A Phase 1, Randomized, Open-Label, Parallel Group Study to Evaluate the Relative Bioavailability of Subcutaneous Bepirovirsen When Delivered From a Vial or Prefilled Syringe Fitted With a Safety Syringe Device in Healthy Adult Participants
Phase: PHASE1
Conditions: Hepatitis B
Sponsor: GlaxoSmithKline

Protocol
Study ID:  219239
Official Title of Study: A Phase 1, randomized, open-label, parallel 
group study to evaluate the relative bioavailability of subcutaneous 
bepirovirsen when delivered from a vial or prefilled syringe fitted 
with a safety syringe device in healthy adult participants
Date of Document: 26-Jul-2023

 
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26 Jul 2023  
1 
 
Clinical Study Protocol 
Primary Study 
Intervention(s) 
Bepirovirsen (GSK3228836) 
Other Study Intervention(s) 
Not Applicable 
Study Identifier 
219239  
Approval Date 
26 Jul 2023 
Title 
A Phase 1, randomized, open-label, parallel group 
study to evaluate the relative bioavailability of 
subcutaneous bepirovirsen when delivered from a 
vial or prefilled syringe fitted with a safety syringe 
device in healthy adult participants 
Compound Number/Name 
Bepirovirsen (GSK3228836) 
Brief Title 
A study to evaluate the relative bioavailability of 
subcutaneous bepirovirsen when delivered from a 
vial or prefilled syringe fitted with a safety syringe 
device in healthy adult participants 
Sponsor 
GSK Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Dickens Theodore, MD, MPH 
Group Senior Clinical Development Director 
Medical monitor name and contact can be found in local study contact 
information document 
©2023 GSK group of companies or its licensor. 
 
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Protocol 219239 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other study 
conduct procedures and/or study conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-site or 
elsewhere without the approval of GSK and the express physical and/or digital  -
informed consent of the participant and/or the participant’s LAR.  
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). 
• 
To co-operate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the study intervention(s), and more generally about their financial 
ties with the sponsor. GSK will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
 
 
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Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership interest 
and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other documents 
required by regulatory agencies for this study. 
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Study identifier 
219239 
 
Approval date 
26 Jul 2023 
 
 
Title 
A Phase 1, randomized, open-label, parallel group 
study to evaluate the relative bioavailability of 
subcutaneous bepirovirsen when delivered from a 
vial or prefilled syringe fitted with a safety syringe 
device in healthy adult participants 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 15 
1.1. 
Synopsis ..................................................................................................... 15 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of activities (SoA) ........................................................................ 18 
2. 
INTRODUCTION .................................................................................................... 22 
2.1. 
Study rationale ............................................................................................ 22 
2.2. 
Background ................................................................................................ 22 
2.3. 
Benefit/risk assessment .............................................................................. 23 
2.3.1. 
Risk assessment .......................................................................... 24 
2.3.2. 
Benefit assessment ..................................................................... 27 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 27 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 28 
4. 
STUDY DESIGN .................................................................................................... 30 
4.1. 
Overall design ............................................................................................. 30 
4.2. 
Scientific rationale for study design ............................................................. 31 
4.2.1. 
Participant input into design ......................................................... 32 
4.3. 
Justification for dose ................................................................................... 32 
4.4. 
End-of-study definition ................................................................................ 32 
5. 
STUDY POPULATION ........................................................................................... 32 
5.1. 
Inclusion criteria .......................................................................................... 32 
5.2. 
Exclusion criteria ......................................................................................... 34 
5.3. 
Lifestyle considerations ............................................................................... 36 
5.3.1. 
Meals and dietary restrictions ...................................................... 36 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 36 
5.3.3. 
Activity ......................................................................................... 36 
5.3.4. 
Other restrictions ......................................................................... 36 
5.4. 
Screen failures ............................................................................................ 36 
5.5. 
Criteria for temporarily delaying .................................................................. 36 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 37 
6.1. 
Study intervention(s) administered .............................................................. 37 
6.1.1. 
Medical devices ........................................................................... 38 
6.2. 
Preparation, handling, storage, and accountability ...................................... 38 
6.3. 
Assignment to study intervention ................................................................ 39 
6.4. 
Randomization ............................................................................................ 39 
6.5. 
Study intervention compliance .................................................................... 40 
6.6. 
Dose modification ....................................................................................... 40 
6.7. 
Continued access to study intervention after the end of the study ............... 40 
6.8. 
Treatment of overdose ................................................................................ 40 
6.9. 
Prior and concomitant therapy .................................................................... 41 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL- .................................................................... 41 
7.1. 
Discontinuation of study intervention ........................................................... 41 
7.1.1. 
Liver chemistry monitoring criteria ............................................... 41 
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7.1.2. 
Hematological monitoring criteria ................................................. 42 
7.1.3. 
Drug induced kidney injury (renal) monitoring .............................. 42 
7.1.4. 
Drug induced vascular injury and complement activation ............. 43 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 43 
7.3. 
Lost to follow-up.......................................................................................... 44 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 44 
8.1. 
Administrative procedures .......................................................................... 45 
8.1.1. 
Collection of demographic data .................................................... 45 
8.1.2. 
Medical history ............................................................................. 45 
8.2. 
Efficacy assessments ................................................................................. 45 
8.3. 
Safety assessments .................................................................................... 45 
8.3.1. 
Physical examination/history directed physical 
examination ................................................................................. 45 
8.3.2. 
Injection site reactions ................................................................. 46 
8.3.3. 
Vital signs .................................................................................... 46 
8.3.4. 
Electrocardiograms ...................................................................... 46 
8.3.5. 
Clinical safety laboratory tests ..................................................... 46 
8.3.6. 
Pregnancy testing ........................................................................ 47 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 47 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 47 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 48 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 48 
8.4.4. 
AESIs .......................................................................................... 48 
8.4.5. 
Regulatory reporting requirements for SAEs ................................ 49 
8.4.6. 
Pregnancy ................................................................................... 50 
8.4.7. 
Contact information for reporting SAEs and pregnancies ............. 50 
8.4.8. 
Medical device deficiencies ......................................................... 51 
8.5. 
Pharmacokinetics ....................................................................................... 52 
8.6. 
Pharmacodynamics .................................................................................... 52 
8.7. 
Genetics ..................................................................................................... 52 
8.8. 
Biomarkers ................................................................................................. 52 
 
 
8.10. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 53 
 
 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 54 
9.1. 
Statistical hypotheses ................................................................................. 54 
9.1.1. 
Multiplicity Adjustment ................................................................. 54 
9.2. 
Analysis sets ............................................................................................... 54 
9.3. 
Statistical analyses ..................................................................................... 55 
9.3.1. 
General considerations ................................................................ 55 
 
 
 
 
 
 
 
 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 59 
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10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 59 
10.1.1. 
Regulatory and ethical considerations ......................................... 59 
10.1.2. 
Financial disclosure ..................................................................... 59 
10.1.3. 
Informed consent process ............................................................ 60 
10.1.4. 
Data protection ............................................................................ 60 
10.1.5. 
Committees structure ................................................................... 60 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 61 
10.1.7. 
Data quality assurance ................................................................ 61 
10.1.8. 
Source documents ....................................................................... 62 
10.1.9. 
Study and site start and closure ................................................... 62 
10.1.10. Publication policy ......................................................................... 63 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 63 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 65 
10.3.1. 
Definition of AE ............................................................................ 65 
10.3.2. 
Definition of SAE .......................................................................... 67 
10.3.3. 
Definition of TEAE ....................................................................... 68 
10.3.4. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies ................................................................................. 68 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 71 
10.4.1. 
Definitions .................................................................................... 71 
10.4.2. 
Contraception guidance ............................................................... 72 
10.5. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments ............................................................................................... 73 
10.6. 
Appendix 7: Medical device AEs, ADEs, SAEs, sADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies .................... 75 
10.6.1. 
Definition of medical device AE and ADE..................................... 75 
10.6.2. 
Definition of medical device SAE, SADE and USADE .................. 76 
10.6.3. 
Definition of device deficiency ...................................................... 77 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE 
and device deficiencies ................................................................ 77 
10.6.5. 
Reporting of medical device SAEs ............................................... 78 
10.6.6. 
Reporting of SADEs ..................................................................... 79 
10.6.7. 
Reporting of medical device deficiencies for associated 
person ......................................................................................... 79 
10.6.8. 
Division of AIDS (DAIDS) Table for Grading Severity of 
Adult and Pediatric AEs ............................................................... 80 
11. REFERENCES ....................................................................................................... 81 
 
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LIST OF TABLES 
PAGE 
Table 1 
Screening Visit ....................................................................................... 18 
Table 2 
Study Session to Final Visit and Early Withdrawal .................................. 19 
Table 3 
Acceptable Visit/Time Point Windows .................................................... 21 
Table 4 
Risk Assessment .................................................................................... 24 
Table 5 
Study Intervention(s) Administered......................................................... 37 
Table 6 
Randomization Schedule ....................................................................... 40 
Table 7 
Hematological Monitoring Criteria .......................................................... 42 
Table 8 
Timeframes for Submitting SAE and Pregnancy Reports to GSK ........... 49 
Table 9 
Contact Information for Reporting SAEs and Pregnancies ..................... 50 
 
 
Table 11 
Protocol-required Safety Laboratory Tests ............................................. 64 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study Design Overview .......................................................................... 16 
Figure 2 
Study Design .......................................................................................... 17 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACR 
Albumin to creatinine ratio 
ADA 
Anti-drug antibodies. 
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransaminase 
ANCA 
Anti-neutrophil cytoplasmic antibodies 
APTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
AUC(0-inf) 
Area under the concentration-time curve from time zero extrapolated 
to infinity 
AxMP 
Auxiliary medicinal product 
C3/C4 
Complement component 3/ Complement component 4 
CA 
Competent authority 
CHB 
Chronic hepatitis B 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus disease 2019 
CRF/eCRF 
Case report form/electronic case report form 
CSR 
Clinical study report 
CV 
Coefficient of variation 
CVb 
Between subject coefficient of variation 
DAIDS 
Division of AIDS 
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Abbreviation 
Definition 
DIVI 
Drug Induced Vascular Inflammation  
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration, United States of America 
GCP 
Good clinical practices 
GFR 
Glomerular filtration rate 
GSK 
GlaxoSmithKline 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HCP 
Healthcare professionals 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICSR 
Individual case safety reports 
IEC 
Independent ethics committee 
IFU 
Instructions for use 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
MDR 
Medical Device Regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIMP 
Non-investigational medicinal product 
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Abbreviation 
Definition 
NQ 
Non-quantifiable 
PCR 
Polymerase chain reaction 
PFS 
Prefilled syringe 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
QTL 
Quality tolerance limit 
RPGN 
Rapidly progressive glomerulonephritis 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome coronavirus 
SoA 
Schedule of activities 
SOC 
System organ class 
SPEP 
Serum Protein Electrophoresis 
SRT 
Safety Review Team 
SSD 
Safety syringe device 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
UPEP 
Urine Protein Electrophoresis 
USADE 
Unanticipated serious adverse device effect 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
 
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Term 
Definition 
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e. by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced 
Intervention number 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational medicinal 
product 
An IMP is a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a 
clinical study, including products already with a 
marketing authorization but used or assembled 
(formulated or packaged) in a way different from the 
authorized form, or when used for an unauthorized 
indication, or when used to gain further information 
about the authorized form. Medicinal products with a 
marketing authorization are IMPs when they are to be 
used as the test substance, reference substance, or 
comparator in a clinical study, provided the 
requirement(s) in the definition is/are met. 
Investigator 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions 
NIMP/AxMPAxMP 
A NIMP or AxMP is a medicinal product that is not 
classified as an IMP in a study, but may be taken by 
participants during the study, e.g., concomitant or 
rescue/escape medication used for preventive, 
diagnostic, or therapeutic reasons or medication given to 
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Term 
Definition 
ensure that adequate medical care is provided for the 
participant during a study. 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Primary Completion Date 
The date on which the last participant in a clinical study 
was examined or received an intervention to collect final 
data for the primary outcome measure. 
Whether the clinical study ended according to 
the protocol or was terminated does not affect this date. 
For clinical studies with more than one primary outcome 
measure with different completion dates, this term refers 
to the date on which data collection is completed for all 
the primary outcome measures.  
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Source data 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 
Study intervention 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Note: “Study intervention” and “study treatment” are 
used interchangeably unless otherwise specified. 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 
collect final data for the primary outcome 
measures, secondary outcome measures, and AEs (that 
is, the last participant's last visit or LSLV). 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, randomized, open-label, parallel group study to evaluate the 
relative bioavailability of subcutaneous bepirovirsen when delivered from a vial or 
prefilled syringe fitted with a safety syringe device in healthy adult participants 
Brief Title: A study to evaluate the relative bioavailability of subcutaneous bepirovirsen 
when delivered from a vial or prefilled syringe fitted with a safety syringe device in 
healthy adult participants 
Rationale: Refer to Section 2.1. 
Objectives, Endpoints, and Estimands: Refer to Section 3. 
Overall Design: Refer to Section 4.1. 
Number of Participants: Refer to Section 9.5. 
Data Monitoring/Other Committee: Refer to Section 10.1.5. 
 
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1.2. 
Schema 
Figure 1 
Study Design Overview 
 
 
 
 
 
 
 
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Figure 2 
Study Design 
 
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1.3. 
Schedule of activities (SoA) 
Table 1 
Screening Visit  
Procedure 
Screening 
(up to 28 days 
before first dose) 
Notes 
Informed consent 
X 
 
Inclusion and exclusion criteria 
X 
 
Demography 
X 
 
Past and current medical conditions 
X 
 
Full physical examination including 
height and weight  
X 
At a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and 
neurological systems. 
Vital signs 
X 
Blood pressure and heart rate in triplicate; mean of 
3 measurements used to confirm eligibility. 
Respiratory rate and temperature, single 
measurements. 
COVID-19 test 
X 
Using a PCR or antigen test approved by the country 
regulatory authorities. 
Human immunodeficiency virus, 
hepatitis B and C screening  
X 
If test otherwise performed within 3 months before first 
challenge day, testing at screening is not required. 
Medication/drug/alcohol history 
X 
Includes substance usage and current medical 
condition.  
Drug, alcohol, and cotinine screen 
X 
As per standard local practice. 
12-lead ECG 
X 
In triplicate; mean of 3 measurements used to confirm 
QTc eligibility. 
Follicle-stimulating hormone 
X 
As needed, to confirm postmenopausal status. 
Serum pregnancy test 
X 
WOCBP only. 
Clinical chemistry, hematology and 
urinalysis 
X 
 
Urine ACR 
X 
 
C3, C4, hs-CRP, p-ANCA, c-ANCA 
X 
MPO-ANCA and PR3-ANCA to be performed if p-
ANCA or c-ANCA is positive. 
Rheumatoid Factor 
X 
 
Coagulation Panel (PT, INR, APTT) 
X 
 
Alpha-fetoprotein (AFP) 
X 
 
AE and SAE review 
X 
From signing consent. AEs and SAEs that occur prior 
to the first administration of IMP should be recorded 
only if assessed as related to study participation (e.g., 
protocol mandated procedures or invasive tests). 
Prior medication 
X 
 
ACR = Albumin to creatinine ratio. AE = adverse event. ANCA = Anti-neutrophil cytoplasmic antibodies. APTT = 
Activated partial thromboplastin time. C3/C4 = Complement. COVID-19 = Coronavirus disease 2019. ECG = 
electrocardiogram. hs-CRP = High-sensitivity C-reactive protein. IMP = Investigational medicinal product. INR = 
International normalized ratio. PCR = polymerase chain reaction. PT = Prothrombin time. SAE = serious adverse 
event. WOCBP = Woman of childbearing potential.  
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Table 2 
Study Session to Final Visit and Early Withdrawal 
Procedure 
Day 
Early 
withdrawal 
Notes 
Refer to Table 3 for acceptable time windows 
Inpatient stay 
<============> 
 
 
 
 
 
 
 
 
Outpatient visit 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Brief physical 
examination 
 
X1 
X1 
 
X1 
X 
X 
X 
X 
X 
X 
An interim symptom-targeted brief physical examination.  
1Within 1 h before dosing and at 24 and 72 h after dosing. 
Vital signs 
X 
X2 
X2 
X2 
X2 
X 
X 
X 
X 
X 
X 
Blood pressure and heart rate in triplicate before dosing, and 
single measurements after dosing. Respiratory rate and 
temperature, single measurements at all time points. 
2Within 1 h before dosing and at 24, 48 and 72 h after dosing. 
COVID-19 test 
X 
 
 
 
 
 
 
 
 
 
 
Using a PCR or antigen test approved by the country 
regulatory authorities. Test can be performed before Day –1 if 
required before admission for inpatient stay. 
Drug, alcohol, 
and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
 
As per standard local practice. 
Safety 12-lead 
ECG 
X 
X3 
X3 
X3 
 
 
 
 
 
 
X 
In triplicate before dosing; single measurements after dosing. 
3Within 1 h before dosing and at 24 and 48 h after dosing. 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
X 
Serum or urine. WOCBP only. 
Clinical 
chemistry, 
haematology 
and urinalysis 
 
X1 
X1 
 
 
X 
X4 
X4 
X4 
X 
X 
1Within 1 h before and at 24 and 72 h after dosing. 
4If results on Day 15 are within normal range, Day 29 and 43 
tests are not required, and the next required time point is 
Day 64.  If results on Day 15 are out of normal range, test 
should be repeated on Day 29; if results are still out of range 
on Day 29, test should be repeated on Day 43. 
Urine ACR 
 
X5 
X5 
 
 
 
X 
 
X 
 
X 
5Within 1 h before and at 24 h after dosing. 
C3, C4, hs-CRP, 
p-ANCA, c-
ANCA 
 
X6 
 
 
 
 
 
 
 
 
 
6Within 1 h before dosing. 
Post-dose sample to be taken only if the investigator 
considered there was an event of vascular inflammation  
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Procedure 
Day 
Early 
withdrawal 
Notes 
Refer to Table 3 for acceptable time windows 
Coagulation 
Panel (PT, INR, 
APTT) 
 
X6 
 
 
 
 
 
 
 
 
 
6Within 1 h before dosing.  
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
dose of 
bepirovirsen  
 
 
 
 
 
 
 
 
 
 
Assessment of 
injection site 
 
X2 
X2 
X2 
X2 
X 
X 
X 
X 
X 
X 
2Within 1 h before dosing and at 24, 48 and 72 h after dosing. 
AE and SAE 
review 
<=============================================> 
AEs and SAEs that occur prior to the first administration of 
IMP should be recorded only if assessed as related to study 
participation (e.g., protocol mandated procedures or invasive 
tests). 
Prior/ 
concomitant 
medication 
review 
<=============================================> 
 
ACR = Albumin to creatinine ratio. AE = adverse event. ANCA = Anti-neutrophil cytoplasmic antibodies. APTT = Activated partial thromboplastin time. C3/C4 = Complement. COVID-19 
= Coronavirus disease 2019. ECG = electrocardiogram. hs-CRP = High-sensitivity C-reactive protein. IMP = Investigational medicinal product. INR = International normalized ratio. 
PCR = polymerase chain reaction. PFS = prefilled syringe. PK = pharmacokinetic. PT = Prothrombin time. SAE = serious adverse event. WOCBP = Woman of childbearing potential 
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Table 3 
Acceptable Visit/Time Point Windows 
Assessment 
Planned Timepoint 
Acceptable window 
Safety assessments*  
Within 1 h before dosing 
Within 90 min before dosing 
Up to Day 3 
+/- 15 min 
Day 4 
+/- 8 h 
Day 8 and 15 
+/- 1 day 
Day 29 onwards 
+/- 3 days 
*Vital signs, 12-lead ECG, clinical laboratory tests, assessment of injection site 
 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
The aim of this study is to provide relative bioavailability data to support the transition 
from the vial presentation of bepirovirsen, which is currently under investigation in the 
Phase 3 trials, to a ready-to-use liquid in a PFS fitted with an SSD. The study in healthy 
participants is intended to demonstrate comparable bepirovirsen pharmacokinetics of SC 
injections of: 
• Vial and PFS SSD presentations, when administered by an HCP; and 
• HCP administration and self-administration of the PFS SSD. 
 
Safety and tolerability will also be assessed.  
2.2. 
Background 
HBV infection, especially chronic infection, is a significant worldwide medical problem. 
Globally, in 2019, an estimated 296 million people were living with chronic HBV 
infection. Viral hepatitis led to 1.34 million deaths and of these deaths, 66% were the 
result of complications of chronic HBV infection [WHO, 2017; WHO, 2021]. 
The goal of therapy for chronic HBV infection is to improve quality of life and survival 
by preventing progression of the disease to cirrhosis, decompensated liver disease, end 
stage-liver disease, HCC, or death. This goal can be achieved if HBV replication is 
suppressed in a sustained manner, thereby decreasing the histological activity of chronic 
HBV infection and reducing the risk of cirrhosis and HCC [Liaw, 2004; Feld, 2009]. In 
both HBeAg positive- and -negative chronic HBV infection, the ultimate treatment 
endpoint is loss of detectable serum HBsAg [Lok, 2017; EASL, 2017]. However, despite 
treatment with approved therapies, including nucleoside or nucleotide (nucleos(t)ide) 
analogue and/or pegylated interferon, rates of HBsAg loss following 12 months of 
treatment generally range- from 0% to 3% in most studies [Lok, 2017; EASL, 2017]. 
Bepirovirsen, an antisense oligonucleotide, was designed to inhibit the synthesis of HBV 
viral proteins. The binding site for bepirovirsen is present within all HBV mRNA and 
pgRNA. Bepirovirsen directly targets HBV RNAs via RNase H mediated degradation, 
resulting in the reduction of viral proteins, including HBsAg. Bepirovirsen treatment 
permits examination of reduction in serum levels (including HBsAg) and HBV 
RNA/DNA [Yuen, 2007]. Bepirovirsen allows resumption of a host immune response 
against HBV and infected cells and can induce HBsAg seroclearance.  
Bepirovirsen Solution for Injection, 
mg/mL is a single-use sterile liquid drug product 
supplied in a clear glass vial. A ready-to-use PFS assembled into an SSD has been 
developed which will be more convenient and may allow the ultimate goal of patient self-
administration.  
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The formulation is unchanged between vial and safety syringe device. Consequently the 
likelihood of clinically significant differences in the systemic exposure, efficacy or safety 
profile is considered to be low. The relative bioavailability study will compare 
bepirovirsen exposures (AUC and Cmax) between vial and PFS SSD to ensure 
comparable PK exposures. The study will also compare bepirovirsen exposures between 
HCP administration and self-administration using the PFS SSD presentation. 
A full description of the liquid drug product (vial and PFS SSD) is given in the 
Investigators’ Brochure Supplement [GSK Document No.: RPS-CLIN-035276]. 
2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks, and 
reasonably expected AEs of bepirovirsen may be found in the IB [GSK Document No.: 
RPS-CLIN-035276]. 
 
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2.3.1. 
Risk assessment 
Relevant risks associated with bepirovirsen treatment in this study are summarized in Table 4. A thorough description of all risks is 
included in the IB (Section 6). Additional monitoring for liver chemistry, DIVI, platelet count, renal function are discussed in Section 7.1. 
For a 
dose administration of 
mg, the risks are of low likelihood but cannot be ruled out. 
Table 4 
Risk Assessment 
Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
  
Mitigation Strategy 
 
Study Intervention(s) [Bepirovirsen] 
Non-clinical Risks: 
Drug Induced Vascular Inflammation (DIVI) and 
Complement Activation 
Inflammatory and immune changes are 
recognized as a class effect of ASOs. Vasculitis 
and/or perivascular inflammation has been 
described in monkey studies with many, if not 
most ASOs. 
DIVI has not been observed in clinical studies 
with bepirovirsen to date. 
Laboratory Evaluations: Inclusion of tests for 
biomarkers of inflammation/complement 
activation that would be expected to accompany 
vascular injury are to be taken at the time of a 
clinical event that is suggestive of vasculitis 
and/or immune activation and compared to 
referenced baseline measurements. 
A monitoring strategy is included (see Section 
7.1.4) 
Clinical Risks: 
Serious liver injury 
The liver is a site of accumulation of ASOs. 
Liver findings in nonclinical studies of 
bepirovirsen were generally limited to mild 
hepatic enzyme elevations associated with 
hepatic vacuolation without concomitant 
histologic evidence of degeneration in mice, 
consistent with findings noted with other 2’-
methoxyethyl (MOE) ASOs. Review of the 
The risk of serious liver injury is very low after a 
single dose of bepirovirsen. Neverless, hepatic 
enzyme monitoring will be performed (see 
Section 7.1.1). 
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Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
  
Mitigation Strategy 
 
available clinical data indicates liver enzymes 
are increased on treatment with ASOs (for 
treatment of diseases other than chronic HBV 
infection) in a low percentage of patients 
compared to placebo. A prior single dose study 
in healthy volunteers (213725) did result in an 
ALT increase > ULN in 1 participant treated with 
 mg bepirovirsen. This was not associated 
with other changes in liver chemistry (e.g., 
bilirubin, INR) and did not have a clinical 
consequence. Review of AE data and laboratory 
data in Phase 2a and Phase 2b studies in 
participants with CHB in which bepirovirsen was 
given weekly for 4 weeks and 24 weeks 
respectively and where ALT increases > 3xULN 
were observed, showed no evidence of DILI. 
Injection site reactions 
ISRs have been reported with ASOs and 
reported in clinical studies with bepirovirsen. 
ISRs were the most common study treatment-
related AEs with the majority reported as Grade 
1 severity (mild). The majority of ISRs are 
reported as injection site erythema, injection site 
pain and injection site pruritus. Few events have 
led to treatment discontinuation. 
Evaluations: Participants are assessed for ISRs 
at all visits as per the SoA. 
 
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Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
  
Mitigation Strategy 
 
Study Procedures  
Blood drawn  
Risks with phlebotomy include bruising, 
bleeding, infection, and nerve damage. 
Procedures to be performed by trained 
personnel (i.e., study nurse). 
 
Handling and usage risks associated with 
PFS SSD  
The IMP will be administered by or under the 
supervision of health care professionals. 
Anticipated device effects are nonserious, 
effects are unlikely, improbable, occasional, or 
remote and any effects are due to user errors. 
Instructions for use on how to handle and use 
the devices will be provided. 
 
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2.3.2. 
Benefit assessment 
As this Phase 1 study will be conducted in healthy adult participants, there will be no 
direct benefit to study participants included in this study.  
Participants in this study will contribute to the development of an improved delivery of 
treatment for patients with CHB. 
2.3.3. 
Overall benefit-risk conclusion 
Whilst there is no benefit of treatment to the participant in this study, measures have been 
taken to minimize the participant’s risk of participation.
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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Objective(s) 
Endpoint(s) 
Primary 
• 
To estimate the relative bioavailability of vial and 
PFS SSD for a single dose of bepirovirsen 
delivered by SC injection by an HCP in healthy 
participants 
• 
Cmax and AUC(0-inf) of bepirovirsen in plasma. 
Secondary 
• 
To estimate the relative bioavailability of HCP 
administered vs self-administration following HCP 
training for a single dose of bepirovirsen delivered 
by SC injection in healthy participants 
• 
Cmax and AUC(0-inf) of bepirovirsen in plasma. 
• 
To estimate the relative bioavailability of HCP 
administered vs self-administration with no HCP 
training for a single dose of bepirovirsen delivered 
by SC injection in healthy participants 
• 
Cmax and AUC(0-inf) of bepirovirsen in plasma. 
Safety 
• 
To compare the safety and tolerability of 
 
 of bepirovirsen 
mg by randomized 
group. 
• 
Occurrences of AEs and SAEs 
• 
Change from baseline at each time point in clinical 
laboratory tests and vital signs 
Exploratory 
 
 
 
Primary estimand 
The primary interest is to estimate the relative bioavailability, measured by Cmax and 
AUC(0-inf), following a
 of bepirovirsen via PFS SSD versus a vial in healthy 
adult participants. 
The primary PK estimands are described by the following attributes: 
• Population: 
Healthy male and female participants aged 18 to 55 years. 
• Treatment Condition: 
 of bepirovirsen injection administered via PFS SSD versus 
 of bepirovirsen administered via a vial. 
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• Variables: 
AUC(0-inf) and Cmax. 
• Summary measure: 
Ratio of geometric means of PFS SSD versus vials for Cmax and AUC(0-
inf). 
• Intercurrent Events: 
Use of prohibited medication. This intercurrent event is not expected to 
impact the PK of bepirovirsen so a treatment policy strategy will be used, 
and the individual PK concentrations after the occurrence of the 
intercurrent event will still be included in the PK analysis. 
Participants who did not receive 
 the injections and had an 
incomplete or erroneous dosing. A principal stratum strategy policy will 
be used, where the strata of interest is the group of participants who are 
able to receive the complete dose. 
A supplemental estimand will also be analyzed as per the primary 
estimand, except for the intercurrent event of incomplete dosing will use a 
treatment policy strategy.  
Secondary estimand(s) 
The secondary interest is to estimate the relative bioavailability, measured by Cmax and 
AUC(0-inf): 
1. Following a
f bepirovirsen via PFS SSD versus self-administration 
of a single dose of bepirovirsen with HCP training  
2. Following a
of bepirovirsen via PFS SSD versus self-administration 
of a single dose of bepirovirsen with no HCP training. 
The secondary PK estimands are described by the following attributes: 
• Population: 
Healthy male and female participants aged 18 to 55 years.  
• Treatment condition: 
 dose of bepirovirsen administered via PFS SSD versus self-
administration of a single dose of bepirovirsen with HCP training. 
 dose of bepirovirsen administered via PFS SSD versus self-
administration of a single dose of bepirovirsen with no HCP training. 
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• Variables: 
AUC(0-inf) and Cmax. 
• Summary measure: 
Ratio of geometric means of PFS SSD versus self-administration with 
HCP training and with no HCP training for Cmax and AUC(0-inf). 
• Intercurrent Events: 
Use of prohibited medication. This intercurrent event is not expected to 
impact the PK of bepirovirsen so a treatment policy strategy will be used, 
and the individual PK concentrations after the occurrence of the 
intercurrent event will still be included in the PK analysis. 
Participants who did not receive 
 the injections and had an 
incomplete or erroneous dosing. A principal stratum strategy policy will 
be used, where the strata of interest is the group of participants who are 
able to receive the complete dose. 
Supplemental estimands will also be analysed as per the secondary 
estimand, except for the intercurrent event of incomplete dosing will use a 
treatment policy strategy.  
4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a Phase 1, open-label, randomized study to investigate SC bepirovirsen when 
delivered via SC injection from vial or PFS SSD in healthy adult participants. The study 
will assess relative bioavailability, safety and tolerability, as well as the usability of the 
PFS SSD for self-administration.  
A total of approximately 
 participants will each complete a single study session, in a 
parallel design, and will each take up to 
 weeks to complete the study.  
Participants will be screened within 28 days before dosing. They will attend the clinical 
unit the day before dosing (Day –1) and will remain inpatient until 2 days after dosing 
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(Day 3). They will receive bepirovirsen 
 mg as 
 mg SC injections on Day 1, 
randomized 3:3:2:2 to:  
 
The randomization will be stratified by body weight (
 
. The site of injection will be randomized in a 1:1:1 ratio to the upper arm, abdomen, 
or thigh in Groups 1 and 2, and in a 1:1 ratio to abdomen or thigh in Groups 3 and 4.  
Participants will return for outpatient visits on Days 
 
Blood samples will be taken to measure levels of bepirovirsen and ADAs against 
bepirovirsen, and safety and tolerability will be assessed from before dosing and until the 
final visit. The observing HCP and participants in Groups 3 and 4 will complete 
questionnaires, respectively, during and after dosing, to assess usability of the PFS SSD 
for self-administration. Blood samples will also be taken for biomarker analysis before 
dosing and up to 48 h after dosing. 
The study design schematic is presented in Section 1.2. 
4.2. 
Scientific rationale for study design 
Conducting the study in healthy participants mitigates the recruitment and patient burden 
limitations with administering a single dose of bepirovirsen to CHB patients. A 
population of healthy participants is frequently used in the assessment of the relative 
bioavailability of both small and large molecules. In addition, healthy participants are a 
suitable population for biopharmaceutical PK comparability studies, and the data can be 
extrapolated to other populations. In addition, usability of the PFS SSD can be reliably 
assessed in healthy participants via questionnaires to support design of the human factors 
summative evaluation.  
 
 
.  
Bepirovirsen has a half-life of approximately 
 in healthy subjects. A 
 
 
 
 
 
 
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A 
dose of bepirovirsen will be administered as  injections at 1 of 3 injection sites 
(upper arm, abdomen, or thigh) when administered by an HCP, or at 1 of 2 injections 
sites (abdomen or thigh) when self-administered. Upper arm is not a feasible 
administration site for self-administration. To prevent bias and maintain balance in 
treatment groups, the injection site will be randomized in addition to the randomization 
for device. To minimize the impact of potential confounding factors and variability, the 
randomization will also be stratified by body weight as this has been associated with 
bepirovirsen exposure. 
Collection of PK blood samples up to Day 
 will ensure that the bepirovirsen plasma 
concentration-time profile is well described with the extrapolated portion of AUC(0-inf) 
below 
 
The study will be open-label. This is acceptable because the primary and secondary 
endpoints are PK parameters, which are not subjective measures. Any potential for 
selection bias will be reduced by central randomization. 
4.2.1. 
Participant input into design 
Participant input into the study design is not deemed necessary for this Phase 1 clinical 
pharmacology study. 
4.3. 
Justification for dose 
A 
 of bepirovirsen 
mg will be administered as 
mg SC injections 
provided as vials or PFS SSD on Day 1. 
 
 
. 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last visit shown in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the 
study.  
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
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AGE 
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, ECGs and vital signs.  
WEIGHT 
3. Body weight 50 kg and body mass index (BMI) within the range 19 to 29.9 kg/m2 
(inclusive). 
SEX 
4. Male and/or female. 
a. There are no contraceptive requirements for male participants.  
b. A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and 1 of the following conditions applies: 
• Is a WONCBP as defined in the protocol (Section 10.4) 
OR 
• 
Is a WOCBP and using a contraceptive method (for a period of 28 days before 
dosing) that is highly effective (with a failure rate of <1% per year), preferably 
with low user dependency, as described in Appendix 4 of the protocol during 
the study intervention period and for at least 7 days after the last dose of study 
intervention and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. The investigator should evaluate the potential 
for contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention.  
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.  
• If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.  
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
INFORMED CONSENT 
5. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
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5.2. 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematologic, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the 
study intervention or interfering with the interpretation of data. 
2. Abnormal blood pressure as determined by the investigator. 
3. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell 
or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
4. Participants with signs or symptoms suggestive of COVID-19 (e.g., fever, cough) 
within 14 days of inpatient admission. 
5. Participants with any other medical conditions which, in the judgement of the 
investigator and Medical Monitor, could jeopardize the integrity of the data derived 
from that participant or the safety of the participant. 
6. Platelets <140x109/L. 
7. ALT >1.5xULN  
8. Total bilirubin >1.5xULN (isolated total bilirubin >1.5xULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%).  
9. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
10. QTcF >450 msec. 
Prior/Concomitant Therapy 
11. Past, current or intended use of over-the-counter or prescription medication 
[including herbal medications] within 7 days or 5 half-lives (whichever is longer) 
before dosing [Specific medications listed in Section 6.9 of the protocol may be 
allowed].  
12. Current or prior use of creatine-containing supplements and intended use up to 
50 days post-dosing. 
13. Prior use of immunosuppressive drugs within 3 months before dosing or interferon 
within 12 months before dosing. 
14. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 
12 months before dosing. 
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Prior/Concurrent Clinical Study Experience 
15. Loss of blood or blood products in excess of 500 mL within any 3-month period 
during the study. 
16. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 
17. Current enrollment or past participation in another investigational study in which an 
investigational intervention (e.g., drug, vaccine, invasive device) was administered 
within 5-half-lives (if known) or twice the duration of biological effect (if known), 
whichever is longer, or within the last 90 days (if half-life and duration of biological 
effect are unknown), before the first dosing day in the current study.  
18. Current enrollment or past participation in this clinical study. 
Diagnostic Assessments 
19. Presence of HBsAg at screening or within 3 months before dosing. 
20. Positive hepatitis C antibody test result at screening or within 3 months before dosing. 
NOTE: Subjects with positive hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained. 
21. Positive hepatitis C RNA test result at screening or within 3 months before dosing. 
NOTE: Test is optional and subjects with negative hepatitis C antibody test are not 
required to also undergo hepatitis C RNA testing. 
22. Positive pre-study drug/alcohol screen, including THC. 
23. Positive HIV antibody test. 
24. Cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening. 
25. A positive test for active COVID-19 infection at or before admission for the inpatient 
stay. The testing should be done using a molecular polymerase chain reaction (PCR) 
or antigen test approved by the country regulatory authorities. 
Other Exclusion Criteria 
26. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >14 units for males or females. One unit is equivalent to 8 g 
of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of spirits.  
27. Regular use of known drugs of abuse, including THC. 
28. History of sensitivity to bepirovirsen or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor 
contraindicates their participation. 
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5.3. 
Lifestyle considerations 
5.3.1. 
Meals and dietary restrictions 
No restrictions. 
5.3.2. 
Caffeine, alcohol, and tobacco 
• 
Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 2 hours before the start of dosing 
until 1 hour after dosing. 
• 
Participants will abstain from alcohol for 24 hours before admission until discharge 
from the clinical unit.  
• 
Use of tobacco- and nicotine-containing products is not allowed from 6 months prior 
to screening until after the final follow-up visit. 
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise (exertion requiring maximum 
physical effort/strength) for 48 hours before each blood collection for clinical 
laboratory tests. Participants may participate in light recreational activities during the 
study (e.g., watching television, reading). 
5.3.4. 
Other restrictions 
Participants will be asked to refrain from donating blood for the duration of their study 
participation. 
5.4. 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened unless discussed and agreed with the Medical Monitor. Individuals 
who fall out of the screening window, may be rescreened at the discretion of the 
investigator. 
5.5. 
Criteria for temporarily delaying  
Not applicable. 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol, and further details in Table 5. 
6.1. 
Study intervention(s) administered 
Table 5 
Study Intervention(s) Administered 
Intervention Label 
Open Label  
Open Label 
Intervention Name 
Bepirovirsen,  
(GSK3228836)  
Bepirovirsen,  
(GSK3228836)  
Intervention Description 
Bepirovirsen solution for 
injection, 
mg/mL 
packaged in a vial. 
 
 required to 
deliver 
mg dose. 
Bepirovirsen solution for 
injection, 
mg/mL 
packaged in a PFS fitted 
with a PFS SSD. 
 
 required to 
deliver 
mg dose. 
Type  
Drug 
Drug 
Dose Formulation 
Solution for injection 
Solution for injection 
Unit Dose Strength(s) 
 mg/mL 
 mg/mL 
Dosage Level(s) 
mg 
 mg 
Route of Administration 
SC Injection 
SC Injection 
Use 
Experimental 
Experimental  
IMP and NIMP/AxMP. 
IMP  
IMP 
Sourcing 
Supplied by GSK 
Supplied by GSK 
Packaging and Labeling 
Study intervention will be 
provided in a carton with 
an insert. Each carton will 
be labeled as required per 
country requirement. 
Study intervention will be 
provided in carton with an 
insert. Each carton will be 
labeled as required per 
country requirement. 
Bepirovirsen Solution for Injection, 
 mg/mL, is a clear, 
solution, 
essentially free from visible particles. Bepirovirsen vial is presented as a 1 mL nominal 
fill volume of Bepirovirsen Solution for Injection 
 mg/mL in a  mL clear glass vial, 
closed with a 
 rubber stopper and sealed with aluminium overseal with 
removeable plastic cap.  
The drug product is administered as  SC injections to deliver the clinical dose of 
 mg. It is recommended to use 27G thin-wall needles or 25G regular-walled needles 
for injection. 
The PFS SSD is a medical device and is described in Section 6.1.1. 
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6.1.1. 
Medical devices 
Bepirovirsen PFS SSD is a single use, prefilled, disposable device intended to enable 
manual delivery of the drug product while providing a needle shielding feature (post-use) 
and enhanced ergonomics. 
 
 
 
 
  
 
 
• 
Instructions for medical device use are provided 
 
• 
All device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.7 and Section 10.6) and appropriately managed by 
GSK. 
6.2. 
Preparation, handling, storage, and accountability 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff or HCP may supply, prepare, or administer study intervention 
(see Section 4.1).  
• 
All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
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• 
The investigator, institution, the head of the medical institution (where applicable), 
or authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the pharmacy manual. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
6.3. 
Assignment to study intervention 
Study intervention will be dispensed on Day 1 as summarized in the SoA (Section 1.3).  
The GSK Randomization Officer will use the Randall NG system to generate a 
randomization schedule.  
With central randomization, knowledge of the randomized treatment group for previous 
participants does not predict which treatment group will be assigned to the next 
randomized participant.  
Randomization and study intervention assignment will be facilitated by the IRT through 
the central RAMOS NG system. 
Following confirmation of fulfilment of study entry criteria, study site personnel will be 
required to register participants using RAMOS NG for assignment of a unique identifier 
which comprises of 4 digits (e.g., 1 001 and increasing) designating each participant’s 
randomization code and treatment sequence assignment.  
Prior to first dosing of each group, participants will be assigned a unique number 
(randomization number) in ascending numerical order. The randomization number 
encodes the participant’s assignment to one of the 4 treatment sequences of the study, 
according to the randomization schedule. 
6.4. 
Randomization 
This is an open-label study; Any potential for selection bias will be reduced by central 
randomization. 
A single randomization schedule will randomly assign participants pre-dose to treatment 
group and injection site according to the ratios shown in Table 6. 
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Additionally, randomization will be stratified by body weight (
 
). 
Table 6 
Randomization Schedule  
 
Injection Site 
Total 
Group 
Arm 
Thigh 
Abdomen 
 
1 
1 
1 
1 
3 
2 
1 
1 
1 
3 
3 
 
1 
1 
2 
4 
 
1 
1 
2 
 
6.5. 
Study intervention compliance 
All participants will be dosed at the clinical site, where they will receive study 
intervention directly from the investigator or designee, or they will self-administer the 
medication provided, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
intervention. 
6.6. 
Dose modification 
This is a 
 study in which dose modification is not permitted. 
6.7. 
Continued access to study intervention after the end of the 
study 
Not applicable. 
6.8. 
Treatment of overdose 
For this study, any dose of bepirovirsen greater than 
 mg within a 24-hour time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. In the event of an 
overdose, the investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until the 
study intervention can no longer be detected systemically (at least 50 days). 
Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF). 
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6.9. 
Prior and concomitant therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days 
if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the 
start of study intervention until completion of the follow-up visit, unless, in the opinion of 
the investigator and sponsor, the medication will not interfere with the study. 
Acetaminophen, at doses of 2 grams/day, is permitted for use any time during the study. 
Other concomitant medications may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor, if required. 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL- 
7.1. 
Discontinuation of study intervention 
Discontinuation of study intervention is not applicable in this study, as it is a single dose 
by design. Monitoring criteria are outlined in the section below. 
7.1.1. 
Liver chemistry monitoring criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event aetiology. Although stopping criteria for 
continued dosing of study intervention are not applicable for single dose studies, if 
participants are found to have values consistent with usual stopping parameters, it is 
appropriate to institute evaluation and monitoring criteria according to standard GSK 
criteria. Therefore, liver function tests should be evaluated according to stopping criteria 
and safety follow-up procedures/tests as specified in Appendix 6 should be instituted if 
defined parameters are reached. 
For ALT values ≥3xULN: 
• 
See Appendix 6 
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• 
if possible Hy’s Law case: ALT ≥3xULN and total bilirubin ≥2xULN (>35% 
direct) or INR>1.5, report as an SAE 
7.1.2. 
Hematological monitoring criteria 
Platelet counts must be re-checked as soon as possible (with a new blood sample) if the 
platelet count is uninterpretable, below the LLN reference range for healthy participants, 
or the sample shows platelet clumping.  
Monitoring criteria are shown in Table 7 
Participants with platelet counts <75x109/L will undergo further assessment including, 
but not necessarily limited to, anti-platelet antibodies. Monitor until platelet abnormalities 
resolve, stabilize, or return to within baseline values.  
After the dose is administered, if a participant develops signs or symptoms of 
thrombocytopenia, obtain a platelet count as soon as possible. 
 
Table 7 
Hematological Monitoring Criteria 
Platelet Count Value 
Monitoring 
75x109/L ≤ platelets <100x109/L 
Monitor weekly until ≥100x109/L 
50x109/L ≤ platelets <75x109/L 
Assess anti-platelet antibodies 
Monitor every 2 to 3 days until 3 successive 
measurements ≥75x109/L, then weekly until 
≥100x109/L  
<50x109/L 
Assess anti-platelet antibodies 
Monitor daily until >25x109/L, then every 2 to 3 days 
until 3 successive measurements ≥75x109/L, then 
weekly until ≥100x109/L 
7.1.3. 
Drug induced kidney injury (renal) monitoring 
If any of the following are observed, results should be confirmed (with a new blood 
sample), and if confirmed, further evaluation for alternative causes should be pursued in 
consultation with the Medical Monitor:  
• Persistent uACR 0.3 mg/mg (300 mg/g)  
• Blood in urinalysis 5 red blood cells per high power field confirmed by urine 
microscopy (unless there is a known cause [e.g., females during menstruation]) 
• Gradual and consistent reductions of eGFR compared with baseline.  
Following confirmation of the criteria above, if underlying cause other than drug-induced 
renal injury is not confirmed, further evaluation may include but not be limited to a 
24 hour urine analysis, consultation with a nephrology specialist, renal ultrasound, urine 
microscopy, serum urea and creatinine, platelet count, urgent serum vasculitis screen 
(including ANCA, ANA, dsDNA, Rheumatoid Factor, cryoglobulins), SPEP/UPEP, and 
complement panel (C3, C4, C5a and Bb). Further evaluation and actions should be 
determined by the investigator in consultation with the Medical Monitor.  
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Participants must be monitored weekly until uACR or eGFR resolve, stabilize, or return 
to within baseline values.  
If acute glomerulonephritis is confirmed or probable [i.e., meets clinical definition of 
RPGN if biopsy not feasible], delay in treatment of suspected RPGN should be avoided. 
 
7.1.4. 
Drug induced vascular injury and complement activation 
If the participant develops signs/symptoms of potential complement activation/DIVI 
including (but not limited to) new onset: persistent joint pain not resolved with simple 
analgesia, peripheral neuropathy, vasculitis/purpuric rash, signs of renal involvement, for 
example (haematuria; increasing presence of blood on urine microscopy, increasing urine 
ACR, rising creatinine, falling GFR), jaundice, haemolysis and/or thrombocytopenia, in 
addition to relevant investigations based on the participant’s symptoms and signs, the 
following tests should also be conducted: C3, C4, Factor Bb, C5a, Rheumatoid factor, 
cryoglobulins (locally if available), ANCA, SPEP, UPEP, hs-CRP and compared to 
baseline values, if available.  
Additional complement analyses for example CH50, Factor Bb level, Factor H level, 
sC5b-9 and samples for MCP-1 should also be considered in discussion with the Medical 
Monitor (who may consult with the internal Safety Panels). 
 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
At the time of discontinuing from the study, if possible, an early withdrawal visit should 
be conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued from the study at that time. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
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The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the CRF/eCRF for reasons including, but not limited to the list below: 
Reasons 
Additional items/Sub-reasons 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Physician Decision 
Specify 
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
Specify 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Other 
Death 
Specify 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE as per 
instructions in Section 10.3.4.5. 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods. These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
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• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Subjects who have signed informed consent 
but are not eligible to proceed should be recorded in the eCRF with a status of 
‘screen failure’. 
• 
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Administrative procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as date of birth, sex, race, and ethnicity in the 
participant’s eCRF.  
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2. 
Medical history 
The participant’s medical history will be obtained by interviewing the participant and/or 
review of the participant’s medical records. Any pre-existing conditions, signs and/or 
symptoms present prior to study start will be recorded in the eCRF. 
8.2. 
Efficacy assessments 
Not applicable for this study. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
Additional time points for safety tests (such as vital signs, physical examinations, and 
laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
8.3.1. 
Physical examination/history directed physical examination 
• 
At screening, a complete physical examination will include, at a minimum, 
assessments of the skin, cardiovascular, respiratory, gastrointestinal, and 
neurological systems. Height and weight will also be measured and recorded. 
• 
Symptoms directed examination will be conducted at all other time points. 
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• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Injection site reactions 
• 
Injection site reactions are any experiences which occur at the site of injection of the 
study treatment. Participants will be monitored closely for ISRs and ISRs should be 
recorded as AEs on a specific ISR eCRF page.  
• 
Injection site reactions will be graded according to the criteria provided in the 
DAIDS grading table (see Appendix 7). 
8.3.3. 
Vital signs 
• 
Temperature, heart rate, respiratory rate, and blood pressure will be assessed as 
outlined in the SoA (Section 1.3). 
• 
Blood pressure and heart rate measurements should be assessed in semi supine 
position (preferred, but not required) with a completely automated device. Manual 
techniques will be used only if an automated device is not available.  
• 
Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones) 
• 
For triplicate blood pressure and heart rate measurements before dosing, 3 
consecutive readings will be recorded at intervals of at least 1 minute. The full set of 
triplicates should be completed within a 5-minute recording period. The average of 
the 3 readings will be recorded.  
• 
Vital signs should be taken before blood collection for laboratory tests. 
8.3.4. 
Electrocardiograms 
• 
12-lead ECGs will be obtained as outlined in the SoA (Section 1.3), using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals. Manual calculation, if an automatic calculation is not available, is 
acceptable. 
• 
For triplicate measurements before dosing, 3 consecutive readings will be recorded 
at intervals of at least 1 minute. The full set of triplicates should be completed within 
a 5 minute recording period. The average of the 3 readings will be recorded.  
• 
ECGs should be taken before blood collection for laboratory tests. 
8.3.5. 
Clinical safety laboratory tests 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed in accordance 
with lab manual and the SoA (Section 1.3). 
• 
The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents. Clinically significant 
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abnormal laboratory findings are those judged at investigator discretion based on 
being more severe than expected for the participant's condition.  
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significantly abnormal by the 
investigator or Medical Monitor.  
o 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the 
Sponsor notified.  
o 
If laboratory values from non-protocol specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.3.6. 
Pregnancy testing 
• 
Female participants of childbearing potential must perform a screening serum 
pregnancy test, and a serum or urine pregnancy test on admission to the clinical unit, 
before the administration of any dose of study intervention. Pregnancy testing must 
be done even if the participant is menstruating at the time of the study visit. The 
study intervention may only be administered if the pregnancy test is negative. 
• 
Refer to Section 8.4.6 for the information on study continuation for participants who 
become pregnant during the study. 
 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and 
other safety reporting 
The definitions of AEs or SAEs can be found in Section 10.3 (Appendix 3). 
AEs will be reported by the participant. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue study intervention (see Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
(Appendix 3).  
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
• 
All AEs and SAEs will be collected from the signing of the informed consent until 
the final follow-up visit at the time points specified in the SoA (Section 1.3). 
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However, AEs and SAEs that occur prior to the first administration of IMP should be 
recorded only if assessed as related to study participation (e.g., protocol mandated 
procedures or invasive tests). 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF not the AE section. 
• 
All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of it 
being available. 
• 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the Sponsor. 
8.4.2. 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.4.5 and/or Section 10.6.4.4. 
8.4.4. 
AESIs  
8.4.4.1. 
ALT increases 
The liver is a site of accumulation of ASOs and this has been exploited in the treatment 
of liver related diseases. ALT increases to levels > ULN were observed in healthy 
participants. These were not associated with concurrent symptoms or increases in 
bilirubin levels and all ALT increases returned to baseline levels during post-treatment 
follow-up. 
 
A monitoring strategy for ALT is presented in Section 7.1.1. 
8.4.4.2. 
Vascular Inflammation and complement activation  
Inflammatory and immune changes are recognized as a class effect of ASOs. Despite the 
low risk for ASO-related vascular AEs in participants, the nature of the toxicity demands 
a conservative approach to care and monitoring to ensure the safety of participants.  
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A monitoring strategy is presented in 7.1.4 
8.4.4.3. 
Thrombocytopenia 
Thrombocytopenia, decreased platelets, is a well-recognized toxicity associated with 
ASOs and is monitorable in the clinic. Two types of thrombocytopenia have been 
described by the FDA amongst the 2-MOE ASOs. One type is a rapid onset, 
unpredictable thrombocytopenia that may present with mild or moderate bleeding, 
however, catastrophic, fatal bleeding can occur. The other more common type is 
characterized by a gradual decline in platelets leading to mild to severe thrombocytopenia 
and can be asymptomatic or associated with mild to severe bleeding. 
A monitoring strategy of platelet count is presented in Section 7.1.2 
8.4.4.4. 
Renal Injury 
Glomerulonephritis, including rapidly progressing glomerulonephritis, has been reported 
with ASOs and is thought to be a result of the proinflammatory effect of ASOs. 
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, is 
thought to sometimes lead to increased tubular proteinuria (as described in preclinical 
studies). Increases in urine protein have been described in the clinic. 
A monitoring strategy of renal function (e.g., serum creatinine, ACR) is presented in 
Section 7.1.3 
8.4.5. 
Regulatory reporting requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met. See Section 8.4.1 
for reporting timeframes. 
• 
For SAEs/ the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.4.3. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
Table 8 
Timeframes for Submitting SAE and Pregnancy Reports to GSK  
Type of event 
Initial reports 
Follow-up of relevant information on 
a previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
electronic AEs 
Report 
24 hours* 
electronic AEs Report 
Pregnancies 
24 hours* 
paper pregnancy 
notification report  
24 hours * 
paper pregnancy follow-
up report  
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
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‡ Paper AEs Report will be dated and signed by the investigator (or designee). For each SAE/AESI, the investigator(s) 
must document in the medical notes that they have reviewed the SAE/AESI and have provided an assessment of 
causality. 
8.4.6. 
Pregnancy 
Female participants who become pregnant after administration of the study intervention 
may continue the study at the discretion of the investigator.  
• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention and until no longer than 6 to 8 weeks following the estimated 
delivery date. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
participant pregnancy. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. See Table 8 for reporting 
timeframes. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Sponsor as described in 
Section 8.4.5. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
 
8.4.7. 
Contact information for reporting SAEs and pregnancies 
Table 9 
Contact Information for Reporting SAEs and Pregnancies  
Study contact for questions regarding SAEs, pregnancies and SAEs linked to device 
deficiencies 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs, pregnancies and SAEs linked to device deficiencies 
Available 24/24 hours and 7/7 days 
For medicines: uk.gsk-rd-gcsp-ctsm-admin@gsk.com  
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8.4.8. 
Medical device deficiencies  
Medical devices (PFS SSD) are being provided for use in this study as the study 
intervention from Groups 2 to 4. To fulfill regulatory reporting obligations worldwide, 
the investigator is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices. 
The definition of a medical device deficiency can be found in Section 10.6. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.6 of the protocol.  
8.4.8.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• If the investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the investigator will promptly 
notify the sponsor. 
The method of documenting medical device deficiencies is provided in Section 10.6. 
8.4.8.2. 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those who discontinue study 
intervention. 
• The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
8.4.8.3. 
Prompt Reporting of Device Deficiencies to the Sponsor 
• Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device deficiency. 
• The medical device deficiency report form will be sent to the sponsor by email to 
gsk-rd.complaints@gsk.com and also to OAX37649@gsk.com if there is an 
associated SAE. If email is unavailable, then fax +44(0)20 8181 4780 should be 
utilized. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
8.4.8.4. 
Regulatory Reporting Requirements for Device Deficiencies 
• The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies. 
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• The investigator, or responsible person according to local requirements (e.g., the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.5. 
Pharmacokinetics 
Blood samples for pharmacokinetic analysis of bepirovirsen will be collected at the time 
points indicated in SoA (Section 1.3). Each PK sample must be collected as close as 
possible to the planned time relative to when the dose is administered to the participant 
(which is 0 hour on Day 1). The actual date and time of each blood sample collection will 
be recorded. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring.  
Each blood sample will be processed into plasma and divided into 2 aliquots (1 each for 
PK and a back-up). Samples collected for analyses of plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study. PK samples will be analyzed using an appropriately validated assay by or under 
the supervision of the Sponsor. 
 
Processing, storage and shipping instructions/procedures are provided in the Laboratory 
Manual. 
8.6. 
Pharmacodynamics 
Not applicable for this study. 
8.7. 
Genetics 
Not applicable for this study. 
8.8. 
Biomarkers 
• 
Blood samples (including serum and plasma) may be used to evaluate 
pharmacodynamic responses and assays related to the pathogenesis of chronic HBV 
infection and the participant’s response to bepirovirsen.  
• 
 
. Samples 
will be collected according to the schedule described in the SoA and as detailed in 
the laboratory manuals provided separately to sites. 
• 
GSK may store samples for up to 20 years after the end of the study to achieve study 
objectives. The archived samples may be used as backup for assessments pre-
specified in protocol 
 
 
 
  
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• 
Additionally, with participants’ consent, samples may be used for further research by 
the GSK or others such as universities or other companies to contribute to the 
understanding of chronic hepatitis B or other diseases, the development of related or 
new treatments or research methods. 
• 
Additional details of biomarker analysis will be provided in the biomarker analysis 
plan and the results will be documented in a separate report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.10. 
Health economics or medical resource utilization and health 
economics 
Not applicable for this study. 
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9. 
STATISTICAL CONSIDERATIONS 
The SAP will include a more technical and detailed description of the statistical analysis 
described in this section. This section is a summary of the planned statistical analysis of 
the most important endpoints including primary and secondary endpoints. 
9.1. 
Statistical hypotheses 
This study is designed to estimate the relative bioavailability of a single dose of 
bepirovirsen administered SC from vial and PFS SSD presentations by a HCP in healthy 
participants. For Cmax and AUC(0-inf), point estimates and corresponding 2-sided 90% 
CIs will be constructed for the ratio of the geometric mean of the vial to the PFS SSD. 
An additional assessment will be made by comparing the 
 
 reference 
range of 0.8 to
9.1.1. 
Multiplicity Adjustment  
No multiplicity adjustment will be implemented because the primary objective is to 
estimate the relative bioavailability of a 
 of bepirovirsen, and no formal 
hypotheses will be tested. 
9.2. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility. 
• 
Study Population 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Enrolled 
• 
All participants who entered the study (who were randomized or 
received study intervention or underwent a post screening study 
procedure).  
• 
Note screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into the 
study (Met eligibility but not needed) are excluded from the 
Enrolled analysis set as they did not enter the study. 
• 
Study Population 
Randomized  
• 
All participants who were randomly assigned to study intervention 
in the study. 
• 
Study Population 
Safety 
• 
Participants who received study intervention 
• 
Participants will be analyzed according to the study intervention 
administered. 
• 
Safety 
PK 
concentration 
• 
All participants in the Safety analysis who received 
 the 
injections and had at least 1 non-missing PK assessment (NQ 
values will be considered as non-missing values). 
• 
Data will be reported according to the actual study intervention. 
• 
PK concentration  
PK 
Parameter 
• 
All participants in the PK concentration population for whom 
valid and evaluable plasma PK parameters are derived. This 
primary analysis population will be used in the assessment and 
characterization of PK parameters (summary and analysis 
tables and figures). 
• 
PK parameter 
9.3. 
Statistical analyses 
9.3.1. 
General considerations  
Based on the individual concentration-actual time data, the following PK parameters will 
be estimated by non-compartmental methods with SMS2000. 
Parameter 
Description 
AUC(0-inf) 
Area under the concentration-time curve 
from time zero extrapolated to infinity 
Cmax 
Maximum observed plasma concentration 
 
PK data will be presented in graphical and/or tabular form and will be listed and 
summarized descriptively by treatment group, weight category and injection site. 
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To assess the secondary objectives of estimating relative bioavailability of group 2 
compared to Groups 3 and 4, approximately 
subjects will be randomized into Groups 
3 and 4 (approximately 
per arm). This will provide the same number of subjects in the 
applicable sites of administration (thigh and abdomen) compared to Groups 1 and 2. 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
o 
Applicable ICH GCP guidelines 
o 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, IFU, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
o 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
o 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
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10.1.3. 
Informed consent process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will 
be required to physically or digitally sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that informed consent was obtained 
before the participant was enrolled in the study and the date the consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A physical or digital copy of the ICF(s) must be provided to the participant. 
 
In case of unexpected pregnancy, participant must be informed that PI such as date of 
birth, sex of the baby will be collected as part of safety follow-up. Consent for the baby 
may be obtained from the participant and/or their partner as per local regulations.  
10.1.4. 
Data protection 
• Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• The participant must be informed that study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be 
explained to the participant, that their data will be used as described in the informed 
consent. 
• The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees structure 
An internal SRT is in place for each GSK product. It comprises of a global cross-
functional team responsible for the ongoing assessment of benefit-risk for a product. The 
SRT contribute to the continual assessment of incoming new efficacy and safety 
information.  
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10.1.6. 
Dissemination of Clinical Study Data 
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines.  
• Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities.  
• GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data provided 
by study participants are used to maximum effect in the creation of knowledge and 
understanding. 
10.1.7. 
Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• QTLs will be predefined in the QTL plan to identify systematic issues that can impact 
participant right, safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
involvement of central reading mechanism) methods, responsibilities, and 
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requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor.  
10.1.8. 
Source documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in source data 
agreement. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. 
Study and site start and closure 
Start of study and first act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant screened and will be the study start 
date. 
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Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.10. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors (ICMJE) authorship 
requirements. 
10.2. 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 11 will be performed by the central laboratory. 
• Outside of specific protocol-defined tests, local laboratory results are only required in 
the event that the central laboratory results are not available in time for either study 
intervention administration and/or response evaluation. If a local sample is required, 
it is important that the sample for central analysis is obtained at the same time. 
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Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
 
Table 11 
Protocol-required Safety Laboratory Tests  
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Indices: 
MCV 
MCH 
 
WBC count (with 
Differential if WBC 
abnormal): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
Total, indirect, and 
direct bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
Total Protein 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Routine 
Urinalysis 
• 
By dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• 
Follicle-stimulating hormone  
• 
Serology (HIV antibody, HBsAg, HBcAb ) 
• 
Highly sensitive urine or serum hCG pregnancy test (as needed for women of 
childbearing potential)1 
• 
Other laboratory: Coagulation Panel (PT, INR, APTT), Alpha-fetoprotein, p-
ANCA, c-ANCA (MPO-ANCA, PR3-ANCA)2, Complement factors C3, C4, 
Rheumatoid factor, hs-CRP 
• 
Urine ACR 
• 
SARS-CoV2 PCR or rapid antigen test3 
• 
Drug, alcohol and cotinine screen 
Additional tests 
listed under 
Liver Chemistry Stopping Criteria4 
• 
Viral hepatitis serology (Hepatitis A IgM; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody, EBV capsid antigen IgM antibody (or if 
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10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1. 
Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
safety follow-up 
processes 
unavailable, heterophile antibody or monospot testing); hepatitis E IgM 
antibody) 
• 
PK sample 
• 
Serum creatine phosphokinase and LDH. 
• 
Fractionate bilirubin, Anti-nuclear antibody, anti-smooth muscle antibody, Type 
1 anti-liver kidney microsomal antibodies and quantitative total immunoglobulin 
G (IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC assay 
Drug Induced Vascular Injury and Complement Monitoring Criteria 
• 
CH50 
• 
Factor Bb level 
• 
Factor H level 
• 
sC5b-9 
• 
cryoglobulins5 
• 
SPEP, UPEP 
• 
hs-CRP 
Hematological Monitoring Criteria 
• 
anti-platelet antibodies 
Drug Induced Kidney Injury Monitoring Criteria 
• 
24-hour urine analysis 
• 
renal ultrasound 
• 
urine microscopy 
• 
serum urea and creatinine 
• 
platelets 
• 
urgent serum vasculitis screen (including ANCA, ANA, dsDNA, cryoglobulins5) 
• 
SPEP/UPEP 
• 
complement panel (C3, C4, C5a, and Bb) 
NOTES: 
1. Urine testing will be standard for the protocol unless serum testing is specified in the SoA, required by local 
regulation or IRB/IEC, or if urine testing is unavailable  
2. MPO-ANCA and PR3-ANCA to be performed if p-ANCA or c-ANCA is positive. 
3. Using PCR or antigen test approved by the country regulatory authorities  
4. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver monitoring 
event are given in Section 7.1.1. All events of ALT≥3×ULN and bilirubin ≥2×ULN (≥35% direct bilirubin) or 
ALT≥3×ULN and INR >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must 
be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
5. Cryoglobulins to be tested locally if available 
Note: The investigator must document their review of each laboratory safety report. 
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• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, admission for routine examination.). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
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10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 
one or more of the criteria listed: 
a. Results in death 
b. Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g. Other situations: 
• 
Possible Hy’s Law case: ALT ≥ 3x ULN AND total bilirubin ≥ 2x ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
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o 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
 
10.3.3. 
Definition of TEAE 
TEAE Definition: 
• 
A TEAE is an event that emerges during treatment, having been absent pre-
treatment or worsens relative to the pre-treatment state. 
10.3.4. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies 
10.3.4.1. 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the sponsors /required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
10.3.4.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE, SAE and device 
deficiency reported during the study and assign it to one of the following categories:  
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate:  
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
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• 
Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  
10.3.4.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency. The investigator will use 
clinical judgment to determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the 
initial report to the sponsor. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.4.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.4.5. 
Follow-up of AEs, SAEs, pregnancies or any other events of interest  
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
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possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the sponsor with a copy of any postmortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
After the initial AE/SAE/pregnancy or any other event of interest, the investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs, 
and nonserious AESI (as defined in the Section 8.4.4), will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up. 
Other nonserious AEs must be followed until the event is resolved, stabilized, otherwise 
explained or until the participant is lost to follow-up. 
Follow-up during the study 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available postmortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy follow-up report 
and the AE Report if applicable. Generally, the follow-up period does not need to be 
longer than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.4.7. 
10.3.4.6. 
Updating of SAE and AESI information after removal of write access to 
the participant’s eCRF 
When additional SAE and AESI information is received after write access to the 
participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the Study contact for reporting SAEs (refer to Section 
8.4.7). 
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10.3.4.7. 
Reporting of SAEs, AESIs and pregnancies  
SAE Reporting to the sponsor via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to the Medical Monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned CA via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
SAE Reporting to the sponsor via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective of the 
occurrence of menarche or following menarche. 
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From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth.  
10.4.1.2. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• Premenarchal: Tanner stage 1 (prepubertal) 
Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. If reproductive 
status is questionable, additional evaluation should be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception guidance 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing systemc 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
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the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
• 
Highly effective methodsb that are user dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure from friction) 
 
10.5. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments  
Liver chemistry monitoring criteria:  
Liver chemistry monitoring criteria have been designed to assure participant safety and 
evaluate liver event etiology. 
The procedures listed below are to be followed if a participant meets liver chemistry 
criteria as specified in Section 7.1.1: 
• Notify the Medical Monitor within 24 hours of learning of the abnormality  
• Complete the Liver Event CRF. 
• Complete the “Safety Follow-up Procedures” listed below. 
• Monitor the participant until liver chemistries resolve, stabilize, or return to within 
baseline (see Monitoring) 
 
 
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Monitoring: 
If ALT≥3xULN AND total bilirubin 2xULN or INR >1.5:  
• Repeat liver chemistries (include ALT, AST, alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow up assessments within 24 hours  
• Monitor participant twice weekly until liver chemistries resolve, stabilize or return to 
within baseline  
• A specialist or hepatology consultation is recommended  
 
If ALT≥3xULN AND total bilirubin <2xULN and INR ≤1.5:  
• Perform liver chemistries (include ALT, AST, alkaline phosphatase, total bilirubin 
and INR) and perform liver event follow up assessments within 24-72 hours  
• Monitor participant weekly until liver chemistries resolve, stabilize or return to within 
baseline  
  
Safety Follow-up Procedures for Participants who Meet any of the criteria: 
Viral hepatitis serology including: 
• 
Hepatitis A IgM antibody; 
• 
HBsAg; 
• 
Cytomegalovirus IgM antibody; 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); 
• 
Hepatitis E IgM antibody; 
• 
Hepatitis C virus RNA load; 
• 
Hepatitis D virus antibody.  
• Obtain a blood sample for PK analysis as soon as possible following the occurrence 
of an event. Record the date/time of the PK blood sample collection and the date/time 
of the last dose of study treatment prior to blood sample collection on the CRF. If the 
date or time of the last dose is unclear, provide the participant’s best approximation. 
Instructions for sample handling and shipping are included in the Laboratory Manual. 
• Serum creatine phosphokinase and LDH. 
• Fractionate bilirubin, if total bilirubin 1.5x ULN 
• Assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia) as relevant on the Liver Event CRF. 
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• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications CRF. 
• Record alcohol use on the Liver Events CRF. 
The following are required for participants who meet the ALT and bilirubin 
criteria: ALT≥3xULN AND total bilirubin 2xULN or INR >1.5. 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in participants with definite or likely acetaminophen 
use in the preceding week [James, 2009]), if available. 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) or 
Liver biopsy to evaluate liver disease. 
• The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed. 
10.6. 
Appendix 7: Medical device AEs, ADEs, SAEs, sADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow-up, and 
reporting in medical device studies 
• 
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155 and the European MDR 2017/745 for clinical device research (if applicable).  
• 
Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
• 
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1  for the list 
of sponsor medical devices. 
 
10.6.1. 
Definition of medical device AE and ADE 
Medical device AE and ADE definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether or not considered related to the investigational medical 
device. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of an investigational medical device. This 
definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in 
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users or other persons, which only include events related to investigational 
devices. 
• 
An ADE is defined as an AE related to the use of an investigational medical 
device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device. 
10.6.2. 
Definition of medical device SAE, SADE and USADE 
A Medical Device SAE is any serious AEs that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• 
A life-threatening illness or injury. The term ‘life-threatening’ in the definition of 
‘serious’ refers to an event in which the participant was at risk of death at the time 
of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
• 
A permanent impairment of a body structure or a body function. 
• 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• 
Chronic disease (MDR 2017/745). 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product 
SADE definition 
• 
A SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less 
fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is 
defined as a serious ADE that by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report/ IB (see Section 
2.3). 
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10.6.3. 
Definition of device deficiency 
Device deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE and 
device deficiencies 
10.6.4.1. 
Medical device AE, SAE, and device deficiency recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the Sponsor’s 
AE/SAE/device deficiency form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the Sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
 
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence. 
• 
If the site during the course of the study becomes aware of any serious, nonserious 
incident (including device deficiencies and malfunctions) related to any GSK non-
IMP product they will report these events to GSK or to the concerned CA via the 
national spontaneous reporting system. These will be classified as spontaneous 
ICSRs. 
10.6.4.2. 
Assessment of intensity 
Refer to Section 10.3.4.2 
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10.6.4.3. 
Assessment of causality 
Refer to Section 10.3.4.3 
10.6.4.4. 
Follow-up of medical device AE/SAE and device deficiency 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE/SAE/device deficiency as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed form. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.6.5. 
Reporting of medical device SAEs 
Medical Device SAE Reporting to the sponsor via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
table) or to the Medical Monitor by telephone. 
• If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK device they will report 
these events to GSK or to the concerned CA via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
Medical Device SAE Reporting to the sponsor via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the Medical Monitor. 
• 
In rare circumstances and in the absence of /facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 
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• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated reporting 
time frames. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.6.6. 
Reporting of SADEs 
SADE Reporting to the sponsor  
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
• 
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.6.7. 
Reporting of medical device deficiencies for associated person 
• 
Reporting to GSK  
If an Associated Person (i.e., e.g., spouse, caregiver, site staff) experiences a device 
deficiency, the medical device deficiency information, and any associated AE/SAE 
information will be reported to GSK. The associated person will be provided with the 
authorization to contact physician letter. 
If follow-up information is required, authorization to contact physician (or other 
licensed medical practitioner) must be signed to obtain consent. 
• 
Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form.  
• 
If the medical device deficiency is related to a nonserious AE and not linked to an 
SAE, please send the medical device deficiency report form with details of the 
associated AE via email to gsk-rd.complaints@gsk.com only. 
• 
If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours. Refer to Section 8.4.7 for reporting.  
• 
GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
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10.6.8. 
Division of AIDS (DAIDS) Table for Grading Severity of Adult and 
Pediatric AEs 
The DAIDS Table [DAIDS, 2017] will be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as Grade 5. 
The DAIDS table is available at the following link: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
 
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11. 
REFERENCES 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Version 2.1. National Institutes of Health; Institute of Allergy and 
Infectious Diseases, Bethesda, MD; July 2017. Accessed 02 June 2023. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
European Association for the Study of the Liver. EASL clinical practice guidelines: 
management of chronic hepatitis B virus infection. ‘EASL 2017 Clinical Practice 
Guidelines on the management of hepatitis B virus infection.’ J Hepatol. 67(2):370-98. 
Feld JJ, Wong DK, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatol 
2009;49(5 Suppl):S96-S102. 
GSK Document No.: RPS-CLIN-035276. GSK3228836 Clinical Investigator’s Brochure. 
Effective Date 19 August 2022.  
 
 
James LP, Letzig L, Simpson PM, et al. Acute liver failure. Drug Metab Dispos. 
2009;37:1779-84. 
Liaw YF, Sung JJ, Chow WC, et al. Cirrhosis Asian Lamivudine Multicentre Study 
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N 
Engl J Med. 2004;351(15):1521-31.  
Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: From discovery to regulatory 
approval. Hepatology. 2017;66(4):1296-1313. 
Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose and 
WHO. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 
2021: accountability for the global health sector strategies 2016–2021. Effective Date 24 
June 2022. 
World Health Organization. Hepatitis B. WHO 2017. Accessed on 15 Jan 2020. 
https://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-
eng.pdf;jsessionid=0F8614666F013AD407B136E056201EB5?sequence=1. 
Yuen LK, Ayres A, Littlejohn M, et al. SeqHepB: a sequence analysis program and 
relational database system for chronic hepatitis B. Antiviral Res. 2007;75:64-74. 
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CCI

Signature Page for  219239 TMF-16092014 v1.0
Signature Page for TMF-16092014 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 26-Jul-2023 17:48:11 GMT+0000
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PPD