Clinical trial NCT03579719
Conditions: Healthy Volunteers
Sponsor: Hoffmann-La Roche
Start date: 2018-07-10; Completion date: 2018-11-09
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study was a non-randomized, open-label, one-sequence, two-period within-subject study to investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy male and female volunteers using itraconazole as a CYP3A inhibitor. The study was conducted at 1 site in the Netherlands.

Detailed description:

Arms: arm 1: Dosing in Period 1 was separated by at least a 7 day washout period before dosing starts in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Interventions: intervention 1: Balovaptan intervention 2: Itraconazole
Intervention descriptions: intervention 1: In Period 1, balovaptan was administered orally once daily (qd) on Days 1 to 10.

In Period 2, balovaptan was administered qd on Days 6 to 20. intervention 2: In Period 2, 200 mg itraconzole was administered bid for 4 days and qd on Days 5-20, approximately 12 hours apart. On Days 6-20, 200 mg itraconazole was administered qd.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
ONE-SEQUENCE, TWO-PERIOD WITHIN-SUBJECT 
STUDY TO INVESTIGATE THE EFFECT OF 
ITRACONAZOLE ON THE PHARMACOKINETICS OF 
MULTIPLE DOSES OF BALOVAPTAN IN HEALTHY 
VOLUNTEERS 
NCT Number: 
NCT03579719 
Document Date: 
Protocol version 1: 18-May-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. 
However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, 
Inc. in the United States. The information contained in this document, especially any unpublished data, 
is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information will not 
be disclosed to others without written authorization from Roche except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered.
Balovaptan—F. Hoffmann-La Roche Ltd
Protocol WP40609, Version 1.0
PROTOCOL
TITLE:
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
ONE-SEQUENCE, TWO-PERIOD WITHIN-SUBJECT 
STUDY TO INVESTIGATE THE EFFECT OF 
ITRACONAZOLE ON THE PHARMACOKINETICS OF 
MULTIPLE DOSES OF BALOVAPTAN IN HEALTHY 
VOLUNTEERS
PROTOCOL NUMBER:
WP40609
VERSION NUMBER:
1.0
EUDRACT NUMBER:
2018-001454-10
IND NUMBER:
NA
TEST PRODUCT:
Balovaptan (RO5285119)
MEDICAL MONITOR:
, MD
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below
 
18-May-2018 06:54:49
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Balovaptan—F. Hoffmann-La Roche Ltd
2/Protocol WP40609, Version 1.0
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 8
PROTOCOL SYNOPSIS ...................................................................................... 9
1.
BACKGROUND .......................................................................................... 17
1.1
Autism Spectrum Disorder..................................................... 17
1.2
Background on Balovaptan.................................................... 18
1.2.1
Previous and Ongoing Clinical Studies.................................. 20
1.2.1.1
Clinical Pharmacology ........................................................... 20
1.2.1.2
Safety .................................................................................... 21
1.3
Study Rationale and Benefit-Risk Assessment...................... 22
2.
OBJECTIVES AND ENDPOINTS ............................................................... 23
3.
STUDY DESIGN......................................................................................... 25
3.1
Description of the Study......................................................... 25
3.2
End of Study and Length of Study......................................... 27
3.3
Rationale for Study Design.................................................... 27
3.3.1
Rationale for Open Label Design........................................... 27
3.3.2
Rationale for Balovaptan and Itraconazole Dose 
and Schedule......................................................................... 27
3.3.2.1
Balovaptan............................................................................. 27
3.3.2.2
Itraconazole........................................................................... 28
3.3.3
Rationale for Sentinel Group ................................................. 28
3.3.4
Rationale for Study Population .............................................. 29
4.
MATERIALS AND METHODS .................................................................... 29
4.1
Subjects................................................................................. 29
4.1.1
Inclusion Criteria.................................................................... 29
4.1.2
Exclusion Criteria................................................................... 30
4.2
Method of Treatment Assignment and Blinding..................... 33
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 33
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 33
4.3.1.1
Balovaptan............................................................................. 33


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3/Protocol WP40609, Version 1.0
4.3.1.2
Itraconazole........................................................................... 33
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 33
4.3.2.1
Balovaptan............................................................................. 34
4.3.2.2
Itraconazole........................................................................... 34
4.3.3
Investigational Medicinal Product Accountability ................... 34
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 35
4.4.1
Permitted Therapy................................................................. 35
4.4.2
Prohibited Therapy ................................................................ 35
4.4.3
Prohibited Food ..................................................................... 36
4.4.4
Additional Restrictions ........................................................... 36
4.5
Study Assessments ............................................................... 36
4.5.1
Informed Consent Forms and Screening Log........................ 36
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 37
4.5.3
Physical Examinations........................................................... 37
4.5.4
Vital Signs.............................................................................. 37
4.5.4.1
Orthostatic Challenge Testing ............................................... 37
4.5.5
Laboratory, Pharmacokinetic, and Genotyping 
Samples................................................................................. 38
4.5.5.1
Laboratory Samples .............................................................. 38
4.5.5.2
Pharmacokinetic Samples ..................................................... 39
4.5.5.3
Genotyping Samples ............................................................. 39
4.5.6
Electrocardiograms................................................................ 39
4.5.7
Columbia Suicide Severity Rating Scale................................ 39
4.5.8
Drug and Metabolite Concentration 
Measurements....................................................................... 39
4.5.9
Timing of Study Assessments ............................................... 40
4.6
Treatment, Subject, Study, and Site 
Discontinuation...................................................................... 40
4.6.1
Study Treatment Discontinuation........................................... 40
4.6.2
Subject Discontinuation from Study....................................... 40
4.6.3
Study Discontinuation............................................................ 41
4.6.4
Site Discontinuation............................................................... 41




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5.3.5.7
Deaths ................................................................................... 54
5.3.5.8
Pre-existing Medical Conditions ............................................ 55
5.3.5.9
Hospitalization or Prolonged Hospitalization.......................... 55
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 56
5.4.1
Emergency Medical Contacts................................................ 56
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 57
5.4.2.1
Events That Occur Prior to Study Drug Initiation ................... 57
5.4.2.2
Events That Occur after Study Drug Initiation........................ 57
5.4.3
Reporting Requirements for Pregnancies.............................. 57
5.4.3.1
Pregnancies in Female Subjects ........................................... 57
5.4.3.2
Pregnancies in Female Partners of Male 
Subjects................................................................................. 58
5.4.3.3
Abortions ............................................................................... 58
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 58
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 58
5.4.5
Reporting Requirements for Medical Device 
Complaints............................................................................. 59
5.5
Follow-Up of Subjects after Adverse Events.......................... 60
5.5.1
Investigator Follow-Up........................................................... 60
5.5.2
Sponsor Follow-Up ................................................................ 60
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 60
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 60
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 61
6.1
Determination of Sample Size ............................................... 61
6.2
Summaries of Conduct of Study............................................ 61
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 61
6.4
Efficacy Analyses .................................................................. 61
6.5
Safety Analyses..................................................................... 62


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6/Protocol WP40609, Version 1.0
6.6
Pharmacokinetic Analyses..................................................... 62
6.7
Other Analyses...................................................................... 63
6.7.1
Genotyping ............................................................................ 63
6.8
Interim Analyses .................................................................... 63
7.
DATA COLLECTION AND MANAGEMENT ............................................... 63
7.1
Data Quality Assurance......................................................... 63
7.2
Electronic Case Report Forms............................................... 64
7.3
Electronic Patient-Reported Outcome ................................... 64
7.4
Source Data Documentation.................................................. 64
7.5
Use of Computerized Systems .............................................. 65
7.6
Retention of Records............................................................. 65
8.
ETHICAL CONSIDERATIONS.................................................................... 65
8.1
Compliance with Laws and Regulations ................................ 65
8.2
Informed Consent.................................................................. 66
8.3
Institutional Review Board or Ethics Committee.................... 66
8.4
Confidentiality........................................................................ 67
8.5
Financial Disclosure .............................................................. 67
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 68
9.1
Study Documentation ............................................................ 68
9.2
Protocol Deviations................................................................ 68
9.3
Site Inspections ..................................................................... 68
9.4
Administrative Structure......................................................... 68
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 68
9.6
Protocol Amendments ........................................................... 69
10. REFERENCES ........................................................................................... 70
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 24
Table 2
Adverse Event Severity Grading Scale ....................................... 50
Table 3
Causal Attribution Guidance ....................................................... 51


Balovaptan—F. Hoffmann-La Roche Ltd
7/Protocol WP40609, Version 1.0
LIST OF FIGURES
Figure 1
Study Schema............................................................................ 26
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 71
Appendix 2
Schedule of Pharmacokinetic Sampling, Electrocardiogram, 
and Vital Signs Measurements ................................................... 74


Balovaptan—F. Hoffmann-La Roche Ltd
8/Protocol WP40609, Version 1.0
PROTOCOL ACCEPTANCE FORM
TITLE:
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-
LABEL, ONE-SEQUENCE, TWO-PERIOD WITHIN-
SUBJECT STUDY TO INVESTIGATE THE EFFECT 
OF ITRACONAZOLE ON THE 
PHARMACOKINETICS OF MULTIPLE DOSES OF 
BALOVAPTAN IN HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
WP40609
VERSION NUMBER:
1.0
EUDRACT NUMBER:
2018-001454-10
IND NUMBER:
NA
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 as instructed by your local study monitor to the contact provided below.
 
Product Development Global Operations
Roche Products Limited
6 Falcon Way, Shire Park
Welwyn Garden City,
AL7 1TW, United Kingdom


Balovaptan—F. Hoffmann-La Roche Ltd
9/Protocol WP40609, Version 1.0
PROTOCOL SYNOPSIS
TITLE:
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, ONE-
SEQUENCE, TWO-PERIOD WITHIN-SUBJECT STUDY TO 
INVESTIGATE THE EFFECT OF ITRACONAZOLE ON THE 
PHARMACOKINETICS OF MULTIPLE DOSES OF BALOVAPTAN 
IN HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
WP40609
VERSION NUMBER:
1.0
EUDRACT NUMBER:
2018-001454-10
IND NUMBER:
NA
TEST PRODUCT:
Balovaptan (RO5285119)
PHASE:
I
INDICATION:
Not applicable
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will investigate the effect of itraconazole treatment on the PK of balovaptan and its 
major metabolites M2 and M3.
Objectives
Endpoints
Primary
To investigate the effect of itraconazole 
treatment on the PK of balovaptan and its 
major metabolites M2 (as applicable) and M3,
at steady state
Primary PK endpoints: balovaptan, M2, and 
M3 maximum observed plasma concentration
(Cmax) and area under the concentration vs 
time curve over the dosing interval (AUC0-τ)
after 15 days of balovaptan once daily (qd)
dosing in Period 2, and after 10 days of 
balovaptan qd dosing in Period 1 
Additional PK endpoints: balovaptan, M2, and 
M3 time to maximum observed plasma 
concentration (Tmax), trough plasma 
concentration (Ctrough), and time to steady 
state 
Secondary
To explore the safety and tolerability of 
balovaptan when given alone and in 
combination with itraconazole in healthy 
subjects
Adverse events (AEs), clinical laboratory 
values, vital signs, electrocardiogram (ECG), 
and physical examination


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10/Protocol WP40609, Version 1.0
Tertiary/Exploratory
Relationship between the CYP3A4 genotype, 
among othersa, and steady state balovaptan 
exposure, and the influence of the CYP3A4 
genotype, among others, on the effect of 
itraconazole on balovaptan PK
The pharmacogeneticsb of metabolizing 
enzymes, transferases, transporters, etc, 
possibly involved in the absorption, 
distribution, metabolism and excretion of 
balovaptan and its major metabolites (eg, 
CYP3A4 and P-glycoprotein)
The plasma exposure of itraconazole and 
hydroxy-itraconazole
Area under the concentration vs time curve 
from time 0 to 24 hours (AUC0-24h), Cmax, and 
Tmax on Day 5 and Day 20 
aThe relationship between other genotypes and PK of balovaptan may also be explored
bResults may be pooled with data from other studies of balovaptan.
Study Design
This study will be a non-randomized, open-label, one-sequence, two-period within-subject study 
to investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy male and female 
volunteers using itraconazole as a CYP3A inhibitor. The study will be conducted at 1 site in the 
Netherlands.
Subjects will receive the following study drugs in 2 periods over a total of 37 days:
Period 1:

Days 1 to 10: oral balovaptan qd

Days 11 to 17: no study drug
Period 2:

Days 1 to 5: 200 mg itraconazole twice daily, approximately 12 h apart (on Day 5, only the 
AM dose of itraconazole will be administered)

Days 6 to 20: balovaptan qd + 200 mg itraconazole qd 
For each study period, subjects will be admitted on Day -1, and dosing will begin on Day 1. 
Subjects will undergo study assessments and procedures, including assessments of AEs and 
concomitant medications, vital signs, 12-lead ECGs, clinical laboratory evaluations, and blood 
sampling for PK assessments and genotyping.
The study will begin with 4 sentinel subjects in the initial cohort (Cohort A) in which the 
balovaptan dose will be 5 mg qd. Depending on the safety, tolerability and PK data of Cohort A, 
the remainder of subjects (Cohort B) may be dosed with balovaptan 5 mg qd or 10 mg qd. The 
dose may be increased to 10 mg qd for Cohort B if the highest exposure values for Cmax and
AUC[0-τ] in the presence of itraconazole in Cohort A and the projected exposures expected for 
Cohort B do not exceed the highest exposures seen with multiple dosing of balovaptan 52 mg in 
a previous study, and there are no prohibitive safety findings based on a review of safety data 
from Cohort A by the Sponsor’s Medical Monitor or designee and the Investigator. If these 
criteria are not met, dosing will be continued at 5 mg qd in Cohort B. 
If the Cohort B balovaptan dose remains at 5 mg qd, 10 subjects will be enrolled in Cohort B. If 
the dose is increased to 10 mg qd, 14 subjects will be enrolled.
Number of Subjects
A total of 14 to 18 subjects will be enrolled. Enrolled subjects who withdraw from the study may 
be replaced at the discretion of the Investigator and Sponsor to ensure adequate numbers of 
evaluable subjects.
Target Population
Healthy male (at least 50% of enrolled subjects) and female subjects between 18 to 65 years of
age, inclusive.


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Inclusion Criteria
Subjects must meet the following criteria for study entry:
1.
Healthy male and female subjects, aged 18 to 65 years, inclusive, at Screening. Healthy 
status is defined by absence of evidence of any active or chronic disease following a 
detailed medical and surgical history, a complete physical examination including vital signs, 
12-lead ECG, hematology, blood chemistry, urinalysis, and serology.
2.
Body Mass Index of 18 to 30 kg/m2, inclusive, at Screening.
3.
For women of childbearing potential: agreement to use at least 2 acceptable contraceptive 
methods during the treatment period and for 90 days after the last dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
The following are acceptable contraceptive methods: bilateral tubal ligation; male 
sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; copper 
intrauterine devices; male or female condom with or without spermicide (male and 
female condom must not be used simultaneously); and cap, diaphragm, or sponge with 
spermicide.
Hormonal contraceptive methods must be supplemented by a barrier method.
4.
For men: agreement to use contraceptive measures, and agreement to refrain from donating 
sperm, as defined below. 
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for until 90 days after 
the last dose of study drug to avoid exposing the embryo. Men must refrain from 
donating sperm during this same period.
5.
Able to participate and willing to give written informed consent and to comply with the study 
restrictions. 
6.
Fluent in English or Dutch.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
1.
Female subjects who are of childbearing potential who do not agree to use at least 2
acceptable methods of contraception. Female subjects who had tubal ligation who do not 
agree to use a barrier method of contraception.
2.
Female subjects who are pregnant or lactating.
3.
Any condition or disease detected during the medical interview/physical examination that 
would render the subject unsuitable for the study, place the subject at undue risk or interfere 
with the ability of the subject to complete the study in the opinion of the Investigator.
4.
In the opinion of the Investigator, any major illness within one month before the screening 
examination or any febrile illness within one week prior to screening and up to first study 
drug administration.
5.
History of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, 
neurological, psychiatric, cardiovascular, endocrinological, hematological, lymphatic, 
musculoskeletal, genitourinary, immunological, dermatological or connective tissue or 
allergic disease, metabolic disorder, or cancer.
6.
No signs and symptoms potentially indicative of peripheral neuropathy.
7.
History or evidence of any medical condition potentially altering the absorption, metabolism 
or elimination of drugs. Surgical history of the gastrointestinal tract affecting gastric motility 
or altering the gastrointestinal tract, with the exception of uncomplicated appendectomy, 
which is allowed.
8.
A history of clinically significant hypersensitivity (eg, to drugs, including itraconazole and 
balovaptan, and excipients) or allergic reactions.


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9.
Known personal or family history of congenital long QT syndrome or sudden death.
10. History or presence of clinically significant ECG abnormalities before study drug 
administration.
11. Subjects with screening or predose baseline mean QT interval corrected using Fridericia’s 
formula (QTcF) >450 msec or <300 msec (using the same upper QTcF limit in both males 
and females).
12. Notable resting bradycardia (mean heart rate [HR] <40 bpm) on screening or predose
baseline ECG. Notable resting tachycardia (mean HR > 90 bpm) on screening or predose
baseline ECG.
13. Screening or baseline ECGs with QRS and/or T-wave judged to be unfavorable for a 
consistently accurate QT measurement (ie, neuromuscular artifact that cannot be readily 
eliminated, arrhythmias, indistinct QRS onset, low amplitude T-wave, merged T- and 
U-waves, prominent U-waves, etc).
14. Screening or baseline ECG with evidence of clinically relevant abnormalities, e.g. atrial 
fibrillation, atrial flutter, complete bundle branch block, Wolf-Parkinson-White Syndrome, or 
cardiac pacemaker.
15. 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. 
16. Subjects experiencing fainting or pre-syncopal events during orthostatic challenge testing at 
screening.
17. 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, tests performed during screening may be repeated on Day -1 of 
Period 1 to confirm eligibility. 
18. History of coagulopathies, bleeding disorders, or blood dyscrasias.
19. Subjects who have smoked within 3 months prior to first dose administration.
20. Any clinically relevant history or any suspicion of alcohol and/or other substance abuse or 
addiction. Past alcohol and/or other substance abuse or addiction is also not allowed.
21. Alcohol consumption of >24 units per week for males and females. One unit of alcohol 
equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of 
spirits.
22. Positive urine alcohol test or urine drug screen at screening or Day -1 of each treatment 
period (barbiturates, benzodiazepines, methadone, amphetamines [including ecstasy], 
methamphetamines, opiates, cocaine, and cannabinoids). 
23. Positive result on human immunodeficiency virus (HIV) 1, HIV 2, hepatitis C virus antibody,
or hepatitis B virus surface antigen. 
24. Participation in an investigational drug or device study within 90 days prior to first dosing, or
within 5 months prior to first dosing in case of a study with a biological, as calculated from 
the day of follow-up from the previous study.
25. Any donation of blood or plasma or significant blood loss within 3 months prior to screening.
26. Dietary restrictions that would prohibit the consumption of standardized meals. 
27. Use of any prohibited medications and food before study start and subjects who do not
agree to refrain from consuming prohibited medications or food during the study. 
28. Subjects likely to need concomitant medication during the study (including for dental 
conditions). 
29. Subjects who have received any prescribed systemic or topical medication within 14 days of 
the first dose administration, unless in the opinion of the Investigator the medication will not 
interfere with the study procedures or compromise safety. Subjects who have received slow 
release medicinal formulations considered to still be active within 14 days of the first dose 
administration will also be excluded unless in the opinion of the Investigator the medication 
will not interfere with the study procedures or compromise safety.


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30. Used the following within 7 days before the first study drug administration, unless in the 
opinion of the Investigator the medication will not interfere with the study procedures or 
compromise safety:

Any non-prescribed systemic or topical medication

Herbal remedies.
Paracetamol (up to 4 g/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.
31. Received any medications known to chronically alter drug absorption or elimination 
processes within 4 weeks before the first study drug administration, unless in the opinion of 
the Investigator the medication will not interfere with the study procedures or compromise 
safety.
32. Use of any drugs or substances, including herbal treatments such as St John’s Wort, that 
are known to be substrates, inducers or inhibitors of CYP3A4 within 4 weeks before the first 
study drug administration.
33. Subjects under judicial supervision, guardianship, or curatorship.
34. Poor venous access for blood sampling.
35. Subjects who have previously taken part in or withdrawn from this study.
36. Subjects who are unwilling to practice safe sex (use male or female condom) for the duration 
of the study.
End of Study
The end of this study is defined as the date when the last subject, last visit occurs or safety 
follow-up is received from the last subject, whichever occurs later. The end of the study is 
expected to occur 12 weeks after the last subject is enrolled.
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 15 weeks.
Investigational Medicinal Products
Balovaptan (Test Product/Investigational Drug): 5 mg dispersible tablets and 10 mg film-coated
tablets
Itraconazole: 100 mg capsule
Statistical Methods
Primary Analysis
The primary PK parameters are Cmax and AUC0-τ for balovaptan, M2, and M3 on Day 10 of 
Period 1 and Day 20 of Period 2.
A linear mixed model analysis will be applied to analyze the log-transformed primary PK
parameters. The model assumes fixed effect for treatment and a random effect for subject. 
Estimates of geometric mean ratios together with the corresponding 90% CIs will be derived for 
the comparisons of the PK parameters as follows:

balovaptan plus itraconazole (test) vs balovaptan alone (reference)
Determination of Sample Size  
This is an exploratory study for which no formal statistical hypothesis will be tested, and 
therefore the sample size is chosen to estimate, with sufficient precision, the CYP3A4 inhibition 
on balovaptan. Between 14 and 18 subjects will be enrolled, so as to have 14 subjects enrolled 
on either 5 mg or 10 mg balovaptan for 10 days to ensure a minimum of 12 completers. The 
sample size was chosen based on balovaptan within-subject variability (CV%) of around 39% 
for AUC0-τ and 36% for Cmax as obtained from the 12 mg repeat dose in study BP25694. Based 


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14/Protocol WP40609, Version 1.0
on the higher value of 39%, it was estimated that with 12 subjects, the half-width of the 90% CI 
for the ratio of treatment geometric means of the combination (balovaptan + itraconazole) 
versus balovaptan alone would be obtained by dividing/multiplying the ratio estimate by a factor 
of 1.30.
Interim Analyses
Interim PK analyses, including the calculation of the PK parameters for both periods, will be 
done for Cohort A. The data from this analysis will be used in the decision whether the 
balovaptan dose should be increased from 5 to 10 mg qd for Cohort B. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASD
Autism Spectrum Disorder
AST
aspartate aminotransferase
AUC0-τ
area under the concentration vs time curve over the 
dosing interval
AUC0-24h
area under the concentration vs time curve from time 0 
to 24 hours
AUC0-120h
area under the concentration vs time curve from time 0 
to 120 hours
Cmax
maximum observed plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
CRO
contract research organization
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
trough plasma concentration
CYP
cytochrome P450
DDI
drug-drug interaction
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EU
European Union
FSH
follicle-stimulating hormone
GLP
Good Laboratory Practice
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
Heart rate
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
MAD
multiple ascending dose


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NOAEL
no observed adverse effect level
NOEL
no observed effect level
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PND
postnatal day
qd
once daily
QTcF
QT interval corrected using of Fridericia’s formula
SAD
single ascending dose
SAE
serious adverse event
T1/2
half-life
Tmax
time to maximum observed plasma concentration
ULN
upper limit of normal
V1a
vasopressin receptor 1A
WBC
white blood cell


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


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al., 2009). Both over- and under-transmission of specific but different alleles of this gene 
have been reported in autistic individuals and are associated with specific traits. One of 
these risk alleles has been found to increase activation of the amygdala during face 
processing and is associated with increased V1a receptor messenger RNA levels in the 
human hippocampus post-mortem. In particular, both nonclinical and clinical research 
supports a specific role of vasopressin in affiliative behavior.
In healthy subjects, intranasal vasopressin administration has been shown to increase 
the perception of ambiguous social stimuli as threatening and to impair emotion 
recognition in males. In non-human mammals, vasopressin receptors are distributed in 
various brain regions associated with central nervous system (CNS) control of stress 
and anxiety and, more importantly in this context, with social behavior, including parental 
care, pair-bonding, social memory, and social aggression. Specifically, vasopressin has 
been implicated more in male-typical social behaviors, including aggression, pair-bond 
formation, scent marking, and courtship. Recently, vasopressin was found to affect 
social recognition and interaction in rodents via its modulatory effect on olfaction 
(Tobin et al., 2010) – a sensory modality that may also be impaired in autism (May et al., 
2011).
In summary, evidence from both human and animal studies strongly implicates the V1a 
receptor in mediating and modulating key social behaviors that are deficient in ASD. 
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.
1.2
BACKGROUND ON BALOVAPTAN
Chronic administration of balovaptan reversed social behavior and cognitive impairments 
induced by prenatal valproate treatment in rats, an animal model that reflects some of 
the behavioral changes seen in patients with ASD. 
 
 
The in vitro metabolism of balovaptan was studied in hepatic preparations from human,
rat, dog, minipig, cynomolgus monkey, mouse, and rabbit. 
The in vivo pharmacokinetic (PK) studies with balovaptan were conducted in rats, dogs, 
and cynomolgus monkeys. In animals, balovaptan showed a high (rats) to moderate or 
low (dogs and cynomolgus monkeys) plasma clearance and moderate extravascular 


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distribution. High to moderate bioavailability, depending on the species, was observed 
after oral application. In human, 2 major metabolites, M2 (RO7045402) and M3
(RO5273004), have been identified, which are present in rats and dogs. M2 and M3 are 
also V1a antagonists. Balovaptan and M2 are mainly metabolized through cytochrome 
P450 (CYP)3A4. Balovaptan and M3 have been shown in vitro to be strong, substrate-
dependent P-glycoprotein (P-gp) inhibitors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.1
Previous and Ongoing Clinical Studies
To date, balovaptan has been investigated in 5 completed Phase I studies including a
proof-of-mechanism study in healthy volunteers (BP29412) in a total of 195 subjects. A 
Phase I relative bioavailability study (Study WP40038) comparing the Phase III tablet 
formulation with formulations used in previous Phase I and II studies is ongoing 
(clinically complete, reporting ongoing).
A Phase II study in 148 adult male ASD patients has been completed (BP28420, also
referred to as VANILLA) and a Phase II study in 127 pediatric ASD patients (male and 
female) is ongoing (BP30153, also referred to as AV1ATION).
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 and between 3 and 4 
hours following multiple dosing. Steady state was achieved after approximately 7 days;
the mean apparent elimination half-life (T1/2) after the last dose (Day 14) was 
approximately 46 hours. Food had no relevant effect on the PK of balovaptan.
In the human mass balance study (Study BP29279), an almost complete absorption of 
the study drug was observed within the first 72 hours following administration.


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The majority of excretion of drug-related material occurred within the first 7 days. Renal 
excretion was found to be the major pathway of elimination (approximately 53% of the 
material recovered, mostly composed of metabolites) with the primary route of excretion 
via metabolism to M1 (
) into urine, accounting for approximately 
23% of the dose. A further 30% of the administered dose was recovered in feces.
In plasma, steady state exposure to the 
 metabolite M3 was similar to or 
slightly higher than that of balovaptan and exposure to the 
 metabolite M2 
was lower than that of parent. M3 and M2 qualify as major metabolites in plasma.
 
 
 
 
There was no clinically/statistically relevant PK interaction with the P-glycoprotein
substrate risperidone, one of only 2 approved medications for ASD symptoms in the US, 
and fluoxetine, a weak CYP3A4 inhibitor often used to treat associated symptoms of 
ASD. Administration of a single dose of balovaptan 12 mg in combination with 
itraconazole, a strong CYP3A4 inhibitor, resulted in an increase in the exposure of 
balovaptan by 1.4-fold for Cmax and an approximately 3.1-fold increase for area under the 
concentration vs time curve from time 0 to 120 hours (AUC0-120h). The exposure of 
metabolite M3 was 1.92- and 1.82-fold lower in terms of Cmax and AUC0-120h, respectively.
1.2.1.2
Safety
To date, balovaptan has been found to be safe and well tolerated in clinical trials. No 
particular safety concern has emerged and no adverse drug reactions have been 
identified. More specifically, creatine phosphokinase (CPK) was monitored in previous 
trials based on observations of muscle toxicity in rats; no changes of any importance 
were noticed. Similarly, no hematology or neurotoxicity findings have been observed in 
clinical trials. The maximum tolerated dose was not reached in either the single 
ascending dose (SAD) study with single doses (up to 76 mg) or the multiple ascending 
dose (MAD) study with multiple doses (up to 52 mg qd for 14 days) in healthy subjects. 
In light of convulsions observed in dogs, dose escalation was stopped so as not to 
exceed a Cmax (mean) of 810 ng/mL in the SAD and MAD studies. In healthy volunteer 
studies, one serious adverse event (SAE) of bacterial infection (suspected Lyme disease) 
was reported in Study BP29412; this SAE was considered unrelated to study drug.
Balovaptan has also been found to be safe and well tolerated in male patients with ASD 
at doses up to 10 mg/day (highest dose administered) for a period of 12 weeks 
(Study BP28420). No particular safety patterns attributable to the administration of 
balovaptan were identified. A total of 8 SAEs (all but one [rhabdomyolysis] considered 
unrelated to study drug) in 4 patients and 1 adverse event of special interest 


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(neutropenia) were reported in the study. No relevant safety concern has emerged from 
the recently started study in ASD pediatric patients (BP30153).
Based on the review of all available data, it is currently recommended not to exceed a 
plasma exposure equivalent to 20 mg qd in adult subjects in clinical trials with a 
continuous treatment duration longer than 4 weeks.
Refer to the Investigator's Brochure for details on nonclinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The study will be performed in healthy subjects who will not receive any health benefit 
from participating in this study. The study is necessary for the further development of 
balovaptan and may be of benefit for future patients. 
To date, balovaptan has been investigated in 195 healthy subjects in 5 completed Phase 
1 studies (Studies BP25694, BP28318, BP28977, BP29279, and BP29412). One oral 
relative bioavailability study (Study WP40038) is ongoing (clinically complete, reporting
ongoing).
Additionally, balovaptan was investigated in a Phase II study in 148 adult male patients 
with ASD (BP28420, “VANILLA”).
Adverse event (AE) reporting in healthy subjects did not reveal any particular safety alert 
for balovaptan. The most frequently reported AE was headache, without an apparent 
dose-response relationship for balovaptan. For the vast majority of AEs, the intensity 
was rated as mild or moderate. The dose range in these studies was 0.5 to 76 mg 
(single dose) and 12 to 52 mg (multiple doses for 14 days).
The effect of inhibition of CYP3A4 was previously investigated using a single dose of 
12 mg of balovaptan. The study showed that balovaptan AUC0-120h increased by 3.1-fold
and Cmax by 1.4-fold in the presence of itraconazole. Mean AUC0-120h and Cmax metabolite
M3 were 1.82- and 1.92-fold lower, respectively, in the presence of itraconazole than in 
the absence of itraconazole. M2 was not measured in that study.
The current study is designed to assess the effect of inhibition of CYP3A4 on the steady 
state pharmacokinetics of balovaptan after 15 days of coadministration with itraconazole, 
as balovaptan showed dose and time-dependent PK. Although not reliably measured,
analysis of AUC0-inf in the presence of itraconazole indicated a 4.6-fold increase in 
balovaptan exposure and plasma T1/2 indicated an increase from 27 to 80 hours. The 
mean (SD) Cmax and AUC0-τ for parent following 14 days of dosing with balovaptan 
52 mg qd was 484 (43.1) ng/mL and 5920 (817) h∙ng/mL, respectively. M3 was only 
measured after balovaptan 40 mg for 14 days: the mean (SD) Cmax and AUC0-τ were 264 
(45.4) ng/mL and 5260 (807) and h∙ng/mL, respectively.


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Due to the anticipated increase in balovaptan exposure when administered with 
itraconazole, to ensure optimal subject safety, the study design includes a sentinel group 
of 4 subjects, who will be dosed with 5 mg balovaptan qd. The dose may be increased to 
the targeted clinical dose, 10 mg, only if exposure data from the sentinel cohort are 
acceptable (see Section 3.1 for exposure criteria), and no safety concerns have 
emerged in the opinion of the Investigator or Sponsor’s Medical Monitor.
Itraconazole is generally well tolerated. Gastrointestinal disturbances are the most 
frequently reported AEs following the oral use of itraconazole. Nausea and vomiting 
have been reported in about 11% and 5% of patients undergoing treatment of systemic 
fungal infections, respectively, diarrhea in 3%, and abdominal pain in about 2%. These 
AEs are dose-related and may be minimized by giving itraconazole with food. Rash was 
observed in 9% of patients, however rash tends to occur more frequently in 
immunocompromised patients receiving immunosuppressive medications. Itraconazole 
has been associated with rare cases of serious hepatotoxicity. Some of these cases had 
neither pre-existing liver disease nor a serious underlying medical condition, and some 
of these cases developed within the first week of treatment. Other adverse effects 
include pruritus and angioedema, and rare cases of anaphylaxis have been reported.
Fatigue, headache, dizziness, hypertension, decreased libido, impotence, and
somnolence may also occur (Janssen Pharmaceuticals, 2001). 
2.
OBJECTIVES AND ENDPOINTS
This study will investigate the effect of itraconazole treatment on the PK of balovaptan 
and its major metabolites M2 and M3. Table 1 presents the objectives and endpoints.


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Table 1
Objectives and Corresponding Endpoints
Objectives
Endpoints
Primary
To investigate the effect of itraconazole 
treatment on the PK of balovaptan and its 
major metabolites M2 (as applicable) and 
M3, at steady state
Primary PK endpoints: balovaptan, M2, 
and M3 Cmax and area under the 
concentration vs time curve over the 
dosing interval (AUC0-τ) after 15 days of 
balovaptan qd dosing in Period 2, and after 
10 days of balovaptan qd dosing in 
Period 1 
Additional PK endpoints: balovaptan, M2, 
and M3 time to maximum observed 
plasma concentration (Tmax), trough
plasma concentration (Ctrough), and time to 
steady state 
Secondary
To explore the safety and tolerability of 
balovaptan when given alone and in 
combination with itraconazole in healthy 
subjects.
Adverse events (AEs), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and physical examination
Tertiary/Exploratory
Relationship between the CYP3A4
genotype, among others,a and steady state 
balovaptan exposure, and the influence of 
the CYP3A4 genotype, among others, on 
the effect of itraconazole on balovaptan PK
The pharmacogeneticsb of metabolizing 
enzyme, transferases, transporters, etc,
possibly involved in the absorption, 
distribution, metabolism, and excretion of 
balovaptan and its major metabolites (eg, 
CYP3A4 and P-glycoprotein)
The plasma exposure of itraconazole and 
hydroxy-itraconazole
Area under the curve from time 0 to 
24 hours (AUC0-24h), Cmax, and Tmax on 
Day 5 and Day 20
aThe relationship between other genotypes and PK of balovaptan may also be explored
bResults may be pooled with data from other studies of balovaptan.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This study will be non-randomized, open-label, one-sequence, two-period within-subject 
study to investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy 
male and female volunteers using itraconazole as a CYP3A inhibitor. The study will be 
conducted at 1 site in the Netherlands.
Subjects will be screened for eligibility for the study for up to 28 days before the first 
dose of study drug. In Period 1, eligible subjects will be admitted to the clinical research 
unit (CRU) in the afternoon of Day -1 and remain in the CRU until discharge in the
morning of Day 11. There will be at least a 7-day washout between the last dose in 
Period 1 and the first dose in Period 2. After this washout period, subjects will return to 
the CRU on Day -1 of Period 2 and remain in the CRU until discharge on Day 21 of 
Period 2. For each study period, dosing will begin on Day 1.
Subjects will receive the following study drugs in 2 periods over a total of 37 days:
Period 1:

Days 1 to 10: oral balovaptan once daily (qd)

Days 11 to 17: no study drug
Period 2:

Days 1 to 5: 200 mg itraconazole twice daily, approximately 12 hours apart (on 
Day 5, only the AM dose of itraconazole will be administered)

Days 6 to 20: balovaptan qd + 200 mg itraconazole qd 




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will be reviewed by the by the Sponsor’s Medical Monitor or designee and the 
Investigator. There will be at least a 20-day period between Cohort A and Cohort B to 
allow for analysis of PK data. After review of the data, a dose of balovaptan will be
selected for the remainder of subjects (Cohort B). The dose may remain 5 mg qd or may 
be increased to 10 mg qd, depending on data from Cohort A. The dose may be 
increased to 10 mg qd for Cohort B if the highest mean exposure values for Cmax and 
AUC[0-τ] in the presence of itraconazole in Cohort A and the projected exposures 
expected for Cohort B do not exceed the highest exposures seen with multiple dosing of 
balovaptan 52 mg (484 ± 43.1 ng/mL for Cmax and 5920 ± 817 h∙ng/mL for AUCtau) and 
there are no prohibitive safety findings based on a review of safety data from Cohort A. If 
these criteria are not met, dosing will be continued at 5 mg qd in Cohort B. 
If a decision is made to keep the dose at 5 mg qd, a total of 10 subjects will enter 
Cohort B. If a decision is made to increase the dose to 10 mg qd, a total of 14 subjects 
will enter Cohort B. 
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last subject, last visit (LSLV) 
occurs or safety follow-up is received from the last subject, whichever occurs later. The 
end of the study is expected to occur 12 weeks after the last subject is enrolled.
The total length of the study, from screening of the first subject to the end of the study, is 
expected to be approximately 15 weeks.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Open Label Design
The primary objective in this study is to assess to what extent exposure to balovaptan 
after repeat dosing may change in the presence of the CYP3A4 inhibitor itraconazole. As 
such, drug concentrations in plasma are assumed to be objective measurements, which 
cannot be affected by volunteer or staff behavior. This is different for tolerability reporting, 
for which it is conceivable that knowing what treatment is being administered may affect 
reporting or causality interpretation. Therefore, it is generally accepted to conduct drug-
drug interaction (DDI) studies with PK or pharmacodynamic (PD) primary endpoints 
using an open-label design, without placebo treatments, and since evaluation of safety 
and tolerability is only a secondary objective, an open-label design was deemed 
appropriate.
3.3.2
Rationale for Balovaptan and Itraconazole Dose and Schedule
3.3.2.1
Balovaptan
A dose of 10 mg balovaptan has shown statistically significant changes in efficacy 
parameters in adult patients with ASD and is the current proposed dose for Phase 3 
trials in adults. However, it is to be expected that exposure in the presence of 
itraconazole may increase, based on the effect of itraconazole on the exposure of a 


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single dose of 12 mg balovaptan (at least 3.1-fold increase in AUC0-120h and 1.4-fold 
increase in Cmax).
Therefore, in the current study, the effect of itraconazole on the multiple dose PK of a 
low dose of 5 mg balovaptan qd will initially be assessed in a sentinel group of 
4 subjects, in order to assess whether it will be safe to assess the effect of itraconazole 
on the higher, clinically relevant dose of 10 mg. Single doses of balovaptan up to 76 mg 
and multiple doses up to 52 mg qd for 14 days were well tolerated. The mean exposure 
seen with multiple dosing of balovaptan 52 mg was 484 ± 43.1 ng/mL for Cmax and 5920 
± 817 h∙ng/mL for AUC0-τ.
Balovaptan is being developed for use in ASD, so it is expected that patients will need to 
take it for prolonged periods of time, likely for years or for life. Hence multiple dose 
testing is relevant from a clinical point of view. The multiple dose PK of balovaptan with 
14 days of dosing was previously characterized in humans and was found to be time and 
dose dependent. Accumulation was observed with multiple dosing, and steady state of 
parent and M3 was observed after approximately 7 days of dosing; the time to steady 
state has only been evaluated with sparse PK measurements for M2. Population 
modelling indicates that steady state of parent, M2, and M3 following a dose of 
balovaptan 10 mg is reached later (after around 10 days). In the presence of 
itraconazole, an increase in plasma T1/2 from 27 to 80 hours was observed. Based on 
these observations, the maximum level of DDI due to inhibition of CYP3A4 is expected 
to be observed with 15 days of coadministration of itraconazole with balovaptan, based 
on a predicted T1/2 of ~ 80 hours for balovaptan when combined with itraconazole.
In addition, exposure to the metabolite M2 has not been previously characterized with 
intensive PK sampling after multiple doses in humans, and this will also be achieved in 
the current design.
3.3.2.2
Itraconazole 
The proposed dose level and dosing regimen for itraconazole, to be used as an inhibitor 
of CYP3A4, is based on published recommendations (Liu et al, 2016). Itraconazole run-
in will include 4 days of bid dosing of 200 mg plus 1 day of qd dosing in order to ensure 
that steady state inhibition has been achieved prior to administering the first dose of 
balovaptan on Day 6 of Period 2.
Itraconazole will be administered in the fed state as capsules, in order to maximize 
exposure to both parent itraconazole and hydroxy-itraconazole. 
3.3.3
Rationale for Sentinel Group
As an increase in balovaptan exposure when administered together with itraconazole is 
expected, to ensure optimal safety of subjects an initial sentinel cohort of 4 subjects
(Cohort A) will be enrolled in which the dose of balovaptan will be 5 mg qd. The safety 
and tolerability and PK data up to 24 hours after the final dose of balovaptan (when 


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given in conjunction with itraconazole), for at least 3 of the 4 subjects, will be reviewed 
by the Sponsor’s Medical Monitor or designee and the Investigator. After review of the 
data, a dose of balovaptan will be selected for the remainder of subjects (Cohort B). The 
balovaptan dose for Cohort B may remain at 5 mg qd or be increased to 10 mg qd. The 
dose may be increased to 10 mg qd for Cohort B if the highest exposure values for Cmax
and AUC[0-τ] in the presence of itraconazole in Cohort A and the projected exposures 
expected for Cohort B do not exceed the highest exposures seen with multiple dosing of 
balovaptan 52 mg (see Section 3.1) and there are no prohibitive safety findings based 
on a review of safety data from Cohort A by the Sponsor’s Medical Monitor or designee 
and the Investigator. 
3.3.4
Rationale for Study Population
Healthy subjects have been chosen as the study population due to the low risk of 
clinically significant toxicity at anticipated exposure levels. Moreover, use of healthy 
subjects as opposed to patients will allow a clearer interpretation of the study results, as 
there will be no confounding factors that result from changes in disease state and/or 
concomitant medication use.
Female and male subjects may be included. Female subjects of childbearing potential 
must use 2 acceptable methods of contraception. Female subjects who have undergone
tubal ligation must use a barrier method of contraception. Male subjects must agree to 
use contraceptive measures and agree to refrain from donating sperm. The study will 
enroll at least 50% male subjects, as ASD is more prevalent in males. 
4.
MATERIALS AND METHODS
4.1
SUBJECTS
The target population will be healthy male (at least 50% of enrolled subjects) and female 
subjects between 18 to 65 years of age, inclusive, on the day of screening. Between 14
and 18 subjects will be enrolled. Enrolled subjects who withdraw from the study may be 
replaced at the discretion of the Investigator and Sponsor to ensure adequate numbers 
of evaluable subjects.
4.1.1
Inclusion Criteria
Subjects must meet the following criteria for study entry:
1.
Healthy male and female subjects, aged 18 to 65 years, inclusive, at Screening. 
Healthy status is defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination 
including vital signs, 12-lead ECG, hematology, blood chemistry, urinalysis, and 
serology.
2.
Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive, at Screening.


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3.
For women of childbearing potential: agreement to use at least 2 acceptable 
contraceptive methods during the treatment period and for 90 days after the last 
dose of study drug.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
The following are acceptable contraceptive methods: bilateral tubal ligation; 
male sterilization; hormonal contraceptives; hormone-releasing intrauterine 
devices; copper intrauterine devices; male or female condom with or without 
spermicide (male and female condom must not be used simultaneously); and 
cap, diaphragm, or sponge with spermicide.
Hormonal contraceptive methods must be supplemented by a barrier method.
4.
For men: agreement to use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 90 
days after the last dose of study drug to avoid exposing the embryo. Men must 
refrain from donating sperm during this same period.
5.
Able to participate and willing to give written informed consent and to comply with 
the study restrictions. 
6.
Fluent in English or Dutch.
4.1.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:
1.
Female subjects who are of childbearing potential who do not agree to use 2 
acceptable methods of contraception. Female subjects who had tubal ligation who 
do not agree to use a barrier method of contraception.
2.
Female subjects who are pregnant or lactating.
3.
Any condition or disease detected during the medical interview/physical examination 
that would render the subject unsuitable for the study, place the subject at undue 
risk or interfere with the ability of the subject to complete the study in the opinion of 
the Investigator.
4.
In the opinion of the Investigator, any major illness within one month before the 
screening examination or any febrile illness within one week prior to screening and 
up to first study drug administration.
5.
History of any clinically significant gastrointestinal, renal, hepatic, 
broncho-pulmonary, neurological, psychiatric, cardiovascular, endocrinological, 
hematological, lymphatic, musculoskeletal, genitourinary, immunological, 
dermatological or connective tissue or allergic disease, metabolic disorder, or 
cancer.


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6.
Signs and symptoms potentially indicative of peripheral neuropathy
7.
History or evidence of any medical condition potentially altering the absorption, 
metabolism, or elimination of drugs. Surgical history of the gastrointestinal tract 
affecting gastric motility or altering the gastrointestinal tract, with the exception of 
uncomplicated appendectomy, which is allowed.
8.
A history of clinically significant hypersensitivity (eg, to drugs, including itraconazole 
and balovaptan, and excipients) or allergic reactions.
9.
Known personal or family history of congenital long QT syndrome or sudden death.
10. History or presence of clinically significant ECG abnormalities before study drug 
administration.
11. Subjects with screening or predose baseline mean QT interval corrected using 
Fridericia’s formula (QTcF) >450 msec or <300 msec (using the same upper QTcF 
limit in both males and females).
12. Notable resting bradycardia (mean HR <40 bpm) on screening or predose baseline 
ECG. Notable resting tachycardia (mean HR > 90 bpm) on screening or predose
baseline ECG.
13. Screening or baseline ECGs with QRS and/or T-wave judged to be unfavorable for 
a consistently accurate QT measurement (ie, neuromuscular artifact that cannot be 
readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T-wave, 
merged T- and U-waves, prominent U-waves, etc.).
14. Screening or baseline ECG with evidence of clinically relevant abnormalities, e.g. 
atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-Parkinson-White 
Syndrome, or cardiac pacemaker.
15. 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.
16. Subjects experiencing fainting or pre-syncopal events during orthostatic challenge 
testing at screening.
17. 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, tests performed during screening may be 
repeated on Day -1 to confirm eligibility. 
18. History of coagulopathies, bleeding disorders, or blood dyscrasias.
19. Subjects who have smoked within 3 months prior to first dose administration.
20. Any clinically relevant history or any suspicion of alcohol and/or other substance 
abuse or addiction. Past alcohol and/or other substance abuse or addiction is also 
not allowed. 
21. Alcohol consumption of >24 units per week for males and females. One unit of 
alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill 
(25 mL) of spirits.


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22. Positive urine alcohol test or urine drug screen at screening or Day -1 of each
treatment period (barbiturates, benzodiazepines, methadone, amphetamines 
[including ecstasy], methamphetamines, opiates, cocaine, and cannabinoids). 
23. Positive result on human immunodeficiency virus (HIV) 1, HIV2, hepatitis C virus 
(HCV) antibody, or hepatitis B virus surface antigen (HBsAg). 
24. Participation in an investigational drug or device study within 90 days prior to first 
dosing, or within 5 months prior to first dosing in case of a study with a biological, as 
calculated from the day of follow-up from the previous study.
25. Any donation of blood or plasma or significant blood loss within 3 months prior to 
screening.
26. Dietary restrictions that would prohibit the consumption of standardized meals. 
27. Use of any prohibited medications and food before study start and subjects who do 
not agree to refrain from consuming prohibited medications or food during the study
(see Section 4.4). 
28. Subjects likely to need concomitant medication during the study (including for dental 
conditions). 
29. Subjects who have received any prescribed systemic or topical medication within 
14 days of the first dose administration, unless in the opinion of the Investigator the 
medication will not interfere with the study procedures or compromise safety, and
subjects who have received slow release medicinal formulations considered to still 
be active within 14 days of the first dose administration will also be excluded unless 
in the opinion of the Investigator the medication will not interfere with the study 
procedures or compromise safety.
30. 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:
o
any non-prescribed systemic or topical medication
o
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.
31. Received any medications known to chronically alter drug absorption or elimination 
processes within 4 weeks before the first study drug administration, unless in the 
opinion of the Investigator the medication will not interfere with the study procedures 
or compromise safety.
32. Use of any drugs or substances, including herbal treatments such as St John’s Wort, 
that are known to be substrates, inducers, or inhibitors of CYP3A4 within 4 weeks
before the first study drug administration.
33. Subjects under judicial supervision, guardianship or curatorship.
34. Poor venous access for blood sampling.


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35. Subjects who have previously taken part in or withdrawn from this study.
36. Subjects who are unwilling to practice safe sex (use male or female condom) for the 
duration of the study.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This study will be non-randomized, open-label, one-sequence, two-period within-subject
study.
Subjects who have met all eligibility criteria will receive a subject number upon inclusion 
in the study (subject numbers: 01 to 14 or 01 to 18). Subject numbers will be allocated 
sequentially in the order in which the subjects are enrolled. The subject number will 
ensure identification throughout the study. Replacement subjects (if needed) will receive 
the number of the subject to be replaced, increased by 100 (eg, 101 replacement 
number for subject number 01), and will be administered the same treatments in the 
same order.
Subjects who drop out or withdraw for any reason without completing all screening
evaluations successfully, will be considered “screening failures”. Such subjects will not 
receive a subject number. The Investigator will keep a screening log of all subjects 
screened in order to assess the numbers and characteristics of the excluded subjects, 
and the reasons for their exclusion.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are balovaptan and 
itraconazole.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Balovaptan
Balovaptan 5 mg will be supplied by the Sponsor as dispersible tablets in high-density 
polyethylene bottles. Balovaptan 10 mg will be supplied by the Sponsor as film-coated 
tablets in high-density polyethylene bottles. For information on the formulation and 
handling of balovaptan, see Investigational Medicinal Product Dossier.
4.3.1.2
Itraconazole
Itraconazole 100 mg capsules will be obtained commercially by the investigational site. 
For information on the formulation, packaging, and handling of itraconazole, see the 
local prescribing information for itraconazole.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). Adverse events 


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associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event Report Form.
Guidelines for treatment discontinuation for subjects who experience AEs are provided 
in Section 5.1.
4.3.2.1
Balovaptan
Balovaptan will be administered alone with food in the morning of Days 1 to 10 of 
Period 1, and in combination with itraconazole on Days 6 to 20 of Period 2. In both 
periods, study drugs will be swallowed whole with 240 mL of still water.
4.3.2.2
Itraconazole
Itraconazole will be administered with food in the morning and evening of Days 1 to 4
and in the morning of Days 5 to Day 20 of Period 2. On Days 6 to 20 of Period 2, 
itraconazole will be administered in combination with balovaptan. In both periods, the 
study drugs will be swallowed whole with 240 mL of still water.
4.3.3
Investigational Medicinal Product Accountability
Balovaptan will be provided by the Sponsor where required by local health authority 
regulations. The study site will acknowledge receipt of IMPs supplied by the Sponsor by 
returning the appropriate documentation form to confirm the shipment condition and 
content. Any damaged shipments will be replaced. Itraconazole will be obtained 
commercially by the site.
The IMPs will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or be returned to the Sponsor (if supplied by 
the Sponsor) with the appropriate documentation. The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor. The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Dispensing Form.


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4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (eg, prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a subject in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the study completion/discontinuation visit. All such 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Subjects who use oral contraceptives or hormone replacement therapy should continue 
their use unchanged.
Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours 
prior to dosing and after the in-house period, but should not exceed 4 g total during the 
week prior to dosing.
4.4.2
Prohibited Therapy
Any prescribed systemic or topical medication within 14 days of the first dose 
administration will be prohibited until the follow-up visit, unless in the opinion of the 
Investigator the medication will not interfere with the study procedures or compromise 
safety. Slow release medicinal formulations considered to still be active within 14 days of 
the first dose administration will also be prohibited until the follow-up visit, unless in the 
opinion of the Investigator the medication will not interfere with the study procedures or 
compromise safety. This is with the exception of medications to treat AEs, unless the 
rationale for exception is discussed and clearly documented between the Investigator, 
the medical and safety monitor and the Roche clinical pharmacologist. All medication 
administered to manage AEs should be recorded on the Adverse Event Report Form
The following concomitant medications in particular are prohibited, unless an exception 
has been agreed as mentioned above.

Any inhibitor of CYP3A taken within 4 weeks (or within 5 half-lives, whichever is 
longest) prior to study drug administration, including but not limited to the following 
drugs: ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, 
clarithromycin, ranitidine, and cimetidine, until follow-up. 

Any inducer of CYP3A taken within 4 weeks prior to study drug administration, 
including but not limited to the following drugs: rifampicin, rifabutin, glucocorticoids, 
carbamazepine, phenytoin, phenobarbital, and St. John's wort, until follow-up.

Investigational drug or device therapy (other than protocol-mandated study 
treatment) is prohibited 90 days prior to first dosing, or within 5 months prior to first 
dosing in case of a study with a biological, as calculated from the day of follow-up 
from the previous study of study treatment and during study treatment.


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4.4.3
Prohibited Food

Consumption of methylxanthine-containing products (eg, coffee, tea, cola, chocolate) 
will be forbidden 48 hours before balovaptan dosing and during the stay in the CRU. 

It is not permitted to take any nutrients known to modulate CYP3A activity (eg, 
grapefruit juice; Seville orange) during the in-house stay.
4.4.4
Additional Restrictions

Between the Screening visit and follow-up, alcohol must be restricted to no more 
than 2 units per day (1 unit is 285 mL of beer, 125 mL of wine or 25 mL of spirits). 
Alcohol consumption will not be allowed 48 hours before balovaptan dosing and 
whilst staying in the study center. Random alcohol/drugs of abuse testing may be 
employed throughout the study period to verify compliance.

Standardized meals similar in content will be served to all subjects at days and the 
times noted in Appendix 1. On these days a standardized breakfast, lunch, snack, 
and dinner will be served at similar times of the day (the same meal for each 
respective meal time), and subjects will be required to complete the meal. All other 
meals will conform to the site’s standards. Breakfast will be provided 30 minutes 
before dosing and completed within approximately 15 minutes prior to balovaptan or 
itraconazole dosing. While in the CRU, subjects will be allowed to consume water 
ad libitum, except for 1 hour before and 2 hours after oral dosing, and a maximum of 
3 liters a day. 

Subjects will not be allowed to perform strenuous exercise within 96 hours before 
screening, Day -1 of Periods 1 and 2, and follow-up. Light ambulatory activities will 
be permitted, with the level of activities kept as similar as possible on all days in the 
CRU.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities must be performed and documented for each subject. 
Subjects will be closely monitored for safety and tolerability throughout the study. 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Informed 
Consent Forms for enrolled subjects and for subjects who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that subjects meet 
all eligibility criteria before enrollment. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.


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4.5.2
Medical History, Concomitant Medication, and Demographic
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history,
and use of alcohol and drugs of abuse, will be performed at the time points specified in 
Appendix 1. In addition, all medications (eg, prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the subject
within 14 days prior to initiation of study treatment will be recorded. At follow-up, any 
changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at the time points specified in Appendix 1, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, neurologic
systems; complaint-driven genitourinary examination may be performed. Any 
abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in subject notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the Adverse Event Report eCRF (and Adverse Event 
Report Form as appropriate).
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, and tympanic temperature at the timepoints indicated in 
Appendix 1. Blood pressure and pulse rate measurements will be performed after the 
subject has rested in a supine position for at least 5 minutes.
4.5.4.1
Orthostatic Challenge Testing
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 blood pressure 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 3 minutes after 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 


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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.
4.5.5
Laboratory, Pharmacokinetic, and Genotyping Samples
For sampling 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.
4.5.5.1
Laboratory Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, absolute 
differential count (neutrophil, eosinophils, basophils, monocytes, lymphocytes)

Blood chemistry panel: sodium, potassium, chloride, bicarbonate, glucose (fasting), 
urea, creatinine, total and conjugated bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-
transferase, CPK

Coagulation: prothrombin time (international normalized ratio) and activated 
thromboplastin time at screening only and at end of study visit

Drugs of abuse, including cannabinoids, amphetamines (including ecstasy), 
methamphetamines, opiates, methadone, cocaine, benzodiazepines, and 
barbiturates, will be measured in urine at Screening and on Day -1 of each study 
period.

Urine alcohol test at Screening and on Day -1 of each study period.

Viral serology at Screening: HIV-1 and HIV-2, HBsAg, HCV antibody.

Pregnancy test
Follicle-stimulating hormone (FSH) test and beta-human chorionic gonadotropin 
(serum pregnancy test) will be performed at Screening in all females. At 
subsequent visits as noted in Appendix 1, a serum pregnancy test will be 
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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 will be 
performed if abnormalities are observed and if it is deemed necessary by the 
Investigator or designee, in particular when blood or protein is positive or strong 
positive. If there is an explanation for the positive dipstick result, it should be 
recorded, and there is no need to perform laboratory for microscopy and culture.
4.5.5.2
Pharmacokinetic Samples
Plasma samples for PK analysis will be shipped to designated bioanalytical laboratories
for analysis.
Plasma samples collected for PK analysis will be destroyed after the final Clinical Study 
Report has been issued.
4.5.5.3
Genotyping Samples
A mandatory 3 mL whole blood sample will be taken for DNA extraction from every 
subject during the study on Day -1 of Period 1. The DNA may be used to determine 
whether genes relating to drug-metabolizing enzymes and/or drug transporter enzymes 
affect the PK and/or the safety profile of balovaptan. Genotyping samples will be sent to 
the Sponsor or a designee for analysis. This specimen will be destroyed no later than 2 
years after the final Clinical Study Report has been issued.
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This number is used 
to code the samples. Subject names are not included in samples that are sent for 
analysis.
4.5.6
Electrocardiograms
Triplicate 12-lead ECG will be performed at the times indicated in Appendix 1.
4.5.7
Columbia Suicide Severity Rating Scale
The Columbia Suicide Severity Rating Scale (C-SSRS) is a clinical tool used to assess 
the lifetime suicidality of a subject (C-SSRS lifetime version) as well as any new 
instances of suicidality (C-SSRS since last visit).
The structured interview prompts recollection of suicidal ideation, including the intensity 
of the ideation, behavior and attempts with actual/potential lethality.
The C-SSRS assessments will be completed by the Investigator or Research Physician
at the time points as specified in Appendix 1.
4.5.8
Drug and Metabolite Concentration Measurements
Plasma concentrations of balovaptan and its metabolites M3 and M2 will be measured 
using a specific and validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) method. Plasma concentrations of itraconazole and its metabolite 


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hydroxy-itraconazole will also be measured using a separate, specific and validated 
LC-MS/MS method.
4.5.9
Timing of Study Assessments
If performed at the same timepoint, assessments should be prioritized as follows, while 
ensuring PK blood sampling is conducted at the scheduled time:

12-lead ECGs

Vital signs measurements

PK blood sampling

Laboratory safety tests 
4.6
TREATMENT, SUBJECT, STUDY, AND SITE 
DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Subjects must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the subject’s safety if he or she continues to receive study treatment (see 
Section 5.1.2 for additional guidance on the management of toxicities and of 
subjects who experience AEs)

Investigator or Sponsor determines it is in the best interest of the subject

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Subjects who discontinue study treatment prematurely may be
replaced.
Subjects will return to the clinic for a follow-up visit 14 to 21 days after the last dose of 
study drug (see Appendix 1 for additional details).
4.6.2
Subject Discontinuation from Study
Subjects will return to the clinic for a follow-up visit 14 to 21 days after the last dose of 
study drug.
Subjects have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the Investigator has the right to withdraw a subject from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following:

Subject withdrawal of consent

Study termination or site closure

Subject non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator or Sponsor


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Every effort should be made to obtain information on subjects who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the Investigator. Subjects
who withdraw from the study may be replaced.
4.6.3
Study Discontinuation
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

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (ie, all subjects have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Balovaptan is not approved, and clinical development is ongoing. The safety plan for 
subjects in this study is based on clinical experience with balovaptan in completed and 
ongoing studies. Potential important safety risks for balovaptan are outlined below. 
Please refer to the RO5285119 (Balovaptan) Investigator's Brochure for a complete 
summary of safety information. 
Several measures will be taken to ensure the safety of subjects participating in this study. 
Eligibility criteria have been designed to exclude subjects at higher risk for toxicities. 
Subjects will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of AEs. In addition, guidelines for managing AEs, 
including criteria for treatment discontinuation, are provided below.


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5.1.1
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1.1
 
 
 
 
 
 
 
 
 
 
5.1.1.2
 
 


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5.1.1.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
5.1.2
Management of Toxicities and of Subjects Who Experience 
Adverse Events
5.1.2.1
Management Guidelines
In general, any emerging adverse events must diligently be watched, treated as 
medically indicated according to common medical practice and documented in terms of 
onset-date, intensity, off-set date, and any measures taken in order to treat the adverse 
event.


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No specific treatment guidance to any potentially emerging adverse events in balovaptan 
clinical trials exist and treatment should be according to the common medical practice for 
the given adverse event. 
The Investigator should also consider discontinuation of treatment with balovaptan and 
itraconazole, in particular, if an adverse event is of severe intensity and considered to be 
possibly related to balovaptan and itraconazole, respectively. 
Temporary dosing interruptions must be discussed with the Sponsor’s Medical Monitor in 
the sense that temporary interruptions will have to be very limited in order to nor 
jeopardize the trial’s pharmacokinetic objectives. Dose modifications because of an 
adverse event are not allowed in this study.
5.1.2.2
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 




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5.1.2.5
 
 
 
 
 
 
 
 
 
5.1.2.6
 
 


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AEs of special interest, performing protocol-specified safety laboratory assessments,
measuring protocol-specified vital signs, and conducting other protocol-specified tests 
that are deemed critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution. An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.8 for more 
information)

Recurrence of an intermittent medical condition (eg, headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (eg, 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 (ie, the AE actually causes or leads to death)

Is life threatening (ie, the AE, in the view of the Investigator, places the subject at 
immediate risk of death)
This does not include any AE that, had it occurred in a more severe form or was 
allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.9)

Results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the Investigator's judgment (eg, may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an AE (eg, rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events; see Section 5.3.3); the event itself 
may be of relatively minor medical significance (such as severe headache without any 
further findings).


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Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (ie, no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (ie, no more than 24 hours after learning of the event; see Section 
5.4.2 for reporting instructions). Adverse events of special interest for this study are as 
follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product. This term applies only
when a contamination of the study drug is suspected.

Clinically relevant decreases in ANC and for which no alternative explanation has 
been identified (ie, the relationship to study drug is rated “yes”)

CPK values that exceed 10ULN for several days without a trend of normalization or 
are associated with relevant dysfunction of kidneys, and if no alternative explanation 
exists 

Neurological abnormalities emerging from adverse event reporting or neurologic 
examination that are potentially indicative of dysfunction of peripheral nerves or 
otherwise represent a neurological deficit and for which no other explanation is 
apparent 

Adverse events such as: arrhythmia, syncope, dyspnea, palpitations, or chest 
pain
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event Report Form and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 to 5.6. The 
Investigator is also responsible for reporting medical device complaints (see Section 
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For each AE recorded on the Adverse Event Report Form, the Investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on AEs at each subject contact. All AEs, whether 
reported by the subject or noted by study personnel, will be recorded in the subject’s 
medical record and on the Adverse Event Report eCRF (and Form, if appropriate).
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (eg, invasive procedures such as biopsies, 
discontinuation of medications) should be reported (see Section 5.4.2 for instructions for 
reporting SAEs).
After initiation of study drug, all AEs will be reported until up to 21 days after the last 
dose of study drug.
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all subject evaluation timepoints. Examples of non-directive questions 
include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing AE severity.
Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer 
to definition of an SAE (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 


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AE is considered to be related to the study drug, indicating "yes" or "no" accordingly. 
The following guidance should be taken into consideration (see also Table 3)

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 3
Causal Attribution Guidance
Is the AE suspected to be caused by the study drug on the basis of facts, evidence, science-based 
rationales, and clinical judgment?
YES 
(RELATED)
There is a plausible temporal relationship between the onset of the 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 (NOT 
RELATED)
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 (eg, pre-existing 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the study drug 
(eg, 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.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event Report eCRF (and Form, if appropriate). Avoid colloquialisms and 
abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event Report 
eCRF (and Form, if appropriate).
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event Report eCRF (and 
Form, if appropriate) rather than individual signs and symptoms (eg, record only liver 
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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 Report eCRF (and Form, if appropriate). 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 (eg, 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 Report eCRF (and Form, if appropriate). 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 Report eCRF (and Form, if 
appropriate) 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 
Report eCRF (and Form, if appropriate). The initial severity (intensity or grade) of the 
event will be recorded at the time the event is first reported. If a persistent AE becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
Report eCRF (and Form, if appropriate). If the event becomes serious, it should be 
reported to the Sponsor immediately (ie, no more than 24 hours after learning that the 
event became serious; see Section 5.4.2 for reporting instructions). If a non-serious AE 
becomes serious, the Investigator will complete the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and send the form to Roche 
drug safety. The Adverse Event Report eCRF if already completed should also be 
updated to serious to correspond with the Adverse Event Reporting Form information 
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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 Report eCRF (and Form if appropriate).
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 (eg, dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (eg, potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, 
alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (ie, cholestasis) should be recorded on the Adverse Event Report eCRF (and 
Form if appropriate).
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event Report eCRF (and Form 
if appropriate), along with a descriptor indicating whether the test result is above or 
below the normal range (eg, "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 Report eCRF (and Form if 
appropriate) (see Section 5.3.5.3 for details on recording persistent AEs).
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 (eg, dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the Investigator’s judgment 


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It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (eg, 
high blood pressure), only the diagnosis (ie, hypertension) should be recorded on the 
Adverse Event Report eCRF (and Form if appropriate).
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event Report eCRF (and Form if 
appropriate)(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, Investigators must report as an AE the occurrence of 
either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event Report eCRF (and Form if 
appropriate)(see Section 5.3.5.1) and reported to the Sponsor immediately (ie, no more 
than 24 hours after learning of the event), either as an SAE or an AE of special interest 
(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 Report eCRF and 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 
concept on the Adverse Event eCRF and 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
Form. If the cause of death later becomes available (eg, 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 (eg, "sudden 
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Deaths that occur after the AE reporting period should be reported as described in 
Section 5.6.
5.3.5.8
Pre-existing Medical Conditions
A pre-existing 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 pre-existing 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 Form, if appropriate), it is important to convey 
the concept that the pre-existing condition has changed by including applicable 
descriptors (eg, "more frequent headaches").
5.3.5.9
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization (ie, inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE
in Section 5.2.2), except as outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or an SAE:

Hospitalization for respite care

Planned hospitalization required by the protocol

Hospitalization for a pre-existing 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
An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead:

Hospitalization that was necessary because of subject requirement for outpatient 
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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious AEs (defined in Section 5.2.2; see Section 5.4.2 for details on reporting 
requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)

Medical device complaints (see Section 5.4.5 for details on reporting requirements)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (ie, no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and Institutional Review Board/Ethics Committee (IRB/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.:
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, 


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provide medical translation service (if necessary), connect the Investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls. The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week. Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible contact information, will be distributed to all 
investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur Prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported. The paper Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (ie, no more than 24 hours after learning of the event), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, SAEs and adverse events of special interest will be 
reported until 21 days after the last dose of study drug. Investigators should record all 
case details that can be gathered immediately (ie, 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 Adverse Event Report Form and 
submitting the report, either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators. 
Instructions for reporting SAEs that occur 21 days after the last dose of study treatment 
are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Subjects
Female subjects of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 90 days after the last 
dose of study drug. A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (ie, no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators. Pregnancy 
should not be recorded on the Adverse Event eCRF. The Investigator should discontinue 
study drug and counsel the subject, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the subject should continue until conclusion 
of the pregnancy. Any SAEs associated with the pregnancy (eg, 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 Form, if appropriate). In 


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addition, the Investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
5.4.3.2
Pregnancies in Female Partners of Male Subjects
Male subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of study drug. A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately (ie,
no more than 24 hours after learning of the pregnancy), either by faxing or by scanning 
and emailing the form using the fax number or email address provided to investigators. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male subject exposed to study drug. When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. If
the authorization has been signed, the Investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. An Investigator who is contacted by the male subject or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF and Form, and reported to 
the Sponsor immediately (ie, no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female subject exposed to study 
drug or the female partner of a male subject exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event Report eCRF and Form, and reported to the 
Sponsor immediately (ie, 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.


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Special situations are not in themselves AEs but may result in AEs. All special situations 
associated with balovaptan, regardless of whether they result in an AE, should be 
recorded on the Adverse Event Report eCRF and Form and reported to the Sponsor 
immediately (ie, no more than 24 hours after learning of the event). Special situations 
should be recorded as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (eg, wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details.
For balovaptan and itraconazole, each AE associated with a special situation should be 
recorded separately on the Adverse Event eCRF and Form. If the associated AE fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(ie, no more than 24 hours after learning of the event; see Section 5.4.2). For balovaptan, 
AEs associated with special situations should be recorded as described below for each 
situation:

Accidental overdose: Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the AE term. Check the 
"Medication error" box.

Medication error that qualifies as an overdose: Enter the AE term. Check the 
"Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages and forms, one to report the accidental 
overdose and one to report the headache. The "Accidental overdose" and "Medication 
error" boxes would need to be checked on both eCRF pages.
5.4.5
Reporting Requirements for Medical Device Complaints
The Investigator must report all medical device complaints to the Sponsor. The 
Investigator should document as much information as possible on the IMP Deviation 
Form, including the product batch number, and forward the form to the Sponsor 
immediately (ie, no more than 24 hours after learning of the event) (refer to the 
pharmacy manual for further details). If the medical device results in an AE to the study 
subject, the event must be reported on the Adverse Event eCRF and Form and 


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submitted through the electronic data capture (EDC) system. If the event is serious, the 
Adverse Event eCRF and Form must be completed immediately (ie, no more than 
24 hours after learning of the event), as outlined in Section 5.4.2.
5.5
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the subject is lost to follow-up, 
or the subject withdraws consent. Every effort should be made to follow all SAEs 
considered to be related to study drug or trial-related procedures until a final outcome can 
be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF (and Form, if appropriate) 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, adverse events of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (eg, from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the Investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined in Section 5.3.1) after the last 
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 Report Form. The 
Investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and adverse events of special interest 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health 
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To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document:

RO5285119 (Balovaptan) Investigator's Brochure

Itraconazole Summary of Product Characteristics
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
A statistical analysis plan will be generated by the biostatistics department of PRA and 
will be finalized prior to database lock.
6.1
DETERMINATION OF SAMPLE SIZE
This is an exploratory study for which no formal statistical hypothesis will be tested, and 
therefore the sample size is chosen to estimate, with sufficient precision, the CYP3A4 
inhibition on balovaptan. Between 14 and 18 subjects will be enrolled, so as to have 14 
subjects enrolled on either 5 mg or 10 mg balovaptan to ensure a minimum of 12 
completers. The sample size was chosen based on balovaptan within-subject variability
(CV%) of around 39% for AUC0-τ and 36% for Cmax as obtained from the 12 mg repeat 
dose in study BP25694. Based on the higher value of 39%, it was estimated that with 12 
subjects, the half-width of the 90% CI for the ratio of treatment geometric means of the 
combination (balovaptan + itraconazole) versus balovaptan alone would be obtained by 
dividing/multiplying the ratio estimate by a factor of 1.30.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of subjects who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study withdrawal will be listed and summarized. 
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
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.
6.4
EFFICACY ANALYSES
Not applicable.


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6.5
SAFETY ANALYSES
All subjects who have received at least one dose of balovaptan, whether prematurely 
withdrawn from the study or not, will be included in the safety analysis.
The safety data, including AEs, laboratory data, and vital signs, will be listed and 
summarized by treatment. Reasons for withdrawal from study will be listed and 
summarized. Concomitant medications, 12-lead ECG data, and clinically significant 
neurological examinations will be listed.
Adverse events will be listed and summarized by treatment, body system and preferred 
term using the Medical Dictionary for Regulatory Activities. All verbatim AE terms will be 
mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and 
AE severity will be graded according to Table 2.
For laboratory and 12-lead ECG data, subject listings will be presented with 
abnormalities flagged.
6.6
PHARMACOKINETIC ANALYSES
Subjects will be excluded from the PK analysis population if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from the protocol, or if data are 
unavailable or incomplete. Excluded cases will be documented together with the reason 
for exclusion. All decisions on exclusions from the analysis will be made prior to 
database closure.
Individual plasma concentrations at each sampling timepoint for balovaptan, M2 (as 
applicable), M3, itraconazole and hydroxy-itraconazole will be presented by listings and 
descriptive summary statistics by treatment, including means, geometric means, ranges, 
standard deviations and coefficients of variation. Individual and mean concentration 
versus time will be plotted on linear and semi-logarithmic scales.
All PK parameters for balovaptan, M2 (as applicable), and M3 will be presented by 
individual listings and summary statistics by treatment including means, geometric 
means, medians, ranges, standard deviations and coefficients of variation.
The following balovaptan PK parameters will be estimated:

Cmax: Day 10 of Period 1; Day 15 and Day 20 of Period 2

AUC0-τ: Day 10 of Period 1; Day 15 and Day 20 of Period 2

Tmax: Day 10 of Period 1; Day 15 and Day 20 of Period 2

Ctrough: Day 10 of Period 1; Day 15 and Day 20 of Period 2)

time to steady state (for balovaptan)


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The primary PK parameters are Cmax and AUC0-τ for balovaptan, M2, and M3 on Day 10 
of Period 1 and Day 20 of Period 2.
A linear mixed model analysis will be applied to analyze the log-transformed primary PK
parameters. The model assumes a fixed effect for treatment and a random effect for 
subject. Estimates of geometric mean ratios together with the corresponding 90% CIs 
will be derived for the comparisons of the PK parameters as follows:

balovaptan plus itraconazole (test) vs balovaptan alone (reference)
For itraconazole and hydroxy-itraconazole, Cmax, AUC0-24h, and Tmax will be estimated on 
Day 5 and Day 20 to evaluate whether adequate levels were reached.
Additional PK parameters may be derived if deemed necessary.
6.7
OTHER ANALYSES
6.7.1
Genotyping
The relationship between CYP3A4 genotype and steady state balovaptan exposure and 
the influence of CYP3A4 genotype on the effect of itraconazole on balovaptan PK and 
CYP3A enzyme activity will be evaluated. Other isoforms may also be analysed.
6.8
INTERIM ANALYSES
Interim PK analyses, including the calculation of the PK parameters for both periods, will 
be done for Cohort A. The data from this analysis will be used in the decision whether 
the balovaptan dose should be increased from 5 to 10 mg qd for Cohort B.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply eCRF specifications for this study. The contract research 
organization (CRO), PRA Health Sciences (PRA), will be responsible for data 
management of this study, including quality checking of the data. Data entered manually 
will be collected via EDC through use of eCRFs. Sites will be responsible for data entry 
into the EDC system. In the event of discrepant data, PRA will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system.
PRA will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. Central laboratory data will be sent directly to 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. 


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Electronic case report forms and correction documentation will be maintained in the EDC 
system’s audit trail. System backups for data stored at the CRO and records retention 
for the study data will be consistent with the CRO’s standard procedures. 
7.2
ELECTRONIC CASE REPORT FORMS 
Electronic case report forms are to be completed through use of a Sponsor-designated 
EDC system. Sites will receive training and have access to a manual for appropriate 
eCRF completion. eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff. Electronic case report 
forms should be reviewed and electronically signed and dated by the Investigator or a 
designee.
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME
Not applicable.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (ie, source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which subject data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient 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 (ie, 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 7.6.


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65/Protocol WP40609, Version 1.0
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review. The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (ie, in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper patient-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.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a US
Investigational New Drug (IND) Application will comply with US Food and Drug 
Administration regulations and applicable local, state, and federal laws. Studies 
conducted in the European Union (EU) or European Economic Area will comply with the 
EU Clinical Trial Directive (2001/20/EC).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed 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 submission. The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The Investigator or authorized designee will explain to each subject the 
objectives, methods, and potential risks associated with each optional procedure. 
Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a subject's agreement to participate in optional procedures. Subjects who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Subjects must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each subject shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the subject or the subject’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time.
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 


Balovaptan—F. Hoffmann-La Roche Ltd
67/Protocol WP40609, Version 1.0
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any subject recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC and archived in the site’s 
study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the subject, 
unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
subjects unless required by law. The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
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 


Balovaptan—F. Hoffmann-La Roche Ltd
68/Protocol WP40609, Version 1.0
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the Investigator will receive 
the subject data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The Investigator should document and explain any protocol deviations. The Investigator
should promptly report any deviations that might have an impact on subject safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs. The Investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor has contracted PRA, 
who will be delegated responsibility for various aspects of this clinical trial.
One site will participate to enroll 14 to 18 subjects. 
Central facilities will be used for certain study assessments throughout the study (eg, 
specified laboratory tests and PK analyses), as specified in Section 4.5. Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 


Balovaptan—F. Hoffmann-La Roche Ltd
69/Protocol WP40609, Version 1.0
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective 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.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by PRA. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (eg, change in Medical Monitor or contact information).


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10.
REFERENCES
Al-Mosalem OA, El-Ansary A, Attas O, et al. Metabolic biomarkers related to energy 
metabolism in Saudi autistic children. Clin Biochem. 2009; 42:949–957
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 
5th ed. Washington, DC: American Psychiatric Association, 2013.
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal
Investigators; Centers for Disease Control and Prevention (CDC). Prevalence of autism 
spectrum disorder among children aged 8 years - Autism and Developmental Disabilities 
Monitoring Network, 11 sites, United States, 2010. MMWR Surveill Summ.
2014;63(2):1–21.
Janssen Pharmaceuticals. Sporanox® (itraconazole) Capsules. 2001 (Revised 2017)
Levy SE, Mandell DS, Schultz RT: Autism. Lancet. 2009;374:1627–1638.
Liu L, Bello A, Dresser MJ, et al. Best practices for the use of itraconazole as a 
replacement for ketoconazole in drug-drug interaction studies. J Clin Pharmacol. 
2016;56(2):143–151
May T, Brewer WJ, Rinehart NJ, et al. Differential Olfactory Identification in Children with 
Autism and Asperger’s Disorder: A Comparative and Longitudinal Study. J Autism Dev 
Disord. 2011;41(7):837–847
Meyer-Lindenberg A, Kolachana B, Gold B, et al. Genetic variants in AVPR1A linked to 
autism predict amygdala activation and personality traits in healthy humans. Mol
Psychiatry. 2009;14(10):968–975.
Tobin VA, Hashimoto H, Wacker DW, et al. An intrinsic vasopressin system in the
olfactory bulb is involved in social recognition. Nature. 2010;464(18):413-419.


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Appendix 1
Schedule of Activities
Procedures
Screening
Period 1
Period 2
Follow-up
-1
1
2 
to 
8
9
10
11
washout 
(at least 7 
days)
-1
1
2
3
4
5
6
to 
11
12
13
14
15
16
17 
to 
19
20
21
14 to 21 
days 
postdose
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demographic data
X
Medical history
X
X
Urine drug screen
and urine alcohol 
test
X
X
X
Urinalysis
X
X
X
X
X
Serology
X
Coagulationa
X
Pregnancy testb
X
X
X
X
Balovaptan
administrationc
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling for 
Balovaptan and 
metabolites M2
and M3d
X
X
X
X
X
X
X
X
X
X
X
X
Itraconazole
administratione
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling for 
Itraconazole and 
hydroxyl-
itraconazolef
X
Xn
X
X
Genotyping 
sample
X
Physical 
examination
X
X
Xg
X
Height, body 
weight and BMIh
X
X
X


Appendix 1
Schedule of Activities (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
72/Protocol WP40609, Version 1.0
Procedures
Screening
Period 1
Period 2
Follow-up
-1
1
2 
to 
8
9
10
11
washout 
(at least 7 
days)
-1
1
2
3
4
5
6
to 
11
12
13
14
15
16
17 
to 
19
20
21
14 to 21 
days 
postdose
Triplicate 12-lead 
ECGi
X
X
X
X
X
X
Xn
X
X
Xo
X
X
Vital signsj
X
X
X
X
Xn
X
X
Xo
X
X
Orthostatic 
challenge testing
X
Xp
X
Xp
Xp
Clinical laboratory 
(hematology, and 
clinical chemistry)k
X
X
X
X
X
Xn
X
X
Xo
X
X
Admission 
X
X
Residential stay
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge
X
X
Ambulatory visit
X
X
Standardized 
meall
X
X
X
X
C-SSRSm
X
X
X
X
Adverse event 
monitoring
X
X
Review 
concomitant 
medications
X
X
Abbreviations: BMI = body mass index; C-SSRS= Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; PK = pharmacokinetic; 
aProthrombin time (international normalized ratio) and activated partial thromboplastin test only.
bFollicle-stimulating hormone test and beta-human chorionic gonadotropin (serum pregnancy test) at screening in all females. At subsequent visits, serum
pregnancy test will be performed in all females.
cOnce daily dosing with food on Period 1, Days 1 to 10 and Period 2, Days 6 to 15, administered in the clinical research unit in the morning between 07:00 and 
10:00 AM. On Period 1, Day 10 and Period 2, Day 20, balovaptan will be dosed at the same time of each day.
dPK sampling on Days 1, 3, 5, 8, 9, 10, and 11 of Period 1, and on Days 6, 8, 10, 13, 14, 15, 16, 18, 19, and 20 of Period 2. See Appendix 2 for specific PK blood 
sampling time points for each study day
eDose with food. Twice daily dosing on Days 1 to 4, Period 2, Days 1 to 4. Once daily dosing on Period 2, Days 6 to 20 in combination with balovaptan. On Period 2, 
Days 5 and 20, itraconazole will be dosed at the same time on each day. 
fPK sampling on Days 5, 6, 8, 10, 14, 15, 16, 18, 19, and 20 of Period 2. See Appendix 2 for specific PK blood sampling time points for each study day.
gPrior to discharge.
hHeight, weight, and BMI at Screening; weight only on Day -1 of Periods 1 and 2.


Appendix 1
Schedule of Activities (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
73/Protocol WP40609, Version 1.0
iSee Appendix 2 for specific ECG time points by study day
jSee Appendix 2 for specific vital signs time points by study day
kPrior to breakfast
lAt predose (breakfast will be provided 30 minutes before dosing and completed within approximately 15 minutes prior to balovaptan or itraconazole dosing), and at
5, 9, and 11.5 hours post dose
mPredose
n Assessments performed on Days 6, 8, and 10 
oAssessments performed on Day 17
pTest performed about 3 hours after the morning dose of balovaptan. On Day 4 in Period 2, when only itraconazole is dosed, the timing of the orthostatic challenge 
test should correspond to 3 hours after the time of balovaptan dosing in Period 2.


Balovaptan—F. Hoffmann-La Roche Ltd
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Appendix 2
Schedule of Pharmacokinetic Sampling, Electrocardiogram, and 
Vital Signs Measurements
Procedure
Study Day
Predose
Hours post dose
1
2
3
4
5
6
8
10
12
16
24
Blood sampling balovaptan, M2, and M3
Period 1
Day 1, 3, 5, 8, 9
Xa
Day 10
Xa
X
X
X
X
X
X
X
X
X
Xb
Xb
Period 2
Day 6, 8, 10, 13, 14, 16, 18, 19
Xa
Day 15
Xa
X
X
X
X
X
X
X
X
X
Xc
Xc
Day 20
Xa
X
X
X
X
X
X
X
X
X
Xd
Xd
Blood sampling itraconazole and hydroxyl-itraconazole
Period 2
Day 5
Xa
X
X
X
Day 6, 8, 10, 14, 15, 16, 18, 19
Xa
Day 20
Xa
X
X
X
Xc
12-lead electrocardiograms
Period 1
Days 1 and 10
X
Period 2
Day 1
Xe
Day 5, 6, 8, 10, 13, 15,17, 20
X
X
Vital signs
Period 1
Day 1
X
Day 11f
Period 2


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (cont.)
Balovaptan—F. Hoffmann-La Roche Ltd
75/Protocol WP40609, Version 1.0
Procedure
Study Day
Predose
Hours post dose
1
2
3
4
5
6
8
10
12
16
24
Day 1
Xe
Day 6
X
X
X
X
X
X
Day 8, 10, 13, and 17
X
X
Day 15
X
X
X
X
X
X
Day 21f
a10 minutes predose (or time matched, when not dosed)
bDay 11
cDay 16
dDay 21
ePre-AM dose
fPrior to discharge

SAP_001.pdf: 
 
Official Title: 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, 
ONE-SEQUENCE, TWO-PERIOD WITHIN-SUBJECT 
STUDY TO INVESTIGATE THE EFFECT OF 
ITRACONAZOLE ON THE PHARMACOKINETICS OF 
MULTIPLE DOSES OF BALOVAPTAN IN HEALTHY 
VOLUNTEERS 
NCT Number: 
NCT03579719 
Document Date: 
SAP version 1: 20-November-2018 
 
 


* PRAHEALTHSCIENCES 
Statistical Analysis Plan 
 
 
 
 
 
Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
Sponsor: 
Protocol No  
Protocol Title: 
 
 
 
PRA Project ID  
Version Date  
F. Hoffmann-La Roche Ltd 
WP40609 
A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, ONE- 
SEQUENCE, TWO-PERIOD WITHIN-SUBJECT STUDY TO 
INVESTIGATE THE EFFECT OF ITRACONAZOLE ON THE 
PHARMACOKINETICS OF MULTIPLE DOSES OF BALOVAPTAN IN 
HEALTHY VOLUNTEERS 
RPU035EC-180351 
14-Nov-2018 
 
1.0 Approvals 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
, Biostatistician 
 
• Representatiye  > · 
LTitle: . . 
Signature of 
Sponsor 
Representative / 
Date  
Name of Author/ 
Title: 
Signature of Author I 
Date  
A6 -- Abv '6J).t 
, Principal Biostatistician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed by: 
 
Principal Biostatistician 
Reason: I am the author  of  this  document  
Date & Time: 20 Nov 2018 02:34 PM +01:00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dacu 
. 
Pharmaceutical Research Associates Group BV , a PRA Health Sciences 
company 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
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2.0 Table of Contents 
1.0 Approvals ................................................................................................................................................ 1 
2.0 Table of Contents .................................................................................................................................... 2 
3.0 Introduction ............................................................................................................................................. 4 
4.0 Changes from Previous Version of Approved SAP ................................................................................. 4 
5.0 Study Objectives ..................................................................................................................................... 4 
5.1 Primary Objective ................................................................................................................................ 4 
5.1.1 Primary PK Endpoints .................................................................................................................. 4 
5.1.2 Additional PK Endpoints ............................................................................................................... 4 
5.2 Secondary Objective ........................................................................................................................... 4 
5.2.1 Secondary Endpoints ................................................................................................................... 4 
5.3 Tertiary/Exploratory Objectives ........................................................................................................... 5 
5.3.1 Tertiary/Exploratory Endpoints ..................................................................................................... 5 
6.0 Study Design ........................................................................................................................................... 5 
6.1 Sample Size Considerations ............................................................................................................... 7 
6.2 Randomization .................................................................................................................................... 7 
7.0 Overview of Planned Analysis ................................................................................................................. 7 
7.1 Changes from Protocol ....................................................................................................................... 7 
7.2 Interim Analysis and Key Results........................................................................................................ 7 
7.3 Final Analysis ...................................................................................................................................... 7 
8.0 Data Review ............................................................................................................................................ 7 
8.1 Data Management ............................................................................................................................... 7 
8.2 Acceptance of Data for Summarization............................................................................................... 7 
9.0 Definitions and General Analysis Methods ............................................................................................. 8 
9.1 Analysis Data Presentation ................................................................................................................. 8 
9.1.1 Rounding ...................................................................................................................................... 8 
9.1.2 Imputation..................................................................................................................................... 8 
9.1.3 Descriptive Statistics .................................................................................................................... 8 
9.1.4 Pooling ......................................................................................................................................... 8 
9.1.5 Unscheduled Measurements ....................................................................................................... 9 
9.2 Analysis Data Definitions .................................................................................................................... 9 
9.2.1 Baseline Definition ....................................................................................................................... 9 
9.2.2 Treatment/Subject Grouping ........................................................................................................ 9 
9.2.3 Common Variable Derivations ................................................................................................... 10 
9.2.4 QC .............................................................................................................................................. 10 
9.2.5 ADaM Datasets and Metadata ................................................................................................... 11 
9.3 Software ............................................................................................................................................ 11 
9.4 Statistical Methods ............................................................................................................................ 11 
9.4.1 Statistical Outlier Determination ................................................................................................. 11 
9.4.2 Predetermined Covariates and Prognostic Factors ................................................................... 11 
9.4.3 Hypothesis Testing ..................................................................................................................... 11 
9.5 TFL Layout ........................................................................................................................................ 11 
10.0 Analysis Populations ........................................................................................................................... 12 
10.1 Safety Analysis Population .............................................................................................................. 12 
10.2 Pharmacokinetic Analysis Population ............................................................................................. 12 
11.0 Subject Disposition .............................................................................................................................. 12 
12.0 Protocol Deviations and Violations ..................................................................................................... 12 
13.0 Demographic and Baseline Characteristics ........................................................................................ 13 
13.1 Demographics ................................................................................................................................. 13 
13.2 Medical History ................................................................................................................................ 13 
13.3 Other Baseline Characteristics........................................................................................................ 13 
14.0 Concomitant Medications .................................................................................................................... 13 
15.0 Treatment Compliance and Exposure ................................................................................................ 13 


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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
16.0 Pharmacokinetic Analyses .................................................................................................................. 13 
16.1 Pharmacokinetic Variables .............................................................................................................. 14 
16.1.1 Concentrations ......................................................................................................................... 14 
16.1.2 Parameters ............................................................................................................................... 14 
16.2 Pharmacokinetic Summaries .......................................................................................................... 16 
16.2.1 Pharmacokinetic Concentrations ............................................................................................. 16 
16.2.2 Pharmacokinetic Parameters ................................................................................................... 16 
17.0 Safety Analyses .................................................................................................................................. 17 
17.1 Safety Variables .............................................................................................................................. 17 
17.1.1 Adverse Events ........................................................................................................................ 18 
17.1.2 Deaths and Serious Adverse Events ....................................................................................... 18 
17.1.3 Laboratory Data ....................................................................................................................... 18 
17.1.4 Vital Signs ................................................................................................................................ 18 
17.1.5 Electrocardiograms .................................................................................................................. 19 
17.1.6 Columbia Suicide Severity Rating Scale .................................................................................. 19 
17.1.7 Other Observations Related to Safety ..................................................................................... 19 
18.0 References .......................................................................................................................................... 19 
Appendix 1: Glossary of Abbreviations ....................................................................................................... 20 
Appendix 2: Schedule of Assessments ....................................................................................................... 22 
Appendix 3: Schedule of PK Sampling, ECG, and Vital Signs Measurements .......................................... 25 
Appendix 4: List of End of Text Outputs...................................................................................................... 27 
Document History ........................................................................................................................................ 31 


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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under F. Hoffmann-La Roche Ltd Protocol WP40609. 
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the plan has been developed using protocol Version 1.0 dated 18-May-2018 [2] and the 
final eCRF(s) dated 05-Jul-2018. 
An approved and signed SAP is a requirement for database lock. 
This SAP only covers the results that will be processed by the PRA Early Development Services (EDS) 
Biostatistics Department. 
PRA EDS will perform the pharmacokinetic (PK), and safety and tolerability evaluation. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant 
changes from the planned analysis in this SAP performed to provide results for inclusion in the clinical 
study report (CSR) but not included in this SAP, will be clearly identified in Section 9.8.2 of the CSR. 
Changes to planned analyses do not require an updated SAP but should be included in the CSR if 
significant. 
 
4.0 Changes from Previous Version of Approved SAP 
This is the first version of the SAP. 
 
5.0 Study Objectives 
This study will investigate the effect of itraconazole treatment on the PK of balovaptan and its major 
metabolites M2 (RO7045402) and M3 (RO5273004). 
 
5.1 Primary Objective 
To investigate the effect of itraconazole treatment on the PK of balovaptan and its major metabolites M2 
(as applicable) and M3, at steady state. 
 
5.1.1 Primary PK Endpoints 
PK parameters for balovaptan, M2, and M3 after 15 days of balovaptan qd dosing in Period 2, and after 
10 days of balovaptan qd dosing in Period 1: 
• 
Maximum observed plasma concentration (Cmax) 
• 
Area under the concentration vs time curve (AUC) over the dosing interval (AUC0-τ) 
5.1.2 Additional PK Endpoints 
Additional PK endpoints: balovaptan, M2, and M3 time to maximum observed plasma concentration 
(Tmax), trough plasma concentration (Ctrough), and time to steady state 
 
5.2 Secondary Objective 
To explore the safety and tolerability of balovaptan when given alone and in combination with  
itraconazole in healthy subjects. 
 
5.2.1 Secondary Endpoints 
• 
Adverse events (AEs), 


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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
• 
clinical laboratory values, 
• 
vital signs, 
• 
electrocardiogram (ECG), and 
• 
physical examination. 
5.3 Tertiary/Exploratory Objectives 
• 
Relationship between the CYP3A4 genotype, among others, and steady state balovaptan 
exposure, and the influence of the CYP3A4 genotype, among others, on the effect of itraconazole 
on balovaptan PK 
• 
The plasma exposure of itraconazole and hydroxy (OH)-itraconazole 
5.3.1 Tertiary/Exploratory Endpoints 
• 
The pharmacogenetics of metabolizing enzyme, transferases, transporters, etc, possibly involved 
in the absorption, distribution, metabolism, and excretion of balovaptan and its major metabolites 
(eg, CYP3A4 and P-glycoprotein). Note that results may be pooled with data from other studies of 
balovaptan, but the results of such pooling will not be included in the CSR for this study. 
• 
Area under the curve from time 0 to 24 hours (AUC0-24h ), Cmax, and Tmax on Day 5 and Day 20 
 
6.0 Study Design 
This study will be non-randomized, open-label, one-sequence, two-period within-subject study to 
investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy male and female volunteers 
using itraconazole as a CYP3A inhibitor. The study will be conducted at 1 site in the Netherlands. 
Subjects will be screened for eligibility for the study for up to 28 days before the first dose of study drug. 
In Period 1, eligible subjects will be admitted to the clinical research unit (CRU) in the afternoon of Day -1 
and remain in the CRU until discharge in the morning of Day 11. There will be at least a 7-day washout 
between the last dose in Period 1 and the first dose in Period 2. After this washout period, subjects will 
return to the CRU on Day -1 of Period 2 and remain in the CRU until discharge on Day 21 of Period 2. For 
each study period, dosing will begin on Day 1. Subjects will receive the following study drugs in 2 periods 
over a total of 37 days: 
Period 1: 
• 
Days 1 to 10: oral balovaptan once daily (qd) 
• 
Days 11 to 17: no study drug 
Period 2: 
• 
Days 1 to 5: 200 mg itraconazole twice daily, approximately 12 hours apart (on Day 5, only the 
AM dose of itraconazole will be administered) 
• 
Days 6 to 20: balovaptan qd + 200 mg itraconazole qd 
Figure 1 presents an overview of the study design. A schedule of activities is provided in Appendix 2. 


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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
Figure 1 Study Schema 
 
On Period 1 Day 10 and Period 2 Day 20, balovaptan will be dosed at the same time of day. On Period 2 
Days 5 and 20 itraconazole will be dosed at the same time of day. On Period 2 Days 6 to 20, itraconazole 
will be administered in combination with balovaptan. 
Subjects will undergo study assessments and procedures, including assessments of AEs and 
concomitant medications, vital signs, 12-lead ECGs, clinical laboratory evaluations and blood sampling  
for PK assessments and genotyping as per the schedule of assessments in Appendix 3. 
The dose of balovaptan to be used during balovaptan alone and balovaptan plus itraconazole dosing 
periods will be 5 mg qd for an initial sentinel cohort of 4 subjects (Cohort A). The safety, tolerability, and 
PK data up to 24 hours after the final dose of balovaptan (when given in conjunction with itraconazole), 
for at least 3 of the 4 subjects, will be reviewed by the by the Sponsor’s Medical Monitor or designee and 
the Investigator. There will be at least a 20-day period between Cohort A and Cohort B to allow for 
analysis of PK data. After review of the data, a dose of balovaptan will be selected for the remainder of 
subjects (Cohort B). The dose may remain 5 mg qd or may be increased to 10 mg qd, depending on data 
from Cohort A. The dose may be increased to 10 mg qd for Cohort B if the highest mean exposure values 
for Cmax and AUC0-tau in the presence of itraconazole in Cohort A and the projected exposures expected 
for Cohort B do not exceed the highest exposures seen with multiple dosing of balovaptan 52 mg (484 ± 
43.1 ng/mL for Cmax and 5920 ± 817 hng/mL for AUC0-tau ) and there are no prohibitive safety findings 
based on a review of safety data from Cohort A. If these criteria are not met, dosing will be continued at 5 
mg qd in Cohort B. 
If a decision is made to keep the dose at 5 mg qd, a total of 10 subjects will enter Cohort B. If a decision 
is made to increase the dose to 10 mg qd, a total of 14 subjects will enter Cohort B. 


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Statistical Analysis Plan 
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Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
 
 
6.1 Sample Size Considerations 
This is an exploratory study for which no formal statistical hypothesis will be tested, and therefore the 
sample size is chosen to estimate, with sufficient precision, the CYP3A4 inhibition on balovaptan. 
Between 14 and 18 subjects will be enrolled, so as to have 14 subjects enrolled on either 5 mg or 10 mg 
balovaptan to ensure a minimum of 12 completers. The sample size was chosen based on balovaptan 
within-subject variability (CV%) of around 39% for AUC0-τ and 36% for Cmax as obtained from the 12 mg 
repeat dose in study BP25694. Based on the higher value of 39%, it was estimated that with 12 subjects, 
the half-width of the 90% CI for the ratio of treatment geometric means of the combination (balovaptan + 
itraconazole) versus balovaptan alone would be obtained by dividing/multiplying the ratio estimate by a 
factor of 1.30 
 
6.2 Randomization 
This study is not randomized. All subjects will receive the same treatment sequence. 
 
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
There are no changes from the protocol. 
 
7.2 Interim Analysis and Key Results 
Interim PK analyses, including the calculation of the PK parameters for both periods, will be done for 
Cohort A. The data from this analysis will be used in the decision whether the balovaptan dose should be 
increased from 5 to 10 mg qd for Cohort B. 
For the interim analysis and reporting a separate plan was written. 
 
7.3 Final Analysis 
Draft TFLs will be provided with the draft CSR. After Sponsor comments have been incorporated, the 
TFLs will be finalized and incorporated in the final CSR. 
 
8.0 Data Review 
8.1 Data Management 
Data handling and transfer will take place under the PRA Data Management Plan for the study. 
 
8.2 Acceptance of Data for Summarization 
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) 
after database lock. Only quality assured (QA’d) results released by the Safety Laboratory, Bioanalytical 
Laboratory, or other external data source will be used for the programming of analysis datasets and TFLs 
for the final report. Any data values requiring investigation or corrections that are identified while 
programming the analysis datasets and TFLs will be sent to the project Data Manager. If the issue affects 
the TFLs the Programmer or Statistician who identified the issue will follow it to resolution. 


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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
9.0 Definitions and General Analysis Methods 
9.1 Analysis Data Presentation 
9.1.1 Rounding 
In listings, all data (except the PK data) will be presented with the same precision as the original data. 
Derived data will be rounded for presentation purposes. 
For descriptive statistics of safety data, range values will be presented with the same precision (number 
of decimals or significant digits) as the data they are calculated from, median, arithmetic mean and 
geometric mean values with 1 more decimal digit, standard deviation (SD) with 2 more decimal digits. 
Percentages will be rounded to integers. 
For descriptive statistics of PK parameters, precision and significant figures as described in Appendix 2 of 
the Roche PK NCA guideline, see [4], will be used. For all PK parameters except tmax; individual subject 
data, range values, median, arithmetic mean, geometric mean and standard deviation (SD) will be 
presented with a precision of 3 significant digits. The coefficients of variation (CV) with 1 decimal digit. 
All individual data and descriptive statistics for tmax will be reported with 2 decimals, except for the CVs 
which will be presented with 1 decimal digit. 
 
9.1.2 Imputation 
Except for the substitution of any PK concentrations below the lower limit of quantification (LLOQ) (see 
Section 16.2) and missing start or end date/times of Adverse Events (AEs) for the calculation of onset  
and duration (see Section 17.1.1), any missing data will not be imputed. 
 
9.1.3 Descriptive Statistics 
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: 
• 
n (number of observations), 
• 
nmiss (number of missing observations) 
• 
(arithmetic) mean, 
• 
SD, 
• 
minimum (min) value, 
• 
median, and 
• 
maximum (max) value. 
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment. 
For categorical data the categories will be presented in the tables exactly as they appear in the CRF / 
database. 
 
9.1.4 Pooling 
Summary statistics will be calculated by treatment (and time point, if applicable). 
In case the dose for Cohort B is not increased from 5 to 10 mg, the data from Cohorts A and B will be 
pooled. In case the dose for Cohort B is increased from 5 to 10 mg, the data from Cohort A will be not be 
pooled but rather reported separately. 






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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
9.2.5 ADaM Datasets and Metadata 
The analysis datasets will be generated in accordance with Clinical Data Interchange Standard 
Consortium (CDISC) Analysis Data Model (ADaM) Version 2.1. At least the following datasets will be 
created: 
• 
ADSL 
• 
ADAE 
• 
Laboratory Analysis Dataset (ADLB) 
• 
Vital Signs Analysis Dataset (ADVS) 
• 
ECG Analysis Dataset (ADEG) 
• 
ADPC 
• 
ADPP 
ADaM compliant datasets will be delivered to the sponsor. A define.xml file version 2 with the 
corresponding metadata will be included. Analysis results metadata are excluded. 
 
9.3 Software 
The statistical analysis and reporting will be done using SAS® for WindowsTM Version 9.4 or higher (SAS 
Institute, Inc.). 
PK parameter calculations will primarily be done using Phoenix® WinNonlin® Version 8.1 or higher 
(Pharsight, Inc.). Additional PK computations may be performed in SAS®. 
 
9.4 Statistical Methods 
9.4.1 Statistical Outlier Determination 
No statistical outlier analysis is planned. 
 
9.4.2 Predetermined Covariates and Prognostic Factors 
CYP3A4 genotype will be investigated as a factor in this study, see also Section 16.2.2.1. 
The pharmacogenetics of other isoforms, metabolizing enzymes, transferases, transporters, etc, possibly 
involved in the absorption, distribution, metabolism and excretion of balovaptan and its major metabolites 
(e.g., CYP3A4 and P-glycoprotein) may be investigated additionally. 
 
9.4.3 Hypothesis Testing 
No formal hypothesis testing will be done. 
 
9.5 TFL Layout 
Report layout will be according to the PRA EDS – ICH E3 compliant – CSR Template. The layout of TFLs 
will be according to the PRA EDS standards. 
No table shells will be provided. The TFLs will be provided in Adobe PDF format. 
Format: 
• 
Page size: A4 
• 
Data in listings will be sorted by subject number and time point. 
• 
Data In tables will be sorted by treatment and time point. 
• 
Column titles will be in title case letters. 
• 
All tables and listings will be in landscape format. 
• 
The treatment labels will be as outlined in Section 9.2.2 Treatment/Subject Grouping Definition 




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Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
13.0 Demographic and Baseline Characteristics 
13.1 Demographics 
All demographic data as collected during the screenings visit will be listed by subject. Genotype 
information will be included. 
Subject demographics will be summarized descriptively for all subjects by genotype and overall. The 
summary will include the subjects’ age (in years), gender, race, ethnicity, weight (in kg), height (in cm), 
and BMI (in kg/m2). Demographics will be summarized for the Safety and (if necessary) for the PK 
analysis set. 
 
13.2 Medical History 
Medical history will be listed including the coding according to the and coded using Medical Dictionary for 
Regulatory Activities (MedDRA; latest version). 
 
13.3 Other Baseline Characteristics 
• 
Drug and alcohol screen: The results of urine drug screen (barbiturates, benzodiazepines, 
methadone, amphetamines [including ecstasy], methamphetamines, opiates, cocaine, and 
cannabinoids and urine alcohol test will be listed. 
• 
Serology: The results of serology (human immunodeficiency virus (HIV)-1 and HIV-2, hepatitis B 
virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody) at screening will be listed. 
• 
Pregnancy test (females only): Serum pregnancy test results (beta-human chorionic 
gonadotropin) and follicle-stimulating hormone (FSH) will be listed for each female subject at 
screening, each admission to the clinical research center and at follow-up. 
• 
Body weight will be listed at screening and at follow-up. 
• 
Non-compliance to in- or exclusion criteria (if any) will be listed. 
 
14.0 Concomitant Medications 
Concomitant medications, categorized by medication group and subgroup according to GNE Drug 
dictionary, will be summarized. The number and percentage of subjects using each medication will be 
displayed with the number and percentage of subjects using at least one medication within each 
medication group and subgroup, by treatment. 
Concomitant medication will be listed. Medications with an end date prior to the first dose of study drug 
will be considered prior medications and will be noted in the listing. If a partial date allows a medication to 
be considered concomitant it will be categorized as such. 
 
15.0 Treatment Compliance and Exposure 
Exposure data will be listed by subject. 
The number of subjects receiving each dose of study drug will be summarized. 
 
16.0 Pharmacokinetic Analyses 
PK concentrations will be collected in plasma. 


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Statistical Analysis Plan 
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Protocol: WP40609 
Version Date: 14-Nov-2018 
 
 
 
16.1 Pharmacokinetic Variables 
16.1.1 Concentrations 
• 
Plasma concentration of balovaptan 
• 
Plasma concentration of M2 (as applicable) 
• 
Plasma concentrations of M3 
• 
Plasma concentrations of itraconazole 
• 
Plasma concentrations of OH-itraconazole 
In Analysis Period 1, pre-dose (trough) balovaptan, M2 and M3 concentrations will be measured on 
Analysis Days 1, 3, 5, 8 and 9. A full PK profile of balovaptan, M2 and M3 concentrations will be 
measured on Analysis Day 10: pre-dose (0), 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24h (where these last 
samples will actually be taken on Analysis Day 11, but as they are related to the dosing on Day 10, will 
considered to belong the Day 10 profile). 
In Analysis Period 2, itraconazole and OH-itraconazole concentrations will be measured on Analysis Days 
5: pre-dose (0), 2, 4, and 8h. The pre-dose sample taken on Analysis Day 1 of Analysis Period 3 can 
considered to be the 24h sample for Analysis Day 5 of Analysis Period 2. 
In Analysis Period 3, pre-dose (trough) balovaptan, M2 and M3 concentrations will be measured on 
Analysis Days 1, 3, 5, 8, 9, 10, 11, 13, 14, 15 and 16. A full PK profile of balovaptan, M2 and M3 
concentrations will be measured on Analysis Days 10 and 15: pre-dose (0), 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 
and 24h (where these last samples will actually be taken on Analysis Day 11 or 16 respectively, but as 
they are related to the dosing on Day 10 or 15, will considered to belong the Day 10 or 15 profile, 
respectively). Note that the 24h sample can also be considered the trough concentration on Day 11 or 15. 
In Analysis Period 3, pre-dose (trough) itraconazole and OH-itraconazole concentrations will be  
measured on Analysis Days 1, 3, 5, 9, (11), 13, and 14. Itraconazole and OH-itraconazole concentrations 
will be also measured on Analysis Days 10 and 15: pre-dose (0), 2, 4, 8h and 24h (where this last sample 
will actually be taken on Analysis Day 11 or 16 respectively, but as it is related to the dosing on Day 10 or 
15, will considered to belong the Day 10 or 15 profile, respectively). Note that the 24h sample can also be 
considered the trough concentration on Day 11 or 15. 
 
16.1.2 Parameters 
• 
PK Parameters for balovaptan, M2, M3, as defined in Table 1. 
• 
PK Parameters for itraconazole and OH-itraconazole, as defined in Table 1., if feasible. 




Statistical Analysis Plan 
RPU035EC-180351 
Protocol: WP40609 
Version Date: 14-Nov-2018 
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16.2 Pharmacokinetic Summaries 
16.2.1 Pharmacokinetic Concentrations 
Plasma concentrations for balovaptan, M2, M3, itraconazole and OH- itraconazole below the quantifiable 
limit (BQL) will be set to ½ lower limit of quantification (LLOQ) in the computation of mean concentration 
values. 
Descriptive statistics (number of subjects, arithmetic mean, SD, coefficient of variation [CV%], median, 
min, and max, geometric mean and geometric CV%) will be used to summarize the serum concentrations 
by treatment at each scheduled time point. If over ½ the subjects in a given cell have values BQL then the 
descriptive statistics will not be presented and will instead display as BQL for the mean and minimum. 
Except for the maximum, all other statistics will be missing. Descriptive statistics will be presented 
together with individual plasma concentration data by analyte, treatment, analysis day and time-point. 
Linear and semi-logarithmic plots of the geometric mean balovaptan, M2 and M3 plasma concentrations 
versus scheduled sampling time will be provided by treatment and analysis day (balovaptan alone on Day 
10 and balovaptan + itraconazole on Day 10 and 15). These plots will show time in hours. The plots will 
match the summary table results and will not have an observation at a given time point if more than half  
of the subjects have values BQL. 
Linear and semi-logarithmic plots of the geometric mean itraconazole and OH-itraconazole plasma 
concentrations versus scheduled sampling time will be provided by treatment and analysis day 
(itraconazole alone on Day 5 and balovaptan + itraconazole on Day 15). These plots will show time in 
hours. The plots will match the summary table results and will not have an observation at a given time 
point if more than half of the subjects have values BQL. 
Combined individual (spaghetti) plots of the individual plasma balovaptan, M2 and M3 plasma 
concentration versus actual sampling time will be provided by treatment and analysis day (balovaptan 
alone on Day 10 and balovaptan + itraconazole on Day 10 and 15). These plots will show time in hours. 
Combined individual (spaghetti) plots of the individual plasma itraconazole and OH-itraconazole plasma 
concentration versus actual sampling time will be provided by treatment and analysis day (itraconazole 
alone on Day 5 and balovaptan + itraconazole on Day 15). These plots will show time in hours. 
Linear and semi-logarithmic plots of the individual plasma balovaptan, M2 and M3 plasma concentration 
by actual sampling time will be provided by subject and treatment (balovaptan alone on Day 1-10 and 
balovaptan + itraconazole on Days 1-15 These plots will show time in days. 
Linear and semi-logarithmic plots of the individual plasma itraconazole and OH-itraconazole  
concentration by actual sampling time will be provided by subject (balovaptan + itraconazole treatment on 
Days 1-15 These plots will show time in days. 
Linear and semi-logarithmic plots of the geometric mean trough balovaptan, M2 and M3 plasma 
concentrations versus day will be provided by treatment (balovaptan alone on Days 1-10 and balovaptan 
+ itraconazole on Days 1-16). These plots will show time in Days. The plots will match the summary table 
results and will not have an observation at a given day if more than half of the subjects have values BQL. 
Individual plots will use the BQL handling procedure described below for “Pharmacokinetic Parameters”. 
16.2.2 Pharmacokinetic Parameters 
PK parameters for balovaptan, M2, and M3 and will be estimated using non-compartmental methods with 
WinNonlin®. 
The plasma PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters, BQL values will be set to zero for the pre-dose PK sample, as well as for all other samples 
being BLQ and occurring before Tmax. For subsequent time points, the result will be set to missing. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving sampling 


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times. If the actual time or dose time is missing, the scheduled time may be substituted in order to 
calculate the PK parameter. 
Descriptive statistics (number of subjects, arithmetic mean, SD, (arithmetic) CV%, median, min, max, 
geometric mean and geometric CV%) will be used to summarize the calculated PK parameters by 
treatment. For Tmax, only median, min and max will be presented. 
 
16.2.2.1 Drug-Drug Interaction 
The effect of itraconazole on the PK of balovaptan on Analysis Days 10 and 15 will be assessed. A linear 
mixed effect model will used to analyze the natural log-transformed Cmax and AUC0-tau values of 
balovaptan, M2 and M3. An analysis variable representing the combination of treatment and analysis day 
(balovaptan alone on Day 10, balovaptan + itraconazole on Day 10, and balovaptan + itraconazole on 
Day 15) will be used as fixed effect and subject will be used as a random effect. The estimates for the 
differences between 
1) balovaptan + itraconazole on Day 15 (test) and balovaptan alone on Day 10 (reference) 
2) balovaptan + itraconazole on Day 10 (test) and balovaptan alone on Day 10 (reference) 
will be back-transformed to derive the geometric mean ratios of balovaptan + itraconazole (on Days 10 
and 15) over balovaptan alone on Day 10 together with the corresponding 90% CIs for the comparisons 
of the PK parameters. 
In addition, as an exploratory analysis, the CYP3A4 genotype will be added as a factor. The relationship 
between other genotypes may also be explored. 
 
17.0 Safety Analyses 
17.1 Safety Variables 
The following safety variables will be summarized: 
• 
Adverse Events (AEs) 
• 
Vital Signs 
o 
Supine Blood Pressure 
▪ 
Systolic Blood Pressure (SBP) 
▪ 
Diastolic Blood Pressure (DBP) 
o 
Pulse rate 
o 
Body temperature (tympanic) 
o 
Respiratory rate 
• 
Electrocardiograms (ECG) 
o 
Heart Rate 
o 
PR Interval 
o 
QRS-Duration 
o 
QT Interval 
o 
QTc (Fridericia) Interval 
• 
Clinical Laboratory Evaluations 
o 
Serum Chemistry 
o 
Hematology 
o 
Urinalysis 
o 
Coagulation 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
o 
Suicidal ideation 
o 
Suicidal behavior 


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17.1.1 Adverse Events 
All AEs will be coded to the current version of Medical Dictionary for Regulatory Activities (MedDRA, the 
latest version) by F. Hoffmann-La Roche, Ltd. 
All AE summaries will include only treatment emergent adverse events (TEAEs). Treatment-emergent 
adverse events are those which occur after the first dose of study drug. AEs starting prior to medication 
dosing in the first period will be regarded as pre-dose AEs (i.e. non-TEAEs). 
TEAEs occurring following dosing in a specific analysis period but before dosing in the next analysis 
period will be attributed to that specific analysis period, thus to the last treatment received. If the time is 
missing for an AE on a dosing day then the AE will be attributed to the treatment given on that day. 
All adverse events (including non-TEAEs) recorded on the eCRF will be listed. Pre-dose AEs will be 
presented in a separate listing. In addition, a separate listing of AEs leading to withdrawal from study will 
be provided. 
TEAEs will be tabulated by system organ class and preferred term: one table with all TEAEs (number and 
percentage of subjects) overall and by treatment; one table with related TEAEs (number and percentage 
of subjects) by treatment; one table with all TEAEs (number and percentage of subjects) by treatment and 
relationship to study drug; one table with TEAEs (number and percentage of subjects) by treatment and 
severity. 
Subjects are counted once, per preferred term per treatment, for the most severe of multiple occurrences 
(in case of severity) or most drug-related event (in case of relationship) of a specific MedDRA term. AEs 
whose causal relationship was characterized as ‘Yes’/’No’ will be regarded as being related/not related to 
the study medication. 
The following missing data will be imputed as defined (for calculations only / will not be presented): 
• 
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times 
• 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
• 
Missing AE start times for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment 
• 
Missing AE start times for the determination of treatment assignment will be assumed to occur 
after treatment on the recorded date one minute after dosing 
• 
Missing AE start date will be attributed to the treatment from analysis period 1 unless the AE end 
date occurs before first IMP administration 
17.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other serious adverse events (SAE) will be provided by subject. 
 
17.1.3 Laboratory Data 
Clinical laboratory data will be presented using units from the study data tabulation model (SDTM) 
Controlled Terminology. 
All laboratory data will be listed, including laboratory variables not listed in the protocol. A separate listing, 
including out-of-range values will also be provided. Normal ranges will be used directly from the clinical 
laboratory. 
Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
urinalysis (observed and derived changes from baseline) by treatment and scheduled time will be 
provided. 
 
17.1.4 Vital Signs 
All vital signs data including derived changes from baseline will be listed. 


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Descriptive statistics will be provided to summarize vital signs including changes from baseline by 
treatment and scheduled time. 
 
17.1.5 Electrocardiograms 
All ECG parameters (including changes from baseline) and the corresponding abnormalities and 
physician’s conclusions will be listed by subject. 
The observed measurements for all ECG parameters (including T-wave, U-wave) and the corresponding 
abnormalities will be listed for all time points. The means of triplicate measurements for continuous 
parameters and the change from baseline of the mean triplicate measurements at each scheduled time 
point will be listed by subject. 
Descriptive statistics will be provided to summarize mean continuous ECG parameters (observed and 
changes from baseline) by treatment and scheduled time. Physicians conclusion (normal /abnormal not 
clinically significant/abnormal clinically significant) will be summarized in a frequency table. 
 
17.1.6 Columbia Suicide Severity Rating Scale 
C-SSRS is a clinical tool used to assess the lifetime suicidality of a subject (C-SSRS lifetime version) as 
well as any new instances of suicidality (C-SSRS since last visit). It captures the occurrence, severity and 
frequency of suicide-related thoughts and behaviors during the assessment period. All individual C-SSRS 
results will be listed. 
 
17.1.7 Other Observations Related to Safety 
Abnormalities and changes in findings at the physical examinations will be listed. 
 
18.0 References 
1. SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC. 
2. Clinical Study Protocol. A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, ONE- 
SEQUENCE, TWO-PERIOD WITHIN-SUBJECT STUDY TO INVESTIGATE THE EFFECT OF 
ITRACONAZOLE ON THE PHARMACOKINETICS OF MULTIPLE DOSES OF BALOVAPTAN IN 
HEALTHY VOLUNTEERS. Version 1.0, Final, 18-May-2018 
3. Interim Analysis Plan A SINGLE-CENTER, NON-RANDOMIZED, OPEN-LABEL, ONE- 
SEQUENCE, TWO-PERIOD WITHIN-SUBJECT STUDY TO INVESTIGATE THE EFFECT OF 
ITRACONAZOLE ON THE PHARMACOKINETICS OF MULTIPLE DOSES OF BALOVAPTAN IN 
HEALTHY VOLUNTEERS, Final Version 1.0, 05-Jul-2018. 
4. F. 
Hoffmann-La 
Roche 
Ltd. 
CLINICAL 
PHARMACOLOGY 
GUIDING 
PRINCIPLES 
CALCULATION 
AND 
ANALYSES 
OF 
NON-COMPARTMENTAL 
PHARMACOKINETIC 
PARAMETERS, Version 4.0, July 2015. 




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SAE 
Serious adverse event 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
TEAE 
Treatment-emergent adverse event 
TFL(s) 
Tables, figures and listings 
WNL 
WinNonlin 


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Appendix 2: Schedule of Assessments 


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Appendix 3: Schedule of PK Sampling, ECG, and Vital Signs 
Measurements 


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Concentrations versus Time by Treatment and Analysis Day 
(Linear and Semi-Logarithmic Scale) 
Figure 14.2.16 
Individual Balovaptan Plasma Concentrations versus Time in 
Days by Treatment (Linear and Semi-Logarithmic Scale) 
Safety 
Figure 14.2.17 
Individual Balovaptan Metabolite (M2, M3) Plasma 
Concentrations versus Time in Days by Treatment (Linear and 
Semi-Logarithmic Scale) 
Safety 
Figure 14.2.18 
Individual Itraconazole and OH-Itraconazole Plasma 
Concentrations versus Time in Days (Linear and Semi- 
Logarithmic Scale) 
Safety 
Figure 14.2.19 
Geometric Mean Trough Balovaptan Plasma Concentrations 
versus Time by Treatment (Linear and Semi-Logarithmic Scale) 
PK 
Figure 14.2.20 
Geometric Mean Trough Balovaptan Metabolite (M2, M3) 
Plasma Concentrations versus Time by Treatment (Linear and 
Semi-Logarithmic Scale) 
PK 
Section 14.3 Safety Data 
Section 14.3.1 Adverse Events 
Table 14.3.1.1 
Summary of TEAEs for Each System Organ Class and 
Preferred Term (Number and Percentage of Subjects) by 
Treatment 
Safety 
Table 14.3.1.2 
Summary of Related TEAEs for Each System Organ Class and 
Preferred Term (Number and Percentage of Subjects) by 
Treatment 
Safety 
Table 14.3.1.3 
Summary of TEAEs for Each System Organ Class and 
Preferred Term (Number and Percentage of Subjects) by 
Treatment and Relationship to Study Drug 
Safety 
Table 14.3.1.4 
Summary of TEAEs for Each System Organ Class and 
Preferred Term (Number and Percentage of Subjects) by 
Treatment and Severity 
Safety 
Section 14.3.2 Lists of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
Listing of Deaths and Other Serious Adverse Events 
Safety 
Section 14.3.3 Clinical Laboratory 
Table 14.3.3.1 
Listing of Abnormal Laboratory Values 
Safety 
Table 14.3.3.2 
Descriptive Statistics of Clinical Laboratory Results - 
Hematology 
Safety 
Table 14.3.3.3 
Descriptive Statistics of Clinical Laboratory Results – Serum 
Chemistry 
Safety 
Table 14.3.3.4 
Descriptive Statistics of Clinical Laboratory Results - Urinalysis 
Safety 
Section 14.3.4 Other Safety 
Table 14.3.3.1 
Descriptive Statistics of Vital Signs 
Safety 
Table 14.3.3.1 
Summary of 12-Lead Electrocardiogram 
Safety