A Multicentre Randomized, Double-blind, Placebo Controlled, Dose-finding, Phase 2 Study (MARS-17) of GSK3858279 in Adult Participants With Moderate to Severe Pain Due to Knee Osteoarthritis
Phase: PHASE2
Conditions: Pain, Osteoarthritis, Knee
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
209978 
Protocol Amendment 3 Final 
26 Jul 2024 
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CLINICAL STUDY PROTOCOL 
Primary study intervention(s) GSK3858279 
Other study intervention(s) 
Not applicable 
Study identifier 
209978 
EU CT number  
2022-502799-22-00 
Pediatric investigational plan 
number 
Not applicable 
Approval date 
26 Jul 2024 
Title 
A multicentre randomized, double-blind, placebo-
controlled, dose-finding, Phase 2 study (MARS-17) 
of GSK3858279 in adult participants with moderate 
to severe pain due to knee osteoarthritis  
Compound number/Name  
GSK3858279 
Brief title 
A Ph2 dose-finding study (MARS-17) to evaluate 
the efficacy and safety of GSK3858279 in adults 
with knee osteoarthritis pain.  
Sponsor 
GSK Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Yulia Green 
Sr. Clinical Development Director 
Medical monitor name and contact information can be found in local study 
contact information document. 
©2024 GSK group of companies or its licensor. Trademarks are property of their 
respective owners. 

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Protocol Amendment 3 Investigator Agreement 
• 
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 clinical study site agreement. 
• 
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 cooperate 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. 

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Study identifier 
209978 
EU CT number 
2022-502799-22-00 
Approval date 
26 Jul 2024 
Title 
A multicentre randomized, double-blind, placebo-
controlled, dose-finding, Phase 2 study (MARS-17) 
of GSK3858279 in adult participants with moderate 
to severe pain due to knee osteoarthritis 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 

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209978 
Protocol Amendment 3 Final 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 3 
26 Jul 2024 
Amendment 2 
02 April 2024 
Amendment 1 
24 July 2023 
Original Protocol 
21 February 2023 
Amendment 3 (26 Jul 2024) 
Overall rationale for Amendment 3: 
Administrative change in Schedule of Activities for the Treatment period was 
implemented to clarify that immunogenicity samples are collected on Early 
Discontinuation visit as this was missed previously in error. This change is aligned with 
the requirement of the immunogenicity sample collection described in Central Laboratory 
Manual and Schedule of Activities for the Off-Treatment Follow-up period. 

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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 12 
1. 
PROTOCOL SUMMARY ........................................................................................ 18 
1.1. 
Synopsis ..................................................................................................... 18 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 32 
2.1. 
Study rationale ............................................................................................ 32 
2.2. 
Background for GSK3858279 in Knee OA .................................................. 32 
2.3. 
Benefit/risk assessment .............................................................................. 33 
2.3.1. 
Risk assessment .......................................................................... 34 
2.3.2. 
Benefit assessment ..................................................................... 42 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 42 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 43 
3.1. 
Efficacy Estimands ..................................................................................... 45 
3.2. 
Safety Estimands ........................................................................................ 48 
4. 
STUDY DESIGN .................................................................................................... 48 
4.1. 
Overall design ............................................................................................. 48 
4.2. 
Scientific rationale for study design ............................................................. 49 
4.2.1. 
Participant input into design ......................................................... 50 
4.3. 
Justification for dose ................................................................................... 50 
4.4. 
End-of-study definition ................................................................................ 52 
4.5. 
Actigraphy sub-study (optional) ................................................................... 53 
5. 
STUDY POPULATION ........................................................................................... 54 
5.1. 
Inclusion criteria .......................................................................................... 54 
5.2. 
Exclusion criteria ......................................................................................... 56 
5.2.1. 
Medical Conditions ...................................................................... 56 
5.2.2. 
Prior/Concomitant Therapy .......................................................... 59 
5.2.3. 
Prior/Concurrent Clinical Study Experience ................................. 59 
5.2.4. 
Diagnostic assessments .............................................................. 60 
5.2.5. 
Other Exclusions .......................................................................... 61 
5.3. 
Lifestyle considerations ............................................................................... 61 
5.3.1. 
COVID-19 related restrictions ...................................................... 61 
5.3.2. 
Meals and dietary restrictions ...................................................... 61 
5.3.3. 
Caffeine, alcohol, and tobacco ..................................................... 61 
5.3.4. 
Activity ......................................................................................... 61 
5.3.5. 
Other restrictions ......................................................................... 62 
5.4. 
Screen failures ............................................................................................ 62 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study intervention .................... 62 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 62 
6.1. 
Study intervention(s) administered .............................................................. 63 

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6.2. 
Preparation, handling, storage, and accountability ...................................... 65 
6.3. 
Assignment to study intervention ................................................................ 65 
6.4. 
Blinding, masking ........................................................................................ 66 
6.5. 
Study intervention compliance .................................................................... 67 
6.6. 
Dose modification ....................................................................................... 67 
6.7. 
Continued access to study intervention after the end of the study ............... 67 
6.8. 
Treatment of overdose ................................................................................ 68 
6.9. 
Prior and concomitant therapy .................................................................... 68 
6.9.1. 
Pain therapies .............................................................................. 68 
6.9.2. 
Immunomodulators ...................................................................... 69 
6.9.3. 
Vaccinations ................................................................................ 69 
6.9.4. 
Rescue medicine ......................................................................... 70 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 70 
7.1. 
Permanent discontinuation of study intervention ......................................... 70 
7.1.1. 
Liver chemistry stopping criteria ................................................... 72 
7.1.2. 
ECG Stopping criteria .................................................................. 72 
7.1.3. 
Renal function stopping criteria .................................................... 73 
7.1.4. 
Hematologic Abnormality stopping criteria ................................... 73 
7.1.5. 
Hepatitis B reactivation stopping criteria ...................................... 73 
7.1.6. 
Temporary discontinuation ........................................................... 73 
7.1.7. 
Rechallenge ................................................................................. 74 
7.1.7.1. 
Study intervention restart or Rechallenge after 
liver stopping criteria are met ...................................... 74 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 74 
7.3. 
Lost to follow-up.......................................................................................... 76 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 77 
8.1. 
Administrative and general/baseline procedures ......................................... 77 
8.1.1. 
Collection of demographic data .................................................... 77 
8.1.2. 
Medical history ............................................................................. 77 
8.2. 
Efficacy assessments ................................................................................. 78 
8.2.1. 
Daily pain ..................................................................................... 78 
8.2.1.1. 
Average daily knee pain ............................................. 78 
8.2.1.2. 
Worst daily knee pain ................................................. 78 
8.2.2. 
Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC) .......................................................................... 78 
8.2.3. 
Patient Global Assessment (PtGA) .............................................. 78 
8.2.4. 
Physician Global Assessment (PhGA) ......................................... 79 
8.2.5. 
The Short Form (36) Health Survey (SF-36) ................................ 79 
8.2.6. 
PROMIS-Sleep Disturbance ........................................................ 79 
8.2.7. 
Patient Global Impression of Severity (PGIS)-Sleep .................... 79 
8.2.8. 
Patient Global Impression of Change (PGIC)-Sleep .................... 79 
8.2.9. 
PainDETECT ............................................................................... 79 
8.2.10. 
Patient Global Impression of Severity (PGIS)-walk ...................... 79 
8.2.11. 
Patient Global Impression of Change (PGIC)-walk ...................... 79 
8.2.12. 
Paracetamol/acetaminophen use ................................................. 80 
8.2.13. 
StepWatch ................................................................................... 80 
8.3. 
Safety assessments .................................................................................... 80 
8.3.1. 
Physical examination/history directed physical 
examination ................................................................................. 80 

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8.3.2. 
Vital signs .................................................................................... 80 
8.3.3. 
Electrocardiograms ...................................................................... 81 
8.3.4. 
Clinical safety laboratory tests ..................................................... 81 
8.3.5. 
Knee X-rays ................................................................................. 82 
8.3.6. 
Pregnancy testing ........................................................................ 83 
8.3.7. 
Hepatitis B reactivation monitoring ............................................... 83 
8.4. 
Safety monitoring and Data Review Committees ........................................ 84 
8.5. 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 85 
8.5.1. 
Time Period and Frequency for collecting AE, SAE, and 
other safety information ............................................................... 85 
8.5.2. 
Method of detecting AEs and SAEs ............................................. 86 
8.5.3. 
Follow-up of AEs and SAEs ......................................................... 86 
8.5.4. 
AESIs .......................................................................................... 86 
8.5.5. 
Regulatory reporting requirements for SAEs ................................ 87 
8.5.6. 
Pregnancy ................................................................................... 87 
8.5.7. 
CV and death events ................................................................... 88 
8.5.8. 
Contact information for reporting SAEs, AESIs, 
pregnancies ................................................................................. 88 
8.5.9. 
Participant card ............................................................................ 89 
8.6. 
Pharmacokinetics ....................................................................................... 89 
8.7. 
Pharmacodynamics .................................................................................... 89 
8.8. 
Target (CCL17) concentrations ................................................................... 90 
8.9. 
Genetics ..................................................................................................... 90 
8.10. 
Biomarkers ................................................................................................. 91 
8.10.1. 
Exploratory Biomarkers ................................................................ 91 
8.10.2. 
Immunophenotyping .................................................................... 91 
8.10.3. 
Serum/plasma protein analysis .................................................... 91 
8.10.4. 
Transcriptomic/Epigenetic analysis .............................................. 91 
8.11. 
Immunogenicity assessments ..................................................................... 91 
8.12. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 92 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 92 
9.1. 
Statistical hypotheses ................................................................................. 92 
9.2. 
Multiplicity adjustment ................................................................................. 93 
9.3. 
Analysis sets ............................................................................................... 93 
9.4. 
Statistical analyses ..................................................................................... 94 
9.4.1. 
General considerations ................................................................ 94 
9.4.2. 
Primary endpoint/estimand analysis ............................................. 94 
9.4.3. 
Secondary endpoints analyses .................................................... 96 
9.4.4. 
Tertiary/exploratory endpoints analyses ....................................... 97 
9.5. 
Interim analyses .......................................................................................... 97 
9.6. 
Sample size determination .......................................................................... 98 
9.6.1. 
Actigraphy sub-study ................................................................... 99 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 100 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations ........ 100 
10.1.1. 
Regulatory and ethical considerations ....................................... 100 
10.1.2. 
Financial disclosure ................................................................... 100 
10.1.3. 
Informed consent process .......................................................... 101 

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10.1.4. 
Recruitment strategy .................................................................. 102 
10.1.5. 
Data protection .......................................................................... 102 
10.1.6. 
Committee structure .................................................................. 103 
10.1.7. 
Dissemination of Clinical Study Data ......................................... 103 
10.1.8. 
Data quality assurance .............................................................. 104 
10.1.9. 
Source documents ..................................................................... 105 
10.1.10. Study and site start and closure ................................................. 106 
10.1.11. Publication policy ....................................................................... 106 
10.2. 
Appendix 2: Clinical laboratory tests ......................................................... 107 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting .......................................... 109 
10.3.1. 
Definition of AE .......................................................................... 109 
10.3.2. 
Definition of SAE ........................................................................ 110 
10.3.3. 
Definition of CV events .............................................................. 111 
10.3.4. 
Definition of treatment-emergent AE (TEAE) ............................. 111 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, AESIs 
and pregnancies ........................................................................ 112 
10.3.5.1. AE and SAE recording .............................................. 112 
10.3.5.2. Assessment of intensity ............................................ 112 
10.3.5.3. Assessment of causality ........................................... 112 
10.3.5.4. Assessment of outcomes.......................................... 113 
10.3.5.5. Follow-up of AEs, SAEs, AESIs, pregnancies 
or any other events of interest .................................. 113 
10.3.5.6. Updating of SAE, AESI and pregnancy 
information after removal of write access to the 
participant’s eCRF .................................................... 114 
10.3.5.7. Reporting of SAEs, AESIs and pregnancies ............. 115 
10.4. 
Appendix 4: Contraceptive and barrier guidance ....................................... 116 
10.4.1. 
Definitions .................................................................................. 116 
10.4.1.1. Woman of Childbearing Potential (WOCBP) ............. 116 
10.4.1.2. Woman of Non-childbearing Potential 
(WNCBP) ................................................................. 117 
10.4.2. 
Contraception guidance ............................................................. 117 
10.5. 
Appendix 5: Genetics ................................................................................ 119 
10.6. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments ............................................................................................. 120 
10.7. 
Appendix 7: Important Study Assessment Details & Study Specific 
Equipment ................................................................................................ 123 
10.8. 
Appendix 8: Country-specific requirements ............................................... 124 
10.8.1. 
Japan specific requirement: ....................................................... 124 
10.8.2. 
FRENCH-SPECIFIC REQUIREMENTS ..................................... 124 
10.8.2.1. Concerning the “SELECTION OF STUDY 
POPULATION AND WITHDRAWAL 
CRITERIA” ............................................................... 124 
10.8.2.2. Concerning the “STUDY GOVERNANCE 
CONSIDERATIONS” ................................................ 125 
10.8.2.3. Concerning the “DATA MANAGEMENT” the 
following text is added: ............................................. 125 
10.8.2.4. Concerning Data Privacy .......................................... 126 
10.8.2.5. INVESTIGATIONAL PRODUCT 
ACCOUNTABILITY, RECONCILIATION, AND 
DESTRUCTION ....................................................... 126 

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10.9. 
Appendix 9: Protocol amendment history .................................................. 127 
11. REFERENCES ..................................................................................................... 133 
 

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities ............................................................................. 20 
Table 2 
Objectives and Endpoints ....................................................................... 43 
Table 3 
Study Intervention(s) Administered......................................................... 63 
Table 4 
Study Arm(s) .......................................................................................... 64 
Table 5 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 87 
Table 6 
Contact information for reporting SAEs, AESIs and pregnancies ........... 88 
Table 7 
Probability of meeting various criteria of interest conditional on 
true treatment differences, and not conditional on interim 
analysis results ...................................................................................... 99 
Table 8 
Protocol-required safety laboratory tests .............................................. 107 

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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 19 
Figure 2 
Predicted Steady-State Reductions in Free CCL17 (median and 
95% CI of the prediction) following weekly (60 mg, 240 mg and 
360 mg) and every 2 weeks (240 mg) SC dosing with 
GSK3858279 over 16 weeks [GSK Document Number TMF-
1521097] ................................................................................................ 52 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-Drug Antibodies 
ADP 
Average daily pain 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC(0-tau) 
Area under the Concentration-time curve over the dosing interval 
BCG 
Bacillus Calmette-Guerin 
BL 
Baseline 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
Cavg  
Average concentration over a dosing interval 
CFR 
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration 
COA 
Clinical outcome assessments 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus strain 19 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
Ctau 
Pre-dose (trough) concentration at the end of the dosing interval 
CTIS 
Clinical Trial Information System 
CV 
Cardiovascular 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic diary 
EU 
European Union 
FSH 
Follicle-Stimulating Hormone 
FTIH 
First time in human 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
h 
Hours 
HBcAb 
Hepatitis B core antibody  
HBsAg 
Hepatitis B Surface Antigen  
HBV 
Hepatitis B Virus 
HBV DNA 
Hepatitis B DNA 
hCG 
Human chorionic gonadotropin 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 

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ICEs 
Intercurrent events 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
iDRC 
Internal Data Review Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG2 
Immunoglobulin G2 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
Kd 
Dissociation Constant 
kg/m2 
Kilograms per square meter 
LAM 
Lactational amenorrhea method 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal Antibody 
MAR 
Missing at random 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
mg/kg 
Milligrams per kilogram 
mg/kg/week 
Milligrams per kilogram per week 
min 
Minute 
mm 
Millimeter 
MSDS 
Material Safety Data Sheet 
msec 
Millisecond 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGF 
Nerve Growth Factor 
NOAEL 
No Observed Adverse Effect Level 
NQ 
Non quantifiable 
NRS 
Numerical Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 

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pH 
Potential Hydrogen 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient reported outcome 
PtGA 
Patient global assessment 
QSS 
Quasi Steady-State 
QTc 
Corrected QT 
QTcF 
Corrected QT using Fridericia’s formula 
RBC 
Red Blood Cell count 
RNA 
Ribonucleic acid 
SAD  
Single ascending dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-36 
The Short Form (36) Health Survey 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SoA 
Schedule of Activities 
SRT 
Safety Review Team 
t½ 
Apparent terminal phase half-life 
TARC 
Thymus and activation regulated chemokine 
TB 
Tuberculosis 
TDAR 
T-cell Dependent Antibody Response 
TE 
Target engagement 
tmax 
Time to Cmax 
TMDD 
Target-Mediated Drug Disposition 
UACR 
Urine albumin-creatinine ratio 
ULN 
Upper limit of normal 
w/v 
Weight by volume 
WBC 
Whole Blood Count 
WNCBP 
Women Of Non-Childbearing Potential 
WOCBP 
Women Of Childbearing Potential 
 

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Term 
Definition 
Adverse Drug Reaction 
An AE where a causal relationship between a medicinal product and the 
AE is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out. 
In the context of a clinical trial, an ADR can be serious or nonserious. 
Serious ADRs may be subject to expedited reporting if they are considered 
unexpected (see SUSAR definition). 
For marketed products, ADRs are subject to expedited reporting within the 
country where they are authorized. 
Auxiliary Medicinal Product (AxMP) 
Medicinal products used in the context of a clinical trial but not as IMPs, 
such as medicinal products used for background treatment, challenge 
agents, rescue medication, or used to assess endpoints in a clinical trial. 
AxMPs should not include concomitant medications, that is medications 
unrelated to the clinical trial and not relevant for the design of the clinical 
trial. 
Authorized AxMP = Medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any member state concerned in 
accordance with Directive 2001/83/EC, irrespective of changes to the 
labeling of the medicinal product. 
Note: Safety reporting with regard to authorized AxMPs shall be made in 
accordance with Chapter 3 of Title IX of Directive 2001/83/EC. 
Unauthoried AxMP = Medicinal product not authorized in accordance with 
Regulation (EC) No 726/2004. 
Blinding 
A procedure in which 1 or more parties to the study are kept unaware of 
the intervention assignment in order to reduce the risk of biased study 
outcomes. The level of blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an acceptable level of quality 
will appropriate personnel be unblinded or when required in case of a SAE. 
In a double-blind study, the participant, the investigator and sponsor staff 
who are involved in the treatment or clinical evaluation of the participants 
and the review or analysis of data are all unaware of the intervention 
assignment. 
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. 
eDiary 
Electronically registered patient data and automated data entries on, for 
example, eDiary, tablet or computer. 
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. 
Home Healthcare Services  
Deployment of mobile health care professional(s) (nurses or 
phlebotomists) to perform study activities remotely. 
Intervention number 
A number identifying an intervention to a participant, according to 
intervention allocation. 

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Term 
Definition 
Investigational medicinal product 
(IMP) 
A pharmaceutical form of an active substance or placebo being tested or 
used as a reference in a clinical trial, 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.  
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. 
Non-IMP 
Any products used in a clinical trial (other than the investigational product 
being tested) which are stipulated to be used to evaluate the efficacy and 
safety of the investigational drug in the protocol including comparators, co-
administration drugs, rescue drugs and premedication drugs. 
• 
Non-IMPs products can be approved in Japan or other countries, or 
can be products that are not approved. 
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. 
Participant number 
A unique identification number assigned to each participant who consents 
to participate in the study. 
Pharmacogenomics 
The ICH E15 Guidance for Industry defines pharmacogenomics as the 
“Study of variation of DNA and RNA characteristics as related to drug or 
treatment response.” 
Pharmacogenetics, a subset of pharmacogenomics, is “the study of 
variations in DNA sequence as related to drug response.” 
Pharmacogenomic biomarkers include germline (host) DNA and RNA as 
well as somatic changes (e.g., mutations) that occur in cells or tissues. 
Pharmacogenomic biomarkers are not limited to human samples but 
include samples from viruses and infectious agents as well as animal 
samples. The term pharmacogenomic experiment includes both the 
generation of new genetic or genomic (DNA and/or RNA) data with 
subsequent analysis as well as the analysis of existing genetic or genomic 
data to understand drug or treatment response (PK, safety, efficacy or 
effectiveness, mode of action). 
Proteomic and metabolomic biomarker research is not pharmacogenomics. 
Placebo 
An inactive substance or treatment that looks the same as, and is given in 
the same way as, an active drug or intervention/treatment being studied. 
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.  

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Term 
Definition 
Randomization 
Process of random attribution of intervention to participants to reduce 
selection bias. 
Remote visit 
This term refers to the visit conducted in the place other than the study 
site. 
Rescue medication 
Medicine(s) identified in the protocol as those that may be administered to 
the participants when the efficacy of the IMP is not satisfactory, or the 
effect of the IMP is too great and is likely to cause a hazard to the 
participant, or to manage an emergency situation. 
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). 
Standard of Care 
Medicine(s) for a specific indication, or a component of the standard care 
for a particular medical indication, based on national and/or international 
consensus; there is no regulatory significance to this term. 
Products/regimens considered standard of care may differ country to 
country, depending on consensus in individual countries. 
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). 
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 monitor 
An individual assigned by the sponsor and responsible for assuring proper 
conduct of clinical studies at 1 or more investigational sites. 
Sub-cohort 
A group of participants for whom specific study procedures are planned as 
compared to other participants or a group of participants who share a 
common characteristic (e.g. ages, vaccination schedule, etc.) at the time of 
enrollment. 
SUSAR 
In a clinical trial, a serious adverse reaction that is considered unexpected, 
i.e., the nature or severity of which is not consistent with the reference 
safety information (e.g., IB for an unapproved IMP). All ADRs that are both 
serious and unexpected are subject to expedited reporting. 
Telemedicine 
The use of electronic information and telecommunications technologies 
(both video-based and audio-only) to facilitate remote health care delivery, 
participant and professional health-related education, public health and 
health administration. 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol title: 
A multicentre randomized, double-blind, placebo-controlled, dose-finding, Phase 2 study 
(MARS-17) of GSK3858279 in adult participants with moderate to severe pain due to 
knee osteoarthritis. 
Brief title: 
A Ph2 dose-finding study (MARS-17) to evaluate the efficacy and safety of 
GSK3858279 in adults with knee osteoarthritis pain. 
Rationale: OA is a debilitating degenerative chronic disease of the large and small joints 
and the most common form of adult arthritis in the developed world. The prevalence and 
the burden associated with disease are steadily increasing worldwide, and currently 
available medication offers insufficient pain alleviation and minimal improvements in 
pain and function. Chemokine CCL17 has been recently identified as a peripheral 
mediator of inflammatory pain and can be therefore considered important target in 
development of new therapies. GSK3858279 is a high affinity (Kd<1pM), human 
immunoglobulin G2σ (IgG2σ) (Fc-silenced), first-in-class, monoclonal antibody (mAb), 
binding specifically to the chemokine CCL17. The purpose of this Phase 2 study is to 
investigate the efficacy, safety, PK, TE and dose-exposure-efficacy (D-E-R) relationship 
of GSK3858279 and to provide the data necessary to select the optimal effective and safe 
dose(s) of GSK3858279 to be carried forward into Phase 3 studies in subjects with 
knee/hip OA, to potentially address unmet needs of patients with OA. Refer to 
Section 2.1 for details. 
Objectives, Endpoints, and Estimands: The primary objective of the study is to 
evaluate the mean change from baseline at Week 12 in weekly average of average daily 
knee pain intensity for each GSK3858279 regimen compared to placebo in adult patients 
with knee osteoarthritis pain, where persistent use of prohibited pain therapy and study 
treatment discontinuation due to lack of efficacy or adverse events are considered a 
negative outcome, in the absence of other study treatment discontinuations and regardless 
of all other use of prohibited pain therapy and use of allowed rescue medication. A 
negative change from baseline is evidence of improvement in pain. The primary efficacy 
analysis will be characterized using Bayesian posterior probabilities for various criteria of 
interest (e.g. posterior probability that the true treatment difference from placebo is less 
than -0.6/-0.7/-0.8), and inferences will be made by comparing these posterior 
probabilities to a threshold of interest e.g. 70%. Refer to Section 3 for details. 
Overall Design: This is a Phase 2, dose-finding, multicentre, randomized, double-blind, 
parallel group, placebo-controlled study of GSK3858279 in participants with moderate to 
severe knee OA pain to investigate the efficacy, safety, PK and dose-exposure- efficacy 
relationship of GSK3858279. Screening will take place within a maximum of 42 days 
before randomization. After the screening visit and washout period, participants will be 

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randomized to one of 5 treatment arms: placebo weekly, GSK3858279 60 mg weekly, 
GSK3858279 240 mg weekly, GSK3858279 240 mg every 2 weeks, or GSK3858279 360 
mg weekly. For the arm which receives 240 mg every 2 weeks, there will be alternate 
placebo administration every 2 weeks. Participants will be randomized in a 2:1:1:1:1 
ratio. Randomization will be stratified by subject region and average of daily pain score 
at baseline <7 or ≥7. GSK3858279 or placebo will be administered as subcutaneous (SC) 
injection. Refer to Section 4.1 for details. 
Number of Participants: The approximate sample size is 420 participants. Recruitment 
may continue to include additional participants, increasing by up to 15% of the target 
sample size, if regional recruitment targets have not been met. Refer to Section 9.6 for 
details. 
Data Monitoring/Other Committee: A Safety Review Team (SRT) is 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 efficacy and safety information. 
An external independent data monitoring committee (IDMC) is implemented in this study 
to review unblinded data regularly and on an as needed basis. An internal data review 
committee (iDRC) will review interim analysis data in an unblinded manner for the 
assessment of futility. Refer to Section 10.1.6 for details. 
1.2. 
Schema 
Figure 1 
Study design overview 
 
For the arm which receives 240 mg every 2 weeks, there will be alternate placebo 
administration every 2 weeks. 

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1.3. 
Schedule of activities (SoA) 
Table 1 
Schedule of activities 
Screening: Although there will be more than one site visit during the screening period 
(the initial screening visit [1] and a second visit at the beginning of the run-in period [2]) 
for the purposes of the SoA these visits will be grouped together and called screening 
period. 
Schedule of activities: Screening period 
 Assessments 
 
Screening period 
Notes 
Visit 
Screening 
(Visit 1, up to 
42 days before 
Day 1) 
 
Start of 
Washout 
period 
(phone call) 
Run-in 
period 
(Visit 2, 7 
days before 
Day 1) 
 
 
Informed consent 
X 
 
 
All screening assessments, with 
the exception of the informed 
consent, must be completed 
within 42 days prior to 
randomization. Register the 
participant in IWRS once the ICF 
is signed. 
 
Screening visit assessments 
could be performed in split visits 
with prior sponsor approval. 
 
A separate optional Genetic ICF 
may be signed at Visit 1, or 
anytime during the study, if 
applicable. 
Demography 
X 
 
 
 
Full physical examination 
(including height and weight) 
X 
 
 
 
Average daily pain score over the 
past 24 hours in the index knee 
X 
 
 
Index joint to be determined by 
whichever knee patient reports 
as being most painful in patients 
with bilateral knee OA. This 
should be performed using the 
ePRO tablet at Visit 1. Index 
knee cannot be changed once 
determined at Visit 1. 
 
Medical History 
X 
 
 
 
OA and OA treatment history 
X 
 
 
Date of diagnosis of OA will be 
recorded along with previous OA 
treatment history. 

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 Assessments 
 
Screening period 
Notes 
Visit 
Screening 
(Visit 1, up to 
42 days before 
Day 1) 
 
Start of 
Washout 
period 
(phone call) 
Run-in 
period 
(Visit 2, 7 
days before 
Day 1) 
 
 
Drug/alcohol/tobacco use history 
X 
 
 
Drug and alcohol use in the last 
year will be recorded. Tobacco 
use history in pack years 
(lifetime) along with the current 
smoking status in average 
number of cigarettes smoked per 
day in the last week will be 
recorded. 
Urine drug screen 
X 
 
 
Amphetamines, barbiturates, 
cocaine, opiates, marijuana 
(THC), benzodiazepines. 
TB 
X 
 
 
QuantiFERON-TB Gold plus test 
(or, if unavailable, T-SPOT TB 
test with prior Sponsor’s 
approval). 
HIV, hepatitis B virus (HBV) and 
hepatitis C virus (HCV) screen 
X 
 
 
See Diagnostic assessments 
Section 5.2.4 for Japan site 
hepatitis B specific requirement  
12-lead ECG 
X 
 
 
Single ECG tracing should be 
obtained. Triplicate ECG can be 
performed based on Investigator 
assessment, if required. 
Vital signs 
X 
 
 
 
Hematology, clinical chemistry, 
urinalysis 
X 
 
 
Refer to Section 10.2 for the full 
list of parameters that will be 
tested. Urinalysis performed 
locally with the use of dipstick. 
Urine sample may be sent to 
central laboratory for further 
testing based on Investigator 
assessment if required.  
COVID-19 (SARS-CoV-2) test 
X 
 
 
PCR assay. 
Pregnancy test (serum in WOCBP) 
or follicle-stimulating hormone 
(FSH) (in WNCBP as appropriate–
see Appendix 4) 
X 
 
 
 
Concomitant medication review 
X 
X 
X 
Concomitant Medications taken 
30 days prior to ICF signature 
along with current treatments will 
be recorded along with start and 
stop dates, doses, routes of 
administration and reasons for 
use. Changes in Concomitant 
Medications throughout the 
screening period will also be 
recorded. 

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 Assessments 
 
Screening period 
Notes 
Visit 
Screening 
(Visit 1, up to 
42 days before 
Day 1) 
 
Start of 
Washout 
period 
(phone call) 
Run-in 
period 
(Visit 2, 7 
days before 
Day 1) 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
Re-check clinical status before 
initiating washout and run-in 
periods. 
Bilateral knee X-rays  
X 
 
 
X-ray can be performed at an 
alternative visit at Investigator’s 
discretion. 
 
Allow at least 7 calendar days for 
the X-ray result to be returned 
from central reading, which 
should be obtained prior to 
initiating wash out of previous 
medications. 
Dispense 
Paracetamol/Acetaminophen as 
rescue medication 
X 
 
X* 
Only if ALL initial eligibility criteria 
were met at the initial screening 
visit. 
Participants should be instructed 
to use only rescue medication 
provided by sites and to follow 
dosage and use restrictions. 
 
*Additional rescue medication 
supply should be provided if 
needed. 
Discontinue and Washout Current 
Pain Medication (if applicable) 
 
At least 3 days 
or 5 half-lives, 
whichever is 
longer prior to 
run-in period 
Start the washout period only if 
ALL other eligibility criteria were 
met at the initial screening 
besides the average of the 
average daily pain score. 
See Section 6.9.1. for further 
details on prohibited analgesics 
and advice for wash-out. 
Training on accurate pain 
reporting 
X 
 
X 
At initial screening visit prior to 
initial NRS pain evaluation, a 
brief training for NRS pain 
assessment will be provided by 
PI or site staff. This is based on 
the Accurate Pain Training video 
from Investigator meeting. 
Before the eDiary is dispensed at 
Visit 2, participants will be trained 
on accurate pain reporting 
course, provided by the third-
party vendor WCG. This web-
based training to be completed 

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 Assessments 
 
Screening period 
Notes 
Visit 
Screening 
(Visit 1, up to 
42 days before 
Day 1) 
 
Start of 
Washout 
period 
(phone call) 
Run-in 
period 
(Visit 2, 7 
days before 
Day 1) 
 
 
on a site computer/tablet device 
with supervision. 
Training and dispensing of eDiary 
 
 
X 
eDiary should only be dispensed 
once the participant passes all of 
the other screening assessments 
(except the weekly mean of daily 
pain score 7 day average) and 
after the washout of prohibited 
pain medications has been 
successful (if applicable). 
 
eDiary training to be completed 
on Clario handheld device at site 
with supervision.  
Training and dispensing of 
StepWatchTM (Actigraphy) 
 
 
X 
StepWatch assessments are 
performed in a subset of 
participants in selected countries 
only. Monitoring will start from 
Day -7 prior to randomization to 
Day 1. 
Average daily and worst daily pain 
scores (eDiary) 
 
 
Starting 7 
days 
preceding 
randomization 
Scores will be recorded on the 
eDiary device over the 7 
consecutive evenings preceding 
randomization. 
 
Compliance for average daily 
pain must be a minimum of 6 out 
of 7 days for inclusion. 
 
An average value of these 
scores will be used for eligibility 
assessment and stratified 
randomization. 
Paracetamol/Acetaminophen 
intake Diary (eDiary) 
 
 
Starting 7 
days 
preceding 
randomization 
Recorded on the eDiary over the 
7 consecutive days preceding 
randomization. 
 
Compliance of data entry must 
be a minimum of 6 out of 7 days 
for inclusion. 
 
Participants exceeding the 
permitted allowance during the 
run-in period will not be included. 
 

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 Assessments 
 
Screening period 
Notes 
Visit 
Screening 
(Visit 1, up to 
42 days before 
Day 1) 
 
Start of 
Washout 
period 
(phone call) 
Run-in 
period 
(Visit 2, 7 
days before 
Day 1) 
 
 
Permitted rescue medication: 
Paracetamol/Acetaminophen is 
used with limitation of doses of 
≤3 grams/day and for a 
maximum of 4 days in a week. 
SAE assessment 
X 
X 
X 
All SAEs will be collected from 
the start of intervention until the 
final follow-up visit at the time 
points specified in the SoA. 
However, any SAEs assessed as 
related to study participation (e.g. 
protocol-mandated procedures, 
invasive tests, or change in 
existing therapy) or related to a 
GSK product will be recorded 
from the time a participant 
consents to participate in the 
study. 
 

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Schedule of Activities: Treatment period 
Procedures 
Treatment Period 
ED a 
Weeks  
Baseline 
(Day 1) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
11 
 
12 
13 
14 
 
15 
 
16 
 
 Visit number  
3 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15b 
16 
17b 
18 
19 
20 
21b 
22 
23b 
24 
 
Visit window 
±2 days [except for Day 1 (Visit 3) and Visits 4, 15, 17, 21 and 23]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
 
Inclusion and 
exclusion criteria d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer: Weekly 
SC IMP injection e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
COAs including PROs 
Average Daily knee 
painf 
============================================= X =============================================  
X 
Worst Daily knee 
painf 
============================================= X =============================================  
X 
Paracetamol/ 
Acetaminophen 
intake eDiaryg 
============================================= X =============================================  
X 
Repeat training on 
accurate pain 
reportingh 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOMACh 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
PtGA & PhGAh  
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 

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Procedures 
Treatment Period 
ED a 
Weeks  
Baseline 
(Day 1) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
11 
 
12 
13 
14 
 
15 
 
16 
 
 Visit number  
3 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15b 
16 
17b 
18 
19 
20 
21b 
22 
23b 
24 
 
Visit window 
±2 days [except for Day 1 (Visit 3) and Visits 4, 15, 17, 21 and 23]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
 
SF-36 h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
PROMIS-Sleep h 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
PGIS-Sleep h 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
PGIC-Sleep h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Walk PGIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Walk PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
PainDETECT h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eDiary 
compliance 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Safety Evaluations and Other Assessments 
Brief physical exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
12-lead ECG i 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Knee X-rays j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
k 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 

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Procedures 
Treatment Period 
ED a 
Weeks  
Baseline 
(Day 1) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
11 
 
12 
13 
14 
 
15 
 
16 
 
 Visit number  
3 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15b 
16 
17b 
18 
19 
20 
21b 
22 
23b 
24 
 
Visit window 
±2 days [except for Day 1 (Visit 3) and Visits 4, 15, 17, 21 and 23]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
 
Hematology, 
Chemistry, Urinalysis  
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Lipid profile l(fasting) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hepatitis B 
monitoring (if 
applicable) 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
TB testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tobacco Use History 
update m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Genetic sample n 
============================================= X =============================================  
X 
SAE/AE review 
============================================= X =============================================  
X 
Concomitant 
medication review 
============================================= X =============================================  
X 
PK/TE, Immunogenicity and Biomarker Samples 
PK /TE  
Xo 
Xc 
Xo 
Xo 
 
Xo 
 
 
 
Xo 
 
Xo 
Xc 
Xo 
Xc 
Xo 
 
Xo 
Xc 
Xo 
Xc 
Xp 
X 
Immunogenicity 
Xq 
 
 
 
 
Xq 
 
 
 
Xq 
 
 
 
Xq 
 
 
 
 
 
 
 
X 
X 

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Procedures 
Treatment Period 
ED a 
Weeks  
Baseline 
(Day 1) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
11 
 
12 
13 
14 
 
15 
 
16 
 
 Visit number  
3 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15b 
16 
17b 
18 
19 
20 
21b 
22 
23b 
24 
 
Visit window 
±2 days [except for Day 1 (Visit 3) and Visits 4, 15, 17, 21 and 23]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
 
Whole blood for RNA 
or epigenetic 
analysis r, 
Xq 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
X 
 
Serum for Protein 
Biomarkers r 
Xq 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
X 
 
Blood for flow 
cytometry r,s 
Xq 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
Optional Sub-study (in selected countries) 
Actigraphy 
(StepWatchTM) t 
 
 
 
 
 
 
 
 
 
 
 
 
 
X ------------  
 
 
 
 
 
 
 
a. 
ED = Early Discontinuation. Participants who discontinue study treatment permanently are requested to complete remaining scheduled visits and assessments up to the Week 16 
visit per above SoA (except for the weekly IMP administration and post-dose [24-72 hours or 96-120 hours] PK/TE sample collection), with a final follow-up visit (Visit 27) 
approximately 16 weeks from the last dose received. However, if this is not possible at a minimum participants will be asked to complete all assessments at both the Early 
Discontinuation visit preferably 1 week from the last dose received (applicable to the treatment period) or as soon as possible after the participant’s decision has been 
communicated to the site staff (applicable to the off-treatment phase) and a final follow-up visit approximately 16 weeks after the last dose (Visit 27) to ensure participant 
monitoring following drug wash out (the knee X-rays are only requested to be completed at one of these visits, preferably the last planned visit). Participants are requested to 
complete average and worst daily pain NRS, Paracetamol/Acetaminophen intake diary and record conmeds up to the final follow-up visit. 
b. 
If country/site and participant agree this visit can be performed by a home nursing team (Accellacare, a third-party vendor or site personnel). If home nursing team is utilized, 
SAE/AE and concomitant medication review should be done by the Investigator over the phone. 
c. 
One post-dose PK sample will be collected either at 24-72 hours or at 96-120 hours after dosing (based on participant/site preference) on Day 1, Weeks 10, 11, 14, 15. Note: PK 
and TE samples should be taken at the same time. 
d. 
Re-check clinical status before each dose of study medication. 
e. 
IMP injections must be administered after completion of all the study assessments applicable for the visit. A window of ±2 days is acceptable between weekly doses (minimum 
gap of 5 days between each dose, for no more than 2 consecutive doses). 
f. 
NRS pain questions (including average daily pain, worst daily pain) should be completed on the eDiary device. 

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g. 
All Paracetamol/Acetaminophen intakes including date, approximate time of dose, dose strength, drug form and reason for use; OA pain or “Other Indication” (eg: headache, fever 
etc.) will be recorded on the eDiary on a daily basis. 
h. 
Perform PROs before any other assessments or procedures to avoid influencing the participant. Repeat training on accurate pain reporting at Week 8 before PROs are completed. 
i. 
Triplicate ECGs will be obtained at Baseline (Day 1). Single ECGs will be taken at all other timepoints unless any abnormalities are found during the study or if any of the ECG 
stopping criteria are met, then triplicate ECG will be obtained. 
j. 
Additional X-ray may be requested if clinically indicated. For the Early Discontinuation visit knee X-rays in both knees should be done if a final follow-up visit is not possible and it 
has been more than 3 months since the last X-ray. 
k. 
Women of childbearing potential only. Must be completed prior to dosing. A serum test will be performed if required by local regulations (e.g.: country or IRB/EC). 
l. 
Participants are required to fast for a minimum of 10 hours if feasible, as deemed by the investigator. 
m. Current smoking status; average number of cigarettes smoked per day in the last week will be recorded. 
n. 
Optional. Not taken at sites in China. Single sample any time post randomization. 
o. 
Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11, 12, 14, 15. 
p. 
Sample to be taken 1 week post last IMP dose. 
q. 
Sample collected before IMP dose. 
r. 
Sample not collected in China. 
s. 
Flow cytometry will only be conducted at selected countries. 
t. 
StepWatch (actigraphy) assessments are performed in a subset of participants in selected countries only. Post-baseline monitoring will start at Week 11 and continue until Week 
12 visit. 
NOTE: Order of assessments as recommended where possible: 
• 
Any scheduled training and completion of participant reported outcome assessments to be completed first. 
• 
ECG, vitals signs, and physical examination should then be followed by blood and urine sampling. 
• 
All assessments (including review of AE/SAEs and concomitant medications) to be completed before any dosing. 
 

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Schedule of Activities: Off-treatment Follow-up period 
 
Procedures 
Off-treatment Follow-Up Visits (Weeks ± 
7 days) 
ED a 
Weeks  
20 
24 
31 
 
Visit number  
25b 
26b 
27 
 
Visit window 
±7 days 
 
Average Daily knee pain c 
=========X==========  
X 
Worst Daily knee pain c 
=========X==========  
X 
Paracetamol/Acetaminophen intake eDiary d 
=========X==========  
X 
WOMAC e 
X 
X 
X 
X 
Review eDiary compliance 
X 
X 
X 
X 
Safety Evaluations and Other Assessments 
Brief physical exam 
 
 
X 
X 
Vital signs 
X 
X 
X 
X 
12-lead ECG f 
 
 
X 
X 
Knee X-rays g 
 
 
X 
X 
Urine pregnancy test h 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis  
X 
X 
X 
X 
Lipid profile (fasting)i 
 
 
X 
X 
Hepatitis B monitoring (if applicable) 
 
 
X 
X 
TB testing 
 
 
X 
X 
Tobacco Use History update j 
 
 
X 
X 
Genetic sample k 
=========X==========  
X 
SAE/AE review 
=========X==========  
X 
Concomitant medication review 
=========X==========  
X 
PK/TE, Immunogenicity and Biomarker Samples 
PK /TE 
X 
X 
X 
X 
Immunogenicity 
 
 
X 
X 
Whole blood for RNA or epigenetic analysis l 
 
 
X 
 
Serum for Protein Biomarkers l 
 
 
X 
 

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a. 
ED = Early Discontinuation. Participants who discontinue study treatment permanently are requested to complete 
remaining scheduled visits and assessments up to the Week 16 visit per above SoA (except for the weekly IMP 
administration and post-dose [24-72 hours or 96-120 hours] PK/TE sample collection), with a final follow-up visit 
(Visit 27) approximately 16 weeks from the last dose received. However, if this is not possible at a minimum 
participants will be asked to complete all assessments at both the Early Discontinuation visit preferably 1 week 
from the last dose received (applicable to the treatment period) or as soon as possible after the participant’s 
decision has been communicated to the site staff (applicable to the off-treatment phase) and a final follow-up visit 
approximately 16 weeks after the last dose (Visit 27) to ensure participant monitoring following drug wash out (the 
knee X-rays are only requested to be completed at one of these visits, preferably the last planned visit). 
Participants are requested to complete average and worst daily pain NRS, Paracetamol/Acetaminophen intake 
diary and record conmeds up to the final follow-up visit. 
b. 
If country/site and participant agree this visit can be performed by a home nursing team (Accellacare, a third-party 
vendor or site personnel). If home nursing team is utilized, SAE/AE and concomitant medication review should be 
done by the Investigator over the phone. 
c. 
NRS pain questions (including average daily pain, worst daily pain) should be completed on the eDiary device. 
d. 
All Paracetamol/Acetaminophen intakes including date, approximate time of dose, dose strength, drug form and 
reason for use; OA pain or “Other Indication” (e.g.: headache, fever etc.) will be recorded on the eDiary on a daily 
basis. 
e. 
Perform PROs before any other assessments or procedures to avoid influencing the participant. 
f. 
Single ECGs will be taken unless any abnormalities are found during the study or if any of the ECG stopping 
criteria are met, then triplicate ECG will be obtained. 
g. 
Additional X-ray may be requested if clinically indicated. For the Early Discontinuation visit knee X-rays in both 
knees should be done if a final follow-up visit is not possible and it has been more than 3 months since the last 
X-ray. X-ray for W31, ED needs to be done within visit window +/- 7days 
h. 
Women of childbearing potential only. A serum test will be performed if required by local regulations (eg: country 
or IRB/EC). 
i. 
Participants are required to fast for a minimum of 10 hours if feasible, as deemed by the investigator. 
j. 
Current smoking status; average number of cigarettes smoked per day in the last week will be recorded. 
k. 
Optional. Not taken at sites in China. Single sample any time post randomization. 
l. 
Sample not collected in China. 

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2. 
INTRODUCTION 
2.1. 
Study rationale 
C-C class chemokine 17 (CCL17) is a member of the CC-chemokine family and plays an 
important role in immune cell migration. Anti-mouse CCL17 surrogate antibodies have 
been shown to be analgesic in mouse models of arthritis pain, inflammatory pain, and 
neuropathic pain [Achuthan, 2016; Lee, 2018; GSK3858279 Investigator’s Brochure]. 
Furthermore, neutralizing GM-CSF, an upstream mediator of CCL17 activity, in patients 
with hand OA led to a significant decrease in circulating CCL17 concentrations, along 
with a non-significant trend towards a reduction in pain [Schett, 2020]. 
The purpose of this Phase 2 study is to investigate the efficacy, safety, PK, TE and dose-
exposure-efficacy (D-E-R) relationship of GSK3858279 and to provide the data 
necessary to select the optimal effective and safe dose(s) of GSK3858279 to be carried 
forward into Phase 3 studies in subjects with knee/hip OA. 
2.2. 
Background for GSK3858279 in Knee OA 
CCL17, previously known as thymus and activation regulated chemokine (TARC), is a 
member of the CC-family of chemokines that binds and signals through the G-protein 
coupled receptor, CCR4 [Imai, 1996; Imai, 1997]. CCL17 is produced by numerous 
immune and non-immune cell types. CCR4 is predominantly expressed on Th2 cells but 
is also present on other immune and non-immune cell types. 
GSK3858279 is a high affinity (Kd<1pM), human immunoglobulin G2σ (IgG2σ) (Fc-
silenced), first-in-class, monoclonal antibody (mAb), binding specifically to the 
chemokine CCL17. It functionally inhibits CCL17 from binding to the chemokine 
receptor CCR4, to prevent downstream consequences of CCR4 signaling. 
OA is a debilitating degenerative chronic disease of the large and small joints and the 
most common form of adult arthritis in the developed world. The prevalence and the 
burden associated with disease are steadily increasing worldwide. Alleviating the chronic 
pain associated with OA is a major unmet need. Paracetamol is the most commonly used 
analgesic for knee and hip OA, but it causes only minimal improvements in pain and 
function and observational studies have raised concerns regarding its safety [Latourte, 
2020]. In addition, current therapies such as non-steroidal anti-inflammatory drugs 
(NSAIDs) or opioids are either only able to provide limited pain relief or have safety 
issues / abuse risks that prevent their effective use in this population [Thakur, 2014]. 
Considerable need remains for therapies that offer sustained efficacy without the 
tolerability or safety concerns in a population with high prevalence of co-morbidities. 
The underlining pain mechanisms in OA are poorly understood [Malfait, 2013]. 
Rationale for CCL17 neutralization in OA pain has been generated pre-clinically using in 
vivo models of inflammatory pain, neuropathic pain, and arthritis. CCL17 has been 
recently identified as a peripheral mediator of inflammatory pain. Intraplantar 
administration of recombinant CCL17 causes pain in mice [Achuthan, 2016], and 
therapeutic dosing of an anti-CCL17 surrogate mAb inhibits pain behavior associated 
with inflammation induced by Complete Freund’s Adjuvant (CFA) [GSK3858279 
Investigator’s Brochure]. Genetic silencing of CCL17 also ameliorates inflammatory pain 

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in various murine arthritis models [Achuthan, 2016], and CCL17 was the 6th most 
upregulated gene in a chemically-induced, monosodium iodoacetate (MIA) murine 
arthritis model of chronic joint pain [Dawes, 2013]. 
The therapeutic administration of an anti-CCL17 surrogate mAb, via intraperitoneal or 
intrathecal routes, inhibits neuropathic-like pain behavior induced by sciatic nerve injury, 
in mice. Furthermore, the systemic therapeutic administration of an anti-NGF (nerve 
growth factor) mAb has no effect on reducing pain behaviors following sciatic nerve 
injury, in mice, suggesting that in this model, anti-CCL17-associated analgesia is not 
mediated via NGF [GSK3858279 Investigator’s Brochure] 
In vitro, the direct application of recombinant CCL17 had no effect on calcium flux 
measured in a mixed culture of murine sensory neurons, or in putative nociceptive 
neurons sensitive to the transient receptor potential vanilloid type 1 (TRPV1) agonist 
capsaicin, or the transient receptor potential A1 (TRPA1) agonist allyl isothiocyanate 
(AITC) [GSK3858279 Investigator’s Brochure], suggesting that CCL17 does not directly 
act on sensory neurons. 
The blockade of CCL17 with the mAb GSK3858279 offers the potential to alleviate OA 
associated chronic pain. There is no literature on CCL17 circulating levels in OA 
patients. The relationship between free CCL17 levels in healthy volunteers versus OA 
participants will be assessed from the data collected from the Phase I/Ib study (207804) 
which has included both healthy volunteers and participants with knee OA. 
The FTIH Study 207804, is a 2-part, phase I, randomized, double-blind (sponsor open), 
placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and target 
engagement of single ascending intravenous doses and a single SC dose of GSK3858279 
in healthy participants (Part A) and to additionally assess the safety and efficacy of repeat 
SC doses in participants with osteoarthritis of the knee (Part B) [GSK Document Number 
TMF-14447953]. 
In Part A of Study 207804, GSK3858279 was administered to 6 cohorts of healthy male 
and female (of non-reproductive potential) participants. The dose range evaluated was 0.1 
mg/kg to 10 mg/kg via a 1-hour intravenous infusion (Cohorts 1 to 5) and 3 mg/kg (up to 
a maximum dose of 240 mg) via SC injection (Cohort 6). No clinically significant change 
was observed for hematology, clinical chemistry or in urinalysis. No clinically significant 
safety signal was observed for vital signs. No clinically significant arrhythmia was 
recorded on telemetry and no clinically significant ECG abnormality or QTcF 
prolongation was recorded on any 12-lead ECG. 
Part B of study 207804 evaluated the safety and efficacy of GSK3858279 administered as 
240 mg weekly SC dose for 8 weeks compared to placebo in participants with knee 
osteoarthritis pain. In this study GSK3858279 demonstrated efficacy on average daily 
pain assessed by NRS. 
2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK3858279 may be found in the Investigator’s Brochure 
(IB) 

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2.3.1. 
Risk assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Risks of Investigational Medicinal Product (IMP) GSK3858279 
Infections 
 
Because of GSK3858279’s effects on immune cell trafficking, there is a 
possibility of increases in the frequency and/or severity of infections 
including opportunistic infections and tuberculosis. 
 
Non-Clinical Data: 
 
No specific studies have been conducted in non-clinical species to 
investigate the effect of GSK3858279 on response to viral or bacterial 
infection. 
CCL17 has an important role in early responses against skin-invading 
pathogens e.g. CCL17 controls filarial larval entry by limiting mast cell-
dependent vascular permeability. Mice deficient for CCL17 had an up 
to 4-fold higher worm burden compared to controls by day 10 of 
infection with murine filaria Litomosoides sigmodontis [Specht, 2011]. 
Anti-CCL17 has been shown to be protective in a mouse model of 
invasive aspergillosis [Carpenter, 2005] suggesting decreased infection 
risk. The role of CCL17 in systemic anti-pathogen responses is 
unclear. 
 
Clinical Data: 
 
While there were reports of infection in the completed phase 1 207804 
FTIH) and 209973 studies, there were no serious infection AEs. 
Eligibility Criteria: 
Exclusion of participants with: 
• 
Participants with active, recurrent or chronic infection (e.g. 
osteomyelitis), who have been receiving treatment within 
three months prior to dosing. 
• 
Current immunodeficiency diseases including but not limited 
to acquired immunodeficiency disorder or immunoglobulin 
deficiency. 
• 
Symptomatic herpes zoster within 3 months prior to 
screening. 
• 
Current or previous active Mycobacterium tuberculosis (TB) 
regardless of treatment. 
• 
Evidence of latent tuberculosis (TB). 
• 
Previous close contact with a person with active TB and did 
not receive satisfactory anti-tuberculosis treatment prior to 
study enrollment. 
• 
Positive human immunodeficiency virus (HIV) antibody test. 
• 
Has a positive test for hepatitis B virus (HBV) defined as 
either: 
o 
positive for hepatitis B surface antigen (HBsAg) OR 
o 
positive for hepatitis B core antibody (HBcAb) AND 
positive for HBV deoxyribonucleic acid (DNA). 
 
Country-specific requirements for participants from sites in Japan only: 
additionally, positive for hepatitis B surface antibody (HbsAb) AND 
positive for HBV DNA 
• 
Positive hepatitis C antibody test result 
o 
NOTE: Participants with positive hepatitis C antibody 
due to prior resolved disease can be enrolled, only if a 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
confirmatory negative Hepatitis C ribonucleic acid (RNA) 
test is obtained. 
• 
Positive hepatitis C RNA test result at screening or within 3 
months prior to first dose of study intervention. 
• 
Active or suspected COVID-19 infection 
 
Monitoring: 
• 
Serious and opportunistic infections and TB are categorized 
as AESIs. 
• 
Monitoring for signs of infection with appropriate diagnostic 
tests as necessary. 
• 
Serious and opportunistic infections will be captured on a 
specific case report form (CRF) to capture additional 
information. 
• 
Instructions to participants as to the signs and symptoms of 
infection, and to contact site personnel should they develop. 
• 
TB evaluation at screening and monitoring for TB throughout 
the study. 
• 
Hepatitis B reactivation monitoring and stopping criteria 
throughout the study. 
 
Withdrawal Criteria for IMP: 
• 
Temporarily discontinue the study intervention for: 
o 
Serious or opportunistic infections, COVID-19 (until the 
infection has resolved), or suspected TB. 
• 
Permanently discontinue the study intervention: 
o 
If the temporary hold for serious or opportunistic 
infections, or COVID-19, or suspected TB is greater than 
2 weeks, investigational product will be permanently 
discontinued but the participant will be requested to 
complete the assessments in the treatment period (up to 
the Week 16 visit) with a final follow-up visit 
approximately 16 weeks from the last dose received. 
o 
For active TB infection. 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
o Hepatitis B reactivation, HBV DNA positive or HBV 
surface antigen positive. 
Hypersensitivity  
The administration of any monoclonal antibody has the potential to 
induce local or systemic immunologic reactions.  
 
Non-Clinical Data: 
 
In the 13-week study, administration of GSK3858279 by weekly IV 
infusion at 100 mg/kg, resulted in infusion reactions after dosing on 
Days 22 and 29, in one female cynomolgus monkey which was 
successfully managed in subsequent administrations by pre-treating 
with anti-histamine. 
 
In the 26-week study, there were inflammatory vascular changes in 
multiple organs and mesangioproliferative glomerulopathy in the kidney 
which is consistent with immune complex disease following the 
formation of ADA. Non-specific injection site reactions caused by the 
subcutaneous dosing route were also noted in some monkeys, which 
was exacerbated by the immune complex deposition in one male. 
These findings were considered non-adverse. 
 
Animal studies are not predictive for ADA-mediated adverse reactions 
in humans, including infusion reactions, hypersensitivity reactions or 
anaphylaxis [Kronenberg, 2017], especially for human proteins such as 
GSK3858279. In addition, given that GSK3858279 binds a soluble 
ligand (CCL17) and is Fc disabled, GSK3858279 is not expected to 
mediate effector functions of antibody dependent cell mediated 
cytotoxicity or complement dependent cytotoxicity. 
 
Clinical Data: 
No serious hypersensitivity reactions have been observed in the Phase 
1 completed studies. 
Eligibility: 
Exclusion of participants with: 
• 
History of significant allergies to monoclonal antibodies. 
• 
Clinically significant multiple or severe drug allergies, or 
severe post-treatment hypersensitivity reactions including, but 
not limited to, erythema multiforme major, linear 
immunoglobulin A [IgA] dermatosis, toxic epidermal 
necrolysis or Stevens-Johnson syndrome, and exfoliative 
dermatitis. 
• 
Sensitivity to any of the study interventions, or components 
thereof. 
 
Monitoring: 
• 
Serious hypersensitivity reactions are categorized as AESIs. 
• 
Instructions to participants as to the signs and symptoms of 
an acute hypersensitivity reaction and to seek immediate 
medical care should they develop. 
• 
Participants will be monitored for a minimum of 2 hours post 
dosing after the first two SC injection regimens. 
• 
Every subcutaneous injection of investigational product will be 
administered by a healthcare professional. 
 
Withdrawal criteria for IMP: 
 
• 
Permanently discontinue study intervention for serious 
hypersensitivity reactions 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Injection Site Reactions 
Subcutaneous injections, including injections of monoclonal antibodies, 
may be associated with local reactions such as swelling, induration, or 
pain. 
 
Non-clinical Data: 
 
No test article-related findings were observed in monkeys at injection 
sites following doses up to 100 mg/kg/week IV and 30 mg/kg/week SC, 
following 13 weekly administrations.  
 
In the 26 week study, non-adverse and reversible microscopic 
changes, comprising slight or moderate hemorrhage, inflammatory cell 
infiltrate, vascular changes and fibrosis, were seen at the SC injection 
site, in some monkeys at all dose levels (10, 30, and 100 mg/kg/week) 
and in all dose sites, but more pronounced in one male given 100 
mg/kg/week.  
 
SC injection site reactions of various degrees of severity are not 
uncommon by this route of administration. Therefore, these changes 
are considered non-specific tissue reaction caused by the dosing 
procedure [Engelhardt, 2008], which were likely exacerbated by 
immune complex deposition in the male given 100 mg/kg/week. 
 
Clinical Data: 
 
There were no serious injection site reactions in the Phase 1 
completed studies evaluating GSK3858279 IV and SC in healthy 
subjects. In the phase 1b OA knee pain study, more subjects reported 
ISRs and there were more total ISRs in the aCCL17 group compared 
to the placebo group: 10 subjects (42%) experienced 24 ISRs aCCL17 
vs 3 subjects (13%) experienced 4 ISRs placebo. However, there was 
insufficient safety data to classify this observation as evidence of a 
causal relationship to GSK2858279. This OA Knee Pain phase 2 study 
will use a different formulation than used in the phase 1b OA and 
overall phase 1 program. 
Monitoring: 
 
• 
Investigators will be required to capture all injection site 
reactions as AEs. 
• 
ISRs will be categorized as AESIs. 
• 
Monitor for injection site reactions throughout study. 
• 
Injection site reactions will be captured on a specific CRF to 
further characterize the events. 
• 
The same injection location site (abdomen or thigh) should be 
used at each weekly dosing visit. 
• 
It is recommended that the injections are rotated between 
different quadrants of the abdomen or different areas of both 
thighs for each weekly dosing visit. 
• 
If the participant is receiving other permitted subcutaneous 
medication, the IMP in this study should be administered in a 
different location. For example, if the participant is using their 
abdomen for the IP than their SC injection should be on the 
other side of the abdomen or in the thigh. 
 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immunogenicity 
Monoclonal antibodies may induce ADAs, which have the potential to 
induce adverse reactions (mentioned above) or affect the PK and 
pharmacodynamics (PD) properties of the drug. GSK3858279 is a 
human antibody, with a lower potential for ADA formation. 
 
Non-Clinical Data: 
 
In the non-clinical studies a significant number of monkeys treated with 
GSK3858279 had confirmed ADA, but mostly the presence of ADA did 
not affect the systemic exposure or PK parameters for GSK3858279; 
however, there was no impact on clinical observations apart from the 
animal which had findings consistent with an infusion-related reaction 
and on the chronic toxicology study, vascular changes consistent with 
ICD were seen (mentioned above). In general, the incidence and titre 
of ADA in non-clinical studies are not predictive of human. 
 
Clinical Data: 
 
The 207804 FTIH Part A study in healthy participants showed there 
was low incidence of ADA, low titre, no pattern of increasing incidence 
of ADAs following single ascending dose (SAD) of GSK3858279 (or 
placebo) and no apparent difference between 3 mg/kg IV vs. 3 mg/kg 
SC. There was no detectable impact on safety. The 207804 FTIH Part 
B study in participants with OA knee pain showed a low incidence of 
ADAs. There was 1 (4%) in the placebo group and 5 (21%) ADAs in 
the GSK3858279 group. The 1 ADA in the placebo group and 4 out of 
5 in the GSK3858279 group were detected in the follow-up period after 
the 8-week dosing period. No pattern of ADA impact on safety was 
detected. 
Study 209973 in healthy participants, observed incidence of treatment 
induced ADA was 1/21 (5%) participants, with no detectable impact on 
safety. 
Blood samples will be drawn for anti-drug antibodies to GSK3858279 
on Day 1 and throughout the study including follow-up. 
 
In addition to scheduled immunogenicity assessments, “event-driven” 
testing will be performed in the context of serious hypersensitivity 
reactions or AEs deemed to be clinically significant in the opinion of the 
Investigator resulting in discontinuation from study intervention. 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Vaccine effects 
There is a theoretical possibility that GSK3858279 could decrease an 
individual’s immune response to vaccines administered while on 
therapy. 
Non-Clinical Data: 
 
Monkeys dosed with GSK3858279 for 13 weeks did not demonstrate 
modulation of the immune system as assessed by T-cell Dependent 
Antibody Response (TDAR), an assessment of humoral immunity, or of 
peripheral blood lymphocyte populations as assessed by flow 
cytometry. 
 
Clinical Data: 
 
Vaccine effects have not been formally tested in clinical studies to 
date. 
For participants who are in screening period, completion of COVID-19 
vaccination 14 days prior to study randomization will be strongly 
recommended. 
Live or live attenuated vaccine(s) must not be administered to 
participants from 30 days prior to the first dose of study drug and for 
five half-lives (16 weeks) after dosing. 
 
Investigators should review and update the vaccination status of 
potential participants as per local guidelines for adult vaccination 
including against COVID, influenza, herpes zoster and pneumococcus 
(according to local guidelines) prior to enrollment. 
 
If indicated, non-live vaccines (e.g. inactivated influenza vaccines) may 
be administered whilst receiving study drug based on an assessment of 
the benefit/risk (e.g. possible risk of decreased responsiveness). 
 
Eligibility: 
Exclusion of participants: 
 
• 
Who received live or live attenuated vaccine(s) within 30 days 
prior to randomization or plans to receive such vaccines 
during the study. 
• 
With current immunodeficiency diseases including but not 
limited to acquired immunodeficiency disorder or 
immunoglobulin deficiency. 
 
Withdrawal criteria for IMP: 
 
• 
Live or live attenuated vaccine use. 
 

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Reproductive Toxicity 
Non-Clinical Data: 
 
No reproductive or fertility studies have been conducted in animals with 
GSK3858279. In the 26-week study mature cynomolgus monkeys did 
not show toxicities in the reproductive organs (organ weights and 
histopathology), nor effects on stage dependent evaluation of 
spermatogenesis in males. 
In the absence of pathological changes in the male reproductive 
organs, the biology of anti-CCL17 mAb and the inability of large Mw 
proteins to access pivotal cells in testes, the risk of adverse effects on 
spermatogenesis in clinical use is considered minimal. 
Clinical Data: 
 
No pregnancies have been reported to date and no women of 
childbearing potential participated in the 207804 FTIH Part A or 
209973 studies. 
Eligibility: 
 
Female participants: 
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
 
• 
Not a woman of childbearing potential (WOCBP) 
 
OR 
 
• 
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 during the treatment period and for at least 16 
weeks after the last dose of study medication. 
 
• 
Exclusion of female participants who are: 
o 
Pregnant (as confirmed by serum pregnancy test), 
lactating, planning to become pregnant or initiating 
breastfeeding. 
 
Male participants: 
 
A male participant with a partner who is a WOCBP is required to use a 
condom during sexual intercourse throughout the study and for 16 
weeks after the last dose of study intervention. 
 
Monitoring: 
 
• 
Refer to Section 10.4 for further details. 
• 
Routine urine pregnancy testing of WOCBP throughout the 
study (serum if required by local regulations). 
• 
Collection of pregnancy information in female participants. 
• 
Collection of pregnancy information in female partners of 
male participants. 
• 
Pregnancy to be followed to determine outcome. 
• 
Report as AE/SAE any pregnancy complication or elective 
termination. 
 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Withdrawal criteria for IMP: 
 
• 
Permanently discontinue study intervention in the event of a 
pregnancy in a female participant. 
Study Procedures 
Blood Draws 
Venous access in some participants may be problematic and the 
needles used may cause bruising (ecchymosis) around the access site. 
• 
The whole blood volume that will be collected from each 
participant over the course of the study, including any extra 
assessments that may be required is provided in the ICF. 
• 
At visits to collect whole blood samples, one or more samples 
of sufficient volume will be collected and divided into suitable 
portions for the various analyses such as PD biomarkers. 
• 
Whole blood samples for genetic research will only be 
collected from those consenting to participate in this 
research. 
• 
Whole blood samples will be collected by site personnel or 
site approved third-party home nurse experienced in 
phlebotomy. 
Bilateral knee X-ray 
Risk is due to ionizing radiation exposure from bilateral knee X-rays at 
screening and Week 31 
• 
The estimated effective radiation dose from the knee X-rays 
is approximately 0.001mSv per scan. 
• 
Total maximum effective dose (including bilateral knees and 
all required angles) is estimated to be 0.012mSv 
• 
The average annual global background radiation dose is 
2.4mSv and therefore the total estimated dose from study 
procedures is minimal and is equivalent to approximately less 
than 2 days of background radiation. 
• 
The additional risk of developing a fatal malignancy as a 
result of this radiation exposure is approximately 1 in 125,000 
(male) and 1 in 100,000 (female). 
• 
Two bilateral knee X-rays are planned with no prescribed 
additional X-rays. 
• 
Total radiation exposure to planned study X-rays is ≈0.012 
mSv which is less than the exposure to annual background 
radiation which is 2.4mSv 
• 
A repeat X-ray is not required at a permitted re-screen if they 
were eligible in the first screening and done within 6 months 
of re-screening. 
• 
Robust pregnancy testing will be required before each X-ray. 
If a female participant has a positive pregnancy test, then no 
further X-rays will be obtained. 
 

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2.3.2. 
Benefit assessment 
• 
OA participants may experience benefit in terms of improvement in joint symptoms 
and physical function. Participants will be allowed to use 
paracetamol/acetaminophen as a rescue pain medication throughout the study (except 
for 24 hours prior to a study visit and during the study visit) to help manage their 
pain and discomfort associated with OA. Participants will only be permitted to use 
rescue medication for 4 out of 7 days in each calendar week. 
• 
By enrolling in this study, participants will be contributing to the process of 
developing new medications to treat OA-related symptoms, a significant area of 
unmet need for patients who have had inadequate response, intolerance or 
contraindication to at least one previous pharmacological therapy for knee OA pain, 
and who could be considered or who may be eligible for treatment with opioids. 
2.3.3. 
Overall benefit-risk conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with GSK3858279 are justified by the anticipated 
benefits that may be afforded to participants with knee OA.  

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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To characterize the efficacy of GSK3858279 
on knee OA pain compared to placebo  
• Change from baseline at Week 12 in 
weekly average of average daily pain 
intensity, assessed on the Numeric 
Rating Scale (NRS) 
Secondary 
 
• To investigate the efficacy of GSK3858279 
on symptoms compared to placebo in 
participants with knee OA  
• Change from baseline at Week 12 in 
Western Ontario & McMaster 
Universities Osteoarthritis Index 
(WOMAC) pain subscale score 
• Change from baseline at Week 12 in 
WOMAC function subscale score 
• Change from baseline at Week 12 in 
patient global assessment of disease 
(PtGA) 
• To evaluate the safety and tolerability of 
repeat doses of GSK3858279  
• Occurrence of adverse events (AEs), 
serious adverse events (SAEs) and AEs 
of special interest (AESI) 
• Occurrence of National Cancer Institute 
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) grade ≥3 
hematological/clinical chemistry 
abnormalities. 
• To evaluate the PK of repeat doses of 
GSK3858279  
• GSK3858279: maximum value (Cmax), 
time of Cmax (tmax), trough value 
(Ctau), average concentration (Cavg) 
and area under the curve over the dosing 
interval (AUC(0-tau)) at Week 12 
Tertiary or Exploratory  
 
• To characterize the longitudinal dose-
exposure-response relationship  
• Population parameters for the model 
describing the relationship between 
Dose, PK and response (assessed on 
the Numeric Rating Scale [NRS]) (over 
time)  
• To investigate the efficacy of repeat doses 
of GSK3858279 compared to placebo on 
additional measures of efficacy  
• Change from baseline in WOMAC pain, 
function, and stiffness subscale scores 
over time 
• Change from baseline in patient global 
assessment of disease (PtGA) over time 
• Change from baseline in Physician 
global assessment of disease (PhGA) 
over time 

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Objectives 
Endpoints 
• Change from baseline in weekly average 
and worst daily knee pain intensity over 
time, assessed on an NRS 
• Change from baseline in the pain on 
walking item score of WOMAC pain 
subscale over time 
• Usage of rescue medication (incidence, 
number of days and occasions of use 
and total dose) over time 
• Treatment Response: Reduction in the 
WOMAC Pain subscale of ≥30%, ≥50%, 
≥70% and ≥90%, over time from 
baseline 
• Treatment Response: Reduction in the 
WOMAC Physical Function subscale of 
≥30%, ≥50%, ≥70% and ≥90%, over 
time from baseline 
• OMERACT-OARSI response over time 
• To investigate the effect of repeat doses of 
GSK3858279 compared to placebo on other 
patient reported outcomes (PROs) 
• Change from baseline in PROMIS-Sleep 
Disturbance Short Form over time 
• Change from baseline in SF-36 to week 
12 
• Change from baseline to week 12 in 
overall sleep disturbance severity (PGIS-
Sleep) 
• Patient global impression of change 
(PGIC-Sleep) in overall sleep 
disturbance at Week 12 
• Change from baseline in PGIS-walk  
• To evaluate the safety of repeat doses of 
GSK3858279 compared to placebo 
• Change from baseline in laboratory 
parameters, vital signs, and ECG. 
• To assess the potential for anti-
GSK3858279 antibody formation (ADA) 
• Incidence, titres, and, for samples with 
confirmed ADA, neutralizing activity. 
• To assess the effects of repeat doses of 
GSK3858279 on exploratory biomarkers 
• Change from baseline in peripheral 
immune cell populations, in particular 
CCR4-expressing cells, at weeks 4 and 
12. 
• Change from baseline in serum protein 
mediators including but not limited to 
inflammatory, immune cell activation, 
and joint remodelling markers, may be 
investigated. 
• Whole blood transcriptomics (ribonucleic 
acid [RNA] sequencing) and epigenetic 
markers may also be explored. 

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Objectives 
Endpoints 
• To evaluate the PK concentration-time 
profile of GSK3858279 following repeat SC 
administration  
• Serum concentrations of total 
GSK3858279 over time 
• Cmax, Ctau, Cavg and AUC(0-tau) after 
1st dose and at Weeks 2, 4, 8, and 16  
• To evaluate the CCL17 profile following 
repeat SC administration  
• Observed total, free CCL17 and 
reduction (%) in free CCL17 
concentrations in serum over time  
Exploratory in a subset of participants in selected countries 
• To investigate the effect of GSK3858279 
compared to placebo on physical 
functioning and walk difficulties measured 
by actigraphy  
• Change from baseline in actigraphy 
measures to week 12 (e.g. walk velocity, 
cadence, step count) 
• Correlations between actigraphy 
measures and PROs (e.g. WOMAC, 
Walk PGIS, Walk PGIC) 
3.1. 
Efficacy Estimands 
Estimand definitions for efficacy endpoints 
Primary estimand for the primary efficacy objective  
Description 
Mean change from baseline at Week 12 in weekly average of average daily 
knee pain intensity for each GSK3858279 regimen compared to placebo in 
adult patients with knee osteoarthritis pain, where persistent use of prohibited 
pain therapy and study treatment discontinuations due to lack of efficacy or 
adverse events are considered a negative outcome, in the absence of other 
treatment discontinuations and regardless of all other use of prohibited pain 
therapy and use of allowed rescue medication. 
Rationale: Interest lies in the treatment effect where participants discontinuing 
study treatment due to lack of efficacy or adverse events, or persistently taking 
prohibited pain therapy are reflected in the estimated effect as treatment 
failures, and irrespective of the use of allowed rescue medication and 
occasional use of prohibited pain therapy.  
Treatment 
Condition 
GSK3858279 360 mg weekly, GSK3858279 240 mg weekly, GSK3858279 
240 mg every 2 weeks and GSK3858279 60 mg weekly compared to Placebo 
weekly 
Endpoint 
Change from baseline at Week 12 in weekly average of average daily knee 
pain intensity, assessed on a Numeric Rating Scale (NRS) 
Population 
Adult patients with symptomatic knee osteoarthritis 

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Primary estimand for the primary efficacy objective  
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation due to lack of efficacy or adverse event. 
• Strategy: composite; study treatment discontinuation is considered a 
negative outcome, and post-ICE assessments will be imputed using 
multiple imputation based on baseline pain scores 
ICE: other study treatment discontinuations 
• Strategy: hypothetical; data collected after the ICE will not be included, 
and outcomes will be assumed to be similar to participants who did not 
experience the ICE 
ICE: persistent use of prohibited pain therapy 
• Strategy: composite; persistent use of prohibited pain therapy is 
considered a negative outcome, and post-ICE assessments will be 
imputed using multiple imputation based on baseline pain scores 
ICE: other use of prohibited pain therapy 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of allowed rescue medication 
• Strategy: treatment policy; all data collected after the ICE will be included 
Population-
level summary 
Difference from placebo in mean change from baseline for each GSK3858279 
treatment arm 
 
Additional estimand #1 for the primary efficacy objective  
Description 
Mean change from baseline to Week 12 in weekly average of average daily 
knee pain intensity for each GSK3858279 regimen and placebo in adult 
patients with symptomatic knee osteoarthritis, in the absence of study 
treatment discontinuations, prohibited pain therapy and allowed rescue 
medication. 
Rationale: this estimand addresses the hypothetical scenario where no 
intercurrent events occurred, and in particular where all participants continued 
in the study on treatment and without taking prohibited pain therapy or rescue 
medication. 
Treatment 
Condition 
GSK3858279 360 mg weekly, GSK3858279 240 mg every 2 weeks, 
GSK3858279 240 mg weekly and GSK3858279 60 mg weekly compared to 
Placebo 
Endpoint 
Change from baseline at Week 12 in weekly average of average daily knee 
pain intensity, assessed on a Numeric Rating Scale (NRS), in the absence of 
treatment discontinuations and use of prohibited pain medications 
Population 
Adult patients with symptomatic knee osteoarthritis 
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation 
• Strategy: hypothetical; data collected after the ICE will not be included, 
and outcomes will be assumed to be similar to participants who did not 
experience the ICE 
ICE: use of persistent prohibited pain therapy 

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Additional estimand #1 for the primary efficacy objective  
• Strategy: hypothetical; data collected after the ICE will not be included, 
and outcomes will be assumed to be similar to participants who did not 
experience the ICE 
ICE: use of other prohibited pain therapy 
• Strategy: hypothetical; assessments up to 24 hours after the ICE will not 
be included in the calculation of the change from baseline outcome 
ICE: use of allowed rescue medications 
• Strategy: hypothetical; assessments up to 24 hours after the ICE will not 
be included in the calculation of the change from baseline outcome 
Population-
level summary 
Difference from placebo in mean change from baseline for each GSK3858279 
treatment arm 
 
Additional estimand #2 for the primary efficacy objective  
Description 
Mean change from baseline at Week 12 in weekly average of average daily 
knee pain intensity for each GSK3858279 regimen compared to placebo in 
adult patients with knee osteoarthritis pain, regardless of study treatment 
discontinuations, use of prohibited pain therapy and use of allowed rescue 
medication. 
Rationale: Interest lies in the treatment effect irrespective of study treatment 
discontinuation, prohibited pain therapy or allowed rescue medication.  
Treatment 
Condition 
GSK3858279 360 mg weekly, GSK3858279 240 mg weekly GSK3858279 240 
mg every 2 weeks and GSK3858279 60 mg weekly compared to Placebo 
weekly 
Endpoint 
Change from baseline at Week 12 in weekly average of average daily knee 
pain intensity on a Numeric Rating Scale (NRS) 
Population 
Adult patients with symptomatic knee osteoarthritis 
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of persistent prohibited pain therapy 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of other prohibited pain therapy 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of allowed rescue medication 
• Strategy: treatment policy; all data collected after the ICE will be included 
Population-
level summary 
Difference from placebo in mean change from baseline for each GSK3858279 
treatment arm 
The primary and additional efficacy estimands will also be applied to secondary 
continuous efficacy endpoints and will use the same strategies to address the same 
intercurrent events: 
• 
Change from Baseline at Week 12 in WOMAC pain and function subscales scores 
• 
Change from Baseline at Week 12 in PtGA 

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3.2. 
Safety Estimands 
Primary estimand for safety objectives in the placebo-controlled phase 
Treatment 
Condition 
GSK3858279 360 mg weekly, GSK3858279 240 mg weekly GSK3858279 240 
mg every 2 weeks and GSK3858279 60 mg weekly compared to Placebo 
weekly 
Endpoints 
• Incidence of adverse events (AEs), serious adverse events (SAEs) and 
AEs of special interest (AESI). 
• Occurrence of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) grade ≥3 hematological/clinical chemistry 
abnormalities. 
Population 
Adult patients with symptomatic knee osteoarthritis 
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of prohibited pain therapy 
• Strategy: treatment policy; all data collected after the ICE will be included 
ICE: use of allowed rescue medication 
• Strategy: treatment policy; all data collected after the ICE will be included 
Population-
level summary 
• AEs, SAEs, AESIs: number and % of participants with at least one event 
by Preferred Term for each treatment arm 
4. 
STUDY DESIGN 
4.1. 
Overall design 
• 
This is a Phase 2, dose-finding, multicentre, randomized, double-blind, parallel 
group, placebo-controlled study of GSK3858279 in participants with moderate to 
severe knee OA pain to investigate the efficacy, safety, PK and dose-exposure- 
efficacy relationship of GSK3858279. 
• 
Approximately 1050 adult participants with knee osteoarthritis will be screened to 
achieve approximately 420 randomized participants. 
• 
Screening will take place within a maximum of 42 days before randomization (See 
Section 1.2). After undergoing the screening visit, a washout period for all pain 
medications is required prior to Day -7, consisting of 3 days or 5 half-lives, 
whichever is longer. 
• 
The total study period is up to 37 weeks which includes, up to a maximum of 6 
weeks of screening period, 16 weeks of treatment period and 15 weeks of off-
treatment follow‑up period (16 weeks from the last treatment dose). 
• 
The approximate sample size is 420 participants. The study team may enroll 
additional participants to within 15% of the planned 420 to ensure regional 
requirements for recruitment are met. All participants will be treated for 16 weeks, 
however the primary efficacy endpoint evaluation will be at Week 12. 

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• 
Participants will be randomized to one of 5 treatment arms. Specifically, placebo 
weekly, GSK3858279 60 mg weekly, GSK3858279 240 mg weekly, GSK3858279 
240 mg every 2 weeks or GSK3858279 360 mg weekly. For the arm which receives 
240 mg every 2 weeks, there will be alternate placebo administration every 2 weeks. 
Participants will be randomized in a 2:1:1:1:1 ratio. Randomization will be stratified 
by subject region (Japan, China and rest of the world) and average of daily pain 
score at baseline <7 or ≥7. GSK3858279 or placebo will be administered as 
subcutaneous (SC) injection. 
• 
Participants who complete the 16-week treatment period will exit the study after 15 
weeks off-treatment follow-up (16 weeks from the last treatment dose). 
• 
Participants who discontinue study treatment are requested to complete the 
remaining scheduled visits and assessments up to week 16 with a final follow-up 
visit approximately 16 weeks from the last dose received. 
• 
An interim analysis for overall study futility will be performed when ~120 
participants complete Week 12 or early withdrawal visit. Further additional interim 
analyses may be considered to support internal decision making and regulatory 
interactions. An iDRC will be set-up for reviewing the results from the interim 
analyses. Full details of all interim analyses will be prospectively outlined in the 
iDRC charter. 
• 
An external IDMC will regularly review the unblinded study data at scheduled 
intervals. IDMC reviews will allow ongoing external safety oversight to protect the 
safety of study participants as the study progresses. Further details on safety 
monitoring by the IDMC are provided in Section 8.4. Further details of the IDMC 
composition are highlighted in Section 10.1.6 and full details of activities are 
provided in the IDMC charter. 
• 
Some study visits may be conducted through home healthcare where applicable 
country and local regulations and infrastructure allow (see SoA) and 
AE/SAE/concomitant medications will be assessed through telemedicine. 
4.2. 
Scientific rationale for study design 
The study is designed to examine the efficacy, safety, tolerability and PK of different 
doses/regimens of GSK3858279 in adult participants with moderate to severe pain due to 
knee osteoarthritis. 
This dose-finding study expands on our existing knowledge on the efficacy and safety of 
GSK3858279, in patients with knee OA pain, including but not limited to validation of 
clinical activity, durability of efficacy, impact of dosing regimen and dose-exposure- 
response (D-E-R) relationship. 
The parallel group design is chosen as the most appropriate one to evaluate effects of a 
mAb analgesic in a chronic pain indication. Due to the nature of the disease and the 
outcome measures used, a placebo arm is necessary to establish efficacy. The primary 
endpoint is change from baseline in weekly average of average daily pain intensity (in the 
index knee), assessed on the Numeric Rating Scale (NRS) at Week 12. A 12-week 

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timepoint for primary efficacy analysis is deemed appropriate as it is consistent with 
assessing efficacy once steady-state reductions in CCL17 are predicted to be achieved 
and with the regulatory expectation on primary endpoint evaluation in chronic pain trials. 
However, to account for any uncertainties in achievement of steady-state levels in CCL17 
and for an indirect relationship between target engagement and efficacy (consistent with 
CCL17 acting via a secondary mediator), a 16-week treatment period has been chosen to 
provide data after an additional 4 weeks of treatment to inform the understanding of the 
longitudinal response of GSK3858279. 
Average daily pain intensity on NRS is a validated clinical endpoint widely used in 
clinical studies of OA pain and is accepted by the regulatory agencies. It is a direct and 
simple way of measuring pain intensity with clear clinical relevance to patients. The 
primary endpoint will be calculated by assessing the average pain score in the 7 days 
prior to each respective time point (i.e: baseline and week 12). The average daily pain on 
NRS is highly correlated with other commonly used disease specific assessment tool such 
as WOMAC pain subscale. Since average daily pain on NRS provides more data points, 
it is conceptually more sensitive to change, which is beneficial in exposure-response 
characterization over WOMAC pain subscale. In this study, WOMAC pain and function 
will be captured as secondary endpoints to inform efficacy for these outcomes. 
All participants will have 3 off-treatment follow-up visits, with the last one occurring 
approximately 15 weeks after their last treatment visit (16 weeks after last dose). This 
equates to a follow-up period over approximately 5 x the observed terminal elimination 
half-life for total GSK3858279. 
4.2.1. 
Participant input into design 
Feedback on study design has been obtained by conducting a patient engagement survey 
[Insites Consulting Report (7805) April 2022)]. 
It is GSK’s intent to continually engage participants whose feedback may influence 
future study designs for this disease area and may improve the participant experience 
within clinical research. 
4.3. 
Justification for dose 
The dose range and regimens have been chosen to allow a full exploration of the dose-
exposure-response of GSK3858279 in Knee OA by selecting doses that are predicted to 
encompass a wide range of target engagement (reductions compared to baseline) of the 
chemokine CCL17. This will facilitate selecting the optimal effective/safe dose(s) for 
investigation in Phase 3 using the longitudinal PK and clinical efficacy data collected 
from all the dose regimens in the current study. 
GSK3858279 target engagement has been demonstrated in healthy participants and 
participants with OA of the knee. Following single IV (0.1-10 mg/kg) and SC (3 mg/kg) 
administrations there were dose related increases in total (free + complex) CCL17 and 
reductions (compared to baseline) in free CCL17 (as measured by a semi-quantitative 
method) over time (207804, Part A, and 209973). Reductions in free CLL17 (as 

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measured by a semi-quantitative method) were maintained over 8 weeks on repeat 
weekly dosing (240 mg) to participants with moderate to severe knee OA in the Phase 1b 
study (207804, Part B). This study provides the only prior information on repeat SC 
dosing of GSK3858279 (240 mg/week) and impact of functional inhibition of CCL17 on 
Knee OA pain. 
The proposed dose levels and regimens have been selected based on an integration of 
model predicted target engagement (reductions from baseline in free CCL17) and free 
CCL17 concentration-time data [GSK Document Number TMF-15210197]. The target-
mediated drug disposition (TMDD) model uses the Quasi Steady-State (QSS) 
approximation and is fitted to the time-matched total GSK3858279 and total CCL17 data 
in healthy and OA participants [GSK Document Number TMF-15210197]. 
The maximum proposed dose is 360 mg/week, and is the maximum dose that can be 
administered within three SC injections (1.2 mL/injection) with the 100 mg/mL 
formulation proposed to be used in this study and is predicted result in high levels of 
target engagement (Figure 2). Although SC doses higher than 240 mg weekly have not 
been studied in human trials, it is considered a low safety risk to proceed with the higher 
360 mg SC dose. The NOAEL based on animal studies is 100 mg/kg/week IV and 
100 mg/kg/week SC and the exposure limits based on mean AUC and Cmax in the 26-
week cynomolgus study are approximately 45 and 50-fold higher than predicted 
maximum GSK3858279 AUC and Cmax exposures, respectively, at the proposed 360 mg 
SC weekly dose in humans. In addition, the single IV dose of 10 mg/kg given in the 
clinical Phase 1 study provides a margin over both Cmax (~5.8-fold) and AUC (~2.2-
fold) following repeat weekly dosing at 360 mg SC. The 360 mg/week dose will allow a 
full exploration of the efficacy, safety and tolerability of GSK3858279 and aligns with 
good practices on understanding efficacy, safety, and tolerability across a wide dose 
range in Phase 2. 
The lowest dose (60 mg/week) is predicted to result in smaller (maximum and trough) 
CCL17 reductions, whilst still maintaining the reduction in CCL17 compared to baseline 
at trough at ~40%, and has a distinct TE profile compared to the higher dose regimens, 
(Figure 2). Granulocyte-macrophage colony stimulating factor (GM-CSF) upregulates 
CCL17 and treatment with the anti-granulocyte-macrophage colony stimulating factor 
(GM-CSF) mAb otilimab (GSK3196165) (180 mg/week SC to week 4, every other week 
until Week 10) resulted in an approximate 30% reduction in circulating levels of CCL17 
compared to baseline over 8 weeks of treatment, with a non-significant trend towards a 
reduction in pain [Schett, 2020]. Otilimab has multiple functional effects that are 
independent of CCL17 regulation which may also impact pain. While the data cannot be 
directly extrapolated to GSK3858279 it may guide to the minimal level of CCL17 
reduction compared to baseline that may be required for an effect in OA pain. Therefore 
60 mg/week (~40% reduction in CCL17 compared to baseline at trough (Figure 2) is 
anticipated to result in minimum efficacy in terms of pain response. 
The dose of 240 mg/week is the same dose that demonstrated efficacy on daily average 
pain (as measured by NRS score) in the Phase 1b study (207804). 240 mg/every 2 weeks 
will investigate the impact of dose frequency. Systemic exposure (over a 2 week period) 
is predicted to be similar to that following 120 mg/week dose of GSK3858279. 

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Furthermore, the bi-weekly regimen will provide additional data on the longitudinal 
exposure-response relationship (Figure 2). 
Figure 2 
Predicted Steady-State Reductions in Free CCL17 (median and 95% 
CI of the prediction) following weekly (60 mg, 240 mg and 360 mg) 
and every 2 weeks (240 mg) SC dosing with GSK3858279 over 16 
weeks [GSK Document Number TMF-1521097] 
 
Through an integrated analysis of longitudinal data from all doses and regimens it is 
predicted that there will be a full understanding of dose-exposure-response (D-E-R) 
relationship across the 6-fold dose range (60-360 mg/week) of GSK3858279 which will 
facilitate dose selection for future studies in this population. 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the final follow-up visit (week 31). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 

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4.5. 
Actigraphy sub-study (optional) 
Actigraphy is a non-invasive method of measuring activity and rest cycles. The type of 
activities and their intensity can be measured continuously over time using motion-based 
devices, such as accelerometers. Actigraphy has been used as a tool to assess daily 
activity of patients with impaired mobility [James, 2015] and may be particularly 
appropriate as OA patients frequently report pain which has a negative impact on their 
daily physical functioning. In adults with knee OA, accurate measurement of both pain 
and function are important, and objective digital measures may supplement traditional 
methods of measuring physical function such as patient reported outcomes and in-clinic 
walking tests. In addition to capturing functional measures within patients’ own 
environments, digital measurement of activity will allow for improved interpretation of 
measured pain scores, given the relationship between activity and pain in OA. The use of 
a digital device in adults with knee OA is expected to capture accurate information about 
patients’ function in real-world settings, particularly in terms of patients’ walking ability 
and behavior, a critical endpoint both for patients and for assessing the risk/benefit of 
investigational products. 
In this study, participants in selected countries will be invited to participate in this 
optional sub-study. Actigraphy assessments using the “StepWatch™”, an ankle-worn 
FDA-listed device will be conducted as a means of objectively measuring changes in 
physical functioning (and particularly changes in patients’ ability to walk). Participants 
will wear the StepWatch™ for one week starting at Day -7 and for one week starting at 
Week 11 and ending at Week 12. 
StepWatch™ (Modus Health LLC, Edmonds, WA) measures steps walked throughout 
the day, cadence, walk velocity and other walk-related metrics. StepWatch™ has 
undergone analytical validation in several populations under controlled and free-living 
conditions and was consistently shown to be both accurate and reliable. GSK is 
conducting a feasibility assessment and analytical validation for knee OA (GSK214427); 
results from an interim analysis indicate that for most of the participants, the overall 
experience from using the StepWatch™ device was positive. This resulted in high levels 
of compliance: average wear time over a 14-day period was greater than 12 hours/day 
(and greater than 16 hours/day for 42.9% of patients). The accuracy of the device in 
measuring step count and cadence was also proven to be very high: the relative mean 
difference of device data was 2.7% when compared to gold standard video monitoring. 
The sub-study will aim to collect further evidence, complementary to that being collected 
in GSK214427, to support the clinical validation of the digital measures. Specifically, the 
sub-study will aim to: 
• 
Evaluate the sensitivity of the digital measures by assessing their change over time 
from baseline. 
• 
Describe concurrent (criterion) validity by evaluating the correlations between the 
digital measures and traditional PROs, including the WOMAC functional scale (and 
sub-components specifically assessing walking). 

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• 
Determine the minimal clinically important difference (MCID) in digital measures 
using an anchor-based methodology, with potential additional support using 
distribution-based methodology. The selected anchors include the WOMAC 
functional scale and a walk-related PGIS. 
The data collected will also be used to conduct additional exploratory analyses of 
physical functioning to support the development of a robust endpoint that could be used 
as a secondary endpoint in future programs. In particular, analyses to develop a 
composite endpoint that measures both pain and function (by combining digital and PRO 
data) will be conducted. 
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: 
AGE 
1. Participant must be 40 to 80 years of age inclusive, at the time of signing the 
informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Symptomatic OA of the index knee as defined by symptomatic for ≥6 months with 
a clinical diagnosis of OA as per American College of Rheumatology (ACR) 
criteria. 
3. Kellgren and Lawrence (KL) score ≥2 on X-ray in the index knee as obtained 
during screening [Kellgren, 1957]. 
4. At screening (Visit 1), pain score ≥4 and ≤9 by the 11-point NRS (0-10) for 
average daily pain intensity over the past 24 hours in index knee. 
5. During the run-in period over the preceding 7 days prior to first dose of study 
intervention: 
a. 
An average of the average daily pain score of ≥4 and ≤9 by the 11-point NRS 
(0-10). For participants with bilateral knee OA, the index knee is determined 
at Visit 1 as the patient reported most painful knee during screening. Pain 
scores must be recorded on at least 6 of 7 days and should not be highly 
variable (standard deviation not greater than 1.5).  The investigator will 
receive confirmation of eligibility if all of these criteria are met. 
b. 
Rescue medication use (if required) must be within the permitted allowance. 
Rescue medication diary must be completed on at least 6 out of 7 days. The 
Investigator must review the rescue medication diary to confirm eligibility 
criteria are met. See Section 6.9.4 for details. 

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6. Participants who have a history of inadequate response, intolerance or 
contraindication to at least one previous pharmacological therapy for knee OA 
pain, and who could be considered for treatment with opioids as judged by the 
investigator. Patients with current or prior use of opioids for any indication within 
the last 30 days prior to screening are not eligible. 
7. Participant must be willing and able to understand and participate in all scheduled 
evaluations and to complete all required tests and procedures including the use of 
patient eDiary. This will be judged by the Investigator during the screening period. 
WEIGHT 
8. BMI <40 kg/m2  
SEX 
9. Male or female. 
• 
Female participants: 
A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
o 
Not a woman of childbearing potential (WOCBP) as defined in Section 
10.4.1.1 
OR 
o 
Is a WOCBP and using a contraceptive method that is highly effective, 
with a failure rate of <1%, as described in Section 10.4 during the study 
intervention period and for at least 16 weeks after the last dose of study 
intervention. The Investigator should evaluate potential for contraceptive 
method failure (e.g. noncompliance, recently initiated) in relationship to 
the first dose of study intervention. 
o 
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. See Section 8.3.6. 
o 
Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.3.6. 
o 
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. 
• 
Male Participants: 
A male participant with a partner who is a WOCBP is required to use a condom 
during sexual intercourse throughout the study and for 16 weeks after the last dose 
of study intervention. 

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INFORMED CONSENT 
10. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the Informed 
Consent Form (ICF) and in this protocol. 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical Conditions 
1. History of significant medical illness including but not limited to cardiovascular, 
renal, gastrointestinal, lymphatic diseases, which in the opinion of the investigator 
would interfere with the study procedures and/or assessments. 
2. Myocardial infarction or unstable angina, or cerebrovascular event in the 6 months 
prior to screening. 
3. Unstable or life-threatening cardiac arrhythmia requiring intervention within 3 
months prior to screening. 
4. New York Heart Association (NYHA) Class III and IV Heart failure. 
5. Corrected QT interval according to Fridericia’s formula (QTcF) >450 msec or 
QTcF >480 msec in participants with bundle branch block at screening or Day 1 
visit. 
6. History or current evidence of any inflammatory arthritis such as rheumatoid 
arthritis, infective arthritis, Paget's disease, osteonecrosis, osteoporotic fracture or 
any other joint disease that in the Investigator's opinion would interfere with the 
assessment of pain and other symptoms of osteoarthritis. 
7. Active flare of gout or pseudogout in any joint within last year. 
8. History of significant trauma or surgery to a knee or hip within the last 6 months. 
9. Radiographic evidence of sub-chondral fractures or radiographic abnormalities not 
consistent with osteoarthritis of the index knee at screening. 
10. History of infected joint prosthesis, chronic leg ulcers, permanent in-dwelling 
catheters, chronic sinusitis, recurrent chest infections or recurrent urinary tract 
infections. 
11. Any focal or widespread pain syndrome, including fibromyalgia and chronic low 
back pain, that may in the opinion of the investigator interfere with understanding 
of pain response in the index knee. 
12. Significant pain in any joint other than the index knee or any referred pain that 
would impact ability to assess pain in index knee as per investigator’s judgment 
(pain in other locations should be less than pain in target knee). 
13. Current immunodeficiency diseases including but not limited to acquired 
immunodeficiency disorder or immunoglobulin deficiency. 

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14. Symptomatic herpes zoster within 3 months prior to screening. 
15. Current or previous active Mycobacterium tuberculosis (TB) regardless of 
treatment. 
16. Evidence of latent tuberculosis (TB) (as documented by medical history, 
examination and TB testing): either a positive (not indeterminate) QuantiFERON-
TB Gold plus test or a positive (not indeterminate) T-SPOT test. 
NOTES: 
• 
QuantiFERON Gold Plus test or, if unavailable, T-SPOT TB test (with prior 
Sponsor’s approval) will be performed. The QuantiFERON Gold Plus test can 
only be used in countries where it is licensed, and the use of this test is 
dependent on previous treatment(s). This test may not be suitable if previous 
treatment(s) produced significant immunosuppression. 
• 
In cases where the QuantiFERON or T-SPOT is indeterminate, the participant 
may have the test repeated once, but they will not be eligible for the study 
unless the second test is negative. 
• 
If there has been recent close contact with persons who have active TB and 
did not receive satisfactory anti-tuberculosis treatment prior to study 
enrollment, the participant will not be eligible. 
17. History, diagnosis, signs or symptoms of any clinically significant psychiatric 
disorder, including but not limited to: psychotic disorders, somatoform disorders, 
bipolar disorders; Depression with hospital admission or suicide attempt within the 
last 5 years (not expected to require initiation of pharmacological treatment for 
depression or anxiety for the duration of the study), any other psychiatric illness 
that in the opinion of the Investigator would render a subject as not suitable to 
participate in the study. 
18. History or evidence of clinically significant multiple or severe drug allergies, 
including to monoclonal antibodies, or severe post-treatment hypersensitivity 
reactions (including, but not limited to, erythema multiforme major, linear 
immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis or Stevens-
Johnson syndrome, and exfoliative dermatitis). 
19. Malignancy 
• 
History of malignancy within the last 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. 
• 
Breast cancer within the past 10 years. 
20. Liver 
• 
Alanine transferase (ALT) >1.5× ULN at screening. 
• 
Bilirubin >1.5×ULN at screening (isolated bilirubin >1.5× ULN is acceptable 
if bilirubin is fractionated and direct bilirubin <35%). 

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• 
Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
21. Evidence of renal insufficiency, indicated by estimated creatinine clearance 
<60 mL/min/1.73m2 at screening. 
22. Hematological laboratory values at screening: 
• 
White blood cell (WBC) count <3.0×109/L 
• 
Platelet count <125×109/L 
• 
Hemoglobin: 
• 
Males and females with hemoglobin <11.0 g/dL are excluded. 
• 
Males with hemoglobin level ≥11.0 g/dL to <13.8 g/dL and females with 
hemoglobin level ≥11.0 g/dL to <12 g/dL will only be eligible in the 
absence of any signs of acute blood loss and if, per the investigator’s 
judgment, the hemoglobin level at screening is considered stable in 
comparison to: 
• 
Prior documented hemoglobin test within 6 months prior to 
screening†. 
OR (if no prior test results are available) 
• 
Repeat hemoglobin test after 3-4 weeks from screening† (Visit 1 
date). 
†Both tests must be ≥11.0 g/dL 
• 
Note: Males with hemoglobin level ≥13.8 g/dL and females with 
hemoglobin level ≥12 g/dL are eligible. 
23. Planned surgical procedure over the duration of the study. 
24. Participants with recurrent or chronic infection (e.g., osteomyelitis), who have been 
receiving treatment within three months prior to randomization or individuals with 
an active infection at screening or Day 1 visit. 
 

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5.2.2. 
Prior/Concomitant Therapy 
25. Live vaccine(s) or live attenuated vaccine(s) within 30 days prior to randomization 
or plans to receive such vaccines during the study. 
26. Intra-articular therapy in either knee within 3 months prior to the screening visit 
27. Immunomodulators, including: 
• 
Corticosteroids (parenteral within 3 months of randomization; oral within 1 
month of randomization, or intra-articular in any joint within 3 months of 
randomization); 
• 
Biologic agents (such as monoclonal antibodies including marketed drugs) 
within 3 months or 5 half-lives (whichever is longer) prior to randomization. 
• 
Non-biologic agents (e.g., methotrexate, azathioprine, JAK inhibitors) within 
4 weeks or 5 half-lives (whichever is longer) prior to randomization. 
are prohibited during the study. 
28. Unable or unwilling to discontinue all pain medications including topical 
analgesics, adjunctive treatment (e.g., TENS machine, acupuncture or other forms 
of pain reduction interventions that might confound protocol assessments) and 
over-the-counter pain products (refer to Section 6.9.1). 
29. Major surgery (as per investigator’s judgment) within 3 months prior to 
randomization. 
 
5.2.3. 
Prior/Concurrent Clinical Study Experience 
30. Current enrollment or past participation in a clinical study of an investigational 
medicinal product intervention within the last 30 days or 5 half-lives (whichever is 
longer) of signing consent. 
31. Exposure to more than 4 investigational medicinal products within 12 months prior 
to randomization. 
32. Previous exposure to GSK3858279. 
33. Participants who are a family member of the Investigator or any associate, 
colleague, and employee assisting in the conduct of the study (secretary, nurse, 
technician). 
34. Participants who cannot be contacted by phone in an emergency. 
35. Participants who are unlikely to comply with the protocol (e.g. uncooperative 
attitude, inability to return for subsequent visits, inability to complete the eDiary 
daily etc.) and/or otherwise considered by the Investigator to be unlikely to 
complete the study. 
 

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5.2.4. 
Diagnostic assessments 
36. Positive human immunodeficiency virus (HIV) antibody test. 
37. Has a positive test for hepatitis B virus (HBV) defined as either: 
a. 
positive for hepatitis B surface antigen (HBsAg) OR 
b. positive for hepatitis B core antibody (HBcAb) AND positive for HBV 
deoxyribonucleic acid (DNA). 
NOTE: Participants who are positive for HBcAb and negative for HBV DNA can be 
enrolled in the study provided they follow the requirement of Section 8.3.7 for hepatitis 
B reactivation monitoring. 
Country-specific requirements for participants from Japan sites only: additionally, 
positive for hepatitis B surface antibody (HbsAb) AND positive for HBV DNA. 
 
38. Positive hepatitis C antibody test result 
NOTE: Participants with positive hepatitis C antibody due to prior resolved 
disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is 
obtained. 
39. Positive hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention. 
40. Active or suspected COVID-19 infection. 
41. Participants who have tested positive for COVID-19 with a PCR assay at screening 
and who are either asymptomatic or who are symptomatic and uncomplicated 
require a negative PCR assay after an asymptomatic period of 14 days prior to first 
dose of study intervention. 
42. Participants who have had a negative PCR assay initially but have since developed 
clinical features suggestive of COVID-19 or have had known exposure to COVID-
19 during the screening period must again test negative with a PCR assay 14 days 
after symptoms resolution prior to first dose of study intervention. 
43. A positive drug screen test at screening. 
NOTE: Positive result, such as opiates and benzodiazepines, on the UDS would 
not automatically exclude participants as long as the results are consistent with the 
participants current medications use and the washout period will be completed per 
protocol before Day 1. 
 

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5.2.5. 
Other Exclusions 
44. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding. 
45. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse 
or dependence within a year prior to Day 1. 
46. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study. 
47. Participants will be excluded from the optional actigraphy sub-study if any of the 
following apply: 
• 
Dependence on wheelchair, walking aids, or unable to walk without assistance 
• 
Prosthetic limbs 
• 
History of severe skin allergy or hypersensitivity 
5.3. 
Lifestyle considerations 
5.3.1. 
COVID-19 related restrictions 
• 
Participants will be required to adhere to the measures and procedures outlined 
locally at each of the investigative sites to reduce the risk of COVID-19 infections 
among trial participants and clinical site staff. 
5.3.2. 
Meals and dietary restrictions 
• 
Participants are required to fast for a minimum of 10 hours before visits on which a 
fasting lipid panel will be drawn when feasible, as deemed by the investigator. 
Specifically at baseline, Week 16 and Week 31. Details are provided as per the SoA. 
5.3.3. 
Caffeine, alcohol, and tobacco 
• 
No restrictions are required; however, extensive use of caffeine, alcohol, and tobacco 
should be avoided. In addition, changes in tobacco usage should also be avoided 
during the study. 
5.3.4. 
Activity 
• 
Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants should maintain stable levels of 
physical activity throughout the duration of screening, treatment and follow-up. 
• 
Participants may continue a regimen of therapeutic exercise, provided it has been 
stable for at least 4 weeks prior to enrollment. No new therapeutic regiments should 
be implemented during the study. 

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• 
Physical therapy/physiotherapy or therapeutic massage should not be initiated during 
this study. Heat or ice therapy can be used during the study, except 2 hours prior to 
eDiary assessments and 24 hours prior to a clinic visit. 
5.3.5. 
Other restrictions 
Not applicable. 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently randomized. 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 
serious adverse events (SAEs) (refer to eCRF completion guideline for further details). 
Individuals who do not meet the criteria for participation in this study (screen failures) 
may be rescreened once. A further re-screen for administrative reasons can be approved 
at the discretion of the Medical Monitor. In cases where additional re-screens are 
permitted, Knee X-rays do not need to be repeated if they were eligible in the first 
screening and done within 6 months of re-screening. Rescreened participants are required 
to sign a new ICF and should be assigned a new participant number. Previously assigned 
participant numbers are to be recorded in the participants’ eCRF. 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study 
intervention 
Not applicable. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions. 

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6.1. 
Study intervention(s) administered 
An overview of the study interventions is provided in table below. Investigators should 
note the following: 
• 
Each participant will receive 3 SC injections of study intervention per week. Study 
SC injections should be administered weekly, preferably on the same day each week. 
The SC injections should be administered to the abdomen or thigh. The same region 
of the body (abdomen or thigh) should be used at each weekly dosing visit. 
• 
The abdomen will be split into 4 quadrants and each thigh, into upper and lower 
parts. All the 3 injections should be administered in the same area (quadrant for 
abdomen, lower or upper half of a thigh) 2-3cm apart. It is recommended that the 
injections are rotated between different quadrants of the abdomen or different areas 
of both thighs for each weekly dosing visit. 
• 
A window of ±2 days is acceptable for the SC injection (except for Visit 3) and 
minimum gap of 5 days between each dose, for no more than 2 consecutive doses. 
Participants should return to their 7-day dosing schedule as soon as possible 
thereafter. 
• 
The injections must be performed at the site after completion of study assessments, 
PK sampling and other blood draws. 
• 
All participants must receive general safety monitoring for 2 hours after the first and 
second doses (doses scheduled on Day 1 and Week 1). Safety monitoring will 
include monitoring of symptoms and signs for systemic hypersensitivity and local 
injection site reactions. 
Table 3 
Study Intervention(s) Administered 
Intervention Label 
GSK3858279 
Diluent/Placebo 
Rescue Medication 
Intervention Name 
GSK3858279 
Placebo 
Paracetamol/Acetaminophen 
Intervention 
Description 
 
GSK3858279 is formulated in 
20 mM Histidine, 180 mM 
Trehalose, 40 mM Arginine, 
8 mM Methionine, 0.05 mM 
EDTA, 0.02% PS80, pH 6.0 
Normal Saline (0.9% 
sodium chloride) 
 
Type 
Biologic 
Placebo 
Drug 
Dose Formulation 
 
Solution for injection 
The drug product is a brown 
to yellow solution stored in 
ISO 2R glass vials with a 13 
mm rubber stopper and a 
gray/violet 13 mm Flip-top 
aluminium overseal. 
Solution for injection 
Oral dosage form, e.g. 
tablet, capsule, solution. 
Unit Dose 
Strength(s) 
100 mg/mL. Each vial has an 
extractable volume of 1.2 mL 
(120 mg per vial). 
0.9% w/v sodium chloride, 
placebo level variable. 
Variable 

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Intervention Label 
GSK3858279 
Diluent/Placebo 
Rescue Medication 
Intervention Name 
GSK3858279 
Placebo 
Paracetamol/Acetaminophen 
Dosage Level(s) 
60 mg, 240 mg and 360 mg 
The appropriate volume of 
GSK3858279 will be injected 
using a syringe at no more 
than 1.2 mL per injection. 
Dilution instructions will be 
provided in the Pharmacy 
Manual 
The appropriate volume 
of normal saline will be 
injected (SC) in the same 
manner as the 
corresponding active 
cohort 
As needed with the following 
restrictions: 
No more than 3 grams/day 
and for a maximum of 4 
days in a week 
Route of 
Administration 
SC injection 
SC injection 
Oral 
Use 
 
IMP 
IMP 
Rescue medication 
Non-IMP 
Not applicable 
Not applicable 
Non-IMP 
Authorized 
AxMP/Unauthorized 
AxMP 
Not applicable 
Not applicable 
Authorized AxMP 
Sourcing 
Study medication is supplied 
by GSK 
0.9% w/v sodium chloride 
is sourced locally by the 
site 
Paracetamol / 
acetaminophen will be 
provided to sites by GSK or 
purchased commercially by 
the site 
 
Packaging and 
Labeling 
Study intervention will be 
provided in a single-use vial 
contained within a carton. 
Each single-use vial and 
carton will be labeled as 
required per country 
requirement. 
 
Dispensed medication will be 
labeled as required per 
country requirement. 
Study intervention will be 
purchased commercially 
by the site and used in its 
commercial container 
closure system as single-
dose product. 
 
Dispensed medication will 
be labeled as required per 
country requirement. 
Dispensed medication will 
be labeled as required per 
country requirement. 
Table 4 
Study Arm(s) 
Arm Title 
Placebo 
 GSK3858279 
 
 GSK3858279 
 
GSK3858279 
 
GSK3858279 
Arm Type 
 
Placebo 
Experimental 
Experimental 
Experimental 
Experimental 
 
Regimen 
number 
N/A as 
parallel 
group study 
N/A as parallel 
group study 
N/A as parallel 
group study 
N/A as parallel group 
study 
N/A as parallel group 
study 
 
Arm 
Description 
 
Participants 
will receive 
Placebo 
(SC) once 
per week 
for 16 
weeks 
Participants will 
receive 
GSK3858279 
(SC) 60 mg once 
per week for 16 
weeks 
Participants will 
receive 
GSK3858279 
(SC) 240 mg 
once per week 
for 16 weeks 
Participants will 
receive 
GSK3858279 (SC) 
240 mg every other 
week for 16 weeks. 
NB: Placebo given in 
intervening week to 
maintain blind 
Participants will 
receive 
GSK3858279 (SC) 
360 mg once per 
week for 16 weeks. 
 

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6.2. 
Preparation, handling, storage, and accountability 
The Investigator or designee must confirm appropriate temperature conditions 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 may supply, prepare or administer study intervention. If allowed by 
country regulation/ethics, study intervention may be administered by a HHS professional. 
All study interventions 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 authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation, and final disposition records). 
Further handling guidance and information for the final disposition of unused study 
intervention 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. 
• 
Placebo (0.9% normal saline) will not be supplied by the sponsor. It will be 
purchased commercially by the study site, subsidiary, or designee and used in its 
commercial container closure system as single-dose product. The manufacture’s drug 
label instructions and/or packet insert should be followed for handling, dose 
preparation, and administration. Sites should use the most up to date version of 
packet insert. 
6.3. 
Assignment to study intervention 
All participants will be centrally assigned to randomized study intervention using an 
Interactive Web Response System (IWRS). Before the study is initiated, the log-in 
information and directions for the IWRS will be provided to each site. 
Study intervention will be dispensed at the study visits as summarized in the SoA. 

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At screening a unique participant number will be assigned to any participant who has at 
least one screening procedure performed, other than informed consent. The unique 
participant number will be used to identify individual participants during the course of 
the study. Participants who meet the eligibility criteria will be randomized to a treatment 
group centrally through the IWRS. Randomization will be in accordance with a 
randomization schedule generated by the GSK Randomization Office, prior to the start of 
the study, using validated internal software. Once a randomization number and 
participant number have been assigned to a participant, they will not be reassigned to any 
other participant in the study. 
6.4. 
Blinding, masking 
This will be a double-blind study with respect to allocation of GSK3858279 or placebo to 
participants and the following will apply: 
• 
Participants will be stratified by region (Japan, China and rest of the world) and 
average of daily pain score at baseline <7 or ≥7 and randomized in a 2:1:1:1:1 ratio 
to receive placebo or one of the 4 GSK3858279 arms. Investigators and blinded site 
staff will remain blinded to each participant’s assigned study intervention throughout 
the course of the study. To maintain this blind, each syringe will be labeled with 
yellow “blinding tape” to mask any visual differences of the liquid between 
interventions. The unblinded authorized site staff who prepare the study intervention 
will not have contact with study participants. 
• 
The unblinded authorized site staff will be responsible for the preparation and 
dispensation of all study intervention and will endeavor to ensure that there are no 
differences in time taken to dispense following randomization. 
• 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding 
of a participant’s intervention assignment is warranted. Participant’s safety must 
always be the first consideration in making such determination. If the Investigator 
decides that unblinding is warranted, the Investigator should make every effort to 
contact GSK prior to unblinding a participant’s intervention assignment unless this 
could delay emergency intervention of the participant. If a participant’s intervention 
assignment is unblinded GSK must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in source 
documents and in the CRF, as applicable. 
• 
A participant will be withdrawn if the participant’s intervention code is unblinded by 
the Investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in source documents 
and in the CRF. The participant will be followed up for safety monitoring if 
treatment was received. 
• 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to 
Investigators in accordance with local regulations and/or GSK policy. 

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• 
Unblinded monitors and, in the event of a quality assurance audit, the auditor(s) will 
be allowed access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been conducted accurately. Unblinded GSK personnel 
(separate roles outside of the blinded study teams), will also be allowed access to 
subject level treatment assignments as required to manage the unblinded aspects of 
study conduct. 
• 
Unblinded personnel independent from GSK will be allowed access to subject level 
treatment assignments as required to manage IDMC/iDRC conduct. 
• 
The Central laboratory will be blinded to the study intervention assignment. Codes 
will be used to link the participant and study to each sample. There will be no link 
between the study intervention groups and the identity of the participant. 
• 
Designated independent representative(s) may be unblinded for preparing population 
PK and PKPD datasets and for draft PK and PKPD model development/refinement 
using PK and PKPD unblinded datasets, including but not limited to: concentration-
time data, dosing information, baseline demographic characteristics, primary efficacy 
and PD information. 
• 
Primary reporting will take place after the target number of participants have 
completed their week 16 (or early withdrawal) visit. GSK staff who have direct 
contact with sites will remain blinded to individual participant allocation until the 
end of study. 
6.5. 
Study intervention compliance 
The Study Pharmacy manual should be followed when preparing study intervention for 
study participants. 
Participants will receive study intervention at the clinical unit directly from the 
Investigator or designee, under medical supervision, via SC route. 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 
Dose modification is not applicable in this study. 
6.7. 
Continued access to study intervention after the end of the 
study 
Participants will not receive any additional treatment from GSK after completion of the 
study. 

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6.8. 
Treatment of overdose 
For this study, any dose of GSK3858279 administered greater than the scheduled dose 
will be considered an overdose. 
In the event of an overdose, the Investigator should: 
• 
Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study intervention should be interrupted. 
• 
Closely monitor the participant for AE/SAE and laboratory abnormalities until the 
study intervention is predicted to be non-quantifiable systemically (at least 16 
weeks). Document the quantity of the excess dose as well as the duration of the 
overdosing in the source documents and in the eCRF. 
6.9. 
Prior and concomitant therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant receives during the study must 
be recorded along with: 
• 
reason for use 
• 
dates/times of administration including start and end dates/times 
• 
dosage information including dose and frequency 
• 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.9.1. 
Pain therapies 
Use of any analgesic medication other than paracetamol/acetaminophen is prohibited 
during the study, from at least 72 hours (or a period that is at least 5 half-lives for that 
analgesic, whichever is greater) prior to the start of baseline pain assessment (Day -7) 
until the completion of Week 16 visit. This includes NSAIDs (other than the exceptions 
described below), opioids, tramadol, duloxetine, over-the-counter pain medications and 
topical analgesics including capsaicin products. Use of opioids within 30 days of 
screening is not allowed. 
Occasional and limited use of an NSAID (including selective COX-2 inhibitors) is 
permitted only for non-OA-related pain or self-limiting conditions, however it should not 
be taken within 24 hours of a study visit. The use of NSAIDs should be restricted to a 
maximum of 3 days during each 4-week interval and should be avoided during 2 weeks 
of treatment period prior to the Week 12 visit. Details of every occasion of NSAID use, 
including medication name and dose, should be captured in the eCRF. The dose of 
NSAID should not exceed the locally approved and recommended maximum dose, and 
combination NSAID products should not be used. Low-dose aspirin for cardiovascular 
prophylaxis is permitted. 

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All knee intra-articular injections are not allowed within 3 months prior to screening and 
throughout the study. Intra-articular injection in joints other than the knee, with 
viscosupplementation only could be allowed within 3 months prior to screening or during 
the study but corticosteroids and/or analgesics intra-articular injections are prohibited 
during this period. Clear documentation of the used injection medications in the medical 
records is required in addition to documentation in the site source notes. 
Nutraceuticals (for example, glucosamine or chondroitin) are permitted if they were used 
at a stable dose at least 30 days prior to screening and will continue to be used during the 
study. Herbal, naturo- and homeopathic medications should not be initiated during the 
study, however patients can continue to take them if they have been receiving a stable 
dose of medication for at least 30 days prior to screening. 
Adjunctive pain therapies such as acupuncture, TENS or other forms of pain reduction 
interventions that might confound protocol assessments are not allowed during the study 
from the screening visit until the completion of Week 16 visit. 
6.9.2. 
Immunomodulators 
Treatment with immunomodulators is prohibited throughout the study, as follows: 
• 
Corticosteroids: parenteral within 3 months of randomization; oral within 1 month of 
randomization. Locally acting corticosteroids including inhaled, intranasal, topical 
and ophthalmic (except intra-articular) are permitted during the study. 
• 
Biologic agents (such as monoclonal antibodies including marketed drugs) within 3 
months or 5 half-lives (whichever is longer) prior to randomization. 
• 
Non-biologic agents (e.g. methotrexate, azathioprine, JAK inhibitors) within 4 weeks 
or 5 half-lives (whichever is longer) prior to randomization. 
6.9.3. 
Vaccinations 
Investigators should review and update the vaccination status of potential participants as 
per local guidelines for adult vaccination including against COVID, influenza, herpes 
zoster and pneumococcus (according to local guidelines) prior to enrollment, with 
particular attention to the vaccination status of participants over 65 years of age. All 
participants may receive inactivated flu vaccines during the study at the discretion of the 
Investigator. 
Live or live attenuated vaccines will need to be given at least 30 days prior to 
randomization and are prohibited throughout the study. 

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6.9.4. 
Rescue medicine 
Paracetamol/Acetaminophen administered orally, at doses of ≤3 grams/day and for a 
maximum of 4 days in a week (the calendar week should be calculated based on Day 1 
visit date), is permitted for use as rescue medication any time during the study except 24 
h before and during a clinical visit. Participants will record any 
paracetamol/acetaminophen use over the past 24 h on the eDiary on a daily basis. 
For eligibility, all paracetamol/acetaminophen use will be recorded in the eDiary from Visit 
2 and evaluated during the 7-day run-in period. If participants exceed the permitted 
allowance during the run-in period they will not be eligible for the study. 
Paracetamol/Acetaminophen will not be supplied by the sponsor, it will be purchased 
commercially or arranged by the study site. Rescue Medicine will be dispensed to study 
participants who initially meet study criteria at the initial screening visit. Additional 
supply will be provided when needed during the study by the study site staff. Participants 
should not be taking their own supply of paracetamol/acetaminophen. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Permanent discontinuation of study intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should be 
requested to remain in the study and complete the planned visits and assessments for the 
double-blind period (up to the Week 16 visit) per SoA (except for the weekly SC IMP 
administration and post-dose [24-72 hours or 96-120 hours] PK/TE sample collection), 
with a final follow-up visit approximately 16 weeks from the last dose received, unless 
they also withdraw consent to remain in the study. However, if this is not possible at a 
minimum participants will be asked to complete all assessments at both the Early 
Withdrawal visit, preferably 1 week from the last dose received (applicable to the 
treatment period) or as soon as possible after the participant’s decision has been 
communicated to the site staff (applicable to the off-treatment phase), and a Follow-Up 
visit approximately 16 weeks after the last IMP dose. The knee X-rays are only requested 
to be completed at one of these visits, preferably the last planned visit. The final follow-
up visit will assess all the items per the SoA for the Week 31 visit. Participants are 
requested to complete their daily pain NRS assessments and Paracetamol/Acetaminophen 
intake Diary up to the final follow-up visit. 
A participant will be permanently discontinued from the study intervention if any of the 
following criteria are met: 
• 
Pregnancy 
• 
Serious hypersensitivity reactions assessed as related to study intervention 
• 
Active TB infection 

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• 
Liver chemistry, renal function, hematological abnormality stopping criteria, ECG 
stopping criteria, or hepatitis B reactivation 
• 
Use of prohibited concurrent medication, vaccine or therapy, where the continuation 
of study intervention would place the participant at risk in the opinion of the 
Investigator and/or Medical Monitor 
• 
Inability to adhere to protocol-specified restrictions or procedures, at the discretion 
of the investigator, after consultation with the GSK Medical Monitor 
• 
Clinically significant deterioration of index knee pain or requiring recurrent rescue 
medication beyond the level permitted, at the discretion of the investigator, after 
consultation with the GSK Medical Monitor 
• 
Other serious or severe adverse events, at the discretion of the Investigator, after 
consultation with the GSK Medical Monitor 
The primary reason for premature discontinuation of the study intervention will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
 
Lack of efficacy 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Liver chemistry 
Renal Function  
Hematological Abnormality  
ECG parameters 
Hepatitis B reactivation 
Physician Decision 
Specify 
Pregnancy 
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
Specify 
Study Terminated by Sponsor 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other, specify 
Other 
Specify 
Death 
 
AE=Adverse event. 

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7.1.1. 
Liver chemistry stopping criteria 
Discontinuation of study intervention for abnormal liver tests is required by the 
Investigator when a participant meets one of the conditions outlined in the algorithm or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules 
if the investigator believes that it is in best interest of the participant. 
Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = 
upper limit of normal, Tbili = Total bilirubin 
Refer to Appendix 6 for required Liver Safety Actions and Follow-up Assessments. 
7.1.2. 
ECG Stopping criteria 
Discontinuation of study intervention for abnormal ECG changes is required by the 
Investigator. Triplicate ECGs should be performed in case of abnormal ECG findings or 
if any of the ECG stopping criteria are met. In such cases, an average value from ECG 
measurements should be used to assess whether IMP administration should be 
discontinued. For other clinically significant ECG finding or abnormal QTc result not 
meeting the protocol-specified stopping criteria, study intervention can be discontinued if 
the Investigator believes it to be in best interest of the participant. This review of the 
ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 

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• 
Absolute QTcF ≥500 msec 
• 
Absolute QTcF <320 msec (clinically significant QTc shortening) 
• 
Increase from baseline in QTcF of >60 msec 
• 
Prolongation in repeated ECG interval measurements of PR or QRS of >40 msec 
seconds from baseline or ventricular arrhythmias (other than occasional premature 
ventricular contractions) 
7.1.3. 
Renal function stopping criteria 
Study intervention will be discontinued if following renal abnormality developed: 
• 
The eGFR decreased >25% compared to baseline; confirmed by a repeat test. 
Participants will not receive any doses of study intervention whilst awaiting the result of 
the repeat test. 
7.1.4. 
Hematologic Abnormality stopping criteria 
Study intervention will be discontinued for the following hematological abnormalities: 
• 
White Blood Cell Count (WBC) <2.0×109/L 
• 
Platelets count <100×109/L 
• 
Hemoglobin <10.0 g/dL for males and females. 
7.1.5. 
Hepatitis B reactivation stopping criteria 
Study intervention will be discontinued if the following hepatitis B stopping criteria are 
met during monitoring of ongoing participants: 
• 
If HBsAg is positive or HBV DNA is detectable, study drug must be discontinued, 
and the participant should be referred for a review by a hepatologist. 
7.1.6. 
Temporary discontinuation 
• 
Serious, Opportunistic Infections or suspected TB 
If a serious, opportunistic infection or suspected TB develops, temporarily 
discontinue study intervention until the infection is controlled and discuss further 
management with the Medical Monitor. If the temporary hold for serious or 
opportunistic infections is greater than 2 weeks, IMP will be permanently 
discontinued but the participant will be requested to complete the assessments in the 
treatment period (up to the Week 16 visit) with a final follow-up visit (week 31) 
approximately 16 weeks from the last dose received. 

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• 
COVID-19 Infection 
For participants with PCR or antigen proven or presumptive COVID-19 infection, 
IMP should be withheld until the resolution of the acute symptoms of infection, and 
IMP should not be re-started until at least 7 days following the resolution of acute 
symptoms at the Investigator’s discretion. 
Of note, for subjects who have a positive PCR or antigen test and are asymptomatic, IMP 
should be withheld for 7 days from the date of the positive test and only resumed if no 
COVID symptoms developed. 
If subjects have IMP withheld for more than 2 weeks, IMP will be permanently 
discontinued but subjects should complete the treatment period (up to the Week 16 visit) 
with a final follow-up visit (Week 31) approximately 16 weeks from the last dose 
received. 
If COVID-19 infection meets the criteria of serious infection, discontinuation guidance 
for serious infections should be followed. 
All confirmed, probable or suspected cases should be reported on AE/SAE eCRFs, as 
appropriate. 
If a participant experiences a clinically significant AE that the investigator believes may 
be possibly, probably or definitely related to the IMP and could potentially be exacerbated 
by the next dose, the investigator may delay IMP dosing by withholding one dose and 
should contact the Medical Monitor. 
7.1.7. 
Rechallenge 
7.1.7.1. 
Study intervention restart or Rechallenge after liver stopping criteria 
are met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study are not allowed. 
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, participants are requested to complete 
remaining scheduled visits and assessments up to the Week 16 visit per above SoA 
(except for the weekly IMP administration and post-dose [24-72 hours or 96-120 hours] 

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PK/TE sample collection), with a final follow-up visit (Week 31) approximately 16 
weeks from the last dose received. However, if this is not possible at a minimum 
participants will be asked to complete all assessments at both the ED visit preferably 1 
week from the last dose received (applicable to the treatment period) or as soon as 
possible after the participant’s decision has been communicated to the site staff 
(applicable to the off-treatment phase), and a final follow-up visit approximately 16 
weeks after the last dose to ensure participant monitoring following drug wash out. The 
knee X-rays are only requested to be completed at one of these visits, preferably the last 
planned visit. Participants should be requested to complete average and worst daily pain 
NRS and Paracetamol/Acetaminophen intake diary up to the final follow-up visit. 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 intervention and 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 available for 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 and inform the sponsor. 
The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
 
Lack of efficacy 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Physician Decision 
Specify 
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
Study Terminated by Sponsor 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
AE=Adverse event. 

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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 until the event 
is resolved (see Section 10.3.5.5). 
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/other contact methods, 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. 
• 
Site personnel, or an independent third-party, will attempt to collect the vital status 
of the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study intervention. Public sources may be searched 
for vital status information, if within legal boundaries. If vital status of the 
participant is determined as deceased, this will be documented and the participant 
will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the Schedule of activities 
(SoA). 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. 
• 
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’. 
• 
Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA. 
• 
In the event of a significant study continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements. 
• 
The whole blood volume that will be collected from each participant over the course 
of the study, including any extra assessments that may be required is provided in the 
ICF. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Administrative and general/baseline procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as year 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 
Obtain the participant’s medical history by interviewing the participant and review of the 
participant’s medical records. Record any pre-existing conditions, signs and/or symptoms 
present prior to study start in the eCRF. 

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8.2. 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
Participants will be provided with the eDiary device (Clario, a third-party vendor) on 
which to record their daily patient reported outcomes including rescue medication use. 
Training on how to use the device (Clario) and on how to accurately report pain at the 
run-in visit will be provided (WCG Clinical Endpoint Solutions) with the accurate pain 
reporting training being repeated at the Week 8 visit. eDiary support will be available 
throughout the trial. 
8.2.1. 
Daily pain 
Participants will record pain scores daily (evening time) on the eDiary device for the 
7 consecutive days preceding dosing (during screening) and then daily from Day 1 to 
Week 31. 
8.2.1.1. 
Average daily knee pain 
This is a single-item measure designed to capture information on the self-reported 
average knee pain intensity in index knee, over the past 24 hours. Participants will be 
asked to mark their pain intensity on a daily basis, using the NRS, on an 11-point scale 
(0-10), with 0 = no pain, and 10 = pain as bad as you can imagine. 
8.2.1.2. 
Worst daily knee pain 
This is a single-item measure designed to capture information on the self-reported worst 
knee pain intensity in index knee, over the past 24 hours. Participants will be asked to 
mark their pain intensity on a daily basis, using the NRS, on an 11-point scale (0-10), 
with 0 = no pain, and 10 = pain as bad as you can imagine. 
8.2.2. 
Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) 
WOMAC will be completed by participants at time points specified in the SoA [Bellamy, 
1988]. The questionnaire covers pain, stiffness and function related to OA in the index 
knee over the past 48 hours. Participants will respond to each question using an 11-point 
NRS (0-10), with 0=no pain/stiffness/difficulty, and 10= extreme pain/stiffness/difficulty. 
8.2.3. 
Patient Global Assessment (PtGA) 
The patient global assessment asks the study participant: “Considering all the ways in 
which your knee osteoarthritis affects you, how do you feel your knee osteoarthritis is 
doing today?” Participants will respond on a Likert scale ranging from 1-5. Higher scores 
indicate worse condition. 

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8.2.4. 
Physician Global Assessment (PhGA) 
The physician global assessment asks the physicians: “What is your assessment of the 
patient’s current disease activity?” Physicians will respond by using an 11-point NRS 
scale (0-10). Higher scores indicate worse condition. 
8.2.5. 
The Short Form (36) Health Survey (SF-36) 
A 36-item questionnaire assessing health-related quality of life scored on a scale of 0–
100, with higher scores indicating a higher quality of life. 
8.2.6. 
PROMIS-Sleep Disturbance 
The PROMIS Short Form Sleep disturbance is a PRO instrument designed to assess self-
reported sleep disturbance for which the recall period is the past 7 days. 
8.2.7. 
Patient Global Impression of Severity (PGIS)-Sleep 
Static, current state patient global impression of the overall severity of sleep disturbance 
over the past 7 days. 
8.2.8. 
Patient Global Impression of Change (PGIC)-Sleep 
Patient global impression of overall change in severity of sleep disturbance from 
baseline. 
8.2.9. 
PainDETECT 
This questionnaire is used to explore the neuropathic aspect of OA pain [Freynhagen, 
2006]. 
8.2.10. 
Patient Global Impression of Severity (PGIS)-walk 
A walking-specific PGIS to describe the overall severity of difficulty walking due to OA 
over the past week. All participants will need to complete the PGIS-walk questionnaire at 
time points specified in the SoA. For those participants in the actigraphy sub-study, the 
walk-specific PGIS will be used as an anchor for calculating the MCID for candidate 
activity endpoints derived from the digital accelerometer data. For those participants not 
in the actigraphy sub-study, the walk-specific PGIS will be used to generalize findings 
from actigraphy sub-study to the entire population. 
8.2.11. 
Patient Global Impression of Change (PGIC)-walk 
The walking-specific PGIC will describe the overall change in difficulty walking due to 
OA since starting the study. This will be supportive of the calculated change in walk-
related PGIS. 

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8.2.12. 
Paracetamol/acetaminophen use 
Paracetamol/Acetaminophen intake including date, approximate time of dose, dose 
strength, drug form and reason for use; OA pain or “Other Indication” (eg: headache, 
fever etc.) will be recorded by participants on the eDiary on a daily basis. 
8.2.13. 
StepWatch 
Actigraphy assessments using the “StepWatch™”, an ankle-worn FDA-listed device 
provided by Modus, a third-party vendor will be conducted as a means of objectively 
measuring changes in physical functioning (and particularly changes in patients’ ability 
to walk). Participants will wear the StepWatch™ for one week starting at Day -7 and for 
one week starting at Week 11 and ending at Week 12. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1. 
Physical examination/history directed physical examination 
• 
A full 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 at the initial screening visit (1). 
• 
A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital signs 
Temperature, pulse rate, respiratory rate, and blood pressure will be recorded before 
blood collection for laboratory tests. All readings will be recorded in source documents 
and in the eCRF. 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. The 
participant should use the same position throughout all visits. 
Blood pressure and pulse 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). 
At specific visits which may occur as home nursing visits (specified in SoA), vital signs 
may be collected and recorded by a HHS professional. 

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8.3.3. 
Electrocardiograms 
12-lead ECG measurements will be obtained as outlined in the SoA (see Section 1.3). 
Participants must be supine for approximately 5-10 minutes prior and during ECG 
collection. 
Single tracing will be obtained at screening visit (triplicate ECGs can be performed based 
on Investigator’s assessment, if required). 
Triplicate ECGs will be obtained at baseline Visit (Day 1) (3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart). All results will be recorded in the eCRF. Eligibility will be assessed based on all 
ECG readings at screening and the average of the triplicated ECG data on Day 1. 
Single ECG measurements will be obtained at all other visits as outlined in the SoA 
unless any abnormalities (including ECG stopping criteria) are found during the study, 
then triplicate ECG measurements will be taken. 
The site will use an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, QTc intervals and QRS axis. Refer to Section 7.1.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary. 
If the ECG machine does not automatically calculate the QTc interval according to 
Fridericia’s formula (QTcF), site staff should use the below equation to manually 
calculate the QTcF and document the result in the participant’s medical record. 
 
𝑄𝑇𝑐𝐹=  𝑄𝑇/∛((60)/𝐻𝑅) 
QTcF result in msec, QT in msec, HR (heart rate) in bpm 
All ECGs will be read locally and paper ECGs will be kept at study sites as source 
documents. 
8.3.4. 
Clinical safety laboratory tests 
• See Section 10.2 for the list of clinical safety laboratory tests to be performed by Q2 
Solutions, a third-party vendor, in accordance with Central lab manual and the SoA 
(Section 1.3). 
• At specific visits in the off-treatment phase as specified in the SoA, if allowed by 
country regulation/ethics, clinical safety laboratory sampling may be conducted 
remotely by a HHS professional. 
• The Investigator must review the laboratory results, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
results must be retained with source documents. 
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 

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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 16 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
o 
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 
as an AE or SAE, if they meet the definition of an AE or SAE (refer to Section 
10.3.1 and Section 10.3.2). 
o 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 
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), then 
the results must be recorded in the site’s source documents Results along with 
reference ranges will also be recorded in the eCRF for SAEs. 
8.3.5. 
Knee X-rays 
• 
Bilateral Knee X-rays will be performed at screening to confirm OA in the index 
knee for eligibility based on a Kellgren Lawrence score ≥2 (see inclusion criteria 
Section 5.1).  Bilateral knee X-rays will allow the characterization of disease activity 
in both knees. In cases where a re-screen is permitted, knee X-rays do not need to be 
repeated if they were eligible in the first screening and done within 6 months of re-
screening. 
• 
Bilateral knee X-rays will also be performed at the end of the study to compare to the 
screening knee X-rays’ Kellgren Lawrence score and to determine if a clinically 
significant radiographic knee film abnormality has developed. 
• 
To minimize reporting variability, the radiographs will be read centrally by 
independent imaging experts (Clario, a third-party vendor contracted by GSK). 
• 
The sponsor and imaging experts will regularly evaluate the knee X-ray data.  If a 
clinically significant abnormality is detected, an appropriate follow-up plan will be 
agreed in collaboration with the Investigator.  Follow-up investigations will be 
determined on a case-by-case basis, depending on the nature of the clinically 
significant abnormal finding, symptoms, and expert clinical judgment. 
• 
A clinically significant abnormal X-ray finding should be captured as an AE or SAE 
if it meets these definitions. 
• 
In addition, if there is a clinical need for knee X-rays beyond the study-planned 
screening and end-of-study knee X-rays, these will also be evaluated by the external 
radiology experts, the sponsor, and the Investigator. 
• 
If a female participant has a positive pregnancy test then no further X-rays will be 
obtained. 

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8.3.6. 
Pregnancy testing 
• 
A serum pregnancy test must be performed for all female participants of childbearing 
potential at screening Visit 1. 
• 
A urine or serum pregnancy test must be performed for all female participants of 
childbearing potential as required by local regulations (e.g.: country or IRB/EC) 
before the administration of all doses 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. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted weekly before the administration of each dose per the SoA during study 
intervention period for all women of childbearing potential (WOCBP). If a urine test 
is positive or cannot be confirmed as negative (e.g. an ambiguous result) a serum 
pregnancy test is required. In such case, the participant must be permanently 
discontinued from study treatment if the serum pregnancy result is positive. 
• 
Refer to Section 8.5.6 for the information on study continuation for participants who 
become pregnant during the study. 
• 
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1 Inclusion Criteria. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the WOCBP’s participation in the study. 
8.3.7. 
Hepatitis B reactivation monitoring 
Participants who are positive for hepatitis B core antibody (HBcAb) and negative for HBV 
DNA can be enrolled in the study provided they follow assessments for hepatitis B during 
the trial as follows: 
• 
ALT, AST, HBsAg and HBV DNA will be tested at Week 4 (Visit 8), Week 8 (Visit 
12), Week 12 (Visit 18), Week 16 (Visit 24) and then at the end of study, Week 31 
(Visit 27) or early discontinuation visit. 
• 
If HBsAg is positive or HBV DNA is detectable, study drug must be discontinued, 
and the participant should be referred for a review by a hepatologist. See Section 
7.1.5 for hepatitis B reactivation stopping criteria. 
• 
ALT elevation in absence of HBV DNA reactivation criteria: refer to protocol-
defined increased monitoring and/or stopping criteria (Section 7.1.1). Evaluate for 
other possible causes of ALT elevation. 

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• 
Additional monitoring requirements for participants at Japan sites only (See Section 
10.8): 
o 
Participants who are HBsAb positive (and negative for HBV DNA), hepatitis B 
reactivation monitoring will only be needed if vaccination history could not be 
confirmed. 
o 
In addition to the hepatitis B reactivation monitoring timepoints above, 
monitoring will also be tested at Week 20 (Visit 25) and Week 24 (Visit 26). 
8.4. 
Safety monitoring and Data Review Committees 
Participant safety will be continuously monitored in a blinded manner by the Medical 
Monitor, designated Safety Lead (or delegate) throughout the study. Pertinent findings 
and conclusions are shared with the product’s Safety Review Team (SRT) for review of 
the overall benefit/risk profile of the product. 
Additionally, an external IDMC will be utilized in this study comprised of clinical and 
statistics experts, none of whom are affiliated with the sponsor (see Section 10.1.6). The 
IDMC will regularly review the unblinded data and will convene at scheduled intervals to 
ensure the safety of study participants as the study progresses. The IDMC charter will 
provide full details of all the activities, including which data will be reviewed and the 
timing and frequency, the schedule for regular IDMC meetings, and how the integrity of 
the study will be maintained. 
In addition, ad hoc IDMC meetings will be called at the earliest convenience, if any of 
the following occurs: 
• 
A death in the study that is considered attributable by the Investigator or GSK safety 
group to the study drug. 
o 
Study enrollment and dosing will be paused AND 
o 
The IDMC will review the unblinded safety data and make a recommendation 
to: 
▪ Resume enrollment and dosing and continue the study without 
modification*, or 
▪ Continue the study with modification, or 
▪ Terminate the study. 
*To preserve the study continuity and scientific integrity, if the IDMC 
recommendation is to resume enrollment and dosing without any study modification, 
this will be implemented immediately. 
• 
Two (2) or more SAEs in separate participants reported in the same active treatment 
arm (same dose level/regimen) that are considered attributable by the investigator or 
GSK safety group to GSK3858279. 
o 
Study enrollment will continue, and dosing will not be paused AND 

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o 
The IDMC will review the unblinded safety data and make a recommendation 
to: 
▪ Continue the study without modification, or 
▪ Continue the study with modification, or 
▪ Terminate the study. 
An internal data review committee will be appointed for this study to oversee and review 
the interim analysis data for futility. No study personnel with direct contact with sites or 
site staff will be involved in the iDRC. Full details of the data to be reviewed, the 
frequency of review and members of the committee will be included in the Internal Data 
Review Committee Charter, to be finalized before study start. 
8.5. 
Adverse Events (AEs) serious adverse events (SAEs), and 
other safety reporting 
For definitions relating to safety information see Section 10.3 
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 study 
procedures, or that caused the participant to discontinue the study intervention (see 
Section 7). This includes events reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant’s legally authorized representative). 
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. 
8.5.1. 
Time Period and Frequency for collecting AE, SAE, and other 
safety information 
All SAEs and AEs will be collected from the start of study intervention until the last 
follow-up visit at the timepoints specified in the SoA. 
• 
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 case report form (CRF), not the AE section. If however this 
medical occurrence meets the definition of an SAE and is assessed as related to study 
participation (e.g. protocol-mandated procedures, invasive tests or change in existing 
therapy) or related to a GSK product, it will be reported as an SAE. 
All SAEs will be recorded and reported to the sponsor immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The investigator 
will submit any updated SAE data to the sponsor within 24 hours of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in this Section. 

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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, after a participant has been discharged from the study, the investigator 
must record it in the medical records, per the local country requirements. If the 
investigator considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor. 
8.5.2. 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrences. 
8.5.3. 
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 and nonserious AEs of special interest 
(as defined in Section 8.5.4)] 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 10.3.5.5. 
8.5.4. 
AESIs 
The potential risks of GSK3858279 are discussed in Section 2.3.1 
Adverse events of special interest (AESIs) for GSK3858279 include: 
• 
Serious infections 
• 
Opportunistic infections 
• 
TB 
• 
Serious hypersensitivity reactions 
• 
Injection site reactions 
Reported AESIs will be adjudicated internally using a pre-defined process. 
• 
Routine monitoring for the signs and symptoms of TB will be performed during this 
study as part of every full or brief physical exam (see SoA in Section 1.3). If at any 
point during the study, the Investigator suspects that a participant may have a new 
TB infection, an immediate and thorough investigation should be undertaken 
including consultation with a physician specializing in TB. The Investigator should 
discuss such cases with the medical monitor and interruption of study intervention 
should be considered. 

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8.5.5. 
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 8.5.1 
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 10.3.5.6. 
• 
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, sign and date and then file the report in site files and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• 
Investigators have to report to the Sponsor pregnancies, medication errors, abuse and 
misuse even in absence of AE/SAE as these may be subjected to local regulatory 
requirements for the Sponsor. 
Table 5 
Timeframes for submitting SAE, pregnancy and other events 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 Adverse Events 
Report 
24 hours* 
electronic Adverse Events 
Report 
Pregnancies  
24 hours* 
paper pregnancy notification 
report and electronic 
pregnancy report 
24 hours * 
paper pregnancy notification 
report and electronic pregnancy 
report  
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
‡ For each SAE, the investigator(s) must document in the medical notes that they have reviewed the SAE and have 
provided an assessment of causality. 
8.5.6. 
Pregnancy 
• 
Female participants who become pregnant after the first study intervention dose must 
not receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
• 
Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until time 
period for reporting pregnancies should align with the time period for 
postintervention contraception determined in Section 5.1. 
• 
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 
female participant pregnancy, or pregnancy in the female partner of a male 
participant. 

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• 
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. 
Pregnancy data from female partners of male participants who become pregnant will 
also be collected. The investigator will collect follow-up information on the 
participant and the neonate and the information will be forwarded to the sponsor. See 
Table 5 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 8.5.4. 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. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
8.5.7. 
CV and death events 
• 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the 
eCRF will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
• 
The CV eCRFs are presented as queries in response to reporting of certain CV 
MedDRA terms. The CV information should be recorded in the specific 
cardiovascular section of the eCRF within one week of receipt of a CV Event data 
query prompting its completion.  
• 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.5.8. 
Contact information for reporting SAEs, AESIs, pregnancies 
Table 6 
Contact information for reporting SAEs, AESIs and pregnancies 
Study contact for questions regarding SAEs and pregnancies 
 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs and AESIs, pregnancies 
Available 24/24 hours and 7/7 days 
uk.gsk-rd-gcsp-ctsm-admin@gsk.com 
AESI = Adverse event of special interest; GSK = GlaxoSmithKline Biologicals SA; SAE = Serious adverse event. 

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8.5.9. 
Participant card 
The Investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician/ 
caregiver/family member that the participant is in a clinical study and that relevant 
information may be obtained by contacting the investigator(s) or their back up. 
8.6. 
Pharmacokinetics 
• 
Blood samples will be collected for measurement of serum concentrations of total 
GSK3858279 at the time points indicated in SoA and used to characterize the PK of 
GSK3858279 in OA participants. The actual date and time (24-hour clock time) of 
each blood sample collection and dose administration will be recorded. Each PK 
sample should be collected as close as possible to the planned time relative to the 
dose (i.e. time zero) administered to the participant on dosing days. Samples 
collected for analyses of serum GSK3858279 concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
• 
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure optimal PK monitoring. 
• 
Details on PK blood sample collection including processing, storage, and shipping 
procedures are provided in the Central Laboratory Worksheet. 
• 
Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility 
selected by the sponsor to enable further analysis. 
• 
Serum analysis will be performed under the control of In Vitro/In Vivo 
Technologies/ Bioanalysis Immunogenicity and Biomarkers (IVIVT/BIB). 
Concentrations of total GSK3858279 will be determined in serum samples using the 
validated bioanalytical methodology. The bioanalytical site will be detailed in the 
relevant sample processing documents. Drug concentration information that may 
unblind the study will not be reported to investigative sites or blinded personnel until 
the study has been unblinded. 
• 
If allowed by country regulation/ethics, PK sampling may be conducted remotely by 
a HHS professional. 
8.7. 
Pharmacodynamics 
Pharmacodynamics will be evaluated as part of analyses for TE (Section 8.8), biomarkers 
(Section 8.10) and immunogenicity assessments (Section 8.11). 

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8.8. 
Target (CCL17) concentrations 
• 
Blood samples will be collected from participants in this study to investigate target 
engagement (TE) at the time points specified in the SoA. Each TE sample should be 
collected as close as possible to the planned time relative to the dose (i.e. time zero) 
administered to the participant. The actual date and time (24-hour clock time) of 
each blood sample collection will be recorded. 
• 
The timing of TE samples may be altered and/or additional TE samples may be 
obtained at additional time points to ensure thorough TE monitoring. 
• 
Details on TE blood sample collection including processing, storage, and shipping 
procedures are provided in the Central Laboratory Manual. 
• 
Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility 
selected by the sponsor to enable further analysis. 
• 
Concentrations of total and free CCL17 will be determined in serum samples using 
the validated bioanalytical methodology. The bioanalytical site will be detailed in the 
relevant sample processing documents (e.g. CLW). CCL17 concentration 
information that may unblind the study will not be reported to investigative sites or 
blinded personnel until the study has been unblinded. 
• 
If allowed by country regulation/ethics, TE sampling may be conducted remotely by 
a HHS professional. 
8.9. 
Genetics 
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study at any time post-randomization. Participation is optional. Participants who do not 
wish to participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. New signed genetic informed consent will be required to 
obtain a replacement sample unless it was included in the original consent. Samples may 
be stored for a maximum of 15 years (or according to local regulations) following the last 
participant’s last visit for the study at a facility selected by the sponsor to enable further 
analysis. 
See Section 10.5 Genetics for information regarding genetic research. Details of the 
processing, storage and shipping procedures along with destruction of these samples can 
be found in the Central Laboratory Manual. 
If allowed by country regulation/ethics, genetic sampling may be conducted remotely by 
a HSS professional. 

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8.10. 
Biomarkers 
8.10.1. 
Exploratory Biomarkers 
Serum and whole blood samples will be collected to assess the effects of repeat doses of 
GSK3858279 on exploratory biomarkers. Samples will be collected according to the 
schedule described in the SoA and as detailed in the Central Laboratory Manual. Details 
on the planned biomarker analysis are provided below. Data analysis will be performed 
independently of the main study and will form the basis of a separate report. 
• 
GSK may store samples for up to 15 years (or according to local regulations) after 
the end of the study to achieve study objectives. Additionally, with participants’ 
consent, samples may be used for further research by GSK or others such as 
universities or other companies to contribute to the understanding of OA pain or 
other diseases, the development of related or new treatments, or research methods. 
• 
If allowed by country regulation/ethics, biomarker sampling may be conducted 
remotely by a HHS professional. 
8.10.2. 
Immunophenotyping 
Blood samples will be collected in Cyto-Chex tubes and analyzed by flow cytometry for 
a panel of immune cell markers. This panel will allow the detection and quantification of 
T cells (including CD4, CD8, T helper 17 and regulatory T-cell subsets), B cells, NK 
cells, NKT cells and monocytes. The expression of CCR4 in the various cell types will 
also be analyzed to investigate proximal pharmacological effects. This analysis will only 
be carried out for subjects in pre-selected sites. 
8.10.3. 
Serum/plasma protein analysis 
Serum samples will be collected for PD exploratory and correlative studies. 
Immunoassays may be used to measure relevant protein biomarkers, including but not 
limited to inflammation and joint remodeling markers. Proteomics analysis of a large 
panel of serum proteins may also be performed to identify proteins, pathways and 
processes regulated by GSK3858279. These protein markers may also be used to identify 
markers predictive of clinical efficacy or responder patient sub-populations. 
8.10.4. 
Transcriptomic/Epigenetic analysis 
Whole blood samples will be collected in RNA stabilization tubes for exploratory studies 
which may include RNA sequencing or the analysis of specific epigenetic markers. 
8.11. 
Immunogenicity assessments 
Serum samples will be collected from all participants administered GSK3858279 
according to the SoA table. The actual date and time of each blood draw will be recorded. 
Details for collecting, processing, storage and shipping of samples are provided in the 
Central Laboratory Manual. 

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Sample analysis will be performed under control of BIB, GSK. The presence of anti-
GSK3858279 antibodies will be determined in serum samples using validated bioanalytical 
methods. A tiered analyses approach will include a screening assay, confirmation assay, 
titration assay, and neutralization assay. A sample that confirms positive in the 
confirmation assay will be reported as positive for ADA. 
Immunogenicity results, including the incidence, titer, and neutralizing activity, will be 
reported. Additional analysis may be performed to further characterize immunogenicity 
results. 
8.12. 
Health economics or medical resource utilization and health 
economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GSK. 
Reporting of study data will be performed in accordance with applicable GSK standards. 
9.1. 
Statistical hypotheses 
The primary objective of the study is to evaluate the mean change from baseline at Week 
12 in weekly average of average daily knee pain intensity for each GSK3858279 regimen 
compared to placebo in adult patients with knee osteoarthritis pain, where persistent use of 
prohibited pain therapy and study treatment discontinuation due to lack of efficacy or 
adverse events are considered a negative outcome, in the absence of other study treatment 
discontinuations and regardless of all other use of prohibited pain therapy and use of 
allowed rescue medication. A negative change from baseline is evidence of improvement 
in pain. 
The primary efficacy analysis will be characterized using Bayesian posterior probabilities 
for various criteria of interest (e.g. posterior probability that the true treatment difference 
from placebo is less than -0.6/-0.7/-0.8), and inferences will be made by comparing these 
posterior probabilities to a threshold of interest e.g. 70%. 

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9.2. 
Multiplicity adjustment 
For strong control of the probability of at least one treatment arm meeting the criteria of 
interest under no treatment effect, a closed testing approach, namely the Holm-
Bonferroni method, will be adapted for the Bayesian primary analysis. The 240 mg 
weekly and 360 mg weekly treatment arms will be first evaluated at the threshold of 77% 
and if either meets the criteria of interest then the second treatment arm will be evaluated 
at the 70% threshold level. The remaining GSK3858279 treatment arms will be evaluated 
in a hierarchy at the 70% threshold level: 240 mg every other week followed by 60 mg 
weekly. 
9.3. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• All participants who were screened for eligibility. 
• Study 
Population 
Enrolled 
• All participants who entered the study (who were 
randomized or received study intervention or 
underwent a post screening study procedure). 
• Note that 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. 
• The screened, enrolled and randomized 
populations must be nested, i.e. the enrolled 
population must be a subset of the screened 
population, the randomized population must be a 
subset of the enrolled population. 
• Study 
Population 
Safety 
• All participants who received at least one dose of 
study intervention. 
• Participants will be analysed according to the 
study intervention they actually received. 
• Safety 
Full Analysis Set 
(FAS) 
• All randomized participants who received at least 
one dose of study intervention. 
• Data will be reported according to the randomized 
study intervention. 
• Efficacy 
• Biomarkers 
• PROs 

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Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Pharmacokinetic 
(PK) 
• All participants in the Safety analysis set who had 
at least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as 
non-missing values). 
• Participants will be analysed according to the 
study intervention they actually received. 
• PK 
9.4. 
Statistical analyses 
9.4.1. 
General considerations 
The primary study analysis and reporting will be conducted when the planned target sample 
size of ~420 randomized participants have completed their week 16 (or early withdrawal) 
study visit. An end-of-study analysis will take place when a target sample size of ~420 
randomized participants have completed the study (including the off-treatment follow-up). 
Recruitment may continue to include additional participants, increasing by up to 15% of 
the target sample size, if regional recruitment targets have not been met. The double-blind 
will be maintained for these additional participants ongoing in the study at the time of the 
primary analysis and these participants will be analysed and reported separately. 
Unless otherwise stated, baseline will be defined as the last assessment prior to first dose. 
The number of participants with each intercurrent event will be summarized by treatment 
group. 
For the cases that repeated measurement model is employed to analyse the data, an 
unstructured correlation matrix will be considered to account for multi-collinearity of 
repeated measurements data. 
Vague priors will be used for the Bayesian analyses. 
9.4.2. 
Primary endpoint/estimand analysis 
Details of the estimands are described in Section 3.1. 
The primary efficacy endpoint is the change from baseline in the weekly average of 
average daily pain intensity at Week 12, assessed on the NRS. The change from baseline 
will be calculated for each participant using the mean of the 7 daily assessments of 
average daily pain up to the Week 12 visit date as the Week 12 assessment, and the mean 
of the 7 daily assessments up to but not including the date of the first dose of study 
treatment as the baseline assessment. Since the diary will be completed in the evening, 
assessment on the date of the first dose of study treatment will include time post-

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treatment and therefore will not be included in the baseline assessment. The change from 
baseline in the weekly average of average daily pain intensity at each of the other study 
weeks will be derived similarly. 
Endpoint 
Statistical analysis methods 
Primary: change from 
baseline at Week 12 in 
weekly average knee pain 
intensity, assessed on a 
Numeric Rating Scale (NRS) 
Primary analysis of the primary endpoint: 
• A Bayesian repeated measures mixed model will be fitted 
including region, baseline, week and treatment as fixed 
effects, as well as interactions for baseline-by-week and 
treatment-by-week. Vague priors will be used. 
• For each GSK3858279 treatment arm, difference from 
placebo in the primary endpoint will be summarized as 
Mean and 95% equal-tail credible interval of the posterior 
distribution. 
• Simple summary statistics (Mean, SD, Min, Max, Median) 
will also be presented for the primary endpoint by treatment 
group. 
• The strategy for handling ICEs is described in the estimand 
section (Section 3.1). 
• For the primary estimand, persistent use of prohibited pain 
therapy or treatment discontinuations due to lack of efficacy 
or adverse events are handled with a composite strategy 
and data post-ICE will be imputed using multiple imputation 
based on baseline pain scores. For other treatment 
discontinuations, data that is set to missing under the 
hypothetical strategy will be assumed to be missing at 
random (MAR). Any other missing data for the primary 
estimand will also be assumed to be MAR. 
• For the first additional estimand, all data that is set to 
missing due to intercurrent events under the hypothetical 
strategy will be assumed to be MAR. Any other missing 
data will also be assumed to be MAR. 
• For the second additional estimand, missing data following 
study withdrawal will be imputed using multiple imputation 
based on off-treatment data under an extended MAR 
assumption conditioning on treatment status. 

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9.4.3. 
Secondary endpoints analyses 
Endpoint 
Statistical analysis methods 
Secondary: 
Incidence of adverse events 
(AEs), serious adverse 
events (SAEs). 
Occurrence of National 
Cancer Institute Common 
Terminology Criteria for 
Adverse Events (NCI-
CTCAE) grade ≥3 
hematological/clinical 
chemistry abnormalities. 
• No formal statistical testing will be performed on safety 
data. Safety data from the treatment period and the off-
treatment follow-up will be summarized together. 
• AEs will be coded using the MedDRA coding dictionary and 
summarized by preferred term and treatment. Separate 
summaries will be provided for all AEs, drug-related AEs, 
SAEs, AESIs and AEs leading to permanent discontinuation 
of study intervention or withdrawal from the study. 
• The strategy for handling ICEs is described in the estimand 
section. No imputations will be performed for the reporting 
of safety. 
• Laboratory data will be presented in tabular and/or 
graphical format and summarized descriptively according to 
GSK standards. 
Secondary: change from 
baseline at Week 12 in 
Western Ontario & McMaster 
Universities Osteoarthritis 
Index (WOMAC) pain and 
function subscales scores 
• A Bayesian repeated measures mixed model will be fitted 
including region, baseline, week and treatment as fixed 
effects, as well as interactions for baseline-by-week and 
treatment-by-week. Vague priors will be used. 
• For each GSK3858279 treatment arm, difference from 
placebo at Week 12 will be summarized as Mean and 95% 
equal-tail credible interval of the posterior distribution. 
• Simple summary statistics (Mean, SD, Min, Max, Median) 
will also be presented for the endpoint by treatment group.  
Secondary: change from 
Baseline at Week 12 in 
Patient Global Assessment of 
disease (PtGA) 
• A Bayesian repeated measures mixed model will be fitted 
including region, baseline, week and treatment as fixed 
effects, as well as interactions for baseline-by-week and 
treatment-by-week. Vague priors will be used. 
• For each GSK3858279 treatment arm, difference from 
placebo at Week 12 will be summarized as Mean and 95% 
equal-tail credible interval of the posterior distribution. 
• Simple summary statistics (Mean, SD, Min, Max, Median) 
will also be presented for the endpoint by treatment group. 

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Endpoint 
Statistical analysis methods 
Secondary: GSK3858279 
maximum (Cmax), time of 
Cmax (tmax), trough value 
(Ctau), average concentration 
(Cavg) and are under the 
curve over the dosing interval 
(AUC(0-tau)) at Week 12 
• GSK3858279 systemic exposure will be assessed by 
calculating the PK parameters over the 7 days (weekly 
dosing) or 14 days (2-weekly dosing regimen) prior to the 
Week 12 timepoint using a model based analysis. 
9.4.4. 
 Tertiary/exploratory endpoints analyses 
Endpoint 
Statistical analysis methods 
Population parameters for the 
model describing the 
relationship between dose-
PK -response, (assessed on 
a Numeric Rating Scale 
(NRS)) over time  
• A dose-exposure-response (D-E-R) model will be fitted 
using total GSK3858279 and longitudinal NRS response 
data from all treatment arms and all time points. Details of 
the model specifications and model selection criteria will be 
provided in the SAP. 
• PK, TE, demographic and efficacy data may be integrated 
with other ongoing or completed studies to inform the D-E-
R relationships in pain. 
• Simulations from the final model will be used to predict 
clinical efficacy profiles in OA participants following SC 
administration of GSK3858279. The predicted difference 
from placebo in the primary endpoint along with confidence 
intervals will be reported.  
Planned analyses of other tertiary/exploratory endpoints will be described in the SAP. 
9.5. 
Interim analyses 
Prior to the primary study analysis, the following interim analyses are planned: 
• 
An interim analysis for overall study futility will be performed when ~ 120 
participants qualify for a Week 12 efficacy assessment (either by attending the Week 
12 visit or through data imputation strategy). Interim NRS pain data will be used to 
build a predictive distribution of end-of-study Week 12 NRS pain, to enable 
decisions on study futility. 

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Interim number 
Objective 
Potential outcomes of Interim 
IA1 
Assess futility based on the 
difference from placebo in 
efficacy endpoints at Week 12. 
 
Additional data (including 
safety and PK/TE) may be 
reviewed. 
Continue with study. 
 
Stop the study for futility. 
 
Additional administrative interim analyses may occur in order to inform internal decision 
making and/or to inform regulatory interactions. No change to the study is planned as a 
result of these additional interim analyses. Full details of all interim analyses will be 
prospectively outlined in the iDRC charter. 
Specific details regarding all interim analyses will be outlined in the iDRC charter, along 
with the outline of how the internal data review committee (see Section 10.1.6) will 
ensure data integrity and appropriate quality control of data prior to making decisions and 
an outline of the committee membership. 
9.6. 
Sample size determination 
Overall, approximately 420 participants will be randomized in a 2:1:1:1:1 ratio between 
placebo, GSK3858279 60 mg weekly, GSK3858279 240 mg weekly, GSK3858279 240 
mg every other week and GSK3858279 360 mg weekly. Recruitment may continue to 
include additional participants, increasing by up to 15% of the target sample size, if 
regional recruitment targets have not been met. 
The probability of achieving various criteria of interest given the target sample size of 420 
participants was assessed, conditional on various true values for the treatment difference. 
Calculations are based on simple pairwise comparisons between a GSK3858279 treatment 
arm and placebo (with vague priors). The results are summarized in Table 7, and are not 
conditional on the planned interim analysis. Based on these results, 70 participants in each 
active arm and 140 participants in the placebo arm is considered sufficient for a comparison 
between a GSK3858279 treatment arm and placebo, while maintaining an overall 
active:placebo ratio of 2:1 to mitigate any risk of increased placebo response with a higher 
active:placebo ratio. 
For sample size calculations, the population standard deviation for the change from 
baseline is assumed to be 2.3 at each treatment arm. [Lane, 2010] report a standard 
deviation of 2.0 for change in WOMAC Pain through week 16. The same study also reports 
change from baseline in Knee Pain while Walking collected on a 0-100 visual analogue 
scale over weeks 1-16, in which the standard deviation is 23. Similarly, [Dakin, 2019] 
report a standard deviation of 2.3 from an MMRM model for change in WOMAC Pain at 
week 16. Table 7 also includes power calculations using a more conservative assumption 
for the population standard deviation. 

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The primary analysis is planned to be a Bayesian repeated measures model including all 
treatment arms and other covariates, which should improve precision and so result in an 
increase in the probability of meeting the criteria of interest when a treatment arm is truly 
efficacious (i.e. delta = -1.2 in Table 7). Therefore, the probabilities in Table 7 (obtained 
from pairwise comparisons) are conservative but provide the confidence to use pairwise 
testing if the parametric model is not a good fit for the data. 
Table 7 
Probability of meeting various criteria of interest conditional on true 
treatment differences, and not conditional on interim analysis 
results 
 
 
 
Probability of meeting criterion of 
interest given true treatment 
difference (delta) 
 
Criterion of Interest 
N 
(placebo: 
active) 
Assumed 
SD 
delta = -0.5 
delta = -1.2 
Observed 
delta 
required 
Posterior probability (true difference 
from placebo <-0.6) >70% 
140:70 
2.3 
21% 
90% 
-0.777 
2.5 
21% 
87% 
-0.792 
Posterior probability (true difference 
from placebo < -0.6) > 77% 
140:70 
2.3 
15% 
85% 
-0.849 
2.5 
16% 
82% 
-0.870 
Posterior probability (true difference 
from placebo <-0.7) >70% 
140:70 
2.3 
13% 
83% 
-0.877 
2.5 
14% 
80% 
-0.892 
Posterior probability (true difference 
from placebo < -0.7) > 77% 
140:70 
2.3 
9% 
77% 
-0.949 
2.5 
10% 
73% 
-0.970 
Posterior probability (true difference 
from placebo <-0.8) >70% 
140:70 
2.3 
8% 
75% 
-0.977 
2.5 
9% 
72% 
-0.992 
Posterior probability (true difference 
from placebo < -0.8) > 77% 
140:70 
2.3 
5% 
67% 
-1.049 
2.5 
6% 
64% 
-1.070 
9.6.1. 
Actigraphy sub-study 
Accurate sample size determination for the actigraphy sub-study is not possible as the 
properties of the endpoints are not known due to their exploratory nature. However, 
based on precedent from previous studies using StepWatchTM in related disease areas, 
approximately 150 participants are planned to be enrolled in the sub-study in selected 
countries. 

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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 CIOMS international ethical guidelines 
▪ 
Applicable ICH GCP guidelines 
▪ 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB 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 (CTIS will be used in EU as per 
the requirements). 
• 
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: 
▪ 
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 
▪ 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
▪ 
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. 
Participants will be required to physically 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. 
• 
Sample testing will be done in accordance with the recorded consent of the 
individual participant. 
• 
By default, collected samples for the study will be stored for a maximum of 15 years. 
This storage period begins when the last participant completes the last study visit. 
This timeline can be adapted based on local laws, regulations or guidelines requiring 
different timeframes or procedures. In all cases, the storage period should be aligned 
with participant’s consent. These additional requirements must be formally 
communicated to, discussed and agreed with GSK. 
• 
The medical record must include a statement that physical informed consent was 
obtained before the participant was enrolled in the study and the date the physical 
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 copy of the ICF(s), must be provided to the participant. 
• 
The participant must provide consent by signing an ICF, which summarizes the 
study, includes a consent statement and provides documentation that the participant 
agrees to continue participating in the study. 
• 
Participants who are rescreened are required to sign a new ICF. 
• 
The ICF will contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research. The investigator or authorized 
designee will explain to each participant the objectives of the exploratory research. 
Participants will be told that they are free to refuse to participate and may withdraw 
their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
• 
In case of unexpected pregnancy, participant must be informed that PI such as date 
of birth and 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. 

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• 
If partners of male participants become pregnant during the study, consent will need 
to be obtained or notification given as per local regulation to the partner before 
collecting their private information such as [e.g. last menstrual period, year of birth] 
or the PI such as [date of birth, sex] of their baby as part of safety follow-up. 
10.1.4. 
Recruitment strategy 
Feedback from patients with OA Pain on the proposed study design was solicited and the 
study design amended accordingly. Prior to selecting a site for inclusion in the study, data 
will be gathered to understand the numbers of participants that they may be able to enroll 
from their own patients and networks. Matthews Media Group, a third-party vendor, and 
the sponsor will develop posters and flyer pads, a dear patient letter and a media kit that 
may be used in local outreach efforts. These items will provide basic information and site 
contact information and are designed to assist with recruitment. In addition, Matthews 
Media Group, a third-party vendor, and the sponsor will develop several items designed 
to help the potential participant understand the study including for example, a schedule of 
activities table to represent the visit tests and procedures, an informed consent flow chart 
to help site staff walk patients through the ICF, an ICF video and a brochure. 
Recruitment will be monitored throughout the study and mitigation plans put in place if 
needed. 
10.1.5. 
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 his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant 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. 
• 
The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 

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• 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure 
or access. GSK third parties working on behalf of GSK and/or institutions working 
with GSK for the purposes of this study are contractually bound to protect participant 
coded data. GSK will protect participant coded data and will only share it as 
described in the ICF. 
• 
GSK has a global, internal policy that requires all GSK staff and complementary 
workers to report data incidents or breaches immediately, using dedicated tools. Clear 
procedures are defined for assessing and investigating data breaches to identify and to 
take appropriate remediation steps, to contain and to mitigate any risks for individuals 
resulting from a breach, in compliance with applicable laws. 
10.1.6. 
Committee structure 
• 
An IDMC will be implemented in this study. The overall responsibility of the IDMC 
is to protect the ethical and safety interests of participants recruited into this study 
while protecting as far as possible the scientific validity of the data. The IDMC will 
include physicians with relevant clinical expertise and a statistician, none of whom is 
affiliated with the sponsor. The IDMC will review unblinded data regularly and on an 
as needed basis. The initial early review, frequency of further reviews and the 
unblinded data, will be detailed in the IDMC charter. 
• 
An iDRC will be appointed for this study to review interim analysis data in an 
unblinded manner for the assessment of futility. No study personnel with direct contact 
with sites or site staff will be involved in the iDRC. Full details of the data to be 
reviewed, the frequency of review and members of the committee will be included in 
the Internal Data Review Committee Charter, to be finalized before study start. 
• 
A SRT is in place for GSK3858279. 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 efficacy and safety information. 
10.1.7. 
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. 

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• 
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 layperson 
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.  
• 
Where required by regulation, the names of the sponsor signatory and investigator 
signatory will be made public. 
• 
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. Data will be shared with researchers in a non-
identifying way, and appropriate measures will be taken to protect PI; these measures 
will comply with data protection and privacy laws that apply. 
10.1.8. 
Data quality assurance 
• 
All participant data relating to the study will be recorded on printed or eCRFs 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 eCRF. 
• 
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 pre-defined in the QTL plan to identify systematic issues that can 
impact participant right, safety and/or reliability of study results. These pre-defined 
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 
requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the monitoring 
plan. 
• 
The sponsor is responsible for the data management of this study, including quality 
checking of the data. 

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• 
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 15 years from the issue of the final CSR/ 
equivalent summary, or in accordance with Applicable Law, whichever is longer. 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. In the event of conflict between this Protocol and fully 
executed clinical study agreement, the protocol shall prevail with respect to record 
retention. 
• 
When copies of source documents are shared externally for review by a central 
reader mechanism (X-ray films to the central reader), documents are stored by the 
external body for 25 years. 
10.1.9. 
Source documents 
• 
For this study there will not be source data recorded directly into the eCRF (i.e., no 
prior written or electronic record of data is available). 
• 
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 
acknowledgment. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The sponsor 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. 
• 
Copies of documents are shared with external third parties contracted by GSK for 
review by a central reader mechanism (e.g. endpoint adjudication committee; expert 
reader). The non-exhaustive list of documents shared to inform the central reader 
may include, discharge summaries, imaging reports, ECG reports etc. Participant 
names or any information which would make the participant identifiable or is not 
essential for the central reader mechanism will be redacted by the investigator sites 
prior to transfer.  These documents will be used by the third-party solely for the 
purpose indicated within this protocol. 

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10.1.10. 
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. 
Study/Site Termination 
GSK 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. 
• 
IDMC recommendation to terminate the study. 
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. 
10.1.11. 
Publication policy 
GSK seeks to publish medically or scientifically significant results in searchable peer-
reviewed scientific literature within 18 months from LSLV. We follow International 
Committee of Medical Journal Editors standards for authorship and use Good Publications 
practices to guide our publications. 

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10.2. 
Appendix 2: Clinical laboratory tests 
• 
The tests detailed in Table 8 will be performed by the central laboratory apart from 
urine pregnancy and dipstick urinalysis tests, and T-SPOT TB test (with prior 
Sponsor’ approval) if applicable. 
NOTE: 
o 
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. Additionally, if the 
local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be recorded. 
o 
For participants from China sites, COVID-19 test will be performed by a local 
laboratory. 
• 
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. 
• 
The addresses of the clinical laboratories in charge of human biological sample 
testing are provided in a separate document (‘List of clinical laboratories and key 
vendors’) and stored in TMF at the time of the protocol finalization. 
Table 8 
Protocol-required safety laboratory tests 
Laboratory 
Assessments 
Parameters 
Hematology1 
Platelet Count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
% Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
Clinical Chemistry2 
Calcium 
Potassium 
Aspartate 
Aminotransferase 
(AST)/Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct bilirubin 
Bicarbonate 
Sodium 
Alanine 
Aminotransferase 
(ALT)/Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 

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Laboratory 
Assessments 
Parameters 
Glucose (non-
fasting) 
Creatine 
phosphokinase 
(CPK) 
Alkaline 
phosphatase 
Albumin 
Blood urea 
nitrogen 
(BUN) 
BUN/creatinine 
ratio 
Gamma glutamyl 
transpeptidase 
(GGT) 
Creatinine 
Estimated 
Creatinine 
Clearance/glo
merular 
filtration rate 
(CKD-EPI3) 
 
 
 
Other labs 
Lipid Panel, 
fasting (LDL 
(direct), HDL, 
total 
cholesterol, 
triglycerides) 
 
 
QuantiFERON-TB Gold 
Plus Test (or, if 
unavailable, T-SPOT 
TB with prior Sponsor’s 
approval) 
Routine Urinalysis 
• 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocytes by dipstick performed locally. 
• 
Urine sample may be sent to central laboratory for further testing based on 
Investigator assessment if required. 
Pregnancy testing 
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)4 
Other Screening Tests 
• 
Follicle-stimulating hormone (FSH) (as needed in women of non-childbearing 
potential only) 
• 
Urine Drug Screen to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, marijuana (THC) and its metabolites, and benzodiazepines 
• 
COVID-PCR 
• 
Serology: HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), hepatitis B virus DNA (HBV DNA), hepatitis C virus antibody, 
and hepatitis C RNA. For participants from Japan sites only; hepatitis B surface 
antibody (HbsAb), and hepatitis B virus DNA (HBV DNA)  
NOTES: 
1. 
Hematological abnormality stopping criteria: White Blood Cell Count (WBC) <2.0x109/L; Platelets count 
<100x109 /L, Hemoglobin <10 g/dL for females and males. 
2. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Section 10.6 All events of ALT >3× ULN and total bilirubin 
>2× ULN (>35% direct bilirubin) or ALT >3× ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s law), must be reported to GSK in an expedited 
manner (excluding studies of hepatic impairment or cirrhosis). 
3. 
Chronic Kidney Disease Epidemiology Collaboration equation will be used for calculating and reporting eGFR. 
For participants from Japan sites, the Japanese coefficient (0.813) -modified CKD-EPI will be used for 
calculating and reporting eGFR. Renal function stopping criteria: the eGFR decreased >25% compared to 
baseline; confirmed by a repeat test. 
4. 
Serum pregnancy test required at screening, thereafter local urine pregnancy testing will be standard for the 
protocol unless serum testing is required by local regulation or IRB/IEC. 
 

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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. 
• 
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. 
• 
“Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE. 
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. 

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• 
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. 
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 AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
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 

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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. 
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 CV events 
CV definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
10.3.4. 
Definition of treatment-emergent AE (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. 

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10.3.5. 
Recording, assessment and follow-up of AE, SAE, AESIs and 
pregnancies 
10.3.5.1. 
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 GSK in lieu of completion of the GSK required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. 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 GSK. 
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 
10.3.5.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE, AESI, and SAE 
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. 
• 
Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
10.3.5.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 

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• 
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 GSK. 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 GSK. 
• 
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. 
10.3.5.4. 
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). 
10.3.5.5. 
Follow-up of AEs, SAEs, AESIs, 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 GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 

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After the initial AE/SAE/AESI/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 8.5.4), 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 they are resolved or until the participant is 
lost to follow-up. 
Follow-up during the study 
AEs/AESIs documented at a previous visit/contact and defined as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until they 
are resolved. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants or the pregnant female partners of male 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 electronic pregnancy report and the Adverse Events 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 post-study 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.5.7. 
10.3.5.6. 
Updating of SAE, AESI and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, AESI or pregnancy 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 8.5.3). 

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10.3.5.7. 
Reporting of SAEs, AESIs and pregnancies 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK 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 post-study 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 competent authority via the national 
spontaneous reporting system.  These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.5.8. 
SAE Reporting to GSK via Paper Data Collection Tool 
• 
Secure email transmission of the scanned 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 email/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 8.5.8. 

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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): 
1. Following menarche. 
2. From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
Notes: 
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 will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Permanent sterilization methods (for the purpose of this study) include: 
• 
Documented hysterectomy. 
• 
Documented bilateral salpingectomy. 
• 
Documented bilateral oophorectomy. 
For individuals with permanent infertility 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. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 

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10.4.1.2. 
Woman of Non-childbearing Potential (WNCBP) 
Women in the following categories are considered WNCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
For individuals with permanent infertility 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. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. 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. 
Male Contraceptive Requirement 
• 
A male participant with a partner who is a WOCBP is required to use a condom 
during sexual intercourse throughout the study and for 16 weeks after the last dose of 
study intervention. 
10.4.2. 
Contraception guidance 
• CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• Highly Effective Methodsb That Have Low User Dependency Failure rate of 
<1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 

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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 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 Failure rate of <1% per 
year when used consistently and correctly. 
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 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) Male condoms must be used in addition to hormonal contraception. If locally 
required, in accordance with Clinical Trial Facilitation Group (CTFG) 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 
(LAM) are not acceptable methods of contraception. Male condom and female condom 
should not be used together (due to risk of failure from friction). 

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10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
• 
Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, and if the participant agrees and signs the 
optional genetic ICF, a blood sample will be collected for DNA analysis. 
• 
DNA samples will be used for research related to GSK3858279 or OA pain and 
related diseases. They may also be used to develop tests/assays (including diagnostic 
tests) related to GSK3858279 or study interventions of this drug class, and pain. 
Genetic research may consist of the analysis of candidate genes or the analysis of 
genetic markers throughout the genome (as appropriate). 
• 
Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3858279 or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on GSK3858279 (or study interventions 
of this class) or OA pain continues but no longer than 15 years after the last 
participant last visit or other period as per local requirements. 

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10.6. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments 
Phase 2 Liver Chemistry Stopping Criteria and Required Follow-Up Assessments 
Liver Chemistry Stopping Criteria  
ALT-absolute 
ALT ≥5x ULN 
ALT Increase 
ALT ≥3x ULN persists for >4 weeks 
 Bilirubin1, 2 
ALT≥3x ULN and total bilirubin ≥2x ULN (>35% direct bilirubin) 
INR2 
ALT ≥3x ULN and INR >1.5 
Cannot Monitor 
ALT ≥3x ULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT ≥3x ULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity 
Required Actions, Monitoring and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• 
Immediately discontinue study intervention. 
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event form and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• 
Perform follow-up assessments as described in 
the Follow-Up Assessment column 
• 
Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline (see 
MONITORING below) 
MONITORING: 
If ALT ≥3x ULN AND total bilirubin ≥2x ULN 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 
For all other stopping criteria (total bilirubin <2x 
ULN and INR >1.5): 
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and INR) and 
perform liver event follow-up assessments within 
24-72 hours 
• 
Viral hepatitis serology4 
• 
Obtain INR and re-check with each liver chemistry 
assessment until the aminotransferases values 
show downward trend 
• 
Obtain blood sample for pharmacokinetic (PK) 
analysis, as soon as possible, and at least 7 days 
after last dose5 
• 
Obtain serum creatine phosphokinase (CPK), 
lactate dehydrogenase (LDH), 
gamma-glutamyltransferase (GGT), glutamate 
dehydrogenase (GLDH), and serum albumin 
• 
Fractionate bilirubin, if total bilirubin ≥2x ULN 
• 
Obtain complete blood count with differential to 
assess eosinophilia 
• 
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
liver event form 
• 
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, recreational 
drugs, and other over-the-counter medications 
• 
Record alcohol use on the liver event alcohol intake 
form 
• 
If ALT ≥3x ULN AND total bilirubin >2x 
ULN or INR >1.5 obtain the following in 
addition to the assessments listed above: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG) or gamma 
globulins 

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Liver Chemistry Stopping Criteria  
• 
Monitor participant weekly until liver chemistries 
resolve, stabilize or return to within baseline 
 
RESTART/RECHALLENGE 
• 
Do not restart/rechallenge participant with study 
intervention since not allowed per protocol; 
continue participant in the study for any protocol-
specified follow-up assessments 
• 
Serum acetaminophen adduct assay should be 
conducted (where available) to assess potential 
acetaminophen contribution to liver injury unless 
acetaminophen use very unlikely in the preceding 
week (e.g. where the participant has been resident 
in the clinical unit throughout) 
• 
Liver imaging (ultrasound, magnetic resonance, or 
computed tomography) to evaluate liver disease; 
complete Liver Imaging form 
• Liver biopsy may be considered and discussed with 
local specialist if available: 
o 
In participants when serology raises the 
possibility of autoimmune hepatitis (AIH) 
o 
In participants when suspected DILI progresses 
or fails to resolve on withdrawal of study 
intervention 
o 
In participants with acute or chronic atypical 
presentation 
• 
If liver biopsy conducted complete liver biopsy form 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for participant if ALT ≥ 3x ULN and total bilirubin ≥2x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2. 
All events of ALT ≥ 3x ULN and total bilirubin ≥ 2x ULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5, 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving 
anticoagulants. 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
4. 
Includes: hepatitis A Immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; Cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); hepatitis E IgM antibody. 
5. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
pk blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are 
provided in the Central Laboratory Manual. 

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Phase 2 Liver Chemistry Increased Monitoring Criteria with Continued Study 
Intervention 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study Intervention 
Criteria 
Actions 
ALT ≥3x ULN and ≤5x ULN and total bilirubin 
<2x ULN or INR ≤1.5, without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be monitored 
weekly for 4 weeks 
• 
Notify the GSK Medical Monitor within 24 hours of learning 
of the abnormality to discuss participant safety 
• 
Participant must return weekly for repeat liver chemistries 
(ALT, AST, alkaline phosphatase, total bilirubin and INR) 
until they resolve, stabilize or return to within baseline 
• 
If at any time participant meets liver chemistry stopping 
criteria, proceed as described above 
• 
If, after 4 weeks of monitoring, ALT <3x ULN and bilirubin 
<2x ULN and INR ≤1.5, monitor participants twice monthly 
until liver chemistry tests resolve or return to within baseline 

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10.7. 
Appendix 7: Important Study Assessment Details & Study 
Specific Equipment 
Efficacy assessment 
Description 
Average Daily Knee pain on 
NRS 
Participants will record pain scores daily (evening time) on the eDiary for the 7 
consecutive days preceding dosing (during screening) and then daily from Day 
1 to week 31. 
This is a single-item measure designed to capture information on the self-
reported average knee pain intensity in index knee, over the past 24 hours. 
Participants will be asked to mark their pain intensity on a daily basis, using the 
NRS, on an 11-point scale (0-10), with 0 = no pain, and 10 = pain as bad as 
you can imagine.  
Western Ontario and McMaster 
Universities Osteoarthritis 
Index (WOMAC) 
The WOMAC is a widely used, proprietary set of standardized questionnaires 
used by health professionals to evaluate the condition of patients with 
osteoarthritis of the knee and hip, including pain, stiffness, and physical 
functioning of the joints. Participants will respond to each question using an 11-
point NRS (0-10), with 0 = no pain/stiffness/difficulty, and 10 = extreme 
pain/stiffness/difficulty. 
Patient Global Assessment 
The patient global assessment asks the study participant: “Considering all the 
ways in which your knee osteoarthritis affects you, how do you feel your knee 
osteoarthritis is doing today?” Participants will respond on a Likert scale 
ranging from 1-5. Higher scores indicate worse condition. 
Worst Daily Knee pain on NRS 
Participants will record pain scores daily (evening time) on the eDiary device 
for the 7 consecutive days preceding dosing (during screening) and then daily 
from Day 1 to week 31. 
This is a single-item measure designed to capture information on the self-
reported worst knee pain intensity in index knee, over the past 24 hours. 
Participants will be asked to mark their pain intensity on a daily basis, using the 
NRS, on an 11-point scale (0-10), with 0 = no pain, and 10 = pain as bad as 
you can imagine. 
Physician Global Assessment 
The physician global assessment asks the physicians: “What is your 
assessment of the patient’s current disease activity?” Physicians will respond 
by using an 11-point NRS scale (0-10). Higher scores indicate worse condition. 
SF-36 
A 36-item questionnaire assessing health-related quality of life scored on a 
scale of 0–100, with higher scores indicating a higher quality of life.  
PROMIS-Sleep Disturbance  
The PROMIS Short Form Sleep disturbance is a PRO instrument designed to 
assess self-reported sleep disturbance for which the recall period is the past 7 
days.  
PGIS 
Static, current state patient global impression of the overall severity of sleep 
disturbance over the past 7 days.  
PGIC 
Patient global impression of overall change in severity of sleep disturbance 
from baseline.  
PGIS-Walk 
A walking-specific PGIS was developed with external expert input to describe 
the overall severity of difficulty walking due to OA over the past week. 
PGIC-Walk 
The walking-specific PGIC will describe the overall change in difficulty walking 
due to OA since starting the study. 
PainDETECT 
This questionnaire is used to explore the neuropathic aspect of OA pain 
[Freynhagen, 2006]. 
Paracetamol/acetaminophen 
use 
Participants will record any Paracetamol/Acetaminophen intakes over the past 
24 h on the eDiary on a daily basis along with date, approximate time of dose, 
dose strength, drug form and primary reason for intake. 

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10.8. 
Appendix 8: Country-specific requirements 
10.8.1. 
Japan specific requirement: 
For evidence of active or past hepatitis B infection participants from Japan are required to 
test for hepatitis B surface antibody (HBsAb) in addition to hepatitis B surface antigen 
(HBsAg) and hepatitis B core antibody (HBcAb). Participants from sites in Japan are not 
eligible if positive for HBsAb AND consequently positive for HBV DNA. 
For participants who are HBsAb positive (and negative for HBV DNA), hepatitis B 
reactivation monitoring will be needed throughout the study if vaccination history could 
not be confirmed. 
In addition to the hepatitis B monitoring timepoints in the schedule of assessments, 
monitoring will also be tested at Week 20 (Visit 25) and Week 24 (Visit 26) in 
participants from sites in Japan. 
Chronic Kidney Disease Epidemiology Collaboration equation will be used for 
calculating and reporting eGFR. For participants from Japan, the Japanese coefficient 
(0.813) modified CKD-EPI will be used for calculating and reporting eGFR. 
10.8.2. 
FRENCH-SPECIFIC REQUIREMENTS 
This appendix includes all applicable requirements of French Public Health Code / 
specific local GSK requirements and identifies, item per item, the mandatory 
modifications or additional information to the study protocol. 
10.8.2.1. 
Concerning the “SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA” 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category (French Public Health Code L.1124-1). 
It is the investigator’s responsibility to ensure and to document (in the source document - 
subject notes) that the subject is affiliated to or beneficiary of a social security category. 
Subjects will be compensated for the inconvenience of participating in the study. The 
amount of compensation is stated in the Informed Consent Form. Subjects not completing 
the study for whatever reason could be compensated generally on a pro rata basis. 

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10.8.2.2. 
Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
• 
In section “Regulatory and Ethical Considerations, including the Informed 
Consent Process” of study protocol 
 Concerning the process for informing the subject, the following text is added: 
French Patient Informed Consent is a document which summarizes the main features 
of the study and allows collection of the subject written consent. It also contains a 
reference to the single scientific and ethical regulatory authorization. 
 Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
French Patient Informed Consent Form is in duplicate. 
The first page of the Patient Informed Consent Form is given to the investigator. The 
copy is kept by the patient. 
• 
NOTIFICATION TO THE HOSPITAL DIRECTOR 
In accordance with Article R.1123-69 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The Hospital 
Director is supplied with the protocol and any information needed for the financial 
disposition, the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial. 
• 
INFORMATION TO THE HOSPITAL PHARMACIST 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning the 
product(s) of the trial (e.g. included in the IB), the name of the investigator(s), the number 
of sites involved in her/his establishment and the estimated time schedule of the trial. 
• 
ETHNIC ORIGIN 
In accordance with the data privacy regulation, the ethnic origin, as any personal data, can 
only be collected if the collection of this data is strictly necessary and relevant for the 
purpose of the study. 
• 
TESTING OF BIOLOGICAL SAMPLES 
In accordance with the French Public Health Code–article L1211-2, a biological sample 
without identified purpose at the time of the sample and subject’s preliminary information 
is not authorized. 
10.8.2.3. 
Concerning the “DATA MANAGEMENT” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the investigators 
and/or co-investigators and/or the pharmacists if applicable, involved in this clinical trial, 
and data regarding the subjects recruited in this clinical trial (subject number, treatment 

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number, subjects status with respect to the clinical trial, dates of visit, medical data) will 
be collected and computerized in GSK data bases by GSK or on its behalf, for reasons of 
follow-up, clinical trial management and using the results of said clinical trial. According 
to the data privacy regulation, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GSK (Clinical Operations 
Department). 
10.8.2.4. 
Concerning Data Privacy 
In accordance with the applicable data privacy regulation, personal data are processed in 
a manner that ensures appropriate security, including protection against unauthorized or 
unlawful processing and against accidental loss, destruction or damage, using appropriate 
technical or organizational measures. The processing is whether deemed to be compliant 
with one of the methodology of reference (MR-001) or has been the subject of a request 
for authorization to the CNIL. The Investigator has, regarding the processing data related 
to her/him, a right of access, of rectification, erasure and of opposition with GSK in 
accordance with the legal provisions. 
10.8.2.5. 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY, RECONCILIATION, 
AND DESTRUCTION 
In specific situations where institutional practices dictate that the site disposes of and/or 
destroys IP prior to allowing the “monitor’ to verify and document IP accountability, the 
following applies: 
“During the conduct of the Study, Investigational Product (IP) will be destroyed by the 
Institution prior to a GSK “monitor” conducting final investigational product 
accountability. Institution agrees that such destruction will comply with Institution’s 
investigational product accountability procedures and will provide GSK with 
investigational product accountability logs and supporting documentation to verify 
adherence to ‘Bonnes Pratiques Cliniques’ (decision dated on the 24th of November 2006). 

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10.9. 
Appendix 9: Protocol amendment history 
Amendment 2 (02 Apr 2024) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the safety monitoring of participants and 
the scientific value of the study. 
Overall rationale for Amendment 2: 
This protocol has been amended to clarify eligibility requirements and improve 
representation of the target population: 
• 
Hemoglobin laboratory values during screening and hematologic abnormalities 
stopping criteria changed to 11 and 10 g/dL, respectively. Following FDA feedback, 
hemoglobin exclusion criterion was revised to ensure hemoglobin levels between 11 
and 12 g/dL for females, and between 11 and 13.8 g/dL for males reflect a stable 
baseline and are not due to potential acute blood loss. 
Further changes include: 
• 
Clarification of pain training, pain scoring and rescue medication use for eligibility. 
• 
Screening period was extended from 5 to 6 weeks to allow additional time for 
medications wash out, if needed. 
• 
Modification of exclusion criteria and associated laboratory tests to allow 
participants who had a previous hepatitis B infection but no evidence of active 
infection. 
Section # and title 
Description of change 
Brief rationale 
1.1. Synopsis 
Summarized sections of the 
protocol. 
To improve readability and 
provide descriptive summary. 
1.2. Schema 
Extended screening period 
from 5 to 6 weeks and total 
study duration from 36 to 37 
weeks. 
Further screening week added 
to provide additional time for 
wash out, if required. 
1.3. Schedule of Activities 
Clarified language around 
pain and device training. 
Clarified language around 
pain reporting. 
Clarified restrictions on rescue 
medication use. 
Clarified language around TB 
To clarify the requirements for 
pain training, pain reporting 
and rescue medication during 
the run-in period of screening. 
To show what TB testing is 
available, subject to Sponsor 
approval. 

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Section # and title 
Description of change 
Brief rationale 
testing. 
Clarified language around 
ECG measurement. 
To provide option of triplicate 
ECG assessment during 
screening, if required. 
2.3.1. Risk assessment 
Removed monitoring for TB 
reactivation. 
Added hepatitis B monitoring 
and stopping criteria. 
To align with exclusion criteria 
(participants with a history of 
active TB and/or latent TB are 
excluded). 
To add risk management of 
viral reactivation for 
participants with previous 
hepatitis B. 
5.1. Inclusion criteria 
Clarified restrictions for rescue 
medication use, recording and 
evaluation. 
To add further clarity on 
eligibility of participants who 
are using excess rescue 
medication during run-in 
period that could confound 
pain scoring. 
5.2. Exclusion criteria 
Hemoglobin laboratory values 
at screening changed from 
<12 g/dL (females) and <13.8 
g/dL (males) to <11 g/dL for 
females and males. 
Eligibility of participants with 
hemoglobin levels between 11 
and 12 g/dL (for females) and 
between 11 and 13.8 g/dL (for 
males) is conditional on the 
absence of signs of acute 
blood loss and if the 
hemoglobin level is 
considered stable. 
 
Clarification of language 
around TB testing. 
 
Requirement of a hepatitis B 
virus DNA test added for 
participants who have a 
positive hepatitis B core 
To allow better representation 
of the target OA population. 
 
Hemoglobin exclusion 
criterion modified based on 
FDA feedback to ensure 
hemoglobin laboratory values 
during screening reflect stable 
baseline and are not due to 
potential acute blood loss. 
 
To show what TB testing is 
available, subject to Sponsor 
approval. 
 
To allow participants who 
have had a previous hepatitis 
B infection but no evidence of 
current infection (HBV DNA 
and HbsAg negative). 
 
To allow clinical interpretation 
of drug screening based on all 
regular medications taken by 
the participant. 

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Section # and title 
Description of change 
Brief rationale 
antibody test result during 
screening. 
 
Clarification of drug screening 
results. 
5.4. Screen failures 
Added option of re-screening 
due to administrative reasons. 
Addition of option for a further 
re-screen at the discretion of 
the Medical Monitor, for 
administrative reason to 
provide logistical flexibility. 
6.1. Study intervention(s) 
administered 
Updated Table 3 to include 
route and mode of 
administration, dose, dosage 
regimen and duration of 
intervention for all study 
interventions (i.e. study drug, 
placebo and rescue 
medication).  
To align with Sponsor 
standards and country-
specific requirements.  
6.4. Blinding 
Added details of blinding 
plans. 
To improve clarity. 
6.9.4. Rescue medicine 
Updated restrictions on 
rescue medication use, 
recording and sourcing. 
Clarification of rescue 
medication use during the run-
in period for evaluation of 
eligibility. 
7.1. Permanent 
discontinuation of study 
intervention 
Removed ‘new latent TB 
infection’. 
To align with exclusion cirteria 
and screening procedures. 
7.1.4. Hematologic 
Abnormality stopping criteria 
Changed hemoglobin 
laboratory values for stopping 
criteria during study from <11 
g/dL (females) and <12.4 g/dL 
(males) to <10 g/dL for 
females and males. 
To improve risk management 
and target OA population. 
7.1.5. Hepatitis B reactivation 
stopping criteria 
Addition of hepatitis B 
reactivation stopping criteria. 
To add risk management for 
reactivation of hepatitis B. 
8.3.3. Electrocardiograms 
Clarified language around 
ECG measurement and 
analysis to allow triplicate 
ECG at screening, if needed. 
To clarify study procedures 
and enable more accurate 
monitoring of cardiac 
functions. 

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Section # and title 
Description of change 
Brief rationale 
8.3.7. Hepatitis B reactivation 
monitoring 
Added details. 
To provide regular monitoring 
of participants with previous 
hepatitis B infection for 
reactivation and advice on 
management. 
8.5.4. AESI 
Removed TB reactivation. 
To align with exclusion criteria 
and screening procedures. 
8.7. Pharmacodynamics 
Added details. 
Clarification of 
pharmacodynamic analysis. 
9.4. Statistical analyses 
Minor clarifications around 
statistical analyses. 
To improve reporting. 
10.1. Regulatory, ethical, and 
study oversight considerations 
Clarified language around 
sample collection and storage. 
Clarified language around 
data protection and updated 
details of GSK publication 
policy. 
Administrative change to align 
with Sponsor’s standard. 
Amendment 1 (24 Jul 2023) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the safety monitoring of participants and 
the scientific value of the study. 
Overall rationale for Amendment 1: 
In response to regulatory feedback, the following changes were made: 
1. Increase in safety laboratory and pregnancy testing during the treatment period. 
2. Establishment of an Independent Data Monitoring Committee (IDMC). 
3. Update to individual participant stopping criteria. 
4. Update to eligibility criteria based on individual participants stopping criteria. 
5. Introduction of contraceptive requirements for male participants and collection of 
information from pregnant female partners of participants. 
6. Update to intercurrent event handling strategy for primary estimand. 

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In addition, the following minor changes were implemented: 
Updated accurate pain reporting training schedule, ECG assessment schedule, provision 
of limited NSAID use, secondary objective of change from baseline in key laboratory 
parameter updated and moved to tertiary, secondary objective of characterizing the 
longitudinal dose-exposure-response relationship moved to tertiary. Added radiology risk 
as a procedural risk from bilateral knee X-ray. 
Minor edits/corrections are made throughout to provide refinement and clarification. 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE:  
Section # and title 
Description of change 
Brief rationale 
Section 1.3 Schedule of 
Activities.  
Added: Urine pregnancy 
testing frequency increased 
from monthly to weekly during 
the treatment period.  
Added following regulatory 
agency request. 
Section 1.3 Schedule of 
Activities. 
Added: Hematology, clinical 
chemistry, and urinalysis 
frequency increased to testing 
at least every 2 weeks during 
the treatment period.  
Added following regualtory 
agency request 
3.1 Efficacy Estimands 
Update to ICE strategy for 
treatment discontinuations 
and persistent prohibited pain 
therapy, renumber additional 
estimands. 
Updated primary estimand per 
regulatory agency’s feedback.  
4.1 Overall Design 
Added: Establishment of an 
IDMC. 
Further details throughout 
protocol in relevant sections. 
Added following regulatory 
agency request. 
5.1 Inclusion criteria 
Added: Inclusion criterion 9: 
Male participant contraceptive 
requirements added.  
Added following a regulatory 
agency request 
5.2 Exclusion criteria 
Added: Exclusion criterion 22: 
White blood cell count, 
hemoglobin and platelet count 
cut-off values added. 
Updated to accommodate 
updated individual participant 
stopping criteria requested by 
a regulatory agency  

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Section # and title 
Description of change 
Brief rationale 
7. Discontinuation of study 
intervention and participant 
discontinuation/withdrawal 
Added: Renal function, 
hematological abnormality, 
and ECG parameters 
individual participant stopping 
criteria.  
Added following a regulatory 
agency request. 
8.5.6 Pregnancy 
Added: Details of monitoring 
for the reporting of pregnancy 
in female partners of male 
participants.  
Added following a regulatory 
agency feedback 

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11. 
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