosing. Subjects 
will be instructed not to exceed these limits.


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4.4.2
Prohibited Therapy
Participation in an investigational drug study within 4 weeks or 5 times the elimination 
half-life, whichever is longer, prior to first dosing, or within 5 months prior to first dosing 
in case of a study with a biologic, as calculated from the day of follow-up from the 
previous study. Participation in an investigational device study within 4 weeks prior to
first dosing is prohibited.
Any prescribed systemic or topical medication is prohibited 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 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 are also 
prohibited unless in the opinion of the Investigator the medication will not interfere with 
the study procedures or compromise safety.
The following concomitant medications in particular are prohibited, unless an exception 
has been agreed as mentioned above.

P-gp substrates

Any inhibitor of CYP3A or CYP2C19 taken within 4 weeks (i.e. more than 5 half-
lives) prior to study drug administration, including but not limited to the following 
drugs: ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, 
ranitidine, cimetidine, fluoxetine, fluconazole, fluvoxamine, until follow-up. 
Any inducer of CYP3A or CYP2C19 taken within 4 weeks 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. Use of any nonprescribed systemic or topical medication or herbal remedies
within 7 days before the first study drug administration through follow-up is prohibited, 
unless in the opinion of the Investigator the medication will not interfere with the study 
procedures or compromise safety.
4.4.3
Prohibited Food

Consumption of methylxanthine-containing products (e.g., coffee, tea, cola, 
chocolate) will be forbidden from 48 hours prior to day of check-in to the CRU and 
during the stay.

Alcohol consumption will not be permitted 96 hours prior to admission in the clinical 
unit and until discharge from the CRU.

It is not permitted to take any nutrients known to modulate cytochrome CYP3A 
activity (e.g., grapefruit juice; Seville orange) within 2 weeks prior to first dosing until 
discharge from the CRU at the end of the study.


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
To avoid false positive drug screen results, participants should refrain from 
consuming any foods containing poppy seeds within 48 hours (2 days) prior to 
screening and day of check-in for each treatment period.
4.4.4
Additional Restrictions/Considerations

For Treatment A, high-fat, high-calorie breakfast with calculated calorific content will 
be provided. An example of a high-fat, high-calorie meal is provided in Table 2; 
components of the high-fat breakfast may be substituted as long as the total calorie 
content from fat, carbohydrates, and protein is approximately the same as listed. 
The high-fat, high-calorie meal should be consumed within 30 minutes.

On Day 1 of each study period, meals standardized with regard to timing and 
content will be provided at approximately 4 and 8 hours post-balovaptan dosing.

On all other days during confinement, there are no specific meal requirements; 
meals and snacks will be provided according to PRA SOPs. 

Subjects should refrain from strenuous exercise at least 72 hours prior to dosing 
until discharge from the unit in each period.

While in the CRU, subjects will be allowed to consume water ad libitum, except for 
1 hour before and 1 hour after oral dosing with balovaptan. Subjects will be provided 
guidance at CRU admission, for each treatment period, that they should avoid 
excessive fluid intake during the study. Excessive fluid intake for this study is 
defined as 3 L (100 fl oz) per day. Clinic staff will provide guidance as to 
approximate number of drinks in 3 liters as part of the subject orientation process at 
admission. However, the clinical site will not be required to measure, or record fluid 
intake.

Alcohol consumption will not be allowed 96 hours before the day of admission to the 
CRU and while staying in the CRU. Additional alcohol/drugs of abuse testing may 
be employed throughout the study to verify compliance. For other days during the 
study, alcohol must be restricted to no more than 2 drinks per day (one drink is 
equal to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80 proof spirits). 
Table 2
Example of a Standard High-Fat, High-Calorie Breakfast
Food item
Calories
Fat (g)
Carbohydrates (g)
Protein (g)
2 large eggs fried in 14 g (1 Tbsp) of 
butter
219
19
0
12
4 strips bacon 
140
12
0
8
½ cup (115 g) fried hash brown 
potatoes
128
0
26
6
2 slices toasted wheat bread
129
1
22
8
4 packets of butter, 5 g each
144
16
0
0
8 oz whole milk
148
8
11
8
Totals
908
56
59
42
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.


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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 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 or designee will maintain a 
screening log to record details of all subjects screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
4.5.2
Medical History, Baseline Conditions, 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 4 weeks prior 
to initiation of study treatment will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination will be performed at screening and at the follow-up visit
(Appendix 1). The examination should include an evaluation of the head, eyes, ears, 
nose, and throat; and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and genitourinary (at the Investigator discretion) systems. Any clinically 
significant abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. Changes from baseline abnormalities should be 
recorded in subject notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF and source form.
4.5.4
Vital Signs
Oral body temperature, pulse rate, blood pressure, and respiratory rate will be measured 
at the time points described 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.
4.5.4.1
Orthostatic Challenge Testing
Orthostatic challenge testing will be performed at Screening. 


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During a 15-minute period during which subjects will remain in a supine position, blood 
pressure according to the Riva-Rocci method and pulse rate will be measured after 10 
and 15 minutes. If the second blood pressure measurement deviates from the previous 
measurement by more than 5 mmHg, another 5-minute extension period will be added, 
and blood pressure and pulse rate will be obtained after 20 minutes in the supine 
position.
The subject will then be asked to erect rapidly into a standing position, and blood 
pressure and pulse rate will be assessed again after 3 minutes of standing.
Standing blood pressure and pulse rates will be compared against the latest blood 
pressure and pulse rate values obtained in the supine position. Orthostatic hypotension 
is defined as a decrease in systolic blood pressure by at least 20 mmHg and/or a 
decrease in diastolic blood pressure by at least 10 mmHg.
Such changes used to define orthostatic hypotension or pre-syncopal/syncopal events 
during standing will result in exclusion.
4.5.5
Clinical Laboratory 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 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 
samples be destroyed, or local laws require destruction of the samples. However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
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 or 
designee if the results of any test falls outside the reference ranges, or clinical symptoms 
necessitate additional testing to monitor subject safety. Subjects must fast for at least 8 
hours prior to laboratory safety assessments (except for urine assessments).
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, MCH, 
MCV, WBC and differential count, including absolute counts and percentages
[neutrophils, eosinophils, basophils, monocytes, lymphocytes] 


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
Urinalysis: A midstream, clean-catch urine specimen will be collected for dipstick 
analysis of pH, glucose, leucocytes, nitrites, protein, and blood. Microscopy to be 
performed if abnormalities are observed and deemed necessary by the Investigator, 
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

Coagulation: prothrombin time (international normalized ratio) and activated 
thromboplastin time 

Blood chemistry panel: sodium, potassium, glucose (fasting), creatinine, albumin, 
total and conjugated bilirubin, alkaline phosphatase, alkaline aminotransferase 
(ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase, creatine 
phosphokinase (CPK), lactate dehydrogenase, total cholesterol and, triglycerides

Drugs of abuse (including amphetamines [including ecstasy], barbiturates, 
benzodiazepines cannabinoids, cocaine, cotinine, opiates, methamphetamines, and 
methadone) and alcohol will be measured in urine at Screening and day of 
admission for each treatment period. Further testing may be performed throughout 
the study to confirm compliance, at the discretion of the Investigator.

Viral serology: HIV -1 and -2 antibodies, hepatitis B core antibody (anti-HBc), 
hepatitis C virus antibody at screening; hepatitis B surface antigen and hepatitis B 
viral DNA will be assessed at screening if anti-HBc is positive

Pregnancy test: beta-human chorionic gonadotropin (serum pregnancy test) will be 
performed at screening and day of admission of each treatment period and at 
follow-up for all female subjects.

Follicle-stimulating hormone: at screening for postmenopausal women to confirm 
menopause
4.5.6
Pharmacokinetic Samples
PK samples for analysis of balovaptan and for analysis of esomeprazole will be taken via 
an indwelling catheter or by direct venipuncture at the time points indicated in 
Appendix 1.
For additional sampling procedures, storage conditions, and shipment instructions, see 
the Pharmacokinetic and Clinical Genotyping Sample Manual.
4.5.7
Genotyping Samples
A mandatory whole blood sample will be taken for DNA extraction from every subject 
during the study on Day -1 of Treatment 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 Clinical Study Report has been issued.


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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. 
4.5.8
Electrocardiograms
Safety 12-lead ECG assessments will be performed in this study at the timepoints 
indicated in Appendix 1. Safety 12-lead ECGs will be performed in triplicate at Screening 
and Day-1; single ECGs will be performed at all other time points. These ECG 
recordings will only be used to assess/define a safety baseline and determine the 
immediate safety of each subject during each treatment period. Safety ECG recordings 
may be obtained at unscheduled timepoints as required by the Investigator, or designee,
to ensure the safety of study subjects. For safety monitoring purposes, the Investigator,
or designee, must review, sign, and date all ECG tracings.
4.5.9
Drug and Metabolite Concentration Measurements
For each treatment period plasma samples will be collected, as described in Appendix 1,
to determine concentrations of balovaptan and its metabolites M2 (as appropriate) and 
M3 utilizing a specific and validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) method. In Period 3, plasma samples to determine concentrations of 
esomeprazole will be collected, and concentrations will be determined using a separate 
specific and validated LC-MS/MS method.
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, when possible: 

12-lead ECGs

Vital signs measurements

PK blood sampling

Laboratory tests
For PK assessments, the following windows are recommended: -30 minutes for predose 
time points; ± 5 minutes for time points within the first 36 hours post dose; ±10 minutes 
for the next time points up to 96 hours post dose; and ±12 hours for Day 7 and Day 9 
samples. Actual sampling times will be recorded.


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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, designee or Sponsor determines may 
jeopardize the subject’s safety if he or she continues to receive study treatment. 
Section 5.1.1 provides additional guidance on the management of toxicities and of 
subjects who experience AEs within the outline of specific stopping rules.

Investigator, designee or Sponsor determines it is in the best interest of the subject

Pregnancy

QTcF > 500 ms or QTcF increase from baseline > 60 ms
 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Subjects who discontinue study treatment may be replaced.
Subjects who terminate the study early while admitted to the CRU will have safety 
assessments performed as indicated for the Follow-up visit in Appendix 1 prior to 
discharge. In addition, subjects will be encouraged to return to the clinic for a Follow-up 
visit at least 14 days after the final dose of balovaptan.
4.6.2
Subject Discontinuation from the Study
Subjects will return to the CRU for a follow-up visit on Day 16 ± 2 of Period 3.
Subjects have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the Investigator or designee has the right to withdraw a subject from the 
study at any time. Reasons for subject discontinuation from the study may include, but
are not limited to, the following:

Subject withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Subject noncompliance, defined as failure to comply with protocol requirements 
as determined by the Investigator, designee or Sponsor
Every effort should be made to obtain a reason for subject discontinuation from the study. 
The primary reason for withdrawal from the study should be documented on the 


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appropriate eCRF. Subject requests to be withdrawn from the study must be 
documented in the source documents and signed by the Investigator (or designee). 
Subjects who withdraw from the study may be replaced at the discretion of the 
Investigator or Sponsor.
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
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Noncompliance with the International Council for Harmonisation (ICH) guideline for 
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 in any country 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. Please refer to the balovaptan (RO5285119) IB for a 
complete summary of the safety information available for the balovaptan.
 
 
 




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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 (AESI), 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. The 
schedule for conducting these activities is provided in Appendix 1.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice (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) (Section 5.3.5.8).

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
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 or designee, places the 
subject at immediate risk of death)
o
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 subject hospitalization (Section 5.3.5.9)




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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all AEs are recorded on the Adverse 
Event eCRF and source form 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 and source form, the Investigator or 
designee will make an assessment of seriousness (see Section 5.2.2), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1
Adverse Event Reporting Period
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 source form.
After informed consent has been obtained but prior to initiation of study drug, only SAEs
caused by a protocol-mandated intervention (e.g., 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 14 days after the final
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 nondirective questioning should be adopted for eliciting AE
information. 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 3 provides guidance for assessing AE severity.


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Table 3
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 an SAE (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigator or designees 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 4)

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 nontreatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the AE suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the AE and 
administration of the study drug, and the AE cannot be readily explained by the 
subject's clinical state, intercurrent illness, or concomitant therapies; and/or the AE
follows a known pattern of response to the study drug; and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge.
NO
An AE will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the study drug 
(e.g., cancer diagnosed 2 days after first dose of study drug).
For subjects receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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5.3.5
Procedures for Recording Adverse Events
Investigator or designees should use correct medical terminology/concepts when 
recording AEs on the Adverse Event eCRF and source form. Avoid colloquialisms and 
abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF and 
source form.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF and source form
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 and source form. 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.
5.3.5.2
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 and source form. 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.
All AEs should be recorded separately on the Adverse Event eCRF and source form if it 
is unclear as to whether the events are associated.
5.3.5.3
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 source form. The initial severity (intensity or grade) of the event will be 


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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 
source form. 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 and source form
should be updated by changing the event from "nonserious" 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 source form.
5.3.5.4
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 or designee’s judgment 
It is the Investigator or designee’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 source 
form.
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 source form, 
along with a descriptor indicating whether the test result is above or below the normal 
range (e.g., "elevated potassium," as opposed to "abnormal potassium"). If the 
laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the 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 and source form (see 
Section 5.3.5.3 for details on recording persistent AEs).


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5.3.5.5
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 or designee’s judgment 
It is the Investigator or designee’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 source form.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF and source form (see 
Section 5.3.5.3 for details on recording persistent AEs).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law). Therefore, Investigator or designees 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 and source form (see 
Section 5.3.5.1) and reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event), either as a SAE or an AESI (see Section 5.4.2).
5.3.5.7
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 source form 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 


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concept on the Adverse Event eCRF and source form. 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 
and source form. 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.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF and source form, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
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 a 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:
o
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
o
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 a 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 or designee
must report such events to the Sponsor immediately; under no circumstances should 
reporting take place more than 24 hours after the Investigator or designee learns of the 
event. The following is a list of events that the Investigator or designee 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)
 see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For SAEs and AESIs, the Investigator or designee must report new significant follow-up 
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
Investigator or designees 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:
, MD (Primary)
Telephone No.:
 
Mobile Telephone No.:
Medical Monitor:
, MD (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 or designee
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 or designees. 
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/AE of Special Interest Reporting Form provided to Investigator or 
designees 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 
Investigator.
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 up to 
14 days after the final dose of study drug. Investigator or designees 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 14 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 or designee if they become pregnant during the study or within 90 days after 
the final 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 the Investigator. Pregnancy 
should not be recorded on the Adverse Event eCRF and source form. The Investigator 
or designee should discontinue the study drug and counsel the subject, discussing the 
risks of the pregnancy and the possible effects on the fetus. Monitoring of the subject


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should continue until conclusion of the pregnancy. Any SAE 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 and source form. In addition, the Investigator or designee 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 Informed Consent Form to immediately 
inform the Investigator or designee if their partner becomes pregnant during the study or 
within 90 days after the final 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 or 
designee should submit a Clinical Trial Pregnancy Reporting Form when updated
information on the course and outcome of the pregnancy becomes available. An 
Investigator or designee 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
A spontaneous abortion should be classified as an SAE (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF and source 
form, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as an 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). A therapeutic or elective abortion 
performed for reasons other than an underlying maternal or embryofetal toxicity is not 
considered an AE.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.


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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 an SAE, recorded on the Adverse Event form, 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

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 adverse events but may result in adverse 
events. 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.
In addition, all special situations associated with balovaptan, regardless of whether they 
result in an AE, should be recorded on the Adverse Event eCRF as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

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.


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
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.
As an example, an accidental overdose that resulted in a headache would require 2
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache. The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.5
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator or designee should follow each AE until the event has resolved to baseline 
grade or better, the event is assessed as stable by the Investigator or designee, the subject
is lost to follow-up, 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 adverse events (with dates) should be documented 
on the Adverse Event eCRF and source form 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, 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 or designee becomes aware of any 
SAE that occurs after the end of the AE reporting period (defined as 14 days after the 
final dose of study drug), if the event is believed to be related to prior study drug 
treatment. These events should be reported through use of the Adverse Event eCRF 
and source form. The Investigator or designee 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.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and AESI against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigator (or designee), IRBs, ECs, and applicable health authorities based on 
applicable legislation.
Independent from the causality assessment, the following SAEs and non-SAEs of 
special interest will be reported to the FDA on an expedited basis: death, arrhythmia, 
syncope, dyspnea, palpitations, and chest pain. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events through use of the reference safety information in the 
documents listed below:
Drug
Document
Balovaptan
RO5285119 V1a Receptor Antagonist (Balovaptan) 
Investigator's Brochure
Esomeprazole
Esomeprazole US Package Insert
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator or designee's assessment 
of causality and seriousness, with allowance for upgrading by the Sponsor as needed.
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
A statistical analysis plan will be generated and will be finalized prior to database lock. 
6.1
DETERMINATION OF SAMPLE SIZE
Sixteen subjects will be enrolled with the target of at least 12 evaluable subjects 
available for the final PK analysis. Considering the observed residual CV% for AUC0-inf 
from Study WP40038 of approximately 14%, with 12 subjects the 90% CI would be 
obtained by dividing/multiplying the ratio estimate by a factor of 1.11.
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. 


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Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
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 treatment 
sequence.
6.4
EFFICACY ANALYSES
Not Applicable
6.5
SAFETY ANALYSES
The Safety population will include all subjects who are randomized and receive at least 
one dose of the study medication (either balovaptan or esomeprazole), whether 
prematurely withdrawn from the study or not.
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.
Study treatment exposure (such as treatment, duration [as applicable], and total dose 
received) will be summarized with descriptive statistics.
All verbatim AE terms will be mapped to Medical Dictionary for Regulatory Activities 
thesaurus terms, and AE severity will be graded according to Table 3. All AEs, SAEs, 
AEs leading to death, AESIs, and AEs leading to study treatment discontinuation that 
occur on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade. For events of varying severity, the highest grade will be used in the summaries.
Deaths and cause of death will be summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, and 
temperature), and ECG data will be displayed by time, with grades identified where 
appropriate. Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum postbaseline severity grade. Changes in vital 
signs and ECGs will be summarized.
6.6
PHARMACOKINETICS ANALYSES
The PK population will include all subjects who receive at least 1 dose of balovaptan and 
have sufficient evaluable concentrations to determine the overall exposure to balovaptan.
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 


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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 lock.
The following balovaptan, metabolites M2 (as appropriate) and M3, and esomeprazole 
PK parameters will be estimated:

Cmax: maximum plasma concentration

AUC(0-inf): area under the concentration-time curve from time extrapolated to infinity 

AUC(0-24h): area under the concentration-time curve from time 0 to 24 hours 

AUClast: area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration 

Tmax: time to reach Cmax in plasma 

Clast: last quantifiable concentration 

Tlast: time to the last quantifiable concentration 

Tlag: time between dosing and time of first balovaptan plasma concentration.

Cl/F: apparent clearance

Vd/F: apparent volume of distribution

T1/2: terminal elimination phase half-life
Individual and mean concentration versus time data will be plotted on linear and 
semilogarithmic scales. Plasma concentrations and derived plasma PK parameters will 
be listed for balovaptan and its metabolites. Summary statistics of PK parameters, 
including means, geometric means, medians, ranges, SD, CV% will be presented for 
each treatment. Analysis of variance models will be applied to the logarithmically 
transformed PK parameters of balovaptan AUC0-inf and Cmax, to investigate 1) the relative 
bioavailability of balovaptan 20-mg dispersible tablets administered following a high-fat, 
high-calorie meal vs in the fasted state, and 2) the relative bioavailability of balovaptan 
20-mg dispersible tablets administered in the fasted state either alone or in combination 
with esomeprazole.
The effect of food on the PK of balovaptan will be assessed using the ratio and 90% CIs 
of the geometric least squares (LS) means of the plasma PK parameters Cmax and 
AUC0-inf for balovaptan. A linear mixed model with fixed effects for treatment, period, 
sequence, and a random effect for subject nested in sequence will be used on the 
natural log-transformed parameters. Point estimates on the natural log scale will be 
exponentiated to obtain point estimates on the original scale of measurement. Geometric 
LS means will be provided for each treatment. Food had no relevant effect on the overall 
exposure of the capsule formulation of balovaptan but Tmax was shifted from 1 hour after 
dosing under fasted conditions to approximately 3 hours in fed conditions.


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The effect of esomeprazole on the PK of balovaptan will be assessed using the ratio and 
90% CIs of the geometric LS means of the plasma PK parameters: Cmax and AUC0-inf for 
balovaptan. A linear mixed model with a fixed effect for treatment and a random effect 
for subject will be used on the natural log-transformed parameters. Point estimates on 
the natural log scale will be exponentiated to obtain point estimates on the original scale 
of measurement. LS geometric means will be provided for each treatment.
In all comparisons, balovaptan under fasted conditions will be used as the reference. No 
adjustments will be made for multiplicity.
PK parameters will be estimated using standard noncompartmental methods. 
Additional PK analyses maybe be conducted as appropriate for balovaptan, M2, and M3.
6.7
OTHER ANALYSES
6.7.1
Clinical Genotyping
The effect of genetic variations in genes associated with drug ADME (see Appendix 2) 
on the PK and/or the safety profile of balovaptan may be evaluated.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
PRA will be responsible for data management of this study, including quality checking of 
the data. Data entered manually will be collected through use of eCRFs. In the event of 
discrepant data, the Sponsor will request data clarification from the sites.
PRA will produce a Data Management Plan that describes the quality checking to be 
performed on the data. Central laboratory data (safety) will be sent directly to PRA using 
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 contract research organization (CRO)
and records retention for the study data will be consistent with the CRO’s standard 
procedures. eCRFs 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. 


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a PRA EDC system. Sites will receive 
training and have access to a manual for appropriate eCRF completion. eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee.
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgment 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, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments (e.g., ECG), 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 Investigator (or designees) 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 


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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 outcome data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer. After that period of time, the documents may be 
destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
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 applicable 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 Application will 
comply with US FDA regulations and applicable local, state, and federal laws. Studies 
conducted in the EU or European Economic Area will comply with the EU Clinical Trial 
Directive (2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site. If applicable, it will be provided in a certified translation of 
the local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission. The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The Investigator or authorized designee will explain to each subject the 
objectives, methods, and potential risks associated with each optional procedure. 
Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a subject's agreement to participate in optional procedures. Subjects who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
subject is participating in the study, the subject or a legally authorized representative
must re-consent by signing the most current version of the Consent Forms or the
addendum, in accordance with applicable laws and IRB/EC policy. For any updated or 
revised Consent Forms, the case history or clinical records for each subject shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the subject or the subject’s
legally authorized representative. All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include subject authorization to allow use and disclosure 
of personal health information in compliance with the US Health Insurance Portability 
and Accountability Act (HIPAA) of 1996. If the site utilizes a separate Authorization Form 
for subject authorization for use and disclosure of personal health information under the 
HIPAA regulations, the review, approval, and other processes outlined above apply 
except that IRB review and approval may not be required per study site policies
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 


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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. Investigator or designees are also 
responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigator or designees must comply with requirements for reporting SAEs to the local 
health authority and IRB/EC. Investigator or designees may receive written IND safety 
reports or other safety-related communications from the Sponsor. Investigator or 
designees are responsible for ensuring that such reports are reviewed and processed in 
accordance with health authority requirements and the policies and procedures 
established by their IRB/EC and archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the subject, 
unless permitted or required by law.
Medical information may be given to a subject's personal physician or other appropriate 
medical personnel responsible for the subject's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law. The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
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.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study. These data 
may be combined with or linked to other data and used for research purposes, to 


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advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease. In addition, redacted Clinical Study Reports
and other summary reports will be provided upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC 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 
or designee 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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan.


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9.4
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 or 
designee 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.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
has contracted PRA Health Science, which will be delegated responsibility for various 
aspects of this clinical trial.
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5. 
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request. For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report. In addition, for all clinical trials in subjects involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation. This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator.


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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
Shin JY, Roughead EE, Park BJ, et al. Cardiovascular safety of methylphenidate 
among children and young people with attention-deficit/hyperactivity disorder 
(ADHD):nationwide self-controlled case series study. BMJ. 2016;353:i2550.
Al-Mosalem OA, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to 
energy metabolism in Saudi autistic children. Clinical biochemistry. 2009 Jul 
1;42(10-11):949-57.
World Medical Association. World Medical Association Declaration of Helsinki: 
ethical principles for medical research involving human subjects. Jama. 2013 
Nov 27;310(20):2191.
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E3: Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95), November 1995
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite
Guideline, E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Note for Guidance on Clinical Safety Data Management, 
June 1995
Olbe L, Cederberg C, Lind T, Olausson M. Effect of omeprazole on gastric acid 
secretion and plasma gastrin in man. Scand J Gastroenterol Suppl. 1989;166:27-
32; discussion 41-2. Review.
Röhss K, Hasselgren G, Hedenström H. Effect of esomeprazole 40 mg vs 
omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of 
gastroesophageal reflux disease. Dig Dis Sci. 2002 May;47(5):954-8.
Lind T, Rydberg L, Kyleback A, Jonsson A, Andersson T, Hasselgren G, Holmberg J, 
Röhss K: Esomeprazole provides improved acid control vs. omeprazole in 
patients with symptoms of gastro-oesophageal reflux disease. Aliment 
Pharmacol Ther 2000;14:861–867. 12 


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Appendix 1
Schedule of Activities
Scr
Period 1
Period 2
Period 3
F/U 
D -28 
to -2
D 
-1
D
1
D
2
D 3 
& 4
D
5
D
7
D
9
w/
o
D 
-1
D1
D
2
D 3 
& 4
D
5
D
7
D 
9
D10 
to 
D12
D 
13a
D
-1a
D
1
D
2
D 3 
& 4
D
5
D
7
D
9
D16
±2 or 
ET
Written informed 
consent
X
12 to 21 days between balovaptan administrations
Inclusion and 
exclusion criteria
X
X
X
X
Demographics
X
Medical history
X
Medication history
X
Confinement
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge
X
X
X
Ambulatory visits
X
X
X
X
X
X
Randomization
X
Balovaptan 
administrationb
X
X
X
Esomeprazole 
administration
X
X
Xc
X
Standardized 
mealsd
X
X
X
PK sampling 
balovaptane
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling 
esomeprazolef
X
Physical 
examination
X
X
Height, weight, 
and BMIg
X
X
12-lead ECGh
X
X
X
X
X
X
X
Vital signsi
Xj
X
Xk
X
X
Xk
X
X
X
Xk
X
X
Hematology
X
X
X
X
X
X
X
X
X


Appendix 1: Schedule of Activities
Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP41047 v1.0
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Scr
Period 1
Period 2
Period 3
F/U 
D -28 
to -2
D 
-1
D
1
D
2
D 3 
& 4
D
5
D
7
D
9
w/
o
D 
-1
D1
D
2
D 3 
& 4
D
5
D
7
D 
9
D10 
to 
D12
D 
13a
D
-1a
D
1
D
2
D 3 
& 4
D
5
D
7
D
9
D16
±2 or 
ET
Biochemistry
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
Coagulation
X
X
X
Urine drug and 
alcohol screenl
X
X
X
X
Serology
X
Pregnancy testm
X
X
X
X
X
FSHn
X
Genotyping 
sample
X
Adverse event 
monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ET=early termination; F/U= follow-up; FSH=follicle-stimulating hormone; w/o=washout
a.
Day 13 of Period 2 is Day -1 of Period 3.
b.
Balovaptan will be administered following a high-fat, high-calorie meal (Treatment A) or after a ≥10 h fast (Treatments B and C). Subjects should fast for 4 hours after balovaptan 
administration and refrain from drinking for 1 hour prior to and 1 hour post dose.
c.
Esomeprazole will be administered 1 hour prior to balovaptan. 
d.
Standardized meals will be provided at approximately 4 and 8 hours post-balovaptan dosing in each treatment period
e.
Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose
f.
Samples at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose of esomeprazole
g.
Height, weight, and BMI calculation at screening; only weight at all follow-up.
h.
Safety ECG will be performed in triplicate at Screening and on Day -1 of each period; at all other time points single ECGs will be performed.
i.
Body temperature and respiratory rate will be measured at Screening and Day -1 of each period only.
j.
Orthostatic challenge testing with be performed at screening.
k.
On Day 1, vital signs measurements will be performed at 1 hour post dose.
l.
Drugs of abuse (amphetamines [including ecstasy], barbiturates, benzodiazepines cannabinoids, cocaine, cotinine, opiates, methamphetamines, and methadone).
m. Serum pregnancy test performed on all female subjects at Screening and Day -1 of each treatment period (Day 13 of Period 2 is Day -1 of Period 3) and at follow-up.
n.
In postmenopausal women to confirm menopause


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Appendix 2: List of DMET™(Drug Metabolism Enzymes and 
Transporters) Genes