Clinical trial NCT03717064
Conditions: Healthy Volunteers
Sponsor: Hoffmann-La Roche
Start date: 2018-11-07; Completion date: 2018-12-17
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of the study is to characterize the interaction between RO7049389 and the cholesterol-lowering drug, pitavastatin, in healthy volunteers. There is no intended clinical benefit to this study. The total duration of the study for each participant is approximately 12 weeks.

Detailed description:

Arms: arm 1: Period 1: Participants will receive a single dose of pitavastatin on Day 1, followed by a wash-out period of at least 7 and up to 21 days.

Period 2: Participants will receive RO7049389 on Days 1-6. Participants will also receive a single dose of pitavastatin on Day 4.
Interventions: intervention 1: RO7049389 intervention 2: Pitavastatin
Intervention descriptions: intervention 1: RO7049389 will be taken orally, in tablet form, BID on Days 1-6 of Period 2. intervention 2: Pitavastatin will be taken orally, in tablet form, once on Day 1 of Period 1, and once on Day 4 of Period 2.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
AN OPEN-LABEL, FIXED SEQUENCE, TWO-PERIOD 
STUDY TO INVESTIGATE THE EFFECT OF RO7049389 
ON THE PHARMACOKINETICS OF PITAVASTATIN IN 
HEALTHY VOLUNTEERS 
NCT Number: NCT03717064 
Document Date: Protocol Version 1: 27-Aug-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 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.
RO7049389 —F. Hoffmann-La Roche Ltd
Protocol YP40218, Version 1
PROTOCOL
TITLE:
AN OPEN-LABEL, FIXED SEQUENCE, TWO-PERIOD 
STUDY TO INVESTIGATE THE EFFECT OF RO7049389 
ON THE PHARMACOKINETICS OF PITAVASTATIN IN 
HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
YP40218
VERSION:
1
IND NUMBER:
137090
TEST PRODUCT:
RO7049389 
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below
27-Aug-2018 06:37:06
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7049389—F. Hoffmann-La Roche Ltd
2/Protocol YP40218, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, FIXED SEQUENCE, TWO-PERIOD 
STUDY TO INVESTIGATE THE EFFECT OF RO7049389 
ON THE PHARMACOKINETICS OF PITAVASTATIN IN 
HEALTHY VOLUNTEERS
PROTOCOL NUMBER:
YP40218
VERSION NUMBER:
1
IND NUMBER:
137090
TEST PRODUCT:
RO7049389
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
Study Monitor.


RO7049389—F. Hoffmann-La Roche Ltd
3/Protocol YP40218, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................... 9
1.1
Synopsis.................................................................................. 9
1.2
Schematic of Study Design.................................................... 15
1.3
Schedule of Activities ............................................................ 15
2.
INTRODUCTION ........................................................................................ 21
2.1
Study Rationale ..................................................................... 21
2.2
Background ........................................................................... 21
2.2.1
Background on Hepatitis B Virus........................................... 21
2.2.2
Background on RO7049389 .................................................. 22
2.2.3
Background on Pitavastatin................................................... 23
2.3
Benefit/Risk Assessment....................................................... 23
3.
OBJECTIVES AND ENDPOINTS ............................................................... 24
4.
STUDY DESIGN......................................................................................... 25
4.1
Overall Design ....................................................................... 25
4.1.1
Length of the Study ............................................................... 25
4.2
Scientific Rationale for Study Design..................................... 25
4.2.1
Rationale for Study Population .............................................. 26
4.2.2
Rationale for Biomarker Assessments................................... 26
4.3
Dose Justification .................................................................. 26
4.4
End of Study Definition .......................................................... 27
5.
STUDY POPULATION................................................................................ 28
5.1
Inclusion Criteria.................................................................... 28
5.2
Exclusion Criteria................................................................... 29
5.3
Lifestyle Considerations......................................................... 31
5.3.1
Meals and Dietary Restrictions.............................................. 31
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 31
5.3.3
Activity ................................................................................... 32
5.4
Screen Failures ..................................................................... 32
5.5
Recruitment Procedures........................................................ 32


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6.
TREATMENTS............................................................................................ 32
6.1
Treatments Administered....................................................... 33
6.2
Preparation/Handling/Storage/Accountability ........................ 33
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 35
6.3.1
Method of Treatment Assignment.......................................... 35
6.3.2
Blinding.................................................................................. 35
6.4
Treatment Compliance .......................................................... 35
6.5
Concomitant Therapy ............................................................ 35
6.5.1
Permitted Therapy................................................................. 35
6.5.2
Prohibited Therapy ................................................................ 36
6.6
Dosage Modification .............................................................. 36
6.7
Treatment after the End of the Study..................................... 36
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 36
7.1
Discontinuation of Study Treatment....................................... 36
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 37
7.3
Lost to Follow-Up................................................................... 37
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 38
8.1
Efficacy Assessments............................................................ 38
8.2
Safety Assessments .............................................................. 38
8.2.1
Physical Examinations........................................................... 38
8.2.2
Vital Signs.............................................................................. 39
8.2.3
Electrocardiograms................................................................ 39
8.2.4
Clinical Safety Laboratory Assessments................................ 40
8.2.5
Medical History and Demographic Data ................................ 41
8.3
Adverse Events and Serious Adverse Events ....................... 41
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 41
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 42


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8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 42
8.3.3.1
Investigator Follow-Up........................................................... 42
8.3.3.2
Sponsor Follow-Up ................................................................ 43
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 43
8.3.4.1
Emergency Medical Contacts................................................ 43
8.3.5
Pregnancy ............................................................................. 44
8.3.6
Non-Serious Adverse Events of Special Interest................... 44
8.4
Treatment of Overdose.......................................................... 44
8.5
Pharmacokinetics .................................................................. 45
8.6
Pharmacodynamics ............................................................... 45
8.7
Genetics ................................................................................ 46
8.7.1
Clinical Genotyping................................................................ 46
8.8
Biomarkers ............................................................................ 46
8.8.1
Samples for Research Biosample Repository ....................... 46
8.8.1.1
Overview of the Research Biosample Repository.................. 46
8.8.1.2
Sample Collection.................................................................. 47
8.9
Health Economics.................................................................. 47
8.10
Timing of Study Assessments ............................................... 47
8.10.1
Screening and Pre-Treatment Assessments .......................... 47
8.10.2
Assessments during Treatment............................................. 48
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 48
8.10.4
Follow-Up Assessments ........................................................ 48
8.10.5
Assessments at Unscheduled Visits...................................... 48
9.
STATISTICAL CONSIDERATIONS ............................................................ 48
9.1
Statistical Hypotheses ........................................................... 49
9.2
Sample Size Determination ................................................... 49
9.3
Populations for Analyses ....................................................... 49
9.3.1
Pharmacokinetic Analysis Population.................................... 49
9.3.2
Safety Analysis Population .................................................... 49
9.4
Statistical Analyses................................................................ 50
9.4.1
Demographics and Baseline Characteristics ......................... 50


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9.4.2
Safety Analyses..................................................................... 50
9.4.3
Pharmacokinetic Analyses..................................................... 51
9.4.4
Pharmacodynamic Analyses ................................................. 52
9.4.5
Other Analyses...................................................................... 52
9.5
Summaries of Conduct of Study............................................ 52
10. REFERENCES ........................................................................................... 53
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.................................................................................... 54
LIST OF TABLES
Table 1
Schedule of Activities – Main Table ............................................ 16
Table 2
Schedule of Activities – Detailed Table (Period 1) ...................... 18
Table 3
Objectives and Endpoints ........................................................... 24
Table 4
Summary of Treatments Administered........................................ 33
Table 5
Analysis Populations................................................................... 50
Table 6
Safety Statistical Analysis Methods ............................................ 51
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 15
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations........... 55
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-Up and Reporting............................................................. 62
Appendix 3
Procedures for Recording Adverse Events ................................. 70
Appendix 4
Clinical Laboratory Tests ............................................................ 75
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information.................................................................................. 78


RO7049389—F. Hoffmann-La Roche Ltd
7/Protocol YP40218, Version 1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AAV-HBV
Adeno-associated virus hepatitis B virus
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BP
Blood pressure
CHB
Chronic hepatitis B
CL
Clearance
CL/F
Apparent clearance
CRO
Contract research organization
CSR
Clinical study report
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ESF
Eligibility screening form
EU
European Commission
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
HAP
Heteroaryldihydropyrimidine
HAV
Hepatitis A virus
HBcAb
Total hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
-HCG
Beta-human chorionic gonadotropin
HCV
Hepatitis C
HDL
High-density lipoproteins
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IC50
Inhibitory concentration
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IMP
Investigational medicinal product


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IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LH
Luteinizing hormone
LPLV
Last participant, last visit
LPLO
Last participant, last observation
MAD
Multiple-ascending doses
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
NUCs
Nucleos(t)ide analogues
OATP
Organic anion-transporting polypeptide
OTC
Over-the-counter
PD
Pharmacodynamic
PK
Pharmacokinetic
PT
Prothrombin time
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RBR
Research biosample repository
RNA
Ribonucleic acid
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SoA
Schedule of activities
SOP
Standard operating procedure
ULN
Upper limit of normal
V
Volume
WBC
White blood cell


RO7049389—F. Hoffmann-La Roche Ltd
9/Protocol YP40218, Version 1
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
AN OPEN-LABEL, FIXED SEQUENCE, TWO-PERIOD STUDY TO 
INVESTIGATE THE EFFECT OF RO7049389 ON THE 
PHARMACOKINETICS OF PITAVASTATIN IN HEALTHY 
VOLUNTEERS
SHORT TITLE
THE EFFECT OF RO7049389 ON THE PK OF PITAVASTATIN
PROTOCOL NUMBER:
YP40218
VERSION:
1
TEST PRODUCT:
RO7049389 
PHASE:
I
RATIONALE
The primary objective of this study is to determine the effect of multiple-doses of RO7049389 on 
the single-dose PK of pitavastatin in healthy participants. Based on the data from in vitro studies 
of RO7049389 there is a possibility of an organic anion-transporting polypeptide 
(OATP)-mediated interaction between RO7049389 and OATP1B1 substrates. In vitro, 
RO7049389 inhibits OATP1B1 mediated transport with a half maximal inhibitory concentration 
(IC50) of 3 M (1796 ng/mL). This IC50 is predicted to be lower than RO7049389 exposures at 
the expected efficacious dose. The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) 
reductase inhibitors or ‘statins’, a class of cholesterol-lowering drugs, are known substrates for 
OATP1B1. In future clinical trials, a statin may be a concomitant medication with RO7049389. 
Therefore, it will be important to understand the effect, if any, of RO7049389 on the 
pharmacokinetics (PK) of such an OATP1B1 substrate. As PK measurements are objectively 
analysed an open-label study design has been chosen. To minimize the number of participants 
needed and reduce inter-subject variability, this study will follow a two-period instead of parallel 
design. The duration of both washout and drug administration periods was established on the 
basis of the known pharmacokinetic profiles of both RO7049389 and pitavastatin. Accordingly, a 
fixed sequence design has been chosen for logistical reasons.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine the effect of multiple-doses 
of RO7049389 on the single-dose 
pharmacokinetics (PK) of pitavastatin in 
healthy participants. 

Primary PK parameters of pitavastatin: 
Cmax, and AUC0-inf

Secondary PK parameters of pitavastatin: 
tmax, CL/F, V/F and t½.

Other parameters may be calculated if 
considered appropriate.


RO7049389—F. Hoffmann-La Roche Ltd
10/Protocol YP40218, Version 1
OBJECTIVES AND ENDPOINTS cont.
Secondary

To evaluate the safety and tolerability of 
the single-dose pitavastatin alone and in 
combination with multiple-doses of 
RO7049389 in healthy participants. 

Incidence and severity of adverse events.

Incidence of laboratory abnormalities 
based on hematology, clinical chemistry, 
coagulation, lipids, and urinalysis test 
results.

ECGs.

Vital signs including blood pressure (BP), 
pulse rate and body temperature.

To explore the effect of the single-dose of 
pitavastatin on steady-state PK of 
RO7049389 in healthy participants.

Primary PK parameters of RO7049389 
and its metabolites (RO7121986, 
RO7255420 and RO7255422): Cmax, and 
AUCtau

To determine the effect of multiple-doses 
of RO7049389 on the single-dose PK of 
pitavastatin lactone in healthy 
participants (if applicable).

PK parameters of pitavastatin lactone: 
Cmax, and AUC0-inf

The AUC ratio of pitavastatin 
lactone/pitavastatin.
Exploratory

To evaluate the effect of multiple-doses 
of RO7049389 on OATP activity as 
assessed by plasma and urine 
coproporphyrins (CP-I and CP-III).

Coproporphyrins (CP-I and CP-III) AUC 
in plasma and amount excreted in urine.
OVERALL STUDY DESIGN
This is an open-label, fixed sequence, two-period (Periods 1 and 2) study designed to evaluate 
the drug- drug interaction between RO7049389 and pitavastatin and the safety and tolerability 
of single-dose pitavastatin alone and in combination with multiple-doses of RO7049389 in 
healthy participants. 
Treatment Groups and Duration
Treatment Groups 
The investigational medicinal products (IMPs) required for completion of this study will be 
RO7049389 and pitavastatin. RO7049389 will be given orally at a dose of 800 mg twice daily 
(BID) at the time of a standard meal (30 minutes before study treatment administration) for a 
total of 6 days. Pitavastatin is administered as a single dose (2 mg), once on Day 1 of Period 1 
and with RO7049389 in the morning of Day 4 of Period 2.
Length of Study
The total duration of the study for each participant will be about 12 weeks divided as follows:

Screening: Up to 28 days.

Period 1:
o
In clinic period: Days -1 to 4.
o
Treatment period: Day 1

Wash-out Period: Defined as from Period 1 Day 1 to Period 2 Day 1 and lasts at least 7 
days but not more than 21 days.


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11/Protocol YP40218, Version 1

Period 2: 
o
In clinic period: Days -1 to 7
o
Treatment period: Days 1 to 6

Safety follow-up: 
o
Period 2 Day 13
o
Period 2 Day 34 (Telephone call)
The participant has the option to stay in-clinic (with overnight stay) during the whole Period 1 
and wash-out period if agreed by Sponsor and the Investigator.
End of Study
A participant is considered to have completed the study if he/she has completed all parts of the 
study including the last scheduled procedure shown in the Schedule of Activities.
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur 28 days after the last dose of RO7049389 is administered.
Data Monitoring Committee: No
PARTICIPANT POPULATION
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to ICH and local regulations.  
Age
2.
18 to 60 years of age, inclusive, at the time of signing the informed consent.
Type of Participants and Characteristics
3.
Healthy, as judged by the Investigator.
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, and based on the laboratory safety test results at screening and Day -1.
4.
Body mass index (BMI) between 18 to 30 kg/m2 (inclusive) at screening.
5.
Male and female participants
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
a)
Female Participants
Female participants must be either surgically sterile (by means of hysterectomy and/or 
bilateral oophorectomy and/or tubal ligation) or post-menopausal for at least one year 
(defined as amenorrhea 12 consecutive months without another cause, and 
confirmed by follicle-stimulating hormone (FSH) level. Participants must not be 
pregnant or lactating.
b)
Male Participants
With female partners who are not pregnant or lactating.


RO7049389—F. Hoffmann-La Roche Ltd
12/Protocol YP40218, Version 1
With agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom during the treatment period and for at least 28 days after the last dose of study 
drug to avoid exposing the embryo. Men must refrain from donating sperm during this 
same period.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Have a history or symptoms of any clinically significant cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematological, oncologic or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a 
risk when taking the study treatment; or of interfering with the interpretation of data.
2.
Confirmed (based on the average of 3 separate resting BP measurements in a supine 
position, after at least 5 minutes rest) systolic BP greater than 140 or less than 90 mmHg, 
and diastolic BP greater than 90 or less than 50 mmHg at screening and Day -1.
3.
Personal history or family history of congenital long QT syndrome and/or cardiac sudden 
death.
4.
History of Gilbert’s syndrome.
5.
Participants who have had significant acute infection, e.g., influenza, local infection, acute 
gastrointestinal symptoms or any other clinically significant illness within two weeks of dose 
administration.
6.
Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or 
multiple drug allergies (non-active hay fever is acceptable).
7.
Any clinically significant concomitant diseases or condition that could interfere with, or 
treatment of which might interfere with, the conduct of the study, or that would, in the opinion 
of the Investigator, pose an unacceptable risk to the participant in this study.
Prior/Concomitant Therapy
8.
Taking any herbal medications or substances (e.g., tea) or supplements (including vitamins), 
or traditional Chinese medicines (TCM) or over-the-counter (OTC) medications within 14 
days of first dosing or within 5 times the elimination half-life of the medication prior to first 
dosing, whichever is longer. 
Exceptions include medications listed under Permitted Therapy and those made on a case-
by-case basis following discussion and agreement between the Investigator and the Sponsor.
9.
History of having received any systemic anti-neoplastic (including radiation) or immune-
modulatory treatment (including systemic oral or inhaled corticosteroids) 6 months prior to 
the first dose of study drug or the expectation that such treatment will be needed at any time 
during the study.
Prior/Concurrent Clinical Trial Experience
10. Are currently enrolled in or have participated in any other clinical study involving an 
investigational product or in any other type of medical research within the last 30 days or 5 
half lives (whichever is longer).
11. Donation or loss of blood or blood products in excess of 500 mL within 3 months of 
screening.


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Diagnostic Assessments
12. Positive test for drugs of abuse (including recreational drugs) and/or positive alcohol test 
and/or positive cotinine test at screening and on Day -1.
13. Clinically relevant ECG abnormalities on screening or Day -1 ECG based upon the average 
of three ECGs, e.g,:
a.
QTcF 450 msec or 300 msec.
b.
Notable resting bradycardia (HR 45 bpm), or HR 90 bpm.
c.
Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolf-
Parkinson-White Syndrome, or cardiac pacemaker.
14. ECG with QRS and/or T-wave judged by the Investigator to be unfavorable for a consistently 
accurate QT measurement (e.g., neuromuscular artifact that cannot be readily eliminated, 
arrhythmias, indistinct QRS onset, low amplitude T-wave, merged T- and U-waves, 
prominent U-waves).
15. Creatinine Clearance (CrCl) 70 mL/min (using the Cockcroft-Gault formula) at screening or 
on Day -1 (may be repeated for confirmation).
16. Positive test at screening of any of the following: Hepatitis A virus (HAV IgM Ab), hepatitis B 
virus (HBsAg or HBcAb), hepatitis C virus (HCV RNA or HCV Ab) or human 
immunodeficiency virus (HIV-1 and HIV-2 Ab).
17. Any other clinically significant abnormalities in laboratory test results at screening or on 
Day -1. In the case of uncertain or questionable results, tests performed during screening 
may be repeated once prior to enrollment to confirm eligibility unless deemed not clinically 
significant by the Investigator.
Other Exclusions
18. History of alcohol consumption exceeding 2 standard drinks per day on average (1 standard 
drink 10 grams of alcohol) and/or drug abuse within 12 months of screening. 
19. Use of 5 cigarettes or equivalent nicotine-containing product per day prior to screening.
20. Participants under judicial supervision, guardianship or curatorship.
21. Medical or social conditions that would potentially interfere with the participant’s ability to 
comply with the study visit schedule or the study assessments.
22. Sensitivity to any of the study treatments, or excipients thereof, or drug or other allergy that, 
in the opinion of the Investigator or Medical Monitor, contraindicates the participation in the 
study.
NUMBER OF PARTICIPANTS
A sample size of 18 participants to target 16 evaluable healthy participants has been chosen.
Evaluable participants who withdraw, or who are withdrawn, for non-safety reasons from the 
study will be replaced to meet the enrollment goal.
CONCOMITANT MEDICATIONS
Permitted Therapy
Any medication or vaccine (including OTC or prescription medicines, approved dietary and 
herbal supplements, nutritional supplements) used by a participant from 30 days prior to 
screening until the follow-up visit must be recorded along with reason for use, dates of 
administration (including start and end dates) and dosage information (including dose and 
frequency).


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The following medications will be permitted:

Medications used to treat AEs may only be prescribed after consultation with the Sponsor 
(with the exception of acetaminophen/paracetamol), unless there is a medical need to 
ensure the well-being of the participant that should not be delayed. All therapy and/or 
medication administered to manage adverse events should be recorded on the Adverse 
Event eCRF.

Hormone replacement therapy (HRT): permitted if initiated at least 2 months prior to study 
start.

Occasional use of acetaminophen (up to a maximum dose of 2g/day up to 48 hours prior to 
dosing, not to exceed 4g total during the week prior to dosing) will be permitted.
Prohibited Therapy
As a general rule, no concomitant medication will be permitted within 14 days prior to the first 
dosing or within 5 half-lives of the medication prior to the first dosing (whichever is longer), until 
the follow-up visit, with the exception of the cases listed in Permitted Therapy. Exceptions may 
be made on a case-by-case basis following discussion and agreement between the Investigator 
and the Sponsor after, the rationale for exception is discussed and clearly documented.


RO7049389—F. Hoffmann-La Roche Ltd
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1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
Period 1
Wash out Period
(Period 1 Day 1 to 
Period 2 Day 1)
≥7 days and ≤21 days
Period 2
Day 1
Days 1 to 3
Day 4
Days 5 to 6
Pitavastatin
2 mg Single dose
Pitavastatin
2 mg Single dose
RO7049389 800 mg Twice Daily (BID)
1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided in Table 1 and Table 2.


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Table 1
Schedule of Activities – Main Table
Protocol Activity
Screening
Washout periodk
Follow Up 
visit
Follow-up call
Day
Day -28 to Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Period 2
Day 14(± 1)
Period 2
Day 35 (± 1)
Time Relative (h)
0
24
48
72
0
24
48
72
96
120
144
Assessments
Informed Consent
x
Eligibility
x
x
Demography
x
Medical History
x
Physical Examinationa
x
x
x
x
x
Vital Signs b
x
x
3
x
x
x
x
7
x
x
7
x
7
x
x
x
ECG-12 leadc
x
x
x
x
x
3
3
3
x
x
x
Hematologyd
x
x
x
x
x
x
x
x
Blood Chemistryd
x
x
x
x
x
x
x
x
Coagulationd
x
x
x
x
x
x
x
x
Urinalysisd
x
x
x
x
x
x
x
x
Viral Serologye
x
Drug/Alcohol Test
x
x
x
Cotinine Test  
x
x
Pregnancy Testf
x
x
x
x
x
Follicle Stimulating Hormoneg
x
Administration of Pitavasatin
x
x
Administration of RO7049389
2
2
2
2
2
2
Plasma PK for Pitavasatin and its Metabolite 
12
2
x
x
12
2
x
x
x
Plasma PK for RO7049389 and its Metabolites 
11
11
x
Plasma PK for Coproporphyrins
10
x
10
x
Urine PK for Coproporphyrins
x
2
2
Clinical Genotypingh
x
RBR Bloodi
x
In-Clinic Stay
x
x
x
x
x
x
x
x
x
x
x
Dischargej
x
x
Adverse Events
Previous and Concomitant Treatments
Period 1
Period 2
Early terminationl
x
x


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17/Protocol YP40218, Version 1
Table 1
Schedule of Activities – Main Table (cont.)
a.
A full physical exam is required at screening, follow-up and early treatment termination visits. At subsequent visits (or as clinically indicated), 
limited, symptom-directed physical examinations should be performed at the discretion of the Investigator. Height will only be recorded at 
screening. BMI will be calculated at screening.
b.
Vital signs include triplicate measurements of blood pressure and pulse rate and single assessment of body temperature (tympanic or oral). 
Blood pressure and pulse measurements will be assessed after at least 5 minutes in a supine position.
c.
Twelve-lead ECGs will be obtained in triplicate (three consecutive interpretable 12-lead ECGs in less than 5 minutes) after the participant has 
been in a supine position for at least 10 minutes. Automated ECG intervals (PR [PQ], QRS, QT, QTcF, RR) and HR will be captured or 
calculated, and the changes in T-wave and U-wave morphology will be documented.
d.
Samples for clinical laboratory tests (hematology, chemistry, coagulation, urinalysis) should be collected in the morning of Period 1 Day 4 and 
Period 2 Day 7 approximately the same time as the 72 hour (Period 1 Day 4) or 12 hour (Period 2 Day 7) post-dose PK samples are collected. 
At all other time points these samples should be taken at the most appropriate time.
e.
Hepatitis A (HAV IgM Ab), total Hepatitis B Core Antibody (HBcAb), Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab), human 
immunodeficiency virus (HIV-1 and HIV-2 Ab).
f.
Serum or plasma beta-human chorionic gonadotropin (-HCG) at screening, urine on all other occasions (females only). If urine is positive, then 
need confirmatory serum or plasma test.
g.
Follicle stimulating hormone (females only; to confirm post-menopausal status).
h.
If the genetic blood sample is not collected at Day 1, it may be collected at any time during the conduct of the clinical study.
i.
RBR blood sample will be collected at pre-dose Period 1.
j.
The participant will discharge in the morning after all the samples for the PK and safety assessments have been taken and the participant has 
the option to stay in clinic during the whole Period 1 and wash-out period if agreed by Sponsor and the Investigator (i.e., discharge Period 2, 
Day 7). 
k.
A washout period of at least 7 days, but not more than 21 days, between the two periods. Washout period is defined as from Period 1 Day 1 to 
Period 2 Day 1. 
l.
In case of early termination, a participant should be called for an early termination visit and assessments should be performed as listed in the 
table.


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Table 2
Schedule of Activities – Detailed Table (Period 1)
Period
Day
Scheduled 
Time (h)
Vital Signsa
ECG-12 Leadb
Administration of 
Pitavasatin
Administration of 
RO7049389
Plasma PK for 
Pitavasatin and its 
Metabolite
Plasma PK for 
RO7049389 and its 
Metabolites 
Plasma PK for 
Coproporphyrins
Urine PK for 
Coproporphyrinsc
Day -28 to Day -2
x
x
Day -1
x
x
x
Pre-dose
x
x
x
x
0
x
0.5
x
x
1
x
x
x
1.5
x
x
2
x
x
3
x
x
4
x
x
6
x
x
x
0-7
x
8
x
x
10
x
12
x
x
16
x
7-24
x
24
x
x
x
36
x
Day 3
48
x
x
Day 4
72
x
x
x
Day 2
Period 1
Day 1


RO7049389—F. Hoffmann-La Roche Ltd
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Table 2
Schedule of Activities – Detailed Table (cont.) (Period 2)
Period
Day
Scheduled 
Time (h)
Vital Signsa
ECG 12 Leadb
Administration of 
Pitavasatin
Administration of 
RO7049389
Plasma PK for 
Pitavasatin and its 
Metabolite
Plasma PK for 
RO7049389 and its 
Metabolites 
Plasma PK for 
Coproporphyrins
Urine PK for 
Coproporphyrinsc
Day -1
x
x
Pre-dose 
x
x
0
x
0.5
x
1
x
2
x
x
4
x
6
x
x
12
x
x
Pre-dose
x
0
x
12
x
Pre-dose
x
x
0
x
0.5
x
1
x
1.5
x
2
x
3
x
4
x
6
x
8
x
10
x
Pre-dose
x
12
x
Pre-dose
x
x
x
x
x
0
x
x
0.5
x
x
x
x
1
x
x
x
x
1.5
x
x
x
2
x
x
x
x
x
3
x
x
x
4
x
x
x
x
6
x
x
x
x
x
0-7
x
8
x
x
x
10
x
x
Pre-dose
x
x
x
x
12
x
16
x
7-24
x
Pre-dose
x
x
x
0
x
Pre-dose
x
12
x
Pre-dose
x
x
x
0
x
0.5
x
1
x
2
x
x
4
x
6
x
x
12
x
x
Day 7
0
x
x
x
Day 14 (± 1)
0
x
x
Early Termination
x
x
x
x
Day 5
Day 6
Period 2
Day 1
Day 2
Day 3
Day 4


RO7049389—F. Hoffmann-La Roche Ltd
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Table 2
Schedule of Activities – Detailed Table (cont.)
a.
Vital signs include triplicate measurements of blood pressure and pulse rate and single assessment of body temperature after the 
participant has been in a supine position for at least 5 minutes.
b.
12-lead ECGs will be obtained in triplicate after the participant has been in a supine position for at least 10 minutes. Automated ECG 
intervals (PR [PQ], QRS, QT, QTcF, RR) and HR will be captured or calculated, and the changes in T-wave and U-wave morphology will 
be documented.
c.
Urine samples will be collected at -7-0 hours pre-dose (Day -1 of Period 1), 0-7 and 7-24 hours post-dose (Day 1 of Period 1), 0-7 and 7-24
hours post-dose (Day 4 of Period 2).


RO7049389—F. Hoffmann-La Roche Ltd
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2.
INTRODUCTION
RO7049389 is an orally administered small molecule that is being developed for the 
treatment of chronic hepatitis B virus (HBV) infection.
2.1
STUDY RATIONALE
Based on the data from in vitro studies of RO7049389 there is a possibility of an organic 
anion-transporting polypeptide (OATP)-mediated interaction between RO7049389 and 
OATP1B1 substrates. In vitro, RO7049389 inhibits OATP1B1 mediated transport with a 
half maximal inhibitory concentration (IC50) of 3 M (1796 ng/mL). This IC50 is predicted 
to be lower than RO7049389 exposures at the expected efficacious dose. The 
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or ‘statins’, a 
class of cholesterol-lowering drugs, are known substrates for OATP1B1. In future clinical 
trials, a statin may be a concomitant medication with RO7049389. Therefore, it will be 
important to understand the effect, if any, of RO7049389 on the pharmacokinetics (PK) 
of such an OATP1B1 substrate.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Background on Hepatitis B Virus
Hepatitis B virus (HBV) infection is a major cause of both acute hepatitis and chronic 
liver diseases, including cirrhosis and hepatocellular carcinoma. Approximately two 
billion people worldwide have serological evidence of past or present HBV infection. An 
estimated 686 000 people are estimated to die each year due to the acute or chronic 
consequences of hepatitis B (WHO 2016).
Currently, there are two classes of drugs available for the treatment of chronic hepatitis 
B (CHB): subcutaneously administered interferon (IFN) preparations and orally 
administered nucleos(t)ide analogues (NUCs). Although both types of treatment can 
induce the loss of HBV envelope antigen with development of anti-HBeAg antibody 
(serological response), the suppression of HBV DNA to an undetectable level by 
sensitive polymerase chain reaction (PCR) methods (virological response), and are able 
to normalize liver transaminases levels (biochemical response), neither treatment 
achieves a high rate of clinical cure. Hepatitis B surface antigen (HBsAg) loss, with 
various therapies (NUCs or INF) only occurs in approximately 3% after one year of 
treatment. HBsAg loss rates increase to 9% at 3 years and 12% at 5 years following 
PEG-IFN-2a therapy (EASL 2017). In clinical studies, the combination of NUCs with 
PEG-IFN has not been proven superior to PEG-IFN alone for the most prevalent 
genotypes in the world, i.e., B, C and D (Marcellin 2016). In addition, IFN-based 
therapies are associated with many side-effects, while NUCs frequently require 
prolonged or possibly life-long therapy, and some are associated with a high risk of viral 
resistance.




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2.2.3
Background on Pitavastatin
Pitavastatin is an approved HMG-CoA reductase inhibitor (i.e., statin), used in the 
treatment of hypercholesterolemia. Statins have been shown to reduce cardiovascular 
morbidity and mortality, and their efficacy and safety for the primary and secondary 
prevention of cardiovascular events have been demonstrated in a large number of 
clinical trials.
Dose-proportional increases in pitavastatin Cmax and AUCinf were observed following 
daily administration ranging from 1 to 24 mg. Given with a high-fat and high-calorie meal, 
Cmax decreased by 43% but the AUC did not decrease significantly. The mean plasma 
elimination half-life (t1/2) is approximately 12 hours (LIVALO® U.S. Package Insert). Per 
the transporter expressing HEK293 cells and human cryopreserved hepatocytes, the 
OATP1B1 and OATP1B3 transporter account for almost all the observed pitavastatin 
uptake clearance into human hepatocytes and OATP1B1 accounts for about 90% of the 
clearance (Hirano et al 2004). Pitavastatin has been reported to be sensitive to OATP1B
inhibition (Prueksaritanont et al 2014). 
Pitavastatin was generally well-tolerated in clinical trials of up to 60-week duration, with a 
tolerability profile broadly similar to that of atorvastatin and simvastatin (Duggan 2012).
The adverse-events (AE) profile of pitavastatin compares favorably with those of other 
available statins. Reported AEs of pitavastatin included gastrointestinal symptoms 
(0.7%–2.2%), myopathies (0.3%–1.1%), and elevated hepatic enzyme concentrations 
(0.0%–8.8%; Yee et al 2011).
A detailed description of the chemistry, pharmacology, efficacy and safety of pitavastatin 
is provided in the pitavastatin package insert hours (LIVALO® U.S. Package Insert).
2.3
BENEFIT/RISK ASSESSMENT
This study has the principal aim of characterizing the drug-drug interaction between 
RO7049389 and an OATP substrate, the cholesterol-lowering drug pitavastatin, a 
representative of the statin class, in a population of healthy volunteers. There will be no 
therapeutic benefit for the healthy volunteers participating in the study. However, 
assessment of the influence of RO7049389 on the safety and PK of pitavastatin brings 
valuable information for the development of RO7049389. The target population could be 
exposed to statins or other OATP1B1 substrates, therefore, the results from the study 
will provide essential information to guide dosing of statins when co-administered with 
RO7049389.
The risks for the individual participant due to exposure to RO7049389 and/or pitavastatin 
or study-related procedures are considered acceptable or low in this study.
 
 
The risks 


RO7049389—F. Hoffmann-La Roche Ltd
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associated with two administrations of 2 mg single dose of pitavastatin in this study are 
also considered acceptable or low due to extensive clinical experience with pitavastatin 
at doses up to 24 mg and over much longer treatment durations, up to 60 weeks 
(Duggan 2012). In addition, careful safety monitoring of all critical safety parameters will 
be performed throughout this study and there will be close monitoring of all participants 
during dosing and in-clinic stay.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected adverse events of RO7049389 is provided in the 
RO7049389 Investigator’s Brochure.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 3.
Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary

To determine the effect of multiple-doses 
of RO7049389 on the single-dose 
pharmacokinetics (PK) of pitavastatin in 
healthy participants. 

Primary PK parameters of pitavastatin: 
Cmax, and AUC0-inf

Secondary PK parameters of pitavastatin: 
tmax, CL/F, V/F and t½.

Other parameters may be calculated if 
considered appropriate.
Secondary

To evaluate the safety and tolerability of 
the single-dose pitavastatin alone and in 
combination with multiple-doses of 
RO7049389 in healthy participants. 

Incidence and severity of adverse events.

Incidence of laboratory abnormalities 
based on hematology, clinical chemistry, 
coagulation, lipids, and urinalysis test 
results.

ECGs.

Vital signs including blood pressure (BP), 
pulse rate and body temperature.

To explore the effect of the single-dose of 
pitavastatin on steady-state PK of 
RO7049389 in healthy participants.

Primary PK parameters of RO7049389 
and its metabolites (RO7121986, 
RO7255420 and RO7255422): Cmax, and 
AUCtau

To determine the effect of multiple-doses 
of RO7049389 on the single-dose PK of 
pitavastatin lactone in healthy 
participants (if applicable).

PK parameters of pitavastatin lactone: 
Cmax, and AUC0-inf

The AUC ratio of pitavastatin 
lactone/pitavastatin.
Exploratory

To evaluate the effect of multiple-doses 
of RO7049389 on OATP activity as 
assessed by plasma and urine 
coproporphyrins (CP-I and CP-III).

Coproporphyrins (CP-I and CP-III) AUC 
in plasma and amount excreted in urine.


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4.
STUDY DESIGN
4.1
OVERALL DESIGN
This is an open-label, fixed sequence, two-period study designed to evaluate the drug-
drug interaction between RO7049389 and pitavastatin and the safety and tolerability of 
single-dose pitavastatin alone and in combination with multiple-doses of RO7049389 in 
healthy participants.
An overview of the study design is provided in Section 1.2.
4.1.1
Length of the Study
The total duration of the study for each participant will be about 12 weeks divided as 
follows:

Screening: Up to 28 days.

Period 1:
–
In clinic period: Days -1 to 4.
–
Treatment period: Day 1

Wash-out Period: Defined as from Period 1 Day 1 to Period 2 Day 1 and lasts at 
least 7 days but not more than 21 days

Period 2: 
–
In clinic period: Days -1 to 7
–
Treatment period: Days 1 to 6

Safety follow-up: 
–
Period 2 Day 13
–
Period 2 Day 34 (Telephone call)
The participant has the option to stay in clinic during the whole Period 1 and wash-out 
period if agreed by Sponsor and the Investigator.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
This is an open-label, fixed sequence, two-period study.
The primary objective of this study is to determine the effect of multiple-doses of 
RO7049389 on the single-dose PK of pitavastatin in healthy participants. As PK 
measurements are objectively analysed an open-label study design has been chosen. 
To minimize the number of participants needed and reduce inter-subject variability, this 
study will follow a two-period instead of parallel design. The duration of both washout 
and drug administration periods was established on the basis of the known 






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The end of the study is defined as the date when the last participant last observation 
(LPLO) occurs. LPLO is expected to occur 28 days after the last dose of RO7049389 is 
administered.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.1.
The participants of this study will be healthy male and female volunteers of 18 to 60 
years of age (inclusive). The study will enroll up to a total of 18 participants to obtain 16 
evaluable participants.
Participants who drop out of the study, or who are withdrawn, for non-safety reasons 
may be replaced. Participants who withdraw from the study due to poor tolerability or 
due to study drugs (RO7049389 or pitavastatin) related adverse events will not be 
replaced.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants will be eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to ICH and local regulations.  
Age
2.
18 to 60 years of age, inclusive, at the time of signing the informed consent.
Type of Participants and Characteristics
3.
Healthy, as judged by the Investigator.
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, and based on the laboratory safety test results at 
screening and Day -1.
4.
Body mass index (BMI) between 18 to 30 kg/m2 (inclusive) at screening.
5.
Male and female participants
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 


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abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
a)
Female Participants
Female participants must be either surgically sterile (by means of hysterectomy 
and/or bilateral oophorectomy and/or tubal ligation) or post-menopausal for at 
least one year (defined as amenorrhea 12 consecutive months without 
another cause, and confirmed by follicle-stimulating hormone (FSH) level. 
Participants must not be pregnant or lactating.
b)
Male Participants
With female partners who are not pregnant or lactating.
With agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom during the treatment period and for at least 28 days after the last 
dose of study drug to avoid exposing the embryo. Men must refrain from 
donating sperm during this same period.
5.2
EXCLUSION CRITERIA
Participants will be excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Have a history or symptoms of any clinically significant cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, hematological, oncologic or neurological 
disorders capable of significantly altering the absorption, metabolism, or elimination 
of drugs; of constituting a risk when taking the study treatment; or of interfering with 
the interpretation of data.
2.
Confirmed (based on the average of 3 separate resting BP measurements in a 
supine position, after at least 5 minutes rest) systolic BP greater than 140 or less 
than 90 mmHg, and diastolic BP greater than 90 or less than 50 mmHg at screening 
and Day -1.
3.
Personal history or family history of congenital long QT syndrome and/or cardiac 
sudden death.
4.
History of Gilbert’s syndrome.
5.
Participants who have had significant acute infection, e.g., influenza, local infection, 
acute gastrointestinal symptoms or any other clinically significant illness within two 
weeks of dose administration.


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6.
Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any 
drug, or multiple drug allergies (non-active hay fever is acceptable).
7.
Any clinically significant concomitant diseases or condition that could interfere with, 
or treatment of which might interfere with, the conduct of the study, or that would, in 
the opinion of the Investigator, pose an unacceptable risk to the participant in this 
study.
Prior/Concomitant Therapy
8.
Taking any herbal medications or substances(e.g., tea) or supplements(including 
vitamins), or traditional Chinese medicines (TCM) or over-the-counter (OTC) 
medications within 14 days of first dosing or within 5 times the elimination half-life of 
the medication prior to first dosing, whichever is longer. 
Exceptions include medications listed under Permitted Therapy and those made on 
a case-by-case basis following discussion and agreement between the Investigator 
and the Sponsor.
9.
History of having received any systemic anti-neoplastic (including radiation) or 
immune-modulatory treatment (including systemic oral or inhaled 
corticosteroids) 6 months prior to the first dose of study drug or the expectation 
that such treatment will be needed at any time during the study.
Prior/Concurrent Clinical Trial Experience
10. Are currently enrolled in or have participated in any other clinical study involving an 
investigational product or in any other type of medical research within the last 30 
days or 5 half lives (whichever is longer).
11. Donation or loss of blood or blood products in excess of 500 mL within 3 months of 
screening.
Diagnostic Assessments
12. Positive test for drugs of abuse (including recreational drugs) and/or positive alcohol 
test and/or positive cotinine test at screening and on Day -1.
13. Clinically relevant ECG abnormalities on screening or Day -1 ECG based upon the 
average of three ECGs, e.g.:
a. QTcF 450 msec or 300 msec.
b. Notable resting bradycardia (HR 45 bpm), or HR 90 bpm.
c.
Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, 
Wolf-Parkinson-White Syndrome, or cardiac pacemaker.
14. ECG with QRS and/or T-wave judged by the Investigator to be unfavorable for a 
consistently accurate QT measurement (e.g., neuromuscular artifact that cannot be 
readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T-wave, 
merged T- and U-waves, prominent U- waves).


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15. Creatinine Clearance (CrCl) 70 mL/min at screening or on Day -1 (may be 
repeated for confirmation).
16. Positive test at screening of any of the following: Hepatitis A virus (HAV IgM Ab), 
hepatitis B virus (HBsAg or HBcAb), , hepatitis C virus (HCV RNA or HCV Ab) or 
human immunodeficiency virus (HIV-1 and HIV-2 Ab).
17. Any other clinically significant abnormalities in laboratory test results at screening or 
on Day -1. In the case of uncertain or questionable results, tests performed during 
screening may be repeated once prior to enrollment to confirm eligibility unless 
deemed not clinically significant by the Investigator.
Other Exclusions
18. History of alcohol consumption exceeding 2 standard drinks per day on average 
(1 standard drink10 grams of alcohol) and/or drug abuse within 12 months of 
screening. 
19. Use of 5 cigarettes or equivalent nicotine-containing product per day prior to 
screening.
20. Participants under judicial supervision, guardianship or curatorship.
21. Medical or social conditions that would potentially interfere with the participant’s 
ability to comply with the study visit schedule or the study assessments.
22. Sensitivity to any of the study treatments, or excipients thereof, or drug or other 
allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates the 
participation in the study.
5.3
LIFESTYLE CONSIDERATIONS  
5.3.1
Meals and Dietary Restrictions
Food and water will be restricted as follows:

Any nutrients known to modulate activity of CYP enzymes or OATP transporters 
(e.g., grapefruit-, apple-, or Seville orange-containing products) will be prohibited 
within 3 days before Period 2 Day -1 through the last dose of RO7049389, which is 
on Period 2 Day 6.

Approximately 240 mL of still water at room temperature will be provided for each 
dose. No water is allowed until 2 hours after each dose, after which time, water is 
allowed ad libitum.
5.3.2
Caffeine, Alcohol, and Tobacco
Caffeine, alcohol, and tobacco will be restricted as follows:

During each period, participants must abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours 
before the start of dosing until after collection of the final PK sample.


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32/Protocol YP40218, Version 1

Alcohol must not be consumed from 48 hours before screening, 48 hours before 
admission until completion of follow-up visit on Day 13 of Period 2.

Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches) will not be allowed from screening 
until after the final follow-up visit.
5.3.3
Activity
Participants must abstain from strenuous exercise for at least 72 hours before each 
blood collection for clinical laboratory tests. Participants may participate in light 
recreational activities during study (e.g., watching television, reading).
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled to study treatment.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure.
If a participant fails an inclusion/exclusion criterion due to a transient and non-clinically 
significant condition at screening, the Investigator may repeat the relevant screening 
assessment(s) within the 28-day screening period. If the participant fails a second time 
they will be classed as a screen failure and cannot be re-screened. 
Re-screening is allowed for participants who were screened in the study and met study 
inclusion/exclusion criteria but failed to be enrolled within 28 days after the start of 
screening period because the enrollment was suspended. In order to re-screen such a 
participant, all inclusion and exclusion criteria should be re-evaluated and all applicable 
screening assessments repeated if done more than 28 days prior to the enrollment. 
5.5
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using, clinical database and 
IEC/IRB approved newspaper/radio/television/Social Network Service/campus poster 
advertisements, mailing lists and other distributable documents, prior to consenting to 
take place on this study.
6.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.
The investigational medicinal products (IMPs) required for completion of this study will 
be RO7049389 and pitavastatin. RO7049389 will be supplied centrally by the Sponsor 


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and pitavastatin (LIVALO® manufactured by Kowa) will be sourced locally and 
reimbursed by the Sponsor. 
All study drug administration will be at the study center under supervision of site staff.
6.1
TREATMENTS ADMINISTERED
Table 4 summarizes the treatments administered.
Table 4
Summary of Treatments Administered
Study Treatment Name:
RO7049389
Pitavastatin
Dosage Formulation:
Tablet
Tablet
Unit Dose Strength(s):
200 mg
2 mg
Dose:
800 mg BID
2 mg
Route of Administration:
Oral
Oral
Dosing Instructions:
4 tablets to be taken, with 
food
1 tablet to be taken, with food
Packaging and Labeling:
Study treatment will be 
provided in labeled 
bottles.
Manufacturer
F. Hoffmann-La Roche Ltd 
Kowa
Study treatments will be administered orally to the participants by investigational staff for 
all dosing with still water at room temperature. 
Pitavastatin will be administered orally to participants by investigational staff in the 
morning on Day 1 of Period 1 and Day 4 of Period 2. Thirty minutes before the 
administration, a standard meal will be served to participants, which should be 
consumed within thirty minutes. RO7049389 will be administered orally to participants by 
investigational staff from Day 1 to Day 6 of Period 2 twice daily. The first daily dosing will 
be administered in the morning and the second daily dose will be in the evening, with 
approximately 12 hours interval. In the morning of Day 4 of Period 2, pitavastatin will be 
administered together with RO7049389.
For RO7049389, please see the RO7049389 Investigator’s Brochure for more details.
For pitavastatin, see the local prescribing information for more details.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
For RO7049389, study drug packaging will be overseen by the Roche clinical trial 
supplies department and bear a label with the identification required by local law, the 
protocol number, drug identification and dosage.
The packaging and labeling of the RO7049389 will be in accordance with Roche 
standard and local regulations.


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The investigational site will acknowledge receipt of RO7049389 and confirm the 
shipment condition and content. Any damaged shipments will be replaced.
Upon arrival of the RO7049389 at the site, site personnel will complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose.
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Pitavastatin (LIVALO® manufactured by Kowa) will be sourced locally and reimbursed by 
the Sponsor.
Only participants enrolled in the study may receive study treatments and only authorized 
site staff may supply or administer study treatments. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. Film-coated tablets of RO7049389 should be stored under the 
recommended storage conditions “Store at 2-8°C, protect from light and moisture’.
The Investigator, Institution, or the Head of the Medical Institution (where applicable) is
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records).
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.


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6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment 
This is a fixed sequence study. Randomization is not applicable.
6.3.2
Blinding
This is an open-label study, blinding procedures are not applicable.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the instructions given in Section 6.1. This individual will record
the date dispensed and participant number on the Drug Accountability Record.
6.5
CONCOMITANT THERAPY
6.5.1
Permitted Therapy
Any medication or vaccine (including OTC or prescription medicines, approved dietary 
and herbal supplements, nutritional supplements) used by a participant from 30 days 
prior to screening until the follow-up visit must be recorded along with reason for use, 
dates of administration (including start and end dates) and dosage information (including 
dose and frequency).
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF.
The following medications will be permitted:

Medications used to treat AEs may only be prescribed after consultation with the 
Sponsor (with the exception of acetaminophen/paracetamol), unless there is a 
medical need to ensure the well-being of the participant that should not be delayed. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF.

Hormone replacement therapy (HRT): permitted if initiated at least 2 months prior to 
study start.

Occasional use of acetaminophen (up to a maximum dose of 2g/day up to 48 hours 
prior to dosing, not to exceed 4g total during the week prior to dosing) will be 
permitted. 


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6.5.2
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF.
As a general rule, no concomitant medication will be permitted within 14 days prior to the 
first dosing or within 5 half-lives of the medication prior to the first dosing (whichever is 
longer), until the follow-up visit, with the exception of the cases listed in Permitted 
Therapy (See Section 6.5.1). Exceptions may be made on a case-by-case basis 
following discussion and agreement between the Investigator and the Sponsor after, the 
rationale for exception is discussed and clearly documented.
6.6
DOSAGE MODIFICATION
No dose modification of RO7049389 or pitavastatin for safety reasons is expected in the 
study.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7049389, pitavastatin or other study 
interventions to participants after conclusion of the study or following early participant 
withdrawal.
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
See the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
Participant must discontinue study treatment if they experience any of the following:

Pregnancy

Clinically significant study treatment-related changes in safety parameters that are 
considered not acceptable by the Investigator and/or the Sponsor.

Poor gastrointestinal (GI) tolerability that is considered to affect the study 
participant’s well-being and/or the PK evaluation


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Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for a study completion/early termination visit (see Section 8.10.3) and may undergo 
follow‑up assessments (see Section 8.10.4). The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. 
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
FROM THE STUDY
Participants 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 participant from the study for 
medical conditions that the Investigator or Sponsor determines, may jeopardize the 
participant’s safety if he/she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will remain as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of specimens 
donated to the Research Biosample Repository (RBR).
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons may be replaced.
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and at 
safety and follow-up visits, and for any further evaluations that need to be completed.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.


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
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed.
Safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-frame defined in the SoA.
At time-points when several assessments coincide, the following sequence is suggested; 
at the discretion of the Investigator, the order can be adjusted to optimize site personnel 
and participant’s time management: 

Urine collection

ECG recordings

Vital signs

PK and safety blood sampling

Administer meal

Study treatment administration
8.1
EFFICACY ASSESSMENTS  
No efficacy assessments will be performed in this study.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination should be performed at time-points indicated in the 
SoA (Section 1.3) and includes, at a minimum, assessments of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems. Any abnormality 


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identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.
At all other visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Height (screening only) and weight will also be 
measured and recorded. Further examination of other body systems may be performed 
in case of evocative symptoms at the Investigator’s discretion.
Changes from baseline abnormalities should be recorded in participant’s notes. New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
8.2.2
Vital Signs
Body temperature (tympanic or oral), pulse rate, and blood pressure will be assessed.
Blood pressure and pulse measurements will be assessed in a supine position for at 
least 5 minutes with a completely automated device. Manual techniques will be used 
only if an automated device is not available. When possible, the same arm should be 
used for all blood pressure measurements.
Vital signs will be taken before blood collection for laboratory tests. They will be 
measured in a supine position after at least 5 minutes rest and will include temperature, 
systolic and diastolic blood pressure, and pulse rate. Three readings of blood pressure 
and pulse will be taken. The mean of three consecutive replicates will be used as the 
value for the defined time-point to be recorded in the eCRF.
8.2.3
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
RR, and QTc intervals.
At each time-point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession. The full set of triplicates should 
be completed in less than 5 minutes. Any clinically significant ECG abnormalities should 
be captured on the eCRF.
To minimize variability, it is important that participants be in a supine position for at least
10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre ECG 
resting period and during ECG recording. ECGs should be performed prior to meals and 
any scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.


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For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcF (Fridericia’s correction) and RR will be calculated by 
the Sponsor. Changes in T-wave and U-wave morphology and overall ECG 
interpretation will be documented on the eCRF. T-wave information will be captured as 
normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
8.2.4
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the separate 
laboratory manual and the SoA (Section 1.3).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.

In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to 
the normal range and/or an adequate explanation of the abnormality is found.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified.

If laboratory values from non-protocol specified laboratory assessments performed 
at the local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or 
dose-modification) then, the results must be recorded in the CRF.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety.


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Where the clinical significance of abnormal lab results is considered uncertain, screening 
lab tests may be repeated prior to enrollment to confirm eligibility.
If there is an alternative explanation for a positive urine or blood test for drugs of abuse, 
e.g., previous occasional intake of a medication or food containing for example, codeine, 
benzodiazepines or opiates, the test could be repeated to confirm washout.
8.2.5
Medical History and Demographic Data
Medical history will include clinically significant diseases, reproductive status, smoking 
history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
OTC drugs, herbal or homeopathic remedies, nutritional supplements) used by the 
participant within 30 days prior to the screening visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 2. 
The non-serious adverse events of special interest are discussed in Sections 8.3.6.
The Investigator and any qualified designees are responsible for ensuring that all 
adverse events (including assessment of seriousness, severity and causality; see 
Appendix 2) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Appendix 2.
Procedures used for recording adverse events are provided in Appendix 3:

Diagnosis versus signs and symptoms

Other AEs

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values

Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Hospitalization or prolonged hospitalization
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.


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Investigators will seek information on adverse events at each participant’s contact. All 
adverse events, whether reported by the participant or noted by study personnel, will be 
recorded in the participant’s medical record and on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (e.g., serious adverse events related to invasive procedures such as biopsies). 
Any other adverse event should not be reported.
After initiation of study treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until 28 days after the last dose of study treatment. 
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period (28 days after the last dose of study treatment).
However, if the Investigator learns of any SAE (including a death) or other adverse 
events of concern that are believed to be related to prior treatment with study treatment, 
at any time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study participation, 
the Investigator must promptly notify the Sponsor. For the procedure of reporting, see 
Appendix 2.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation time-points.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the event is 
otherwise explained, the participant is lost to follow-up (Section 7.3), or the participant 
withdraws consent. Every effort should be made to follow all serious adverse events 
considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant’s medical record to facilitate source 


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data verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators and regulatory authority as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB and EC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study patients, access to the Medical monitors is available 
24 hours a day 7 days a week. Medical monitors contact details will be available on a 
separate list generated by the study management team.


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8.3.5
Pregnancy
Female healthy participants of childbearing potential will not be allowed to participate in 
this study. However, female participants will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 28 
days after the last dose of study drug. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest 
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Appendix 2 for reporting instructions).
Non-serious adverse events of special interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only
when a contamination of the study treatment is suspected.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied. An overdose or incorrect administration of study 
treatment is not an adverse event unless it results in untoward medical effects (see 
Appendix 2 for further details).
Decisions regarding dose-interruptions or modifications will be made by the Investigator
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.


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In the event of an overdose, the Investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Obtain a blood sample for PK analysis within 24 hours from the date of the last dose 
of study treatment, if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the CRF.
For this study, any dose of pitavastatin greater than 2 mg, and/or any dose of 
RO7049389 greater than 1600 mg within a 24-hour time period (+ 1.0 hours) will be 
considered an overdose.
The Sponsor does not recommend specific treatment for an overdose.
8.5
PHARMACOKINETICS
Mandatory blood samples to evaluate concentrations of study treatment (RO7049389
and its metabolites, RO7121986, RO7255420 and RO7255422, pitavastatin and its 
metabolite, pitavastatin lactone (as applicable)) will be collected. The date and time of 
each sample collection will be recorded in the eCRF. Plasma concentrations of 
RO7049389, RO7121986, RO7255420 and RO7255422, pitavastatin and pitavastatin 
lactone (as applicable) levels will be analyzed by using validated liquid chromatography 
tandem mass chromatography (LC-MS/MS) methods. The PK samples will be taken as 
outlined in the Schedules of Activities (see Section 1.3). A PK sample will also be 
collected following occurrence of a dose-limiting event or serious adverse event.
If required, remaining PK samples may also be used for assay development/validation 
experiments.
The plasma samples will be destroyed within 2 years after the date of final CSR, unless 
regulatory authorities require specimens to be maintained for a longer time period. 
Details on sampling procedures, sample storage and shipment are given in the Sample 
Handling Manual.
8.6
PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated in this study.


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8.7
GENETICS
8.7.1
Clinical Genotyping  
A mandatory whole blood sample will be taken for DNA extraction from every participant. 
If the sample is missed on Day 1, it can be collected at any other scheduled visit. The 
DNA will be used for, but analysis is not limited to:

Genetic variants of transporters (e.g., OATP), which might affect pharmacokinetics 
of RO7049389 and pitavastatin.
Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to confidentiality standards described in Appendix 1. For participants who 
consent to RBR, leftover samples will be transferred to RBR (see Section 8.8.1).
The samples will be destroyed within 2 years after the date of final CSR, unless 
regulatory authorities require specimens to be maintained for a longer time period. 
Details on sampling procedures, sample storage and shipment are given in the Sample 
Handling Manual.
8.8
BIOMARKERS
Endogenous substances levels will be investigated to assess the effect of multiple oral 
dosing of RO7049389 on OATP1B1 activity. Individual AUC ratios (before and after 3 
days of RO7049389 treatment) of plasma and amount excreted in urine of 
coproporphyrins (CP-I and CP-III) will be listed and summarized using descriptive 
statistics. Geometric mean ratio of after RO7049389 treatment relative to before 
RO7049389 treatment and the 90% confidence intervals will be computed.
Any remaining material from plasma or urine may also be used for additional assay 
validation experiments.
The plasma and urine samples will be destroyed within 2 years after the date of final 
CSR.
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
8.8.1
Samples for Research Biosample Repository
8.8.1.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of these 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.


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Specimens will be collected from participants who give specific consent to participate in 
this optional RBR. Collected specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, AEs, or progressive disease

To increase knowledge and understanding of disease biology

To study treatment response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.
8.8.1.2
Sample Collection
RBR samples will be collected at the time-point indicated in the SoA (Section 1.3). The 
following samples will be stored in the RBR and used for research purposes, including, 
but not limited to, research on biomarkers related to RO7049389 or diseases:

RBR blood sample
For all samples, dates of consent and specimen collection should be recorded on the 
associated Research Biosample Repository page of the eCRF. For sampling procedures, 
storage conditions, and shipment instructions, see the separate Laboratory Manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The Research Biosample Repository storage period will be in accordance 
with the IRB/EC‑approved Informed Consent Form and applicable laws (e.g., Health 
Authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1).
8.9
HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.


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An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study.
All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of 
assessments. 
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the last dose administration or discontinue from the study 
early will be asked to return to the clinic 7 days after the last dose of study treatment for 
a follow‑up visit and 28 days after the last dose of study treatment for a follow-up call.
The follow-up visit and follow-up call will be reported as the study completion visit in 
eCRF
In case of early termination of a participant, a blood sample for PK assessment of 
RO7049389 and pitavastatin should be collected at the time of discontinuation. Please 
also see Section 1.3 for activities that are required to be performed in case of an early 
termination.
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 8.3.1 and 8.3.3.
8.10.5
Assessments at Unscheduled Visits 
Please see Section 1.3 for activities that are required to be performed in case of an 
unscheduled visit.
If an unscheduled visit is required to ensure safety of study participants, necessary 
assessments will be undertaken at the discretion of the Investigator. All unscheduled 
assessments should be reported in eCRF.
Unscheduled local laboratory tests may be ordered per Investigator’s discretion and may 
be used for the individual management of study participants. 
9.
STATISTICAL CONSIDERATIONS
The primary objective of this study is to characterize the pharmacokinetics profile of 
pitavastatin in healthy participants following multiple dose of RO7049389 on the single-


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dose of pitavastatin. Statistical summaries will be descriptive in nature. All participants 
who receive any amount of study medication will be included in the safety analysis.
9.1
STATISTICAL HYPOTHESES 
Not Applicable
9.2
SAMPLE SIZE DETERMINATION
A sample size of 18 participants to target 16 evaluable healthy participants has been 
chosen. Evaluable participants who withdraw for non-safety reasons from the study will 
be replaced to meet the enrollment goal.
Assuming a coefficient of within participant variation of 30% for Cmax and AUC, with a 
sample size of 16 evaluable participants per period, the entire 90% confidence interval 
for a geometric mean ratio (using pitavastatin alone as the reference) in the Cmax and 
AUC will be entirely within a range from 80% to 125% of the true (but unknown) 
geometric mean ratio with a probability of at least 80% (i.e., estimation power).
9.3
POPULATIONS FOR ANALYSES
9.3.1
Pharmacokinetic Analysis Population
All participants who have received at least one dose of study treatment (RO7049389 or 
pitavastatin) and who have data from at least one post-dose sample will be included in 
the PK analysis population. Participants 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 which may influence the PK analysis. 
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.
9.3.2
Safety Analysis Population
All participants, who received at least one dose of the study treatment (RO7049389 or 
pitavastatin), whether prematurely withdrawn from the study or not, will be included in 
the safety analysis.


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For purposes of analysis, the following populations are defined in Table 5.
Table 5
Analysis Populations
Population
Description
Safety
All participants, who received at least one dose of the study 
treatment, whether prematurely withdrawn from the study or 
not, will be included in the safety analysis. 
Pharmacokinetic
All participants who have received at least one dose of study 
treatment (RO7049389 or pitavastatin) and who have data 
from at least one post-dose sample will be included in the PK 
analysis population. Participants 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 which may influence the 
PK analysis. 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.
9.4
STATISTICAL ANALYSES
9.4.1
Demographics and Baseline Characteristics
Descriptive statistics will be used for demographic and baseline characteristics as 
applicable and will include sex, race (Asian and non-Asian, Chinese among Asian), 
ethnicity, age, weight, height and body mass index. For continuous variables, mean, 
standard deviation, median, and minimum and maximum values will be presented. For 
categorical data, the proportion of participants in each category will be summarized. 
9.4.2
Safety Analyses
All safety analyses will be based on the safety analysis population.


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Table 6
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor. Adverse events will be summarized by 
appropriate thesaurus level and grouped according to treatment period.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Participant listings and summary statistics at 
each assessment time will be presented using the International System of 
Units (SI units; Système International d’Unités). Laboratory data not 
reported in SI units will be converted to SI units before processing.
Laboratory test values will be presented by individual listings with flagging 
of values outside the reference ranges. See Appendix 4 for details on 
standard reference ranges and data transformation and the definition of 
laboratory abnormalities.
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings with flagging of values 
outside the normal ranges and flagging of marked abnormalities. Summary 
descriptive statistics for the actual values and changes from baseline will be 
tabulated by nominal time for HR, QRS duration, PR and QTcF.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
9.4.3
Pharmacokinetic Analyses 
Analyses will be carried out on the PK analysis population. 
Individual and mean plasma concentrations at each sampling time-point for RO7049389 
and its metabolites (RO7121986, RO7255420 and RO7255422), pitavastatin and 
pitavastatin lactone as appropriate will be presented by listings and descriptive summary 
statistics, including means, geometric means, ranges, standard deviations and 
coefficients of variation. Individual and mean concentration versus time will be plotted on 
semi-logarithmic scales. 
Non-compartmental analysis will be employed for estimation of PK parameters. All PK 
parameters will be presented by individual listings and summary statistics for each 
period including means, geometric means, medians, ranges, standard deviations and 
coefficients of variation. 
To assess the effect of RO7049389 on the PK of pitavastatin, the logarithmically 
transformed variables Cmax and AUC0-inf of pitavastatin and its metabolite pitavastatin 
lactone will be subjected to an ANOVA (with factors RO7049389 and participant) for 
which measurements are available for healthy participants in both with/without 


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RO7049389. 90% confidence intervals for the ratio of geometric means will be 
calculated using the pitavastatin alone as the reference.
The same analysis of variance will be applied to the secondary parameters AUC0-12hr and 
Cmax of RO7049389 and its metabolites (RO7121986, RO7255420 and RO7255422) to 
assess the effect of pitavastatin on the PK of RO7049389.
In case AUC0-inf cannot be determined reliably, an appropriately truncated AUC will be 
used.
9.4.4
Pharmacodynamic Analyses 
Not Applicable.
9.4.5
Other Analyses
Individual ratios (before and after 3 days of RO7049389 treatment) of coproporphyrins 
(CP-I and CP-III) will be listed and summarized using descriptive statistics. Geometric 
mean ratio of after RO7049389 treatment relative to before RO7049389 treatment and 
the 90% confidence intervals will be computed. 
9.5
SUMMARIES OF CONDUCT OF STUDY
The number of participants who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study withdrawal will be listed and summarized by 
treatment period. Protocol deviations will be listed and evaluated for their potential 
impact on interpretation of study results. Study drug administration will be summarized 
by treatment period. Descriptive statistics will be used in evaluating the conduct of the 
study.


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10.
REFERENCES
Duggan ST. Pitavastatin: A Review of Its Use in the Management of 
Hypercholesterolaemia or Mixed Dyslipidaemia. Drugs. 2012;72(4):565-584.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines 
on the management of hepatitis B virus infection. J Hepatol (2017), in press. 
http://dx.doi.org/10.1016/j.jhep.2017.03.021
Hasunuma T, Nakamura M, Yachi T, et al. The drug-drug interactions of pitavastatin 
(NK-104), a novel HMG-CoA reductase inhibitor and cyclosporine. J Clin Therap 
Med. 2003;19:381–389.
Hirano M, Maeda K, Shitara Y, et al. Contribution of OATP2 (OATP1B1) and OATP8 
(OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 
2004;311(1):139-146.
Marcellin P et al. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a 
Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. 
Gastroenterology. 2016 150(1):134-144.
Investigator’s Brochure, RO7049389, Version 3.
LIVALO (pitavastatin) U.S. Package Insert, Patheon, Inc.
Prueksaritanont T, Chu X, Evers R, et al. Pitavastatin is a more sensitive and selective 
organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J 
Clin Pharmacol. 2014;78(3):587-598.
WHO Fact Sheet N°204, updated July 2016 
http://www.who.int/mediacentre/factsheets/fs204/en/
Yee LL, Wright EA. Pitavastatin calcium: clinical review of a new antihyperlipidemic 
medication. Clin Ther. 2011;33(8):1023-1042.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
and Appendix 3 (procedures of recording), Appendix 5 (contraceptive guidance and 
collection of pregnancy information). Additional study-related appendices are in order of 
appearance in the protocol.


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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
1.2.
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the participant (e.g. 
advertisements, diaries etc), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any participant 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 (Section 2.3.1 of this 
Appendix).
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. 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.
1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, where applicable, and the IRB/IEC or study center. 
The Sponsor or its designee must review and approve any proposed deviations from the 


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Sponsor's sample ICFs or any alternate consent forms proposed by the site (collectively, 
the “Consent Forms”) before IRB/EC submission. The final IRB/EC‑approved Consent 
Forms must be provided to the Sponsor for Health Authority submission purposes 
according to local requirements. Participants must be re-consented to the most current 
version of the ICF(s) during their participation in the study. A copy of the ICF(s) signed 
by all parties must be provided to the participant or the participant’s legally authorized 
representative.
The Consent Forms must be signed and dated by the participant before his or her 
participation in the study. The case history or clinical records for each participant 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
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants 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 participant 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 participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s study file or in the site file and must be available for 
verification by study monitors at any time.
Consent to Participate in the Research Biosample Repository
The ICF will contain a separate section that addresses participation in the RBR. The 
Investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of participation in the RBR. Participants will be told that 
they are free to refuse to participate and may withdraw their specimens at any time and 
for any reason during the storage period. A separate, specific signature will be required 
to document a participant’s agreement to provide optional RBR specimens. Participants 
who decline to participate will not provide a separate signature.
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.


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In the event of death or loss of competence of a subject who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
If the site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information, the review, approval, and other processes 
outlined above apply except that IRB review and approval may not be required per study 
site policies.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the ICF by each site's Institutional Review Board or 
Ethics Committee (IRB/EC) and, if applicable, an appropriate regulatory body. If a site 
has not been granted approval for RBR sampling, this section of the protocol will not be 
applicable at that site
Withdrawal from the Research Biosample Repository
Participants who give consent to provide specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a participant wish to withdraw 
consent to the testing of his or her specimens, the Investigator must inform the Medical 
Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if the 
trial is ongoing, must enter the date of withdrawal on the RBR Withdrawal of Informed 
Consent eCRF. The participant will be provided with instructions on how to withdraw 
consent after the trial is closed. A participant's withdrawal from Study YP40218 does not, 
by itself, constitute withdrawal of specimens from the RBR. Likewise, a participant’s 
withdrawal from the RBR does not constitute withdrawal from Study YP40218. Data 
already generated before time of withdrawal of consent to RBR will still be used.
1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.


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The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
1.5.
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant 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, COAs (paper or eCOA), 
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.


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Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification to 
the Sponsor.
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 


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eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
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.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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.
2.3.3.
Dissemination of Clinical Study Data
A clinical study report containing the results of this trial will be made available to anyone 
who requests a copy. A description of this clinical trial and a summary of its results will 
be available at http://www.ClinicalTrials.gov.
2.3.4.
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ 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.
3.
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for the 
study management, data management, statistical analysis and medical writing for the
clinical study report.


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4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to, the 
following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants.

Participant enrollment is unsatisfactory.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
The study site will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.


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Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.
An adverse event can therefore be:

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.
Events Meeting the AE Definition:

Any deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 
or other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to 
a change in study treatment or concomitant treatment or discontinuation from study 
treatment.

Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies).
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments, unless judged by the Investigator to be more severe than expected 
for the participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).


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A serious adverse event is defined as any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.

Other significant events:
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.


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3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
The Investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Medical Monitor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Medical Monitor.
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
ASSESSMENT OF SEVERITY
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing adverse event severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event.


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Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see above).
3.2.
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.  

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.


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5.
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 treatment:

Serious adverse events

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)

Accidental overdoses or medication errors (see Appendix 2, Section 5.2 for details 
on reporting requirements)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).


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Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period, if the event is believed to be related to prior study 
treatment the event should be reported directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or 
email address provided to investigators.
5.2 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error are defined as follows:

Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with RO7049389 and pitavastatin, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.


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
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For RO7049389 and pitavastatin, each adverse event associated with a special situation 
should be recorded separately on the Adverse Event eCRF. If the associated adverse 
event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Appendix 2, 
Section 5.1). For RO7049389 and pitavastatin, adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document{s}:

RO7049389 Investigator's Brochure

Local prescribing information for pitavastatin


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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.


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Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time-points. Such events should only be recorded once on the 


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Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between participant evaluation 
time-points and subsequently recurs. Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


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5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 3, 
Section 4) and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event), either as a serious adverse event or a non-serious adverse event 
of special interest (see Appendix 2, Section 5.1).


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7.
DEATHS
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
9.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration and intensive PK sampling).


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
All study-required laboratory assessments will be performed by a local laboratory:
Laboratory Assessments
Parameters

Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes), 
mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC) 
and reticulocyte counts.

Clinical Chemistry

Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total, direct and indirect 
bilirubin, alkaline phosphatase (ALP), gamma 
glutamyl transferase (at screening only), creatinine 
phosphokinase (at screening only), total protein, 
albumin, urea, creatinine, creatinine clearance 
(CrCl) (at screening and Day 1 only using the 
Cockcroft-Gault formula), uric acid, fasting
glucose, sodium, chloride, potassium, calcium, 
phosphorus.

Coagulation

INR, aPTT, PT.

Viral Serology

Hepatitis A virus (HAV IgM Ab), hepatitis B virus 
(HBsAg and HBcAb), hepatitis C virus (HCV RNA 
or HCV Ab), human immunodeficiency virus (HIV-
1 and HIV-2 Ab).

Lipids

Cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides.


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Table 1
Protocol-Required Safety Laboratory Assessments (cont.)

Hormone  

FSH (females only to confirm post-menopausal 
status).

Pregnancy Test

Serum or plasma beta-human chorionic 
gonadotropin (-HCG) at screening, urine on all 
other occasions (females only). If urine is positive, 
then need confirmatory serum or plasma test.

Urinalysis

Dipstick: pH, glucose, protein, blood, and 
leucocytes

If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine 
will be sent to the laboratory for microscopy and 
culture. If there is an explanation for the positive 
dipstick results (e.g., menses), it should be 
recorded and there is no need to perform 
microscopy and culture.

Microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.

Urine drug screen

Cannabinoids, amphetamines, 
methamphetamines, opiates, methadone, cocaine, 
benzodiazepines, and barbiturates.

Cotinine

Cotinine test as per local practice.

Alcohol

Alcohol breath test.
The results of each test must be entered into the CRF.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.


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
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in participant listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.


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Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high FSH level in the 
post-menopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of post-menopausal status before study enrollment.


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2.
CONTRACEPTION GUIDANCE

Female Participants
Female participants of childbearing potential will not be allowed to participate in this 
study.

Male Participants
Male Participants are eligible to participate if they and their female sexual partner agree 
to use a highly effective method of contraception consistently and correctly as described 
in Table 1 below.
Table 1 Highly Effective Contraceptive Methods
Highly Effective Methods That Are User-Independenta
Highly effective non-hormonal contraception

Intrauterine device (IUD)

Bilateral tubal occlusion
Vasectomy
Vasectomy is a highly effective contraception method.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a) Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants participating in clinical studies.
3.
PREGNANCY TESTING
Female participants of childbearing potential will not be allowed to participate in this 
study. Blood sample and urine pregnancy tests will be performed according to Schedule 
of Activity tables (see Section 1.3). If a urine pregnancy test is positive, it must be 
confirmed by a blood pregnancy test.


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4.
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy).
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
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 update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant 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. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.

Female participants who become pregnant
Female participants of childbearing potential will not be allowed to participate in this 
study. However, the Investigator will collect pregnancy information on any female 
participant, who becomes pregnant while participating in this study (see Section 8.3.5
Pregnancy). Information will be recorded on the appropriate form and submitted to the 
Sponsor within 24 hours of learning of a participant's pregnancy. The participant will be 
followed to determine the outcome of the pregnancy. The Investigator will collect 
follow-up information on the participant and the neonate, which will be forwarded to the 
Sponsor. Monitoring of the participant should continue until conclusion of the pregnancy.
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 


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treatment by the Investigator, will be reported to the Sponsor as described in Appendix 2.
While the Investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.
5
ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant exposed to study treatment should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Appendix 3, Section 5.1).