A Phase 1, Open-label, Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects
Phase: PHASE1
Conditions: Drug Interaction Potentiation
Sponsor: F-star Therapeutics, Inc.

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CLINICAL STUDY PROTOCOL 
 
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, DRUG-DRUG INTERACTION STUDY 
BETWEEN MULTIPLE ORAL DOSES OF INARIGIVIR SOPROXIL AND A SINGLE 
ORAL DOSE OF MIDAZOLAM IN HEALTHY SUBJECTS 
 
CONFIDENTIAL 
 
Sponsor code: SBP-9200-HBV-202 
PRA code: SPB881EC-178881 
EudraCT number: 2018-000607-16 
 
Inarigivir/midazolam drug-drug interaction study 
 
Investigational product 
Inarigivir soproxil (further named inarigivir and formerly 
known as SB 9200) 
Clinical phase 
Phase 1 study 
Indication to be studied 
Not applicable 
 
SPONSOR 
Spring Bank Pharmaceuticals, Inc. 
 
86 South Street 
 
Hopkinton, MA 01748 
 
USA 
 
CONTRACT RESEARCH 
PRA Health Sciences (PRA) - Early Development Services (EDS) 
ORGANIZATION 
Van Swietenlaan 6 
 
9728 NZ Groningen 
 
The Netherlands 
 
CLINICAL SITE 
PRA-EDS 
 
University Medical Center Groningen 
 
Entrance 23 
 
Hanzeplein 1 
 
Groningen 
 
The Netherlands 
 
PRINCIPAL INVESTIGATOR 
Jeroen van de Wetering, MD 
 
Phone +31 50 402 2502 
 
Fax 
+31 50 402 2622 
 
E-mail weteringjeroenvande@prahs.com 
 
PROTOCOL AUTHORS 
Peter Kok, MSc, Senior Medical Writer, PRA-EDS 
 
Justyna Laba, PhD, Biostatistician, PRA-EDS 
 
Version 1.0, 06 March 2018 
 
This study will be performed in compliance with the principles of Good Clinical Practice. 

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SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In case of a serious adverse event (See Appendix 8.2), the Principal Investigator will send a 
report within 24 hours of notification to: 
Sponsor 
Nezam Afdhal, MD, Chief Medical Officer 
VP Operations & Corporate Development 
Spring Bank Pharmaceuticals, Inc. 
86 South Street 
Hopkinton, MA 01748 
USA 
E-mail 
nafdhal@springbankpharm.com 
Phone 
+1 508 689 7696 
 
Jody Schiloski  
Director, Regulatory Affairs  
Spring Bank Pharmaceuticals, Inc. 
86 South Street  
Hopkinton, MA 01748  
USA  
E-mail 
jschiloski@springbankpharm.com 
Phone 
+1 508 202 1688 
 
3rd Party Drug Safety Contract Research Organization (CRO)  
ICON  
Radica Manasijevic  
Sr. Drug Safety Associate  
E-mail 
radica.manasijevic@iconplc.com 
Phone 
+49 221 5999 351 
 
3rd Party Drug Safety CRO  
ICON  
Frank Schafmeister  
Drug Safety Associate  
E-mail 
frank.schafmeister@iconplc.com 
Phone 
+49 221 5999 175 
 
CRO 
PRA Health Sciences (PRA) Drug Safety Center Europe, Asia-Pacific and Africa (EAPA) 
E-mail 
mhgsafety@prahs.com 
Fax 
+44 1792 525 720 
Phone 
+49 621 8782 154 
 

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CONTACT INFORMATION 
Sponsor 
Spring Bank Pharmaceuticals, Inc. 
86 South Street 
Hopkinton, MA 01748 
USA 
 
Sponsor's Contact 
Donald Mitchell 
Vice President, Operations & Corporate Development 
Phone 
+1 508 689 9737 
Fax: 
+1 508 381 0347 
E-mail 
dmitchell@springbankpharm.com 
 
Contract Research Organization 
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2222 
Fax 
+31 50 402 2223 
 
Clinical Site 
PRA-EDS 
Visiting address: 
University Medical Center Groningen 
Entrance 23 
Hanzeplein 1 
Groningen 
The Netherlands 
Phone 
+31 50 402 2220 
Fax 
+31 50 402 2622 
 
Postal address (also express parcels): 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
 
Clinical Site Contacts 
Jeroen van de Wetering, MD 
Principal Investigator 
Phone 
+31 50 402 2502 
Fax 
+31 50 402 2622 
E-mail 
weteringjeroenvande@prahs.com 
 

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Marieke Geel, PhD 
Project Manager 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2286 
Fax 
+31 50 402 2223 
E-mail 
geelmarieke@prahs.com 
 
Laboratories 
Clinical Laboratory and Laboratory for RNA Extraction from Peripheral Blood Mononuclear Cells 
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2555 
Fax 
+31 50 402 2223 
 
Laboratory for Analysis of Pharmacokinetic Samples 
Q2 Solutions, a Quintiles Quest Joint Venture  
Responsible Project Manager: Raj Mangaraj, BioServices 
19 Brown Road  
Ithaca, NY 14850 
USA 
Phone 
+1 607 330 9899 
Fax 
+1 607 266 0749 
E-mail 
raj.mangaraj@q2labsolutions.com 
 
Laboratory for Analysis of Pharmacodynamic Samples (Cytokine Panel) 
MLM Medical Labs GmbH 
Responsible: Prof. Dr. Stephan Wnendt, CEO 
Dohrweg 63 
41066 Moenchengladbach 
Germany 
Phone 
+ 49 2161 4642 101 
Cell phone + 49 1718 987 489 
Fax 
+ 49 2161 4642 190 
E-mail 
swnendt@mlm-labs.com 
 

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Medical Screening Center 
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 850 5798 
Fax 
+31 50 850 5782 
 
PRA-EDS 
Yin Yang Building 
Euclideslaan 1 
3584 BL Utrecht 
The Netherlands 
Phone 
+31 50 851 5830 
 
Study Monitor 
Research Drive 
Visiting address: 
Brink 1 
9331 AA Norg 
The Netherlands 
Phone 
+31 592 614 812 
Fax 
+31 592 615 422 
 
Postal address: 
PO Box 85 
9330 AB Norg 
The Netherlands 
 

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SYNOPSIS 
Study Title 
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, DRUG-DRUG INTERACTION STUDY BETWEEN MULTIPLE ORAL 
DOSES OF INARIGIVIR SOPROXIL AND A SINGLE ORAL DOSE OF MIDAZOLAM IN HEALTHY SUBJECTS 
 
Note: Inarigivir soproxil will be further named inarigivir in this document and is formerly known as SB 9200. 
 
Short Study Title 
Inarigivir/midazolam drug-drug interaction study 
 
Study Codes 
Sponsor code 
: SBP-9200-HBV-202 
PRA code 
: SPB881EC-178881 
EudraCT number 
: 2018-000607-16 
 
Sponsor 
Spring Bank Pharmaceuticals, Inc., 86 South Street, Hopkinton, MA 01748, USA 
Sponsor’s Contact 
: Donald Mitchell, Vice President, Operations & Corporate Development 
 
Contract Research Organization 
PRA-EDS, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands 
 
Clinical Site 
Visiting address: PRA-EDS, University Medical Center Groningen, Entrance 23, Hanzeplein 1, Groningen, The 
Netherlands 
Postal address (also express parcels): PRA-EDS, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands 
 
Principal Investigator 
Jeroen van de Wetering, MD 
 
Objectives 
Primary 
 
To assess the effect of steady-state oral inarigivir on the single dose pharmacokinetics (PK) of oral midazolam in 
healthy subjects 
Secondary 
 
To evaluate the safety and tolerability of a single oral dose of midazolam, a single oral dose of inarigivir, and 
multiple oral doses of inarigivir administered without and with a single oral dose of midazolam in healthy subjects 
 
To assess the PK of inarigivir after single and multiple oral doses in healthy subjects 
Exploratory 
 
To evaluate the pharmacodynamics (PD) following single and multiple oral doses of inarigivir in healthy subjects 
 
Design and Treatments 
This will be a Phase 1, single-center, open-label, fixed-sequence, drug-drug interaction study in 16 healthy subjects to 
assess the effect of multiple doses of oral inarigivir on the single dose PK of oral midazolam. Also, the PK and PD of 
inarigivir after single and multiple oral doses, and the PK of midazolam after single oral doses will be assessed. 
 
The following treatments are planned to be administered under fasted conditions: 
 
On Day 1, a single oral dose of 2 mg midazolam will be administered (Treatment A) 
 
On Day 3, a single oral dose of 400 mg inarigivir will be administered (Treatment B) 
 
From Day 6 to Day 18, a single oral dose of 400 mg inarigivir will be administered once daily each day 
(Treatment C) 
 
On Day 19, a single oral dose of 400 mg inarigivir will be co-administered with a single oral dose of 2 mg 
midazolam (Treatment D) 

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Study Schedule 
Screening 
: Between Day -28 and Day -1 (admission) 
Confinement period 
: 1 period in the clinic from Day -1 (admission) to approximately 24 hours after the last 
study drug administration on Day 19 (Day 20: day of discharge) 
Follow-up 
: 5 to 9 days after day of discharge (between Day 25 and Day 29) 
 
Subjects 
Sixteen healthy male or female subjects are planned to be dosed in the study. 
 
Main Criteria for Inclusion 
Gender 
: Male or female 
Age 
: 18-55 years, inclusive, at screening 
Body mass index 
: 18.0-30.0 kg/m2, inclusive, at screening 
 
Study Drug 
Active medication 
Active substance 
: Inarigivir soproxil 
Activity 
: Antiviral agent 
In development for 
: Hepatitis B virus infection 
Strength 
: 100 mg 
Dosage form 
: Oral tablet 
Manufacturer 
: Patheon, Inc., Mississauga, Ontario, Canada 
 
Probe substrate 
Active substance 
: Midazolam 
Activity 
: Cytochrome P450 (CYP)3A4 substrate 
Indication 
: Sleep disorder 
Strength 
: 1 mg/mL; a dose of 2 mg will be administered 
Dosage form 
: Oral administration of intravenous solution formulation 
Manufacturer 
: Will be commercially acquired 
 
Variables 
Pharmacokinetics 
: Plasma concentrations of inarigivir and its active metabolites Rp-SB 9000 and 
Sp-SB 9000, urine concentrations of Rp-SB 9000 and Sp-SB 9000, and plasma 
concentrations of midazolam and its metabolite 1′-OH midazolam will be determined. 
The following PK parameters will be estimated using noncompartmental analysis, as 
appropriate:  
 
 - Single dose plasma PK parameters: Cmax, tmax, kel, t½, AUC0-t, AUC0-inf, %AUCextra, 
CL/F and Vz/F for inarigivir and midazolam; Cmax, tmax, kel, t½, AUC0-t, AUC0-inf, 
%AUCextra, and metabolite to parent ratio for Cmax, AUC0-t, and AUC0-inf for 
Rp-SB 9000, Sp-SB 9000 and 1′-OH midazolam 
 
 - Multiple dose plasma PK parameters (steady-state): Cmax, tmax and AUC0- (for 
inarigivir, Rp-SB 9000 and Sp-SB 9000) and Rac (based on Rp-SB 9000 and 
Sp-SB 9000 Cmax and AUC parameters) 
 
 - Single dose urine PK parameters: Ae0-t, CLR and fe (for Rp-SB 9000 and 
Sp-SB 9000) 
Safety 
: Adverse events, clinical laboratory, vital signs and 12-lead electrocardiogram 
Pharmacodynamics 
: Cytokine panel: serum levels of C-X-C motif chemokine 10 (also known as interferon 
gamma-induced protein 10), interleukin 6, tumor necrosis factor alpha, interferon 
(IFN)- and IFN-γ 
 
 Cytokine RNA expression in peripheral blood mononuclear cells 
 

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Statistical Methods 
Sample size calculation 
: Based on the intra-subject coefficient of variation of 19.7% found for AUC0-t of 
midazolam in a previous interaction study and assuming an expected geometric mean 
ratio (test/reference) of 1.00, a significance level of 5% (α=0.05) and a default no-effect 
boundary of 80-125%, a sample size of 14 subjects results in at least 80% power 
(calculated using SAS PROC POWER). Accounting for early-termination subjects, a 
sample size of 16 subjects is considered to be sufficient. 
PK parameters 
: Descriptive statistics for all relevant PK parameters: n, mean, standard deviation, 
minimum, median, maximum, geometric mean, and coefficient of variation; analysis of 
variance on midazolam and 1′-OH midazolam Cmax, AUC0-t and AUC0-inf to determine 
the interaction between inarigivir (including metabolites) and midazolam 
Safety parameters 
: Descriptive statistics 
PD parameters 
: Descriptive statistics (including change from baseline) 
 

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Table 1 
Schedule of Assessments 
 
Treatment A (Midazolam) 
Treatment B (inarigivir 
single dose) 
Treatment C 
(inarigivir 
multiple dose) 
Treatment D (inarigivir 
and midazolam) 
 
Visit 
Screening 
Pre-Treatment 
Treatment 
Pre-
Treatment 
Treatment 
Treatment 
Pre-
Treatment 
Treatment 
Follow-up 
Study Day 
-28 to -1 
-1 
1 (Pre-
dose) 
1 
2 
3 (Pre-
dose) 
3 
4 
5 
6-18 
19 (Pre-
dose) 
19 
20 
5 to 9 days 
after day of 
discharge 
(Day 25 to 
Day 29) 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ambulatory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight and height (including 
BMI calculation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (females only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical chemistry, hematology and 
coagulation2 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG3 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Vital signs4 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Eligibility check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Midazolam administration5 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Inarigivir administration6 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Blood sampling for PK: midazolam 
and metabolite7 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
Blood sampling for PK: inarigivir and 
its metabolites Rp-SB 9000 and 
Sp-SB 90008 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Treatment A (Midazolam) 
Treatment B (inarigivir 
single dose) 
Treatment C 
(inarigivir 
multiple dose) 
Treatment D (inarigivir 
and midazolam) 
 
Visit 
Screening 
Pre-Treatment 
Treatment 
Pre-
Treatment 
Treatment 
Treatment 
Pre-
Treatment 
Treatment 
Follow-up 
Study Day 
-28 to -1 
-1 
1 (Pre-
dose) 
1 
2 
3 (Pre-
dose) 
3 
4 
5 
6-18 
19 (Pre-
dose) 
19 
20 
5 to 9 days 
after day of 
discharge 
(Day 25 to 
Day 29) 
Urine collection for PK: metabolites 
Rp-SB 9000 and Sp-SB 90009 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Blood sampling for PD: cytokine 
panel10 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Blood sampling for PD: PBMCs11 
 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
Blood sampling for 
pharmacogenomics12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Serology at screening will consist of HBsAg, anti-HCV and anti-HIV 1 and 2. 
2 
Clinical chemistry, hematology and coagulation: at screening, at admission on Day -1 and at 24 hours after dosing on Day 1, at pre-dose on Day 3 and at 24 hours after dosing on Day 3, at 
pre-dose on Days 6, 11, 15 and 19, at 24 hours after dosing on Day 19, and at follow-up. 
3 
12-lead ECG: at screening, at pre-dose on Day 1, at 24 hours after dosing on Day 1, at pre-dose on Day 3 and at 24 hours after dosing on Day 3, at pre-dose on Days 6, 11, 15 and 19, at 
24 hours after dosing on Day 19, and at follow-up. 
4 
Vital signs (supine systolic and diastolic blood pressure, pulse, body temperature and respiratory rate): at screening, at pre-dose on Day 1, at 24 hours after dosing on Day 1, at pre-dose on 
Day 3 and at 24 hours after dosing on Day 3, at pre-dose on Days 6, 11, 15 and 19, at 24 hours after dosing on Day 19, and at follow-up. 
5 
On Day 1 and Day 19, a single oral dose of midazolam will be administered. 
6 
On Day 3, a single oral dose of inarigivir will be administered; from Day 6 to Day 18, a single oral dose of inarigivir will be administered each day; on Day 19: a single oral dose of inarigivir 
will be administered. 
7 
Blood sampling for PK of midazolam and metabolite in plasma: at pre-dose on Days 1 and 19, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours after dosing on Days 1 and 19. 
8 
Blood sampling for PK of inarigivir and its metabolites Rp-SB 9000 and Sp-SB 9000 in plasma: at pre-dose on Day 3 and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 and 
48 hours after dosing on Day 3, at pre-dose on Days 8, 9, 10, 12, 13, 14, 16, 17, 18 and 19, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after dosing on Day 19. 
9 
Urine collection for PK of metabolites Rp-SB 9000 and Sp-SB 9000: at pre-dose on Day 3 (within 12 hours prior to dosing) and over 0-6, 6-12, 12-24, 24-36 and 36-48 hour collection 
intervals after dosing on Day 3.  
10 
Blood sampling for PD (cytokine panel) in serum: at pre-dose on Day 3 and at 2, 4, 6, 12, 24 and 48 hours after dosing on Day 3, at pre-dose on Days 11 and 18, at 2, 4, 6 and 12 hours after 
dosing on Day 18, and at pre-dose on Day 19. 
11 
Blood sampling for PD (PBMCs): at pre-dose on Day 3 and at 2, 6 and 24 hours after dosing on Day 3, and at pre-dose on Day 18 and at 4 and 12 hours after dosing on Day 18. 
12 
Blood sampling for pharmacogenomics is optional for all subjects. The blood sample will be taken at pre-dose on Day 1. 
BMI: body mass index; ECG: electrocardiogram; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; PBMC: peripheral blood mononuclear cell; 
PD: pharmacodynamic(s); PK: pharmacokinetic(s) 
 

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TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................................... 1 
AUTHORIZATION OF CLINICAL STUDY PROTOCOL ...................................................... 2 
SERIOUS ADVERSE EVENT CONTACT INFORMATION ................................................. 3 
CONTACT INFORMATION .................................................................................................. 4 
SYNOPSIS ............................................................................................................................ 7 
TABLE OF CONTENTS...................................................................................................... 12 
TABLE OF TABLES ........................................................................................................... 14 
LIST OF ABBREVIATIONS ................................................................................................ 15 
1.  INTRODUCTION .......................................................................................................... 17 
1.1 
Background ................................................................................................................... 17 
1.2 
Overview of the Investigational Product .................................................................... 17 
1.3 
Nonclinical Summary ................................................................................................... 18 
1.3.1  Pharmacodynamics ............................................................................................. 18 
1.3.2  Pharmacokinetics ................................................................................................ 18 
1.3.3  Toxicology ........................................................................................................... 20 
1.4 
Clinical Experience ....................................................................................................... 20 
1.5 
Risk-Benefit Assessment ............................................................................................. 21 
1.6 
Study Rationale ............................................................................................................. 21 
2.  OBJECTIVES ............................................................................................................... 23 
2.1 
Primary .......................................................................................................................... 23 
2.2 
Secondary ..................................................................................................................... 23 
2.3 
Exploratory .................................................................................................................... 23 
3.  INVESTIGATIONAL PLAN .......................................................................................... 24 
3.1 
Overall Study Design and Plan .................................................................................... 24 
3.1.1  Type of Study ...................................................................................................... 24 
3.1.2  Screening Period ................................................................................................. 24 
3.1.3  Treatment Period ................................................................................................ 25 
3.1.4  Follow-up ............................................................................................................. 25 
3.2 
Discussion of Study Design ........................................................................................ 25 

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3.3 
Selection of Study Population ..................................................................................... 25 
3.3.1  Inclusion Criteria ................................................................................................. 25 
3.3.2  Exclusion Criteria ................................................................................................ 26 
3.3.3  Removal of Subjects from Assessment .............................................................. 27 
3.4 
Treatments .................................................................................................................... 28 
3.4.1  Treatments Administered .................................................................................... 28 
3.4.2  Identity of Investigational Product ....................................................................... 28 
3.4.3  Method of Assigning Subjects to Treatment Groups ........................................... 28 
3.4.4  Selection of Doses in the Study .......................................................................... 28 
3.4.5  Timing of Doses in the Study .............................................................................. 29 
3.4.6  Meals During the Study ....................................................................................... 29 
3.4.7  Blinding ............................................................................................................... 30 
3.4.8  Concomitant Medication and Other Restrictions During the Study ..................... 30 
3.4.9  Treatment Compliance ........................................................................................ 30 
3.5 
Pharmacokinetic, Safety and Pharmacodynamic Variables ..................................... 31 
3.5.1  Pharmacokinetic, Safety and Pharmacodynamic Measurements Assessed 
and Schedule of Assessments ............................................................................ 31 
3.5.1.1 
Pharmacokinetic Measurements ..................................................... 31 
3.5.1.1.1 
Blood Sampling ................................................................ 31 
3.5.1.1.2 
Urine Collection ................................................................ 31 
3.5.1.2 
Safety and Tolerability Measurements ........................................... 31 
3.5.1.2.1 
Adverse Events ................................................................ 31 
3.5.1.2.2 
Clinical Laboratory ........................................................... 32 
3.5.1.2.3 
Vital Signs ........................................................................ 33 
3.5.1.2.4 
Electrocardiogram ............................................................ 33 
3.5.1.2.5 
Physical Examination ....................................................... 33 
3.5.1.3 
Pharmacodynamic Measurements .................................................. 33 
3.5.1.4 
Pharmacogenomic Measurements .................................................. 33 
3.5.1.5 
Total of Blood Volume ...................................................................... 34 
3.5.2  Appropriateness of Measurements ..................................................................... 34 
3.5.2.1 
Timing of Assessments .................................................................... 34 
3.5.3  Pharmacokinetic, Safety and Pharmacodynamic Variables ................................ 35 
3.5.3.1 
Pharmacokinetic Variables .............................................................. 35 
3.5.3.2 
Safety Variables ................................................................................ 37 
3.5.3.3 
Pharmacodynamic Variables ........................................................... 37 
3.5.4  Drug Concentration Measurements .................................................................... 37 
3.6 
Statistical Procedures and Determination of Sample Size ....................................... 37 
3.6.1  Analysis Sets ....................................................................................................... 37 
3.6.1.1 
Pharmacokinetic Set ......................................................................... 37 
3.6.1.2 
Safety Set ........................................................................................... 37 
3.6.1.3 
Pharmacodynamic Set ..................................................................... 38 
3.6.2  Statistical and Analytical Plan for Pharmacokinetic, Safety and 
Pharmacodynamic Evaluation ............................................................................. 38 
3.6.2.1 
Pharmacokinetic Evaluation ............................................................ 38 
3.6.2.2 
Evaluation of Safety and Tolerability .............................................. 38 
3.6.2.2.1 
Adverse Events ................................................................ 38 

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3.6.2.2.2 
Clinical Laboratory ........................................................... 38 
3.6.2.2.3 
Vital Signs and Electrocardiograms ................................. 39 
3.6.2.2.4 
Physical Examination ....................................................... 39 
3.6.2.3 
Pharmacodynamic Evaluation ......................................................... 39 
3.6.3  Determination of Sample Size ............................................................................. 39 
3.7 
Data Quality Assurance ............................................................................................... 39 
4.  ETHICS ......................................................................................................................... 41 
4.1 
Independent Ethics Committee ................................................................................... 41 
4.2 
Ethical Conduct of the Study ....................................................................................... 41 
4.3 
Subject Information and Consent ............................................................................... 42 
4.4 
Privacy ........................................................................................................................... 42 
5.  STUDY ADMINISTRATIVE STRUCTURE ................................................................... 43 
5.1 
Distribution of Activities .............................................................................................. 43 
5.2 
Documentation .............................................................................................................. 44 
5.2.1  Archiving ............................................................................................................. 44 
5.2.2  Recording of Data in Source Documents and CRFs ........................................... 44 
6.  CONFIDENTIALITY AND PUBLICATION POLICY .................................................... 45 
7.  REFERENCES ............................................................................................................. 46 
8.  APPENDICES ............................................................................................................... 47 
8.1 
Drug Accountability ...................................................................................................... 47 
8.2 
Adverse Events and Serious Adverse Events Evaluation and Reporting ............... 47 
8.2.1  Adverse Events ................................................................................................... 47 
8.2.2  Serious Adverse Events ...................................................................................... 49 
8.2.3  Suspected Unexpected Serious Adverse Reactions ........................................... 50 
8.2.4  Follow-up of Adverse Events .............................................................................. 50 
 
TABLE OF TABLES 
Table 1 
Schedule of Assessments .............................................................................................. 10 
Table 2 
Number and Volume of Blood Samples and Total Blood Volume Collected per 
Subject ............................................................................................................................ 34 
Table 3 
Plasma Pharmacokinetic Parameters ............................................................................. 36 
Table 4 
Urine Pharmacokinetic Parameters ................................................................................ 37 
 

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LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
AE 
Adverse event  
ALAT (ALT) 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASAT (AST) 
Aspartate aminotransferase 
β-hCG 
β-human chorionic gonadotropin 
BMI 
Body mass index 
CA 
Competent Authority 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
CRO 
Contract research organization 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical Trial Directive 
CXCL10 
C-X-C motif chemokine 10 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic acid 
DDI 
Drug-drug interaction 
dsRNA 
Double-stranded RNA 
EAPA 
Europe, Asia-Pacific and Africa 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
gamma-GT 
Gamma glutamyl transferase 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IL 
Interleukin 
INR 
International normalized ratio 
IP-10 
Interferon gamma-induced protein 10 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MEB  
Medicine Evaluation Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
No observed adverse effect level 
OATP 
Organic anion transporting polypeptide 
PAMP 
Pathogen-associated molecular pattern 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PRA 
PRA Health Sciences 

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PRA-EDS 
PRA Early Development Services 
PT 
Prothrombin time 
RIG-I 
Retinoic acid inducible gene 
RNA 
Ribonucleic acid 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNF- 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WMA 
World Medical Association 
WMO 
Wet medisch-wetenschappelijk onderzoek met mensen (Medical research 
involving human subjects act) 
 
Note: Definitions of pharmacokinetic (PK) parameters are provided in Section 3.5.3 
 

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1. 
INTRODUCTION 
1.1 
Background 
Inarigivir soproxil (further named inarigivir and formerly known as SB 9200) is being 
developed as a monotherapy and in combination with approved and investigational 
antiviral agents for hepatitis B virus (HBV). Inarigivir is also highly active against 
hepatitis C virus (HCV), but no further clinical development is planned unless an unmet 
clinical need can be identified for combination with other direct acting antiviral agents.  
 
HBV is a deoxyribonucleic acid (DNA) virus that leads to chronic hepatitis, cirrhosis 
and liver cancer. The World Health Organization (WHO) estimates that 257 million 
people worldwide were living with chronic hepatitis B in 20151 despite the presence 
and utilization of a highly effective vaccine. Current treatment involves lifelong viral 
suppression with oral nucleosides/nucleotides, which prevent HBV replication but do 
not cure the disease. HBV cure remains elusive and can only be achieved in 10% of 
the small number of patients who are willing or able to undergo a year of interferon 
(IFN) therapy. New agents that focus on the cure of HBV with viral clearance represent 
a significant unmet need. 
1.2 
Overview of the Investigational Product 
Inarigivir is a dinucleotide prodrug, which is being developed as an oral antiviral agent 
for the treatment of chronic hepatitis infections in humans. In vitro and in vivo studies 
have established that inarigivir has antiviral activity against HBV and HCV ribonucleic 
acid (RNA) viruses.  
 
Inarigivir has a novel dual mechanism of action involving: (a) the activation of the host 
cytosolic protein - retinoic acid inducible gene (RIG-I) - involved in recognition of viral 
nucleic acids, which results in the stimulation of type I IFN production and induction of 
antiviral state in cells, and (b) direct inhibition of viral replication by blocking the access 
of the viral polymerase to the viral nucleic acid template; this is due to the interaction of 
inarigivir with the nucleotide-binding domain of RIG-I, which engages the viral RNA 
template. Given that inarigivir activates RIG-I, which is a cellular cytoplasmic protein 
involved in the detection of viral RNA in cells, it is unlikely to elicit resistance.  
 
The regulation of IFN expression in the cells involves in part the activation of 
intracellular viral sensors such as RIG-I, which are pathogen recognition receptors. 
Inarigivir and the active moiety, SB 9000, cause the activation of RIG-I, and this 
mechanism may play an important role in its antiviral activity. RIG-I is a host cytosolic 
protein that recognizes double-stranded viral RNA (dsRNA) as a pathogen-associated 
molecular pattern (PAMP), blocks viral replication, and activates type 1 IFN production. 
RIG-I is a multimeric protein and consists of a C-terminal regulatory domain, two 
caspase activation and recruitment domains, as well as an ATPase domain. Viral 
dsRNA and 5’-triphosphate are 2 molecular patterns that enable RIG-I to discriminate 
viral RNA from host messenger RNA. RIG-I is known to recognize dsRNA structure as 
a PAMP present in HCV.  

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Inarigivir is the prodrug form of the active SB 9000 species. Inarigivir is a 60:40 mixture 
of two isomers designated as Rp and Sp. Upon oral administration, the inarigivir 
isomers are converted with similar efficiency to the corresponding active isomers Rp 
and Sp by esterases. In vitro studies using liver microsomes from different species, 
and in vivo studies in both rodents and woodchucks have demonstrated that SB 9000 
is not subject to phase I metabolism or phase II conjugation reactions. 
1.3 
Nonclinical Summary 
1.3.1 
Pharmacodynamics 
Inarigivir has been shown to be a potent inhibitor of HBV in in vitro assays against wild 
type and resistant variants of HBV, and was found to have synergistic antiviral activity 
when combined with other anti-HBV agents such as tenofovir and entecavir. Orally 
administered inarigivir has been shown to have potent antiviral activity in transgenic 
and woodchuck models of HBV including reduction in serum and hepatic viral DNA and 
viral antigens, as well as reduction in covalently closed circular DNA and viral RNA. 
Inarigivir has also been shown to have pan-genotypic antiviral activity against HCV 
including activity against resistant variants.  
 
Inarigivir was evaluated in a battery of Good Laboratory Practice compliant safety 
pharmacology studies that assessed the central nervous system, cardiovascular 
system and pulmonary system. Oral administration of inarigivir produced no effects on 
cardiovascular function in Cynomolgus monkeys at doses up to and including 
500 mg/kg, the highest dose tested. Likewise, oral administration of inarigivir, at doses 
up to and including 500 mg/kg, was not associated with any effects on pulmonary or 
neurobehavioral function in rats. 
1.3.2 
Pharmacokinetics 
The PK of inarigivir have been characterized in in vitro studies in multiple species as 
well as in vivo studies in rats, rabbits, woodchucks and monkeys. In all species 
studied, a pattern of delayed plasma peaks of the active metabolites Rp SB 9000 and 
Sp SB 9000 was observed after oral dosing of inarigivir. In woodchucks, a pattern of 
delayed peak plasma levels was observed after intravenous (IV) dosing, confirming 
that enterohepatic cycling was the likely cause. Consistent with billiary excretion and 
reabsorption, in vitro transporter studies show that SB 9000 is a substrate for liver 
organic anion transporting polypeptide (OATP) 1A1 and OATP1A3 transporters located 
on the hepatocytes. It is common to observe high levels of OATP substrates in rat and 
human liver after oral dosing.2 Indeed, SB 9000 has all of the characteristics common 
to OATP substrates.2 It is an anion at physiological pH, it has a molecular weight 
between 400 and 600 g/mol and it has poor lipid solubility and high levels in the liver 
after oral dosing. The high liver levels of SB 9000 observed in rat liver relative to those 
in the plasma suggest that high liver levels of SB 9000 might also be expected in 
patients because the rat has been shown to be a highly predictive model of human 
OATP transport.2 This paradigm is further supported by the observation that uptake of 

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SB 9000 into rat liver was a saturable process. Clinical trials will exclude concomitant 
medications that are taken up by OATP transport mechanisms. 
 
Inarigivir and SB 9000 show no metabolic lability with liver metabolizing enzymes other 
than the conversion of inarigivir to SB900, and neither are not considered at risk as a 
drug-drug interaction victim. The compounds were evaluated in vitro for their potential 
as cytochrome P450 (CYP) 3A4 inhibitors or CYP inducers. Indeed, neither compound 
showed a potential to inhibit the standard battery of CYP enzymes. When hepatocytes 
were incubated with 0.1, 1 and 10 μM of inarigivir or SB 9000, inarigivir induced 
CYP1A2 mRNA levels by ≥2-fold at 1 and 10 μM, and induced CYP2B6 by <2-fold at 
all concentrations tested. SB 9000 induced CYP1A2 and CYP2B6 mRNA levels by ≥2-
fold at 10 μM SB 9000; however, the maximum changes observed for CYP1A2 
(3.3-fold increase) and CYP2B6 (2.5-fold increase) were only 18% and 10% of the 
positive controls, respectively. Therefore, there were no significant effects on either 
CYP1A2 or CYP2B6 as compared to their respective positive controls in those 
experiments. Inarigivir and SB 9000 induced CYP3A4 by >2-fold at all concentrations 
tested. The maximum change in CYP3A4 mRNA for 1 µM (6-fold increase) and 10 µM 
(13.4-fold increase) were 42% to 97% of the positive control, respectively. Both 
compounds, therefore, led to a dose-dependent increase in CYP3A4 gene expression 
over the 72-hour incubation period that was considered biologically relevant in 
comparison to the positive control. 
 
Inarigivir and SB 9000 were also evaluated for their potential as substrates of the drug 
transporters. An in vitro study in LLC-MDR1 cells showed that apparent permeability of 
inarigivir and SB 9000 at 5 μM was low in parental and P-gp expressing cells, transport 
of these compounds across the cell was not polarized, and transport was unaffected by 
the P-gp inhibitor, GF120918. Therefore, inarigivir and SB 9000 are not considered 
P-gp substrates. An in vitro study was also done with sandwich cultured human 
hepatocytes to study the hepatobiliary transport of inarigivir and SB 9000. Based on 
this study, biliary excretion of SB 9000 (~30%) following incubation with 10 and 20 μM 
inarigivir was observed. 
 
In rats, inarigivir was rapidly converted to its active form, SB 9000 (both isomers), such 
that only SB 9000 could be detected in plasma after either oral or IV dosing. A time 
course of SB 9000 levels after the last dose of a 3-month daily dosing regimen in rats 
demonstrated that SB 9000 was distributed to the liver with levels that were up to 20- 
to 40-fold higher than those in the plasma, but it was almost completely cleared from 
both the liver and plasma 24 hours post-dose. The plasma bioavailability of SB 9000 
(oral plasma AUC compared with IV plasma AUC corrected for dose) was below 2% 
for rats and monkeys. However, consistent with a large first-pass uptake of SB 9000 
into the liver from the portal blood, 58% of the SB 9000 administered after oral dosing 
was found in the rat liver compared with the systemic exposure after IV dosing (oral 
liver AUC compared with IV plasma AUC corrected for dose).  

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1.3.3 
Toxicology 
A 13-week repeat-dose study with a 4-week recovery period was initiated in 
Cynomolgus monkeys that were administered inarigivir daily at doses of 0, 15, 30, or 
60 mg/kg/day for 13 weeks. Clinical chemistry alterations at 60 mg/kg/day which were 
characterized by increased gamma glutamyl transferase (gamma-GT) and triglycerides 
(both sexes), increased alanine aminotransferase (ALAT) (both sexes), increased 
aspartate aminotransferase (ASAT) (females), and increased globulin and decreased 
albumin/globulin ratio (males). The liver was the primary target organ and at doses of 
≥30 mg/kg/day, there were dose-dependent findings of hepatocyte enlargement, 
hepatocyte vacuolar degeneration, mixed leukocyte infiltration/inflammation, and 
increased pigment and hypertrophy of Kupffer cells. Additional microscopic findings at 
60 mg/kg/day included individual hepatocyte necrosis, increased mitotic figures, 
multinucleated hepatocytes, and bile duct hyperplasia. Following the recovery period, 
the findings at 60 mg/kg/day were reversing, although incomplete. No dose-limiting 
toxicity was observed over the course of the study. Doses up to and including 
60 mg/kg/day for a period of 91 days were tolerated. The microscopic findings in the 
liver at the terminal and recovery necropsies, in conjunction with increased serum 
enzyme values and decreased serum albumin and fibrinogen values (changes 
generally associated with hepatocellular injury), were considered adverse in both 
sexes at ≥30 mg/kg/day. Accordingly, oral administration of inarigivir produced adverse 
effects in both sexes at ≥30 mg/kg/day; therefore, the no observed adverse effect level 
(NOAEL) was determined to be 15 mg/kg/day.  
 
In summary, the nonclinical data to date show that inarigivir has significant antiviral 
activity, is well tolerated, produces no effects on cardiovascular function and 
preferentially distributes to the liver. Nonclinical toxicology studies in monkeys show 
effects in the liver that were dose dependent and either completely reversed or trended 
towards reversal. These overall findings provide a favorable risk-benefit ratio and 
indicate that monitoring of ALT and AST levels in patients will be important. 
1.4 
Clinical Experience 
A completed Phase 1 study (SB12-9200-101) evaluated the safety, PK and 
pharmacodynamics of inarigivir in treatment naïve HCV infected adults. The study was 
conducted in 2 parts: 1) a single ascending dose (SAD) under fed or fasting conditions 
(Part A); 2) a placebo-controlled multiple ascending dose (MAD) under fasting 
conditions (Part B).  
 
PK profiles of inarigivir and its metabolites were determined; increases in area under 
the plasma concentration-time curve from start to the time of the last quantifiable 
concentration post-dose (AUC0-t) and maximum drug concentration (Cmax) were found 
to be dose-proportional.  
 
Inarigivir was well tolerated up to the highest dose level of 800 mg in the SAD part and 
up to the highest dose level of 900 mg daily for 7 days in the MAD part. The most 
frequently reported treatment-emergent adverse event (TEAE) following multiple 
dosing with inarigivir was headache (12 events reported by 10 subjects). Diarrhea, 

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nausea, ALT increase, AST increase and insomnia were reported for 2 subjects each. 
Headache was mild and self-limited. All ALT/AST elevations on treatment were less 
than 5 x the upper limit of normal (ULN), occurred after cessation of inarigivir and were 
deemed to be within the acceptable spontaneous fluctuation range that is common in 
HCV. No patient had hyperbilirubinemia.  
 
The results on HCV RNA showed a similar viral kinetic response as that seen with IFN 
with approximately 30% of patients (6 of 22) having a greater than 0.9 log10 reduction 
in HCV RNA. The HCV RNA reduction was maximal at Day 3 and a comparison of 
non-responders (<0.5 log10 decline) to responders showed there was an associated 
increased in IFN stimulating gene 15 gene induction and IFN alpha. The responders 
demonstrated a PK profile with a greater AUC than the non-responder population. 
 
The results of the Phase I study established a dose range for the Phase 2 study, 
generated a safety and PK profile of inarigivir as a monotherapy agent, and provided 
supportive data to advance inarigivir’s clinical program as a part of a combination 
therapy in HBV, and HCV. 
 
Based on the results from the Phase 1 Study SB12-9200-101, a 2-part Phase 2 study 
has been initiated to evaluate the safety, PK, and antiviral efficacy of inarigivir in 
subjects infected with chronic hepatitis B virus. Part A is being conducted as an 
ascending dose double-blind, placebo-controlled study. Part B will be an open-label, 
randomized combination therapy design study to evaluate safety, tolerability, and 
antiviral response of the chosen dose and regimen from Part A. Cohort 1 (25 mg 
inarigivir) and Cohort 2 (50 mg inarigivir) have completed dosing with no serious 
adverse events (SAEs) and antiviral activity confirmed as measured by a decline in 
HBV DNA. 
 
A full description of the nonclinical and clinical studies with inarigivir can be found in 
the Investigator's Brochure (IB).3 
1.5 
Risk-Benefit Assessment 
Overall, on the basis of the available nonclinical and clinical data, and prior knowledge, 
the risk-benefit profile of inarigivir is judged acceptable for the proposed clinical study. 
1.6 
Study Rationale 
As described in Section 1.2, inarigivir and SB 9000 were evaluated for their potential 
effect to induce CYP-isoforms in cryopreserved human primary hepatocytes. The 
effects of 0.1, 1 and 10 uM of each compound were separately assessed on the 
expression of CYP1A2, CYP2B6, and CYP3A4. There were no significant effects on 
either CYP1A2 or CYP2B6 as compared to their respective positive controls in those 
experiments. However, incubation of either compound led to a dose-dependent 
increase in CYP3A4 gene expression over the 72-hour incubation period that was 
considered biologically relevant in comparison to the positive control. 
 

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Since many drugs are metabolized by CYP3A4, it is deemed relevant to perform an in 
vivo interaction study with a test drug that is a CYP3A4 substrate such as midazolam. 
The present study has therefore been designed to determine whether inarigivir impacts 
the single dose PK of midazolam.  
 
Midazolam (a benzodiazepine used for induction and maintenance of anesthesia 
during surgical procedures and also for short term management of insomnia) is an 
ideal CYP3A4 probe because: 
 
It is entirely metabolized by CYP3A4 to 1 major metabolite (1′-OH midazolam).4 
 
It undergoes an intestinal and hepatic CYP3A4 first-pass effect (hepatic and 
intestinal extraction ratio of about 44% each).5 The magnitude of the interaction is 
higher with drugs undergoing high CYP3A4 pre-systemic first-pass. 
 
It is entirely absorbed since almost 90% of an orally administered dose of 
[14C]-midazolam is excreted in urine within 24 hours.6 
 
 

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2. 
OBJECTIVES 
2.1 
Primary 
 
To assess the effect of steady-state oral inarigivir on the single dose PK of oral 
midazolam in healthy subjects 
2.2 
Secondary 
 
To evaluate the safety and tolerability of a single oral dose of midazolam, a single 
oral dose of inarigivir, and multiple oral doses of inarigivir administered without and 
with a single oral dose of midazolam in healthy subjects 
 
To assess the PK of inarigivir after single and multiple oral doses in healthy 
subjects 
2.3 
Exploratory 
 
To evaluate the pharmacodynamics (PD) following single and multiple oral doses 
of inarigivir in healthy subjects 

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3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 
Type of Study 
This will be a Phase 1, single-center, open-label, fixed-sequence, drug-drug interaction 
(DDI) study in 16 healthy subjects to assess the effect of multiple doses of oral 
inarigivir on the single dose PK of oral midazolam. Also, the PK and PD of inarigivir 
after single and multiple oral doses, and the PK of midazolam after single oral doses 
will be assessed. 
 
The following treatments are planned to be administered under fasted conditions: 
 
On Day 1, a single oral dose of 2 mg midazolam will be administered 
(Treatment A). 
 
On Day 3, a single oral dose of 400 mg inarigivir will be administered 
(Treatment B). 
 
From Day 6 to Day 18, a single oral dose of 400 mg inarigivir will be administered 
once daily each day (Treatment C). 
 
On Day 19, a single oral dose of 400 mg inarigivir will be co-administered with a 
single oral dose of 2 mg midazolam (Treatment D). 
 
For each subject, the study will consist of: 
 
An eligibility screening period of a maximum of 28 days (Day -28 to Day -1). 
 
One study period from Day -1, the day of admission, to Day 20, the day of 
discharge. 
 
Admission to the clinical research center in the afternoon of Day -1. 
 
Administration of midazolam and inarigivir on the days as described above. 
 
Safety assessments, blood sampling and urine collection for PK purposes and 
blood sampling for PD purposes from Day -1 up to 24 hours after the last drug 
administration on Day 19. 
 
Discharge at 24 hours after the last study drug administration on Day 19 (Day 20: 
day of discharge). 
 
A follow-up visit 5 to 9 days after the day of discharge (between Day 25 and 
Day 29). 
3.1.2 
Screening Period 
Subjects will report to the medical screening center for the eligibility screening (see 
Section 3.3 for inclusion and exclusion criteria) within 4 weeks prior to the first study 
drug administration. 
 
Subjects will sign the study-specific informed consent form (ICF) prior to any 
study-specific screening procedures being performed. The written informed consent 
will be obtained for all subjects, regardless of their eligibility for the study; the signed 
ICFs will be retained and archived at PRA Health Sciences (PRA) and a copy will be 
provided to the subject. 
 

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Eligibility screening will consist of the assessments as presented in the schedule of 
assessments (Table 1). 
3.1.3 
Treatment Period 
Subjects will be in the clinic for 1 treatment period. The subjects will be admitted to the 
clinical research center in the afternoon of Day -1, which is the day prior to Day 1, the 
day of the first drug administration.  
 
Subjects will be discharged on Day 20 (24 hours after the last study drug 
administration on Day 19) after completion of the assessments. 
 
Assessments during the treatment periods will be performed as presented in the 
schedule of assessments (Table 1). 
3.1.4 
Follow-up 
The follow-up assessments will be performed 5 to 9 days after the day of discharge 
(between Day 25 and Day 29).  
 
Assessments during follow-up will be performed as presented in the schedule of 
assessments (Table 1). 
3.2 
Discussion of Study Design 
The fixed-sequence design was chosen to allow each subject to serve as his/her own 
control with respect to midazolam PK characteristics with and without inarigivir 
coadministration.  
 
The Principal Investigator (PI) will take all the usual precautions necessary for studies 
at an early stage in the development of a new drug. 
 
See Section 3.6.3 for sample size determination. 
3.3 
Selection of Study Population 
Sixteen healthy male or female subjects are planned to be dosed in the study. 
3.3.1 
Inclusion Criteria 
Note: Restrictions that apply to the period after admission are described in 
Section 3.4.8, except when they concern a statement of willingness. 
 
The following inclusion criteria must be met for a subject to be eligible for inclusion in 
the study: 
1. 
Gender 
: male or female 
2. 
Age 
: 18-55 years, inclusive, at screening 
3. 
Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening 
4. 
Status 
: healthy subjects 
5. 
At screening, females must be non-pregnant and non-lactating, or of 
non-childbearing potential (either surgically sterilized or physiologically incapable 

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of becoming pregnant, or at least 1 year post-menopausal [amenorrhoea duration 
of 12 consecutive months]); non-pregnancy will be confirmed for all females by a 
serum pregnancy test conducted at screening, and a urine pregnancy test at 
each admission and at follow-up 
6. 
Female subjects of childbearing potential, with a fertile male sexual partner, must 
agree to use adequate contraception from screening until 90 days after the 
follow-up visit. Adequate contraception is defined as using a non-hormonal 
intrauterine device combined with at least 1 of the following forms of 
contraception: a diaphragm or cervical cap, or a condom; please note that 
hormonal contraceptives are not allowed. Also, total abstinence, in accordance 
with the lifestyle of the subject, is acceptable 
7. 
Male subjects, if not surgically sterilized, must agree to use adequate 
contraception and not donate sperm from admission to the clinical research 
center until 90 days after the follow-up visit. Adequate contraception for the male 
subject (and his female partner) is defined as using hormonal contraceptives or 
an intrauterine device, combined with at least 1 of the following forms of 
contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence, 
in accordance with the lifestyle of the subject is acceptable  
8. 
All prescribed medication, including hormonal contraceptives for female subjects, 
must have been stopped at least 30 days prior to admission to the clinical 
research center  
9. 
All 
over-the-counter 
medication, 
vitamin 
preparations 
and 
other 
food 
supplements, or herbal medications (eg, St. John’s Wort) must have been 
stopped at least 14 days prior to admission to the clinical research center. An 
exception is made for paracetamol, which is allowed up to admission to the 
clinical research center 
10. Ability and willingness to abstain from alcohol, methylxanthine-containing 
beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) 
from 72 hours prior to admission to the clinical research center  
11. Good physical and mental health on the basis of medical history, physical 
examination, clinical laboratory, electrocardiogram (ECG) and vital signs, as 
judged by the PI  
12. Willing and able to sign the ICF 
3.3.2 
Exclusion Criteria 
Note: Restrictions that apply to the period after admission are described in 
Section 3.4.8, except when they concern a statement of willingness. 
 
A subject who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
1. 
Employee of PRA or the Sponsor 
2. 
History of relevant drug and/or food allergies 
3. 
Using tobacco products within 60 days prior to the first drug administration  
4. 
History of alcohol abuse or drug addiction (including soft drugs like cannabis 
products) 

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5. 
Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines 
[including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic 
antidepressants and alcohol) at screening and admission to the clinical research 
center 
6. 
Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) 
7. 
Positive screen for hepatitis B surface antigen (HBsAg), anti-HCV antibodies or 
anti-human immunodeficiency virus (HIV) 1 and 2 antibodies 
8. 
Participation in a drug study within 60 days prior to the first drug administration in 
the current study. Participation in more than 4 other drug studies in the 12 months 
prior to the first drug administration in the current study 
9. 
Donation or loss of more than 100 mL of blood within 60 days prior to the first 
drug administration. Donation or loss of more than 1.5 liters of blood (for male 
subjects) / more than 1.0 liters of blood (for female subjects) in the 10 months 
prior to the first drug administration in the current study 
10. Significant and/or acute illness within 5 days prior to the first drug administration 
that may impact safety assessments, in the opinion of the PI 
 
Please note that subjects should refrain from consumption of any foods containing 
poppy seeds within 48 hours (2 days) prior to screening and admission to the clinical 
research center to avoid false positive drug screen results. In addition, they should 
refrain from strenuous exercise within 96 hours (4 days) prior to screening and 
admission as this could result in abnormal clinical laboratory values. 
3.3.3 
Removal of Subjects from Assessment 
Participation in the study is strictly voluntary. A subject has the right to withdraw from 
the study at any time for any reason. 
 
The PI has the right to terminate participation of a subject for any of the following 
reasons: difficulties in obtaining blood samples, violation of the protocol, severe 
adverse events (AEs) or SAEs, or for any other reason relating to the subject's safety 
or integrity of the study data. 
 
If a subject is withdrawn from the study, the Sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision 
of the PI until satisfactory health has returned. 
 
If a subject is withdrawn from the study for any reason, whether related to the study 
drug or not, or if a subject voluntarily withdraws before or after receiving the study 
drug, such subject will be considered an early-termination subject. If a subject is 
withdrawn for a reason related to the study drug, according to the judgment of the PI, 
the early-termination subject will not be replaced. If a subject does not complete the 
study for a reason not related to the study drug, the early-termination subject may be 
replaced after mutual agreement between the Sponsor and PRA. 
 
The decision regarding the replacement of subjects will be documented. 

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PRA will make every effort to ensure that early-termination subjects who have received 
study drug complete the safety follow-up assessments. 
3.4 
Treatments 
3.4.1 
Treatments Administered 
The treatments planned are described in Section 3.1.1. 
3.4.2 
Identity of Investigational Product 
Active medication 
Active substance 
: Inarigivir soproxil 
Activity 
: Antiviral agent 
In development for 
: HBV infection 
Strength 
: 100 mg 
Dosage form 
: Oral tablet 
Manufacturer 
: Patheon, Inc., Mississauga, Ontario, Canada 
 
Probe substrate 
Active substance 
: Midazolam 
Activity 
: CYP3A4 substrate 
Indication 
: Sleep disorder 
Strength 
: 1 mg/mL; a dose of 2 mg will be administered 
Dosage form 
: Oral administration of IV solution formulation 
Manufacturer 
: Will be commercially acquired 
 
For details concerning drug storage and drug accountability see Appendix 8.1. 
3.4.3 
Method of Assigning Subjects to Treatment Groups 
After obtaining informed consent, subjects will be screened according to the inclusion 
and exclusion criteria. Subjects who have met all eligibility criteria will receive a subject 
number upon inclusion in the study (subject numbers 001-016). They receive the 
subject number prior to dosing. The subject number will ensure identification 
throughout the study. Any replacement subjects will receive the number of the subject 
to be replaced, increased by 100 (eg, 101 replacement number for subject number 1), 
and will be administered the same treatments in the same order. 
 
All subjects will be assigned to the same fixed treatment sequence.  
 
Subjects who drop out or withdraw for any reason without completing all screening 
evaluations successfully, will be considered “screening failures“. Such subjects will not 
receive a subject number, and only applicable data will be entered in the electronic 
case report forms (eCRFs).  
3.4.4 
Selection of Doses in the Study 
A Phase 1 study (SB12-9200-101) was completed in which inarigivir was administered 
to treatment naïve HCV infected adults as single ascending and multiple ascending 

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doses. Inarigivir was well tolerated up to the highest dose level of 800 mg in the SAD 
part and up to the highest dose level of 900 mg daily for 7 days in the MAD part. The 
most frequently reported TEAE following multiple dosing with inarigivir was headache 
(12 events reported by 10 subjects). Diarrhea, nausea, ALT increase, AST increase 
and insomnia were reported for 2 subjects each. Headache was mild and self-limited. 
All ALT/AST elevations on treatment were less than 5 x ULN, occurred after cessation 
of inarigivir and were deemed to be within the acceptable spontaneous fluctuation 
range that is common in HCV. No patient had hyperbilirubinemia. 
 
A single oral dose of 2 mg midazolam will be administered on 2 occasions (alone and 
in combination with inarigivir). As the usual oral dose of midazolam for induction of 
sedation without anesthesia ranges between 7.5 and 15 mg, the selected dose of 2 mg 
should be safe and well tolerated with minimal pharmacodynamic effect. Additionally, 
an oral dose of 2 mg is recommended to investigate the maximal inhibitory effect in a 
DDI study with midazolam.7 
3.4.5 
Timing of Doses in the Study 
The study drugs inarigivir and midazolam will be administered with the subject in the 
upright position. Each dosing day, study drug will be administered between 08:00 and 
11:00 hours in the morning after an overnight fast of at least 10 hours. The inarigivir 
dose will be swallowed together with 240 mL tap water (room temperature) and should 
not be chewed. During fasting, no fluids are allowed except water; however, water is 
not allowed from 2 hours pre-dose until 1 hour post-dose (apart from the water taken 
with the dose as described above). 
 
On Days 1, 3 and 19, fasting will continue for a period of 4 hours after drug 
administration, ie, until scheduled lunch. On other dosing days, breakfast will be given 
approximately 1 hour after study drug administration. 
 
When not fasting, non-caffeinated fluids are allowed ad libitum. 
 
Dosing for each individual subject will be at around the same time (± 15 min) on each 
dosing day.  
 
On Days 1, 3 and 19, subjects will not lie down for 4 hours after drug administration, 
except when required by assessments that need to be performed. 
 
Administration of the study drug will be supervised by the PI or authorized designee. 
After drug administration a mouth and hand inspection will take place. 
3.4.6 
Meals During the Study 
A fasting period of at least 4 hours is required before obtaining clinical laboratory 
samples at all time points. 
 
There are no special requirements related to food and beverage intake other than 
described in Sections 3.4.5 and 3.4.8. When not fasting, meals and snacks (such as 

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decaffeinated coffee, herbal tea, fruit, biscuits) will be provided according to PRA 
standard operating procedures (SOPs). A light supper will be provided on the evening 
before those days where fasting is required until lunch-time; a snack will be provided 
on the evening before those days where fasting is required until breakfast. 
3.4.7 
Blinding 
This is an open-label study. 
3.4.8 
Concomitant Medication and Other Restrictions During the Study 
Note: Restrictions that apply to the period before admission are described in 
Sections 3.3.1 and 3.3.2. 
 
The use of all prescribed medication is not allowed from admission to the clinical 
research center up to follow-up. The use of all over-the-counter medication, vitamin 
preparations and other food supplements, or herbal medications (eg St. John’s Wort) is 
not allowed from admission to the clinical research center up to follow-up. An exception 
is made for paracetamol: from admission onwards, the PI may permit a limited amount 
of paracetamol for the treatment of headache or any other pain. Other medication to 
treat AEs may only be prescribed if deemed necessary by the PI. If medication is used, 
the name of the drug, the dose and dosage regimen will be recorded in the eCRF.  
 
The use of alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, 
chocolate, energy drinks), grapefruit (juice) and tobacco products is not allowed during 
the stay in the clinical research center. 
 
Strenuous exercise is not allowed during the stay in the clinical research center.  
 
Male subjects, if not surgically sterilized, are required to use adequate contraception 
and not donate sperm from admission to the clinical research center until 90 days after 
the follow-up visit. Adequate contraception for the male subject (and his female 
partner) is defined as using hormonal contraceptives or an intrauterine device, 
combined with at least 1 of the following forms of contraception: a diaphragm or 
cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the 
subject is acceptable. 
 
Female subjects of childbearing potential, with a fertile male sexual partner, are 
required to use adequate contraception from screening until 90 days after the follow-up 
visit. Adequate contraception is defined as using a non-hormonal intrauterine device 
combined with at least 1 of the following forms of contraception: a diaphragm or 
cervical cap, or a condom; please note that hormonal contraceptives are not allowed. 
Also, total abstinence, in accordance with the lifestyle of the subject, is acceptable. 
3.4.9 
Treatment Compliance 
Study drug will be administered in the clinical research center. To ensure treatment 
compliance, administration of the study drug will be supervised by the PI or authorized 

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designee. Compliance will be further confirmed by bioanalytical assessment of inarigivir 
and midazolam in plasma samples (see Section 3.5.4).  
 
The exact times of study drug administration and the number of units administered will 
be recorded in the eCRF.  
3.5 
Pharmacokinetic, Safety and Pharmacodynamic Variables 
3.5.1 
Pharmacokinetic, Safety and Pharmacodynamic Measurements Assessed and 
Schedule of Assessments 
The schedule of assessments is presented in Table 1. 
3.5.1.1 
Pharmacokinetic Measurements 
3.5.1.1.1 
Blood Sampling 
At the time points defined in the schedule of assessments, blood samples of 4 mL 
each will be taken for the analysis of inarigivir and its metabolites Rp-SB 9000 and 
Sp-SB 9000 in plasma samples. At the time points defined in the schedule of 
assessments, blood samples of 1 mL each will be taken for the analysis of midazolam 
and its metabolite 1′-OH midazolam in plasma samples. The blood samples will be 
taken via an indwelling IV catheter or by direct venipuncture. Details on sample 
collection, sample aliquoting, sample handling, sample storage and sample shipping 
will be described in the laboratory manual prepared by PRA. 
3.5.1.1.2 
Urine Collection 
During the intervals defined in the schedule of assessments, urine will be collected for 
the analysis of metabolites Rp-SB 9000 and Sp-SB 9000. The subjects will be 
instructed to empty their bladders completely before study drug administration and at 
the end of each collection interval. A blank urine sample will be collected within 12 
hours prior to the first study drug administration. The exact times of urine collection and 
the urine weight of the entire interval will be recorded in the eCRF. Details on sample 
collection, sample aliquoting, sample handling, sample storage and sample shipping 
will be described in the laboratory manual prepared by PRA. 
3.5.1.2 
Safety and Tolerability Measurements 
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, 
12-lead ECG and physical examination. Assessments will be performed in accordance 
with the schedule of assessments. 
3.5.1.2.1 
Adverse Events 
Adverse events will be recorded from admission until completion of the follow-up visit. 
Any clinically significant observations in results of clinical laboratory, 12-lead ECGs, 
vital signs or physical examinations will be recorded as AEs. 
 
A TEAE is defined as any event not present prior to the first administration of the study 
drug or any event already present that worsens in either severity or frequency following 
exposure to the study drug.  

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An AE which occurs prior to the first administration of the study drug will be considered 
a pre-treatment AE. 
 
At several time points before and after drug administration, subjects will be asked 
non-leading questions to determine the occurrence of AEs. Subjects will be asked in 
general terms about any AEs at regular intervals during the study. In addition, all AEs 
reported spontaneously during the course of the study will be recorded. 
 
All answers will be interpreted by the PI using the Medical Dictionary for Regulatory 
Activities (MedDRA; most recent version) for AEs and will be recorded in the eCRF.  
 
The severity of the AEs will be rated as “mild”, “moderate”, “severe”, “life-threatening” 
or “death”, and the relationship between the AEs and the study drug will be indicated 
as “none”, “unlikely”, “possibly”, “likely” or ‘’definitely”. Adverse events that will be 
assessed as “possibly”, “likely” or ‘’definitely” will be considered to be related to the 
study drug whereas AEs that will be assessed as “none” or “unlikely” will be considered 
not to be related to the study drug. Details on the rating of the severity of the AEs and 
relationship to the study treatment are given in Appendix 8.2. 
3.5.1.2.2 
Clinical Laboratory  
Blood and urine samples for clinical laboratory assessments will be collected according 
to PRA SOPs. 
The following parameters will be measured: 
 
Clinical chemistry (serum quantitatively): 
 
total 
bilirubin, 
alkaline 
phosphatase, 
gamma-GT, 
ASAT, 
ALAT, 
lactate 
dehydrogenase (LDH), creatinine, urea, total protein, glucose, inorganic 
phosphate, sodium, potassium, calcium and chloride 
 
Hematology (blood quantitatively): 
 
leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, partial automated 
differentiation: lymphocytes, monocytes, eosinophils, basophils, neutrophils, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean 
corpuscular hemoglobin concentration (MCHC) 
 
Coagulation (blood quantitatively): 
prothrombin time (PT) (reported in seconds and as international normalized ratio 
[INR]), activated partial thromboplastin time (aPTT), fibrinogen 
 
Urinalysis (urine qualitatively): 
 
hemoglobin, urobilinogen, ketones, glucose and protein 
 
Serology: 
 
HBsAg, anti-HCV and anti-HIV 
 
Drug and alcohol screen: 
 
opiates, methadone, cocaine, amphetamines (including ecstasy), cannabinoids, 
barbiturates, benzodiazepines, tricyclic antidepressants and alcohol 
 
Pregnancy test (females only): 
 
β-human chorionic gonadotropin (β-hCG) in serum/urine  
 

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In case of unexplained or unexpected clinical laboratory test values, the tests will be 
repeated as soon as possible and followed up until the results have returned to the 
normal range and/or an adequate explanation for the abnormality is found. The clinical 
laboratory will clearly mark all laboratory test values that are outside the normal range 
and the PI will indicate which of these deviations are clinically significant. These 
clinically significant deviating laboratory results will then be recorded as AEs and the 
relationship to the treatment will be indicated (see also Appendix 8.2). 
3.5.1.2.3 
Vital Signs 
Systolic and diastolic blood pressure and pulse will be recorded after the subject has 
been resting for at least 5 minutes in the supine position. These assessments will be 
made using an automated device. Body temperature and respiratory rate will be 
measured subsequently. 
3.5.1.2.4 
Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has been resting for at least 
5 minutes in the supine position. The ECG will be recorded using an ECG machine 
equipped with computer based interval measurements. The following will be recorded: 
heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval (Fridericia's) and the 
interpretation of the ECG profile by the PI. 
3.5.1.2.5 
Physical Examination 
Physical examination will be performed according to PRA SOPs. In addition, body 
weight and height will be measured according to PRA SOPs. 
3.5.1.3 
Pharmacodynamic Measurements 
Cytokine panel 
At the time points defined in the schedule of assessments, blood samples of 4 mL 
each will be taken for the analysis of the cytokines C-X-C motif chemokine 10 
(CXCL10; also known as IFN gamma-induced protein 10 [IP-10]), interleukin (IL)-6, 
tumor necrosis factor alpha (TNF-), IFN- and IFN-γ in serum. The blood samples will 
be taken via an indwelling IV catheter or by direct venipuncture. Details on sample 
collection, sample aliquoting, sample handling, sample storage and sample shipping 
will be described in the laboratory manual prepared by PRA. 
 
Peripheral blood mononuclear cells (PBMCs) 
At the time points defined in the schedule of assessments, blood samples of 16 mL 
each will be taken for the collection of PBMCs. RNA will be extracted from these 
PBMCs for potential future analysis of cytokine RNA expression. The blood samples 
will be taken via an indwelling IV catheter or by direct venipuncture. Details on sample 
collection, sample aliquoting, sample handling, sample storage and sample shipping 
will be described in the laboratory manual prepared by PRA. 
3.5.1.4 
Pharmacogenomic Measurements 
One blood sample of 4 mL will be collected per subject for potential future genotyping 
of DNA sequence variants to explore potential relationships with PK/PD and or 

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tolerability. The sample is optional for all subjects; subjects who do not consent to 
collection of this sample will not be excluded from participation in this study provided all 
other inclusion and exclusion criteria have been met. The blood sample will be double 
coded (one code at PRA and one code at the Sponsor) and the sample will be kept 
until 15 years after completion of the study. The blood sample will be taken via an 
indwelling IV catheter or by direct venipuncture. Details on sample collection, sample 
aliquoting, sample handling, sample storage and sample shipping will be described in 
the laboratory manual prepared by PRA. 
3.5.1.5 
Total of Blood Volume 
Table 2 presents the number and volume of blood samples and the total volume of 
blood that will be collected throughout the study per subject. 
 
If deemed necessary by the PI or the Sponsor, the number and/or volume of blood 
samples per assessment in each study part may be increased as long as the total 
volume of blood drawn for a subject does not surpass 500 mL (except when extra 
blood samples need to be taken for safety reasons). 
 
Table 2 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject 
Assessment 
Maximum # samples Volume of blood per 
sample (mL) 
Total volume of 
blood (mL) 
PK 
- Inarigivir and its metabolites  
- midazolam and 1′-OH 
midazolam 
 
42 
28 
 
4 
1 
 
168 
28 
PD 
- Cytokine panel 
- PBMCs 
 
14 
7 
 
4 
16 
 
56 
112 
Genotyping 
1 
4 
4 
Clinical chemistry 
11 
3.5 
38.5 
Hematology  
11 
3 
33 
Coagulation 
11 
4.5 
49.5 
Serology 
1 
5 
5 
Total volume of blood drawn 
 
 
494 
3.5.2 
Appropriateness of Measurements 
The assessments, which will be made in this study are standard, and generally 
recognized as reliable, accurate and relevant.  
3.5.2.1 
Timing of Assessments 
For PK, pre-dose samples will be obtained between waking up and dosing. For 
pre-dose (trough) samples during multiple dosing, a 5% time window since the last 
dose is allowed, but the sample must be taken before the next dose. Post-dose 
samples up to 20 minutes post-dose will be obtained with a time window of ± 1 minute. 

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Thereafter, post-dose samples will be obtained with time margins of ± 5% of the time 
that has passed since (last) dosing. The ±5% time window also applies to the start and 
end times of urine collection intervals and in addition to the total duration of each 
consecutive collection interval.  
 
For PD, pre-dose samples will be obtained between waking up and dosing. Post-dose 
samples up to 40 minutes post-dose will be obtained with a time window of ±2 minutes. 
Thereafter, post-dose samples will be obtained with time margins of ±5% of the time 
that has passed since (last) dosing. 
 
For safety assessments, pre-dose assessments will be performed between waking up 
and dosing. For safety assessments up to 2.5 hours post-dose a time window of 
±15 minutes is allowed. Thereafter, serial post-dose assessments (eg, multiple 
assessments within any given day) will be performed with time margins of ±10% of the 
time that has passed since (last) dosing. 
 
In the event assessments are planned for the same scheme time, the order of the 
assessments should be arranged in such a way that PK blood sampling will be done 
after the ECG and vital signs recordings have been conducted, with PK blood sampling 
exactly on time. 
3.5.3 
Pharmacokinetic, Safety and Pharmacodynamic Variables 
3.5.3.1 
Pharmacokinetic Variables 
PK variables will be the plasma concentrations of inarigivir and its metabolites 
Rp-SB 9000 and Sp-SB 9000, urine concentrations of Rp-SB 9000 and Sp-SB 9000, 
and plasma concentrations of midazolam and its metabolite 1′-OH midazolam and their 
PK parameters. The plasma and urine PK parameters to be determined or calculated 
using non-compartmental analysis include but are not limited to the parameters as 
given in Table 3 and Table 4, respectively. A complete list of PK parameters will be 
provided in the Statistical Analysis Plan (SAP). 
 
 
 

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Table 3 
Plasma Pharmacokinetic Parameters 
Parameter 
Inarigivir 
and 
midazolam 
following a 
single dose 
Rp-SB 9000, 
Sp-SB 9000 and 
1′-OH midazolam 
following a 
single dose 
Inarigivir, 
Rp-SB 9000 and 
Sp-SB 9000 
following 
multiple doses 
Description 
Cmax 
X 
X 
X 
Maximum observed plasma concentration 
tmax 
X 
X 
X 
Time to attain maximum observed plasma concentration 
AUC0-t  
X 
X 
 
Area under the plasma concentration-time curve up to time t, where t is 
the last point with concentrations above the lower limit of quantitation 
(LLOQ)  
AUC0-inf  
X 
X 
 
Area under the plasma concentration-time curve from time 0 to infinity 
calculated as: AUC0-inf = AUC0-t + Clast/kel, 
where Clast is the last measurable plasma concentration 
%AUCextra 
X 
X 
 
Percentage of estimated part for the calculation of AUC0-inf 
((AUC0-inf-AUC0-t)/AUC0-inf)*100% 
AUC0- 
 
 
X 
Area under the plasma concentration-time curve over a dosing interval  
kel 
X 
X 
 
Terminal elimination rate constant 
t1/2 
X 
X 
 
Terminal elimination half-life, calculated as 0.693/kel 
Rac 
 
 
X (Rp-SB 9000 
and Sp-SB 9000 
only) 
Accumulation ratio for Cmax of Day 19 versus Cmax of Day 3 and AUC0- of 
Day 19 versus AUC0-inf of Day 3 
CL/F 
X 
 
 
Apparent oral clearance, calculated as dose/AUC0-inf  
Vz/F 
X 
 
 
Apparent volume of distribution at terminal phase  
MR 
 
X 
 
Metabolite to parent ratio for Cmax, AUC0-t, and AUC0-inf 
 
 

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Table 4 
Urine Pharmacokinetic Parameters 
Parameter 
Rp-SB 9000 and 
Sp-SB 9000 
following single 
doses 
Description 
Ae0-t 
X 
Amount excreted up to time t, where t is the last 
point with concentrations above the LLOQ 
CLR 
X 
Renal clearance 
fe 
X 
Fraction of the dose administered excreted in 
urine (%) 
3.5.3.2 
Safety Variables 
The safety variables will be as follows: 
 
AEs 
 
Clinical laboratory 
 
Vital signs 
 
ECG 
3.5.3.3 
Pharmacodynamic Variables 
The PD variables will be the serum levels of the cytokines CXCL10, IL-6, TNF-, IFN- 
and IFN-γ and cytokine RNA expression in PBMCs. 
3.5.4 
Drug Concentration Measurements 
The analysis of inarigivir and its metabolites Rp-SB 9000 and Sp-SB 9000 in plasma, 
metabolites Rp-SB 9000 and Sp-SB 9000 in urine, and midazolam and its metabolite 
1′-OH midazolam in plasma will be performed at Q2 Solutions (New York, USA) using 
validated liquid chromatography-mass spectrometry/mass spectrometry methods. The 
Bioanalytical Report for the determinations will be included in the clinical study report 
(CSR).  
 
The analysis of the cytokine panel will be conducted at MLM Medical Labs GmbH 
(Moenchengladbach, Germany).  
3.6 
Statistical Procedures and Determination of Sample Size 
3.6.1 
Analysis Sets 
3.6.1.1 
Pharmacokinetic Set 
All subjects who have received at least a single dose of midazolam or inarigivir and 
provided sufficient bioanalytical assessment results to calculate reliable estimates of 
the PK parameters. 
3.6.1.2 
Safety Set 
All subjects who have received at least 1 dose of study drug. 

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3.6.1.3 
Pharmacodynamic Set 
All subjects belonging to the safety set and for whom the PD data are considered to be 
sufficient and interpretable. 
3.6.2 
Statistical and Analytical Plan for Pharmacokinetic, Safety and 
Pharmacodynamic Evaluation 
A SAP will be generated by the Biostatistics Department of PRA; the SAP will be 
finalized prior to database lock. Full details of the analysis to be performed will be 
included in the SAP.  
 
Any deviation from the SAP will be reported in the Section “Changes in Planned 
Analysis” in the CSR. 
3.6.2.1 
Pharmacokinetic Evaluation 
The PK parameters and their statistical evaluation will be included in the CSR of this 
study. 
 
All data will be summarized using descriptive statistics (n, mean, standard deviation, 
minimum, median, maximum, geometric mean, and coefficient of variation) and will be 
listed and summarized in tabular and/or graphical form. 
 
A mixed-effects model with subject as a random effect and treatment as a fixed effect 
will be performed on the following natural logarithm (ln)-transformed PK parameters of 
midazolam and 1′-OH midazolam: Cmax, AUC0-t and AUC0-inf. The point estimates will 
be calculated for each parameter listed above as the geometric mean ratio of Day 19 
(coadministration of midazolam + inarigivir) relative to Day 1 (midazolam alone), with 
corresponding 90% confidence intervals (CIs). The absence of interaction will be 
concluded if these CIs are included in the bioequivalence range (80-125%).  
3.6.2.2 
Evaluation of Safety and Tolerability 
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, 
ECGs and physical examination findings, and any other parameter that is relevant for 
safety assessment. 
3.6.2.2.1 
Adverse Events 
A listing of all individual AEs will be provided. Summary tables of TEAEs will be 
presented by system organ class based on the MedDRA terminology list (preferred 
terms): 1 containing the number of TEAEs (frequency of occurrence, number of 
subjects experiencing the event) by treatment and 1 containing the number of 
drug-related TEAEs (frequency of occurrence, number of subjects experiencing the 
event) per treatment. Additional tables of total counts by treatment and relationship and 
by treatment and severity will be created. 
3.6.2.2.2 
Clinical Laboratory 
Clinical laboratory data will be listed and accompanied by an indication if the parameter 
is outside the reference range. A summary of all data outside the reference range of 

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the clinical laboratory parameters will be provided. Clinical laboratory data will be 
presented descriptively, where applicable. 
3.6.2.2.3 
Vital Signs and Electrocardiograms 
Vital signs and ECG parameters will be listed and they will be presented descriptively, 
where applicable. 
3.6.2.2.4 
Physical Examination 
Changes from baseline for physical examination will be described and listed. 
3.6.2.3 
Pharmacodynamic Evaluation 
The PD parameters and their statistical evaluation will be included in the CSR of this 
study. 
 
All data, including change from baseline, will be summarized using descriptive 
statistics and will be listed and summarized in tabular and/or graphical form. 
3.6.3 
Determination of Sample Size 
Based on the intra-subject coefficient of variation of 19.7% found for AUC0-t of 
midazolam in a previous interaction study8 and assuming an expected geometric mean 
ratio (test/reference) of 1.00, a significance level of 5% (α=0.05) and a default no-effect 
boundary of 80-125%, a sample size of 14 subjects results in at least 80% power 
(calculated using SAS PROC POWER). Accounting for early-termination subjects, a 
sample size of 16 subjects is considered to be sufficient. 
3.7 
Data Quality Assurance 
The study may be audited by the Quality Assurance Department at PRA to assess 
adherence to the clinical study protocol (CSP) and Quality System. During the conduct 
of the study, process-related audits may be performed. An audit certificate will be 
provided in the appendices of the final CSR outlining any audits and other related 
activities performed.  
 
The clinical research site will be monitored by the study monitor to ensure correct 
performance of the study procedures and assure that the study will be conducted 
according to the relevant regulatory requirements. The eCRF entries will be verified 
with the source documentation, if applicable (in some cases there are no source 
pages, therefore verification is not necessary). 
 
Regulatory authorities, the Independent Ethics Committee (IEC) and/or the Sponsor’s 
clinical quality assurance group may request access to all source documents, eCRFs, 
and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the PI, who must provide support at all times for 
these activities. 
 

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Quality control principles will be applied throughout the performance of this study. 
Review procedures will be followed at PRA for all documents that are generated in 
relation with the study.  
 
An explanation will be given for all missing, unused and spurious data in the relevant 
sections of the CSR. 

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4. 
ETHICS 
4.1 
Independent Ethics Committee 
The CSP and the ICFs will be submitted for review and approval by the IEC of the 
foundation 
“Beoordeling 
Ethiek 
Biomedisch 
Onderzoek” 
(English 
translation: 
“Evaluation of Ethics in Biomedical Research”) (Stationsstraat 9, 9401 KV Assen, The 
Netherlands) prior to the eligibility screening. The composition of the IEC is in 
accordance with the recommendations of the WHO, the International Council for 
Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP)9, and the 
European Union (EU) Clinical Trial Directive (CTD) (Directive 2001/20/EC)10 (see 
below). 
 
PRA will keep the IEC informed about the progress of the study. All changes in 
research activities and all unanticipated problems involving risks to human subjects will 
be immediately reported to the IEC. In accordance with Section 10, Subsection 1, of 
the Dutch law on Medical Research in Human Subjects (WMO, revised 
December 2015)11, PRA will inform the subjects and the IEC if anything occurs on the 
basis of which it appears that the disadvantages of participation may be significantly 
greater than was foreseen in the research proposal, or if further recruitment of subjects 
in the study has been put on hold for that reason, whichever occurs first. The study 
may be suspended pending further review by the IEC, except insofar as suspension 
would jeopardize the subjects’ health. PRA will take care that all subjects are kept 
informed.  
 
No changes will be made in the study without IEC approval, except when required to 
eliminate apparent immediate hazards to human subjects. 
 
Notification of the end of the study will be sent by PRA to the Competent Authority (CA) 
in The Netherlands and to the IEC within 90 days after completion of follow-up for the 
last subject. In case a study is temporarily halted, PRA will notify the IEC immediately, 
including the reason for this. In case a study is ended prematurely, PRA will notify the 
IEC and the CA in The Netherlands within 15 days, including the reasons for the 
premature termination. A summary of the results of the study will be sent by PRA to the 
CA and the IEC within 1 year after the end of the study.  
4.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent 
amendments.12  
 
This study is also designed to comply with ICH E6 Guideline for GCP 
(EMA/CHMP/ICH/135/1995)9, 
and 
the 
EU 
CTD 
Directive 
2001/20/EC10, 
as 
incorporated into Dutch Law.11 
 

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ICH adopted guidelines and other relevant international guidelines, recommendations 
and requirements will be taken into account as comprehensively as possible, as long 
as they do not violate Dutch law. 
 
The PI will be responsible for the care of the subjects throughout the study. If the PI is 
not present at the clinical site, he will leave instructions for the staff and a telephone 
number where he can be reached. 
 
The PI will be responsible for the medical follow-up of the subjects. 
 
If a subject refuses to follow the instructions of the PI, the latter is released from any 
legal responsibility. 
4.3 
Subject Information and Consent 
All subjects will be informed verbally and in writing regarding the objectives, 
procedures and risks of study participation. The subjects will have to sign the Dutch or 
English version of the ICF before any study-related procedures are started. The ICF 
contains information about the objectives of the study, about the procedures followed 
during the study and about the risks and restrictions of the study, with special 
reference to possible side effects of the medication and potential interactions. In 
addition, insurance coverage provided during the study is explained. The elements 
addressed in the ICF are according to the ICH E6 Guideline for GCP 
(CPMP/ICH/135/95).9  
4.4 
Privacy 
All personal details will be treated as confidential by the PI and staff at PRA and 
handling of personal data will be in compliance with the Dutch Data Protection Act. 
Personal details are stored in databases that have been registered with the Dutch Data 
Protection Authority. 
 

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5. 
STUDY ADMINISTRATIVE STRUCTURE 
5.1 
Distribution of Activities 
Preparation of study drug 
Inarigivir will be provided by the Sponsor. Midazolam will be obtained by the PRA 
Pharmacy. 
 
Laboratory assessments 
The analysis of inarigivir and its metabolites Rp-SB 9000 and Sp-SB 9000 in plasma, 
metabolites Rp-SB 9000 and Sp-SB 9000 in urine, and midazolam and its metabolite 
1′-OH midazolam in plasma will be performed at Q2 Solutions (New York, USA). 
 
The analysis of the cytokine panel will be conducted at MLM Medical Labs GmbH 
(Moenchengladbach, Germany). 
 
The analysis of clinical laboratory samples and the extraction of RNA from PBMCs will 
be performed at the PRA Clinical Laboratory.  
 
eCRF design 
The eCRF design will be performed with the computer program Oracle Clinical (Oracle, 
Redwood Shores, Redwood City, CA, USA) by the Database Programming 
Department of PRA. 
 
Data management 
Data management will be performed with the computer programs Oracle Clinical 
(Oracle, Redwood Shores, Redwood City, CA, USA), SAS® (SAS Institute Inc., Cary, 
NC, USA) and EXACT (Kinship EXACTTM, Kinship technologies, a technology 
subsidiary of PRA) by the Data Management Department of PRA. 
 
Statistics 
A SAP will be provided by the Biostatistics Department of PRA. The safety analysis 
and the statistical evaluation of PK and PD parameters will be conducted by the 
Biostatistics Department of PRA. Statistical analysis will be performed with the 
computer program SAS® (SAS Institute Inc., Cary, NC, USA). Pharmacokinetic 
parameters will be calculated using Phoenix® WinNonlin® (Certara, Princeton, NJ, 
USA). Additional PK computations can also be performed in SAS for Windows® (SAS 
Institute Inc., Cary, NC, USA). 
 
CSR writing 
The CSR, structured in accordance with the guideline ‘Structure and Content of Clinical 
Study Reports - ICH E3’13, will be written by PRA. 

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5.2 
Documentation 
5.2.1 
Archiving 
All documents concerning the study will be kept on file in the Central Archives of PRA 
for at least 15 years after conduct of the study. The Sponsor will receive the completed 
eCRFs (upon request, as PDF file). 
5.2.2 
Recording of Data in Source Documents and CRFs 
Wherever possible, all data will be entered directly into the eCRFs. In some cases 
source documents will be used. 
 
A Data Management Plan will be written by the Data Management Department of PRA, 
which will be finalized prior to performing any data validation. An appendix to the data 
management plan (source identification list) will identify any data to be recorded 
directly in the eCRF (ie, no prior written or electronic record of data), and which data 
should be considered source data.  
 

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6. 
CONFIDENTIALITY AND PUBLICATION POLICY 
By signing this CSP, the PI reaffirms to the Sponsor that he will maintain in confidence 
all information furnished to him, or resulting from this study. The PI will only divulge 
such information as may be necessary to the IEC, the members of the staff and the 
subjects who are involved in this study. 
 
All relevant aspects regarding publication will be part of the contract (or similar 
document) between the Sponsor and PRA.  
 

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7. 
REFERENCES 
1. 
World Health Organization (2017) Media Centre. Hepatitis B. Available from: 
http://www.who.int/mediacentre/factsheets/fs204/en/. 
2. 
Mikkaichi T, Nakai D, Yoshigae Y, Imaoka T, Okudaira N, and Izumi T, 
Liver-selective distribution in rats supports the importance of active uptake into 
the liver via organic anion transporting polypeptides (OATPs) in humans. Drug 
Metabolism and Pharmacokinetics, June 24, 2015. 30 (2015) 334-340. 
3. 
Investigator’s Brochure SB 9200. Version 0.6. 05 September 2017. 
4. 
Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of midazolam by 
the human intestine. Clin Pharmacol Ther 1996; 60(1): 14-24. 
5. 
Thummel KE, O’Shea D, Paine MF, et al. Oral first-pass elimination of 
midazolam involves both gastrointestinal and hepatic CYP3A-mediated 
metabolism. Clin Pharmacol Ther 1996; 59(5): 491-502. 
6. 
Heizmann P, Ziegler WH. Excretion and metabolism of 14C-midazolam in 
humans following oral dosing. Arzneimittelforschung 1981; 31(12a): 2220-2223. 
7. 
Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo 
drug-drug interaction studies: A Pharmaceutical Research and Manufacturers 
of America (PhRMA) perspective. Drug Metab Dispos 2003; 31(7): 815-832. 
8. 
Winter H, Egizi E, Erondu N, Ginsberg A, Rouse DJ, Severynse-Stevens D, 
Pauli E, Everitt D, 2013. Evaluation of Pharmacokinetic Interaction between 
PA-824 and Midazolam in Healthy Adult Subjects. Antimicrob Agents 
Chemother 2013 Aug; 57(8): 3699-3703. 
9. 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2), November 2016. Guideline for 
Good Clinical Practice E6(R2) (EMA/CHMP/ICH/135/1995), December 2016. 
10. 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative 
provisions of the Member States relating to the implementation of good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 
11. 
Medical 
Research 
in 
Human 
Subjects 
Act 
(WMO, 
Wet 
Medisch-Wetenschappelijk Onderzoek met mensen), revision December 2015 
12. 
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 
64th World Medical Association General Assembly, Fortaleza, Brazil, October 
2013. 
13. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, 
E3: 
Structure 
and 
Content 
of 
Clinical 
Study 
Reports 
(CPMP/ICH/137/95), November 1995. 
14. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, Note for Guidance on Clinical Safety Data 
Management, June 1995. 
 

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8. 
APPENDICES 
8.1 
Drug Accountability 
Upon receipt of the study drug, it will be inspected and counted by the responsible 
pharmacist. If necessary, all study drug will be re-packed per dosing occasion, and 
labeled according to PRA SOPs. 
 
The study drug will be kept in the PRA Pharmacy or in a locked and secured storage 
facility accessible to the pharmacist and the pharmacy assistant only. 
 
The responsible pharmacist will keep an inventory. This will include a description of the 
formulation and the quantity of study drug received for the study and a record of what is 
dispensed, to whom and when. 
 
On termination of the study the responsible pharmacist will conduct a final inventory of 
the study drug supply and will record the results of this inventory in the Drug 
Accountability Form. Unused study drug will be returned to the Sponsor at the end of 
the study or will be locally destroyed according to PRA standard procedures. 
8.2 
Adverse Events and Serious Adverse Events Evaluation and Reporting 
8.2.1 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical 
treatment or procedure. AE definitions will be followed as stated in the ‘Note for 
Guidance on clinical safety data management: definitions and standards for expedited 
reporting’ (ICH topic E2A).14  
 
All AEs reported by the subjects or apparent from their physical appearance during the 
clinical study will be reported on the AE eCRF page. 
 
The severity of AEs will be graded using the most current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) 5-point scale: 
 
Mild (Grade I): Asymptomatic or mild symptoms: clinical or diagnostic observations 
only; intervention not indicated. 
 
Moderate (Grade II): Minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
 
Severe (Grade III): Severe or medically significant but not immediately 
life-threatening: hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Life-threatening (Grade IV): Life-threatening consequences; urgent intervention 
indicated.  
 
Death (Grade V): Death related to AE. 
 
If an AE has multiple aspects, the aspect with the highest severity will be graded. 

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It is emphasized that the term severe is a measure of severity; thus, a severe AE is not 
necessarily serious. For example, itching for several days may be rated as severe, but 
may not be clinically serious. 
 
In addition, clinically significant changes in physical examination findings and abnormal 
objective test findings (eg, laboratory, x-ray, ECG) should also be recorded as AEs. 
Test findings and physical examination findings can result in AEs if they:  
 
Are associated with accompanying symptoms, and/or 
 
Require additional diagnostic testing or medical/surgical intervention, and/or 
 
Lead to a change in study dosing or discontinuation from the study; result in the 
addition of significant additional concomitant drug treatment or other therapy, 
and/or 
 
Lead to any of the outcomes included in the definition of an SAE, and/or 
 
Are considered to be an AE by the PI or Sponsor. 
 
Reporting as an AE should not be triggered by: 
 
Merely repeating an abnormal test or  
 
Any abnormal test result that is determined to be an error. 
 
The relationship of any AE to the study drug will be assessed and graded on a 5-point 
scale: none, unlikely, possibly, likely or definitely.  
 
Relationship between use of study drug and AE (Causality) 
AE (is) 
None 
Unlikely 
Possibly 
Likely 
Definitely 
Clearly the result of an 
external factor 
Yes 
No 
No 
No 
No 
Probably/possibly the 
result of another factor 
No 
Yes 
Yes 
No 
No 
Has a chronological 
relationship with the time 
of study drug 
administration and/or 
represents a known 
reaction to study drug 
No 
No 
Yes 
Yes 
Yes 
Disappears or decreases 
after discontinuation of 
the study drug 
NA 
NA 
NA 
Yes 
Yes 
Recurs on renewed 
administration 
(re-challenge) 
No 
No 
NA 
NA 
Yes or 
NA* 
* 
A re-challenge is not required; if done, re-challenge would be expected to be positive 
NA 
Not applicable 

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8.2.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, on the basis of medical and scientific 
judgment: 
 
Results in death, or 
 
Is life-threatening (this refers to an event in which the subject 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 were more severe), or  
 
Requires inpatient hospitalization for a medical reason or prolongation of existing 
hospitalization (this refers to hospital admission required for treatment of the AE). 
(Note: this does not include confinement in, for example, a respite unit; a skilled 
nursing unit; rehabilitation facility; the clinical research center; or confinement due 
to planned or unplanned reason unrelated to study), or 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. 
 
SAEs will be collected from admission until the final study visit. SAEs that are related to 
the investigational drug and continue beyond the normal collection period (ie, are 
ongoing at the time a subject exits the study) will be followed until resolution or until 
stabilized with sequelae. SAEs that begin after the subject’s participation in the study is 
complete, but that the PI considers to be related to study drug, may be reported at any 
time.  
 
The PI or clinical site personnel must notify the Sponsor’s Chief Medical Officer, the 3rd 
Party Drug Safety CRO and the PRA Drug Safety Center Europe, Asia-Pacific and 
Africa (EAPA) of all SAEs, regardless of relationship to the investigational drug, within 
24 hours of clinical site personnel becoming aware of the event. The PI will provide the 
initial notification by sending a completed “SAE Notification Form”, which must include 
the PI’s assessment of the relationship of the event to investigational drug, and must 
be signed by the PI. 
 
In addition, notification is sent by PRA to the IEC, and the subject’s general 
practitioner. 
 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the Sponsor’s Chief Medical Officer, the 3rd Party Drug Safety CRO and 
the PRA Drug Safety Center EAPA. 

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All SAE reports should be sent to the contacts provided on page 3: SAE Contact 
Information. 
8.2.3 
Suspected Unexpected Serious Adverse Reactions 
An SAE that is also an unexpected adverse drug reaction is called a Suspected 
Unexpected Serious Adverse Reaction (SUSAR). Unexpected adverse reactions are 
adverse reactions, of which the nature, or severity, is not consistent with the applicable 
product information (eg, IB for an unapproved investigational medicinal product or the 
Summary of Product Characteristics for an authorized medicinal product). 
 
The Sponsor or its representative (eg, PRA if agreed to before start of the study) will 
urgently report the following SUSARs to the IEC: 
 
SUSARs that have arisen in the current clinical study that was assessed by the IEC 
 
SUSARs that have arisen in other clinical studies of the same Sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the current clinical study that was assessed by the IEC 
 
The Sponsor will urgently report all SUSARs to the CA and the Medicine Evaluation 
Board (MEB) of the country where this study is being conducted and to the CAs in 
other Member States, as applicable. 
 
SUSARs that have already been reported to the European Medicines Agency 
Eudravigilance database do not have to be reported again to the CA and the MEB 
because they have direct access to the Eudravigilance database. 
 
Expedited reporting will occur no later than 15 calendar days after the Sponsor or its 
representative has first knowledge of the adverse reactions. For fatal or life-threatening 
cases the term will be a maximum of 7 calendar days for a preliminary report with 
another 8 days for completion of the report.  
8.2.4 
Follow-up of Adverse Events 
Follow-up of AEs will continue until resolution, stabilization or death. In case of ongoing 
AEs at the moment of database closure, the data obtained at the moment of database 
closure will be used in the statistical analysis. The follow-up of the AE will be 
documented in the source documents and will be described in the final CSR only if 
considered relevant by the PI.