A Multicenter Randomized, Double-blind, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Target Engagement of GSK3858279 in Adult Participants With Chronic Diabetic Peripheral Neuropathic Pain (DPNP) /NEPTUNE-17
Phase: PHASE2
Conditions: Pain
Sponsor: GlaxoSmithKline

 
 
CONFIDENTIAL 
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Protocol Amendment 2 Final 
26 Mar 2024 
1 
CLINICAL STUDY PROTOCOL 
Primary study intervention(s) GSK3858279 
Other study intervention(s) 
Not Applicable 
Study identifier 
214221 
EU CT number 
2022-502313-28-00 
Pediatric investigational plan 
number 
Not Applicable 
Approval date 
26 Mar 2024 
Title 
A multicenter randomized, double-blind, placebo-
controlled Phase 2 study to evaluate efficacy, safety, 
tolerability, pharmacokinetics and target engagement 
of GSK3858279 in adult participants with chronic 
Diabetic Peripheral Neuropathic Pain (DPNP) / 
NEPTUNE-17 
Compound number/Name  
GSK3858279 
Brief title 
A Phase 2 study (NEPTUNE-17) to evaluate efficacy 
and safety of GSK3858279 in DPNP 
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 the 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 2 Final 
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2 
Protocol Amendment 2 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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Protocol Amendment 2 Final 
26 Mar 2024 
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Study identifier 
214221 
EU CT number 
2022-502313-28-00 
Approval date 
26 Mar 2024 
Title 
A multicenter randomized, double-blind, placebo-
controlled Phase 2 study to evaluate efficacy, safety, 
tolerability, pharmacokinetics and target engagement 
of GSK3858279 in adult participants with chronic 
Diabetic Peripheral Neuropathic Pain (DPNP) / 
NEPTUNE-17 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 

 
 
CONFIDENTIAL 
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Protocol Amendment 2 Final 
26 Mar 2024 
4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
26 Mar 2024 
Amendment 1 
24 July 2023 
Original Protocol 
22 February 2023 
Amendment 2 
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 had been amended to clarify eligibility requirements and improve 
representation of the target population.  The main 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 washout, 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.  
• 
Modification of eGFR measure of renal function for exclusion from <60 
mL/min/1.73 m2 to <45 mL/min/1.73 m2. 

 
 
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LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
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 32 to 33 
weeks. 
Further screening week added 
to provide additional time for 
washout, 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 
testing. 
Clarified language about 
ECG measurement. 
Addition of mandatory (not 
optional) laboratory urinalysis 
at Day 1 and Week 12 visits. 
 
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. 
To provide option of triplicate 
ECG assessment during 
screening, if required. 
Addition of urine protein 
evaluation at baseline and 
end of treatment. 
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. 

 
 
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Section # and title 
Description of change 
Brief rationale 
5.1. Inclusion criteria 
Clarification of language 
around recent hospitalization 
related to diabetes. 
Clarified restrictions for 
rescue medication use, 
recording and evaluation. 
To focus hospitalizations to 
important unplanned medical 
events related to diabetes and 
not to routine scheduled 
hospital care in some 
countries. 
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 
Clarification of language 
around TB testing. 
Reduction of eGFR measure 
of renal function for exclusion 
from <60 mL/min/1.73 m2 to 
<45 mL/min/1.73 m2. 
Addition of exclusion for any 
previous exposure to 
GSK3858279. 
Requirement of a hepatitis B 
virus DNA test added for 
participants who have a 
positive hepatitis B core 
antibody test result during 
screening. 
Clarification of drug 
screening results. 
To show what TB testing is 
available, subject to Sponsor 
approval. 
Reduction of eGFR from 
60 mL/min/1.73 m2 to 
45 mL/min/1.73 m2 to allow a 
better representation of the 
target DPNP population. 
To prevent the unlikely 
chance of previous exposure 
to GSK3858279 to allow 
accurate calculation of 
exposure numbers. 
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. 
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. 

 
 
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Section # and title 
Description of change 
Brief rationale 
6.1. Study intervention(s) 
administered 
Updated Table 4 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. 
6.9.3. 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 criteria 
and screening procedures. 
7.1.5. Hepatitis B reactivation 
stopping criteria 
Addition of hepatitis B 
reactivation stopping criteria 
section 
To add risk management for 
the 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. 
8.3.6. Hepatitis B reactivation 
monitoring 
Added details for monitoring. 
Additional monitoring 
requirements for participants 
at Japan sites only. 
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 
Updated details of 
pharmacodynamic analysis. 
Clarification of 
pharmacodynamic analysis. 
9.4. Statistical analyses 
Minor clarifications around 
statistical analyses. 
To improve reporting. 

 
 
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Section # and title 
Description of change 
Brief rationale 
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 changes to 
align with Sponsor’s 
standards. 

 
 
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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: ............ 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 15 
1. 
PROTOCOL SUMMARY ........................................................................................ 22 
1.1. 
Synopsis ..................................................................................................... 22 
1.2. 
Schema ...................................................................................................... 23 
1.3. 
Schedule of Activities (SoA) ........................................................................ 24 
2. 
INTRODUCTION .................................................................................................... 37 
2.1. 
Study rationale ............................................................................................ 37 
2.2. 
Background ................................................................................................ 37 
2.2.1. 
The role of C-C class chemokines 17 (CCL17) in 
neuropathic pain .......................................................................... 37 
2.3. 
Benefit/Risk assessment ............................................................................. 38 
2.3.1. 
Risk assessment .......................................................................... 39 
2.3.2. 
Benefit assessment ..................................................................... 46 
2.3.1. 
Overall benefit/risk conclusion ..................................................... 46 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 46 
3.1. 
Efficacy estimands ...................................................................................... 48 
3.2. 
Safety estimands ........................................................................................ 51 
4. 
STUDY DESIGN .................................................................................................... 52 
4.1. 
Overall design ............................................................................................. 52 
4.2. 
Scientific rationale for study design ............................................................. 53 
4.2.1. 
Participant input into design ......................................................... 53 
4.3. 
Justification for dose ................................................................................... 53 
4.4. 
End-of-study definition ................................................................................ 55 
5. 
STUDY POPULATION ........................................................................................... 55 
5.1. 
Inclusion criteria .......................................................................................... 56 
5.2. 
Exclusion criteria ......................................................................................... 58 
5.3. 
Lifestyle considerations ............................................................................... 62 
5.3.1. 
Meals and dietary restrictions ...................................................... 62 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 62 
5.3.3. 
Activity ......................................................................................... 62 
5.3.4. 
Other restrictions ......................................................................... 62 
5.4. 
Screen failures ............................................................................................ 62 
5.5. 
Criteria for temporarily delaying administration of study intervention ........... 63 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 63 
6.1. 
Study intervention(s) administered .............................................................. 63 
6.2. 
Preparation, handling, storage, and accountability ...................................... 65 
6.3. 
Assignment to study intervention ................................................................ 66 
6.4. 
Blinding ....................................................................................................... 66 
6.5. 
Study intervention compliance .................................................................... 68 
6.6. 
Dose modification ....................................................................................... 68 

 
 
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6.7. 
Continued access to study intervention after the end of the study ............... 68 
6.8. 
Treatment of overdose ................................................................................ 68 
6.9. 
Prior and concomitant therapy .................................................................... 69 
6.9.1. 
Concomitant treatments ............................................................... 69 
6.9.1.1. 
Immunomodulators ..................................................... 69 
6.9.1.2. 
Analgesics .................................................................. 70 
6.9.1.3. 
Diabetic therapy ......................................................... 70 
6.9.1.4. 
Prohibited concomitant pain interventions .................. 71 
6.9.2. 
Vaccinations ................................................................................ 71 
6.9.3. 
Rescue medicine ......................................................................... 71 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 72 
7.1. 
Permanent discontinuation of study intervention ......................................... 72 
7.1.1. 
Liver chemistry stopping criteria ................................................... 73 
7.1.2. 
ECG stopping criteria ................................................................... 75 
7.1.3. 
Renal function stopping criteria .................................................... 75 
7.1.4. 
Hematologic Abnormality stopping criteria ................................... 75 
7.1.5. 
Hepatitis B reactivation stopping criteria ...................................... 75 
7.1.6. 
Temporary discontinuation ........................................................... 76 
7.1.7. 
Rechallenge ................................................................................. 76 
7.1.7.1. 
Study intervention restart or rechallenge after 
liver stopping criteria are met ...................................... 76 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 77 
7.3. 
Lost to follow-up.......................................................................................... 78 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 78 
8.1. 
Administrative and general/baseline procedures ......................................... 79 
8.1.1. 
Collection of demographic data .................................................... 79 
8.1.2. 
Medical/vaccination history .......................................................... 79 
8.2. 
Efficacy assessments ................................................................................. 79 
8.2.1. 
Average Daily Pain NRS .............................................................. 79 
8.2.2. 
Worst Daily Pain NRS .................................................................. 79 
8.2.3. 
Nighttime Pain NRS ..................................................................... 80 
8.2.4. 
Brief Pain Inventory Short Form (BPI-SF) .................................... 80 
8.2.5. 
Patient Global Impression of Change (PGIC) ............................... 80 
8.2.6. 
Patient Global Impression of Severity (PGIS) .............................. 80 
8.2.7. 
McGill Pain Questionnaire Short Form 2 (SF-MPQ-2) .................. 80 
8.2.8. 
Glycated Hemoglobin (HbA1c) ..................................................... 81 
8.3. 
Safety assessments .................................................................................... 81 
8.3.1. 
Physical examination/history, directed physical 
examination ................................................................................. 81 
8.3.2. 
Vital signs .................................................................................... 81 
8.3.3. 
Electrocardiograms ...................................................................... 81 
8.3.4. 
Clinical safety laboratory tests ..................................................... 82 
8.3.5. 
Pregnancy testing ........................................................................ 83 
8.3.6. 
Hepatitis B reactivation monitoring ............................................... 84 
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 ............................................................... 86 

 
 
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8.5.2. 
Method of detecting AEs and SAEs ............................................. 86 
8.5.3. 
Follow-up of AEs and SAEs ......................................................... 86 
8.5.4. 
AESI ............................................................................................ 87 
8.5.5. 
Regulatory reporting requirements for SAEs ................................ 87 
8.5.6. 
Pregnancy ................................................................................... 88 
8.5.7. 
Cardiovascular and death events ................................................. 89 
8.5.8. 
Contact information for reporting SAEs, AESIs, and 
pregnancies ................................................................................. 89 
8.5.9. 
Participant card ............................................................................ 89 
8.6. 
Pharmacokinetics ....................................................................................... 89 
8.7. 
Pharmacodynamics .................................................................................... 90 
8.8. 
Target (CCL17) concentrations ................................................................... 90 
8.9. 
Genetics ..................................................................................................... 91 
8.10. 
Biomarkers ................................................................................................. 91 
8.11. 
Immunogenicity assessments ..................................................................... 92 
8.12. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 92 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 92 
9.1. 
Statistical hypotheses/comparisons ............................................................ 93 
9.2. 
Multiplicity Adjustment ................................................................................ 93 
9.3. 
Analysis sets ............................................................................................... 93 
9.4. 
Statistical analyses ..................................................................................... 94 
9.4.1. 
General considerations/definitions ............................................... 94 
9.4.2. 
Primary endpoint(s)/estimand(s) analysis .................................... 95 
9.4.3. 
Secondary endpoint(s)/estimand(s) analysis ................................ 95 
9.4.3.1. 
Safety analysis ........................................................... 95 
9.4.3.2. 
Efficacy analysis ......................................................... 96 
9.4.3.3. 
Pharmacokinetic (PK) ................................................. 96 
9.4.4. 
Tertiary endpoints ........................................................................ 97 
9.5. 
Interim analysis ........................................................................................... 97 
9.6. 
Sample size determination .......................................................................... 97 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 99 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 99 
10.1.1. 
Regulatory and ethical considerations ......................................... 99 
10.1.2. 
Financial disclosure ................................................................... 100 
10.1.3. 
Informed consent process .......................................................... 100 
10.1.4. 
Recruitment strategy .................................................................. 101 
10.1.5. 
Data protection .......................................................................... 101 
10.1.6. 
Committees structure ................................................................. 102 
10.1.7. 
Dissemination of clinical study data ........................................... 103 
10.1.8. 
Data quality assurance .............................................................. 103 
10.1.9. 
Source documents ..................................................................... 104 
10.1.10. Study and site start and closure ................................................. 105 
10.1.11. Publication policy ....................................................................... 106 
10.2. 
Appendix 2: Clinical laboratory tests ......................................................... 106 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting .......................................... 108 
10.3.1. 
Definition of AE .......................................................................... 108 
10.3.2. 
Definition of SAE ........................................................................ 110 

 
 
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10.3.3. 
Definition of cardiovascular 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 ........................................................................ 111 
10.3.5.1. AE and SAE recording .............................................. 111 
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 
10.3.6. 
Reporting of SAEs, AESIs and pregnancies .............................. 114 
10.4. 
Appendix 4: Contraceptive and barrier guidance ....................................... 115 
10.4.1. 
Definitions .................................................................................. 115 
10.4.1.1. Women of Childbearing Potential (WOCBP) ............. 115 
10.4.2. 
Contraception guidance ............................................................. 117 
10.5. 
Appendix 5: Genetics ................................................................................ 118 
10.6. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments ............................................................................................. 119 
10.7. 
Appendix 7: Important study assessment details & study-specific 
equipment ................................................................................................. 122 
10.7.1. 
Douleur Neuropathique 4 (DN4) questionnaire .......................... 122 
10.8. 
Appendix 8: Country-specific requirements ............................................... 123 
10.9. 
Appendix 9: Protocol amendment history .................................................. 125 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: ........ 126 
11. REFERENCES ..................................................................................................... 128 
 

 
 
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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities: Screening period ................................................ 24 
Table 2 
Schedule of Activities: Treatment and Off-treatment Follow-Up 
period ..................................................................................................... 30 
Table 3 
Objectives and endpoints ....................................................................... 46 
Table 4 
Study intervention(s) administered ......................................................... 64 
Table 5 
Study arm(s) .......................................................................................... 65 
Table 6 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 88 
Table 7 
Contact information for reporting SAEs, AESIs, and pregnancies .......... 89 
Table 8 
Probability of meeting various criteria of interest, conditional on 
different true treatment differences, standard deviations and 
sample sizes. ......................................................................................... 98 
Table 9 
Protocol-required safety laboratory tests .............................................. 107 
 

 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 23 
Figure 2 
Model Predicted Reductions (median and 95% CI of the 
prediction) in free CCL17 following weekly SC dosing with 
GSK3858279 (60 mg or 360 mg) over 12 weeks [GSK Document 
Number TMF-14616324]. ....................................................................... 55 
 

 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
21 CFR 
Title 21 of the Code of Federal Regulations 
µg/mL 
Micrograms per milliliter 
μg*day/mL 
Micrograms day per milliliter 
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 
BIB 
Bioanalysis, Immunogenicity and Biomarker 
BL 
Baseline 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CFR 
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
COA 
Clinical Outcome Assessment  
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus strain 19 
CPPD 
Calcium Pyrophosphate Dihydrate 
CRF 
Case Report Form 
Cavg  
Average concentration over a dosing interval 
CSR 
Clinical Study Report 
Ctau 
Pre-dose (trough) concentration at the end of the dosing interval 
CTIS 
Clinical Trial Information System 
CV 
Cardiovascular 
DN4 
Douleur Neuropathique 4 
DPNP 
Diabetic Peripheral Neuropathic Pain 
DRG 
Dorsal Root Ganglion 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EU 
European Union 
eDiary 
Electronic Diary 
FTIH 
First Time In Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
Gamma Glutamyl Transpeptidase 

 
 
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h 
Hours 
hCG 
Human Chorionic Gonadotropin 
HbA1c 
Glycated Hemoglobin 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen  
HBcAb 
Hepatitis B Core Antibody  
HBV 
Hepatitis B Virus 
HBV DNA 
Hepatitis B DNA 
HHS 
Home Healthcare Services 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICEs 
Intercurrent Events 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IDFU 
Investigational Directions For Use 
IDMC 
Independent Data Monitoring Committee 
iDRC 
Internal Data Review Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG2 
Immunoglobulin G2 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IUD 
Intrauterine Device 
IUS 
Intrauterine hormone-releasing System 
IWRS 
Interactive Web Recognition System 
Kd 
Dissociation Constant 
kg/m2 
Kilograms per square meter 
LAM 
Lactational Amenorrhea Method 
LDH 
Lactate Dehydrogenase 
LLQ 
Lower Limit of Quantification 
LSLV 
Last Subject Last Visit 
MAR 
Missing At Random 
mAb 
Monoclonal Antibody 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/day 
Milligrams per day 
mg/kg 
Milligrams per kilogram 
mg/kg/week 
Milligrams per kilogram per week 

 
 
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min 
Minute 
mm 
Millimetre 
MSDS 
Material Safety Data Sheet 
msec 
Millisecond 
Nab 
Neutralizing antibody 
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 
NYHA 
New York Heart Association 
OA 
Osteoarthritis 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
pH 
Potential Hydrogen 
PK 
Pharmacokinetics 
PGx 
Pharmacogenetics 
PRO 
Patient Reported Outcome 
PtGA 
Patient Global Assessment 
PTS 
Platform Technology and Science 
QSS 
Quasi Steady State 
QTc 
Corrected QT 
QTcF 
Corrected QT using Fridericia’s formula 
RA 
Rheumatoid Arthritis 
RBC 
Red Blood Cell count 
RNA 
Ribonucleic Acid 
SAD  
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SMG 
Safety and Medical Governance 
SMP 
Safety Management Plan 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitors 
SoA 
Schedule of Activities 
SRT 
Safety Review Team 
SSRI 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TDAR 
T-cell Dependent Antibody Response 

 
 
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TE 
Target Engagement 
THC 
Tetrahydrocannabinol 
tmax 
Time to Cmax 
TMDD 
Target-Mediated Drug Disposition 
TST 
Tuberculin Skin Test 
t½ 
Apparent terminal phase half-life 
UACR 
Urine Albumin Creatinine Ratio 
UDS 
Urine Drug Screen 
ULN 
Upper Limit of Normal 
UPCR 
Urine Protein Creatinine ratio 
WBC 
White Blood Count 
WNCBP 
Women Of Non-Childbearing Potential 
WOCBP 
Women Of Childbearing Potential 
w/v 
Weight by volume 
 

 
 
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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 non-serious. 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 labelling 
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 an 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, a handheld mobile device, 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. 
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 

 
 
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Term 
Definition 
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 number 
A unique identification number assigned to each participant who consents to 
participate in the study. 
Participant 
Term used throughout the protocol to denote an individual who has been 
contacted to participate or who participates in the clinical study as a recipient of 
the study intervention (vaccine(s)/product(s)/control). 
Synonym: subject. 
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 (pharmacokinetics, 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.  
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 intervention 
Term used throughout the clinical study to denote a set of Investigational 
Medicinal 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. 

 
 
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Term 
Definition 
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 adverse events (that is, the last 
participant's last visit or LSLV). 
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 multicenter randomized, double-blind, placebo-controlled Phase 2 study to evaluate 
efficacy, safety, tolerability, pharmacokinetics and target engagement of GSK3858279  
in adult participants with chronic Diabetic Peripheral Neuropathic Pain (DPNP) /  
NEPTUNE-17. 
Brief Title: 
A Phase 2 study (NEPTUNE-17) to evaluate efficacy and safety of GSK3858279 in 
DPNP. 
Rationale: Diabetic Peripheral Neuropathic Pain (DPNP) is a common chronic pain 
condition. Several pharmacological treatments are used to manage neuropathic pain; 
however, considerable variations in treatment plan, dosage and sequencing, may lead to 
inadequate pain control, with considerable morbidity among patients. GSK3858279 is a 
high affinity (Kd<1pM), human immunoglobulin G2σ (IgG2σ)(Fc-silenced), first in 
class, monoclonal antibody (mAb). It binds specifically to the chemokine CCL17 which 
is implicated in pain pathogenesis. Based on non-clinical and clinical studies, where 
aCCL17 has demonstrated an efficacy signal in osteoarthritis pain, this study aims to 
investigate the safety, efficacy, pharmacokinetic and target engagement of GSK3858279 
to address the unmet needs of participants with DPNP. Refer to Section 2.1 for details. 
Objectives, Endpoints, and Estimands: The primary objective of this study is to 
estimate the difference in means between GSK3858279 60 mg SC and placebo and 
GSK3858279 360 mg SC and placebo, in change from baseline in the weekly average of 
average daily pain intensity at Week 12, assessed on the NRS, in adult participants with 
DPNP, 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 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. Refer to Section 3 for details. 
Overall Design: This is a randomized, double-blind, parallel group, placebo-controlled 
Phase 2 study to evaluate the efficacy, safety, tolerability, PK and TE of GSK3858279 vs. 
placebo when administered with repeated weekly SC injections in participants with 
DPNP. After the screening visit and washout period, participants will be stratified based 
on region and an average of the average daily pain score at baseline and then randomized 
at 1:1:1 ratio to either GSK3858279 at 60 mg SC weekly or GSK3858279 at 360 mg SC 
weekly or placebo SC weekly within each stratum. Refer to Section 4.1 for details. 
Number of Participants: Approximately 240 participants will be enrolled in this study. 
The number of participants may be increased by approximately 15% to ensure regional 
requirements for recruitment are met. Refer to Section 9.6 for details. 

 
 
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Data Monitoring/Other Committee: A Safety Review Team (SRT) is an internal cross-
functional team responsible for the ongoing assessment of benefit/risk. 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 

 
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1.3. 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities: Screening period 
Note: Although there will be more than one site visit during the screening period (the initial screening visit [1a] and a second visit at the 
beginning of the run-in period [1b]) for the purposes of the SoA these visits will be grouped together and called screening period. 
Assessments 
Screening period 
Notes 
Visit 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
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 1a, or 
anytime during the study, if applicable. 
Demography 
X 
 
 
 
Medical history 
X 
 
 
 
DPNP and DPNP treatment history 
X 
 
 
Date of diagnosis of diabetes and DPNP will be recorded along 
with previous DPNP treatment history. 

 
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Assessments 
Screening period 
Notes 
Visit 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
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. 
Full physical examination 
(including height and weight) 
X 
 
 
 
DN4 questionnaire / examination 
X 
 
 
Diagnosis of DPNP confirmed by a positive DN4 questionnaire. 
Average daily pain score over the past 24 
hours 
X 
 
 
 
12-lead ECG 
X 
 
 
Single ECG tracing should be obtained. Triplicate ECG can be 
performed based on Investigator assessment, if required. 
Vital signs 
X 
 
 
 
Urine drug screen 
X 
 
 
Amphetamines, barbiturates, cocaine, opiates, marijuana (THC), 
benzodiazepines. 
Hematology, clinical chemistry, urinalysis 
X 
 
 
Refer to Section 10.2 for the full list of parameters that will be 
tested. Urinalysis will be performed locally with the use of 
dipstick. Urine sample may be sent to the central laboratory for 
further testing based on Investigator assessment, if required. 

 
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Assessments 
Screening period 
Notes 
Visit 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
HbA1c 
X 
 
 
 
HIV, hepatitis B virus (HBV) and hepatitis 
C virus (HCV)  
X 
 
 
See diagnostic assessments in Section 5.2 for country-specific 
hepatitis B requirement for participants from sites in Japan. 
COVID-19 (SARS-CoV-2) test 
X 
 
 
PCR assay. 
TB testing 
X 
 
 
QuantiFERON TB Gold Plus Test (or, if unavailable, T-SPOT TB 
with prior Sponsor’s approval). 
Pregnancy test (serum in WOCBP) or 
follicle stimulating hormone (FSH) (in 
WNCBP as appropriate – see Appendix 4 
(Section 10.4) 
X 
 
 
 
Rescue Medication: dispense 
Paracetamol/Acetaminophen 
X 
 
X* 
Only if ALL initial eligibility criteria were met at the initial 
screening visit. 
Participants should be instructed to only use rescue medication 
provided by sites and to follow dosage and use restrictions. 
*Additional rescue medication supply should be provided if 
needed. 
Concomitant medication review 
X 
X 
X 
All concomitant medications taken within 30 days prior to ICF 
signature and current DPNP treatment(s) (if applicable) 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 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
Inclusion and exclusion criteria 
X 
X 
X 
Recheck clinical status before initiating washout and run-in 
periods. 
Washout period: washout of all pain 
medications (if applicable) 
 
At least 3 days or 5 
half-lives, 
whichever is longer 
(according to 
Investigator and 
local guidance) 
 
Start the washout period only if ALL eligibility criteria were met at 
the initial screening besides the average of the average daily pain 
score. 
See Section 6.9.1.2 for further details on prohibited analgesics 
and advice for washout to prevent withdrawal symptoms, if 
required. 
Run-in period: after washout of all pain 
medications (if applicable) 
 
 
7 days preceding 
randomization 
Only rescue pain medication is permitted within allowance 
(Rescue Medication Section 6.9.3). 
Permitted rescue medication (if needed): 
Paracetamol/Acetaminophen, administered orally, at doses of ≤3 
grams/day and for a maximum of 4 days in a week. 
Participants exceeding the permitted allowance during the run-in 
period will not be eligible. 
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 1b, participants will be 
trained on accurate pain reporting course, provided by the third-
party vendor WCG.  This web-based training to be completed on 
a site computer/tablet device with supervision. 

 
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Assessments 
Screening period 
Notes 
Visit 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
Training on and dispensing of the eDiary 
 
 
X 
eDiary should only be dispensed once the participant passes ALL 
of the screening assessments besides the average of the 
average daily pain score and washout of prohibited pain 
medications has been successful (if applicable). 
eDiary training to be completed on Clario handheld device at site 
with supervision. 
Average daily, worst daily and nighttime 
pain scores (eDiary) 
 
 
Starting 7 days 
preceding 
randomization 
Scores will be recorded on the eDiary over the  
7 consecutive days preceding randomization. 
Compliance for average daily pain scoring must be a minimum of 
6 out of 7 days for eligibility. 
An average of the average daily pain score will be evaluated for 
inclusion. 
Paracetamol/Acetaminophen intake Diary 
(eDiary) 
 
 
Starting 7 days 
preceding 
randomization 
Recorded on the eDiary over the 7 consecutive days preceding 
randomization. 
Compliance of rescue medication data entry must be a minimum 
of 6 out of 7 days for eligibility. 
Participants exceeding the permitted allowance during the run-in 
period will not be eligible. 
Permitted rescue medication (if required): 
Paracetamol/Acetaminophen, administered orally, at doses of ≤3 
grams/day and for a maximum of 4 days in a week. 

 
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Assessments 
Screening period 
Notes 
Visit 
Initial screening  
(Visit 1a) 
Start of washout 
period 
(phone call) 
Run-in period  
(Visit 1b) 
 
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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Table 2 
Schedule of Activities: Treatment and Off-treatment Follow-Up period 
 
Assessments 
Treatment period 
Off-treatment 
EDa 
Week  
Day 1 
BLa 
 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
16 
20 
27 
 
Visit No 
2 
3b 
4 
5 
6 
7 
8 
9 
10 
11b 
12 
13 
14 
15 
16b 
17 
18b 
19b 
20 
 
Visit window 
± 2 days [except for Day 1 (Visit 2) and Visits 3, 11 and 16]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
± 7 days 
 
Inclusion and 
exclusion criteria d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer: Weekly 
SC IMP injections e 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
COAs including PROs 
Average Daily Pain 
NRS f 
<===========================================X===========================================> 
X 
Worst Daily Pain  
NRS f 
<===========================================X===========================================> 
X 
Nighttime Pain  
NRS f 
<===========================================X===========================================> 
X 
Paracetamol/ 
Acetaminophen 
intake eDiary g 
<===========================================X===========================================> 
X 

 
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Assessments 
Treatment period 
Off-treatment 
EDa 
Week  
Day 1 
BLa 
 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
16 
20 
27 
 
Visit No 
2 
3b 
4 
5 
6 
7 
8 
9 
10 
11b 
12 
13 
14 
15 
16b 
17 
18b 
19b 
20 
 
Visit window 
± 2 days [except for Day 1 (Visit 2) and Visits 3, 11 and 16]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
± 7 days 
 
Dispense 
Paracetamol/ 
Acetaminophen  
if needed 
<===========================================X===========================================> 
X 
PGIS h 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
PGIC h 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
McGill Pain 
Questionnaire SF2 h 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Brief Pain Inventory 
Short Form Domains 
h 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Repeat training on 
accurate pain 
reportingh 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Review eDiary 
compliance 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 

 
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Assessments 
Treatment period 
Off-treatment 
EDa 
Week  
Day 1 
BLa 
 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
16 
20 
27 
 
Visit No 
2 
3b 
4 
5 
6 
7 
8 
9 
10 
11b 
12 
13 
14 
15 
16b 
17 
18b 
19b 
20 
 
Visit window 
± 2 days [except for Day 1 (Visit 2) and Visits 3, 11 and 16]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
± 7 days 
 
Safety Evaluations and Other Assessments 
Symptom driven brief 
physical exam 
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 
12-lead ECG i 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Urine pregnancy  
test j 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Hematology,  
clinical chemistry, 
urinalysis k 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Fasting lipid panell 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Xm 
Hepatitis B 
monitoring (if 
applicable) 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 

 
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Assessments 
Treatment period 
Off-treatment 
EDa 
Week  
Day 1 
BLa 
 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
16 
20 
27 
 
Visit No 
2 
3b 
4 
5 
6 
7 
8 
9 
10 
11b 
12 
13 
14 
15 
16b 
17 
18b 
19b 
20 
 
Visit window 
± 2 days [except for Day 1 (Visit 2) and Visits 3, 11 and 16]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
± 7 days 
 
TB testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Tobacco Use History 
Update n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Genetics sample o, p 
<==========================================X===============================================> 
X 
SAE/AE review 
<==========================================X===============================================> 
X 
Concomitant 
medication review 
<==========================================X===============================================> 
X 
PK/TE, Immunogenicity and Biomarker Samples 
PK/TE blood  
sample q 
X 
Xc 
X 
 
 
X 
 
 
 
Xc 
X 
 
 
X 
Xc 
Xc 
X 
X 
X 
X 
Immunogenicity q 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Whole blood for RNA 
or epigenetic  
analysis p, q 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 

 
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Assessments 
Treatment period 
Off-treatment 
EDa 
Week  
Day 1 
BLa 
 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
16 
20 
27 
 
Visit No 
2 
3b 
4 
5 
6 
7 
8 
9 
10 
11b 
12 
13 
14 
15 
16b 
17 
18b 
19b 
20 
 
Visit window 
± 2 days [except for Day 1 (Visit 2) and Visits 3, 11 and 16]c 
Minimum 5 days between IMP injections for no more than 2 consecutive dosing visits 
± 7 days 
 
Serum for protein 
biomarkers p, q 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Blood for flow 
cytometry q, r 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
a. 
BL = Baseline, ED = Early Discontinuation/Withdrawal. 
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 a 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/TE sample after visits 3, 11 and 16 is to be taken either at 24-72 hours OR at 96-120 hours post the last IMP dose (based on participant/site preference). 
PK/TE sample at visit 17 is to be taken approximately 7 days post the last IMP dose at visit 15. 
d. 
Recheck clinical status before randomization. 
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 dosing visits). 
f. 
NRS pain questions (including average daily pain, worst daily pain and nighttime pain) should be completed on the eDiary on a daily basis. 
g. 
All Paracetamol/Acetaminophen intakes including date, approximate time of dose, dose strength, drug form and reason for use (DPNP or other) should 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 ECG measurements will be taken at Baseline (Day 1) visit. Single ECGs will be obtained at all subsequent visits per SoA 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. 
Women of childbearing potential only. Must be completed prior to dosing. Serum pregnancy test should be done if required by local regulations (e.g. country or IRB/EC). 
k. 
Check Section 10.2 for the full list of parameters that will be tested. Urinalysis will be performed locally with the use of dipstick. At Day 1 and Week 12 visits the urine samples 
must be sent to the central laboratory for further testing. For all other visits, urine samples may be sent to the central laboratory for further testing based on Investigator 
assessment, if required. 
l. 
Participants are required to fast for a minimum of 10 hours if feasible, as deemed by the Investigator. 

 
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m. Only required if the participant is unlikely to return for the final follow-up visit (Week 27) and it has been more than 3 months since the last HbA1c test. 
n. 
Current smoking status in average number of cigarettes smoked per day in the last week will be recorded. 
o. 
Optional. Single sample any time post randomization. 
p. 
Sample not collected in China. 
q. 
Sample collected before IMP dose (on dosing days).  
r. 
Flow cytometry will only be conducted in selected countries. 

 
 
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NOTE: Order of assessments as recommended where possible: 
• 
Any scheduled training and completion of participant reported outcome assessments 
to be completed first. 
• 
ECG, vital 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. 
If study intervention is permanently discontinued, the participant will be requested to 
remain in the study and complete the planned visits and assessments for the treatment 
period (up to the Week 12 visit) per above SoA (except for the weekly SC IMP injections 
and post-dose [24-72 hours or 96-120 hours] PK/TE sample collection), with a final 
follow-up visit (Visit 20) approximately 16 weeks from the last dose received. 
If a participant wishes to withdraw consent during the study, they will be requested to 
return for an Early Discontinuation/Withdrawal visit, preferably 1 week from the last 
dose received (applicable during the treatment period) or as soon as possible after the 
participant’s decision has been communicated to the site staff (applicable during the off-
treatment phase), and to return for a final follow-up visit (Visit 20) approximately 16 
weeks from the last dose received prior to withdrawal of consent. 
In either case the final follow-up visit (Visit 20) will assess all the items per the SoA for 
the Week 27 visit. Participants should be requested to complete average daily pain, worst 
daily pain, nighttime pain NRS scoring and Paracetamol/Acetaminophen intake Diary up 
to the final follow-up visit (Visit 20). 
The timing of planned study assessments may change during the study based on 
emerging data/in-stream data review (e.g. to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. The timing of PK/TE samples may be 
altered and/or PK/TE samples may be obtained at additional time points to ensure 
optimal PK/TE monitoring. 
Any changes in the timing of time points for any planned study assessments as the result 
of emerging pharmacokinetic and target engagement data from this study must be 
documented and approved by the relevant study team member and then archived in the 
sponsor and site study files but will not constitute a protocol amendment. 
The Competent Authority (CA) and Ethics Committee (EC) will be informed of any 
safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form (ICF). The changes will 
be approved by the CA and the EC before implementation. 

 
 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
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 activating the chemokine receptor 
CCR4, to prevent downstream consequences of CCR4 signaling. 
The purpose of this Phase 2 study is to investigate the safety, efficacy, pharmacokinetic 
(PK) and target engagement (TE) of GSK3858279 in participants with Diabetic 
Peripheral Neuropathic Pain (DPNP), as the proof-of-concept for this indication. It is the 
first time that GSK3858279 is tested in DPNP population. 
2.2. 
Background 
Diabetic Peripheral Neuropathic Pain (DPNP) is a common complication of diabetes, 
which affects a wide fraction of participants, and it is likely to increase due to the 
prevalence of diabetes. Diabetic neuropathy is a complication associated with patient age, 
illness course and hyperglycemia severity [Hicks, 2019]. 
DPNP is a common chronic pain condition that can be challenging to treat, particularly 
for non-specialists. A number of pharmacological treatments are used to manage 
neuropathic pain outside of specialist pain management services. However, there is 
considerable variation in how treatment is initiated, the dosages used and the order in 
which drugs are introduced, whether therapeutic doses are achieved and whether there is 
correct sequencing of therapeutic classes. A further complication is that a number of 
commonly used treatments are unlicensed for treating neuropathic pain, which may limit 
their use. These factors may lead to inadequate pain control, with considerable morbidity. 
Commonly used pharmacological treatments include antidepressants (tricyclic 
antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs] and serotonin-
norepinephrine reuptake inhibitors [SNRIs]), antiepileptic (anticonvulsant) drugs, topical 
treatments and opioid analgesics. In addition to their potential benefits, all of these drug 
classes are associated with a spectrum of adverse effects [Professional Practice 
Committee. 4, 2022]. 
With limited treatment options and comparatively few recent approvals, considerable 
unmet need remains for participants with neuropathic pain. Physician research indicates 
that polypharmacy is common and there is strong demand for novel drug classes, with 
strong uptake expected for successful new agents [Yang, 2015]. 
2.2.1. 
The role of C-C class chemokines 17 (CCL17) in neuropathic pain 
In vivo preclinical models of nerve-injury-induced neuropathic pain have indicated a role 
of CCL17 in pain pathogenesis. 

 
 
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The administration of an anti-CCL17 surrogate monoclonal antibodies (mAb), via 
intraperitoneal or intrathecal routes, inhibits pain-like behavior induced by multiple 
sciatic nerve injury models, in mice [GSK3858279 Investigator’s Brochure RPS-CLIN-
034028]. Furthermore, the inhibition of the C-C chemokine receptor 4 (CCR4) using the 
CCR4 antagonist C021, via intraperitoneal or intrathecal routes, also inhibits neuropathic 
pain-like behavior associated with sciatic nerve injury, or streptozotocin-induced diabetic 
pain, in mice [Bogacka, 2020a; Bogacka, 2020b]. The observation that CCL17/CCR4 
inhibition causes a reduction in pain-like behavior following both intraperitoneal and 
intrathecal dosing routes suggests a site of action accessible through both routes of 
administration, such as the dorsal root ganglion (DRG). 
The systemic administration of an anti-CCL17 surrogate mAb had no effect on acute pain 
behaviors in mice, including acute inflammatory and neurogenic pain caused by formalin 
or capsaicin injection, respectively, as well as basal pain thresholds to heat, cold and 
pinprick stimulation. Furthermore, the neutralization of CCL17 had no effect on 
proprioception as measured by grip strength or motor performance as measured by the 
Rotarod test [GSK3858279 Investigator’s Brochure RPS-CLIN-034028]. 
In vitro, the direct application of recombinant CCL17 had no effect on calcium flux 
measured in a mixed culture of murine sensory DRG neurons, or in putative nociceptive 
DRG 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 RPS-CLIN-034028], 
suggesting that CCL17 does not directly act on sensory neurons. 
2.3. 
Benefit/Risk assessment 
The biological treatment with aCCL17 has demonstrated an efficacy signal in 
osteoarthritis pain [GSK Document Number TMF-14616324]. There is no clinical data of 
aCCL17 in human patient population suffering from Diabetic Peripheral Neuropathic 
Pain (DPNP), therefore no benefit/risk assessment can be derived for aCCL17 in this 
population yet. More detailed information about the known and expected benefits and 
risks and reasonably expected adverse events of GSK3858279 may be found in the 
Investigator’s Brochure (IB) [GSK3858279 Investigator’s Brochure RPS-CLIN-034028]. 
Participants with DPNP have significant morbidity. Current DPNP treatment options are 
limited and have associated adverse events. Non-clinical and clinical data support the 
potential efficacy of GSK3858279 in treating DPNP.

 
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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 207804 FTIH Part A and 
209973 studies in healthy participants, there were no severe or serious 
infection AEs.  
Eligibility Criteria: 
Exclusion of participants with: 
• 
Current immunodeficiency diseases including but not limited to 
acquired immunodeficiency disorder or immunoglobulin deficiency. 
• 
History of infected joint prosthesis, chronic leg ulcers, permanent 
in-dwelling catheters, chronic sinusitis, recurrent chest infections or 
recurrent urinary tract infections. 
• 
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 not followed by 
a satisfactory anti-tuberculosis treatment prior to first dose of study 
intervention. 
• 
Positive human immunodeficiency virus (HIV) antibody test. 
• 
Has a positive test for hepatitis B virus (HBV) defined as either: 
− 
positive for hepatitis B surface antigen (HBsAg) OR 
− 
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 
− 
NOTE: Participants with positive hepatitis C 
antibody due to prior resolved disease can be 

 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
enrolled, only if a 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. 
Monitoring: 
• 
Serious and opportunistic infections and TB are categorized as 
AESIs. 
• 
Monitoring for signs of infection. 
• 
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: 
• 
Temporarily discontinue the study intervention for: 
− 
Serious or opportunistic infections, COVID-19 (until the 
infection has resolved) or suspected TB. 
• 
Permanently discontinue the study intervention: 
− 
If the temporary hold for serious or opportunistic 
infections is greater than 2 weeks, Investigational 
Medicinal Product will be permanently discontinued. The 
participant will be requested to complete the treatment 
period (up to the Week 12 visit) with a final follow-up visit 
approximately 16 weeks from the last dose received. 
− 
For active TB infection. 
− 
Hepatitis B reactivation, HBV DNA positive OR HBV 
surface antigen positive. 

 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 Criteria: 
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 IMP will be administered by a 
health professional. 
Withdrawal Criteria: 
• 
Permanently discontinue study intervention for serious 
hypersensitivity reactions.  
Injection Site Reactions 
Subcutaneous injections, including injections of monoclonal antibodies, 
may be associated with local reactions such as swelling, induration, or 
pain. 
Monitoring: 
• 
Investigators will be required to capture all injection site reactions 
(ISRs) as AEs, ISRs will be categorized as AESIs. 
• 
Monitor for injection site reactions throughout study. 
• 
ISRs will be captured on a specific eCRF to further characterize 
the events. 

 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 DPNP Phase 2 study will use a different formulation 
than used in the Phase 1b OA and overall Phase 1 program. 
• 
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 IMP than their SC injection should be on the other 
side of the abdomen or in the thigh. 
 
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. 
Blood samples will be drawn for anti-drug antibodies to GSK3858279 
analysis according to SoA (Table 2). 
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 
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 immune 
complex disease were seen (mentioned above). In general, the incidence 
and titer 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 titer, 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. 
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. 
For participants who are in the screening period, completion of COVID-
19 vaccination 14 days prior to first dose of study intervention will be 
strongly recommended. 
Live or live attenuated vaccines must not be administered to participants 
from 30 days prior to first dose of study intervention and for 5 half-lives 
(16 weeks) after dosing has completed. 
Investigators should review and update the vaccination status of 
potential participants as per local guidelines for adult vaccination 

 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Clinical Data: 
Vaccine effects have not been formally tested in clinical studies to date. 
including against COVID, influenza, herpes zoster and pneumococcus 
(according to local guidelines) prior to first dose of study intervention. 
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 Criteria: 
Exclusion of participants: 
• 
Who received live or live attenuated vaccine(s) within 30 days prior 
to first dose of study intervention or plan to receive such vaccines 
during the study. 
• 
With current immunodeficiency diseases including but not limited 
to acquired immunodeficiency disorder or immunoglobulin 
deficiency. 
Withdrawal Criteria: 
Live or live attenuated vaccine use. 
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 molecular weight 
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 Criteria: 
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 (Section 10.4) during the treatment period and for at 
least 16 weeks after the last dose of study medication. 
• 
Exclusion of female participants who are: 
− 
Pregnant (as confirmed by serum pregnancy test), 
lactating, planning to become pregnant or initiating 
breastfeeding. 

 
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Potential Risk of 
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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 medication. 
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. 
Withdrawal Criteria: 
• 
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 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. 

 
 
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2.3.2. 
Benefit assessment 
Participants may experience the benefits of pain relief and from extensive monitoring of 
their disease activity. By enrolling in this study, participants will be contributing to the 
process of developing new analgesic medications for pain control in DPNP, a significant 
area of unmet need. 
2.3.1. 
Overall benefit/risk conclusion 
Taking into account the measures taken to minimize risk to participants from this study, 
the potential risks identified in association with GSK3858279 are justified by the 
anticipated benefits that may be afforded to participants with DPNP. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 3 
Objectives and endpoints 
Objective(s) 
Endpoint(s) 
Primary 
To characterize the efficacy of GSK3858279 on pain 
compared to placebo in participants with DPNP 
• 
Change from baseline in the weekly average of 
average daily pain intensity at Week 12, assessed 
on the Numeric Rating Scale (NRS)  
Secondary 
To determine the safety and tolerability of repeated 
doses of GSK3858279 compared to placebo in 
participants with DPNP 
• 
Occurrence of AEs, SAEs and AEs of Special 
Interest (AESIs) 
• 
Occurrence of National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-
CTCAE) grade ≥3 hematological/clinical chemistry 
abnormalities 
To characterize the PK following repeated dosing of 
GSK3858279 in participants with DPNP 
• 
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)) after the last planned dose  
To determine the efficacy of GSK3858279 compared 
to placebo in various dimensions of pain in participants 
with DPNP 
• 
Change from baseline in the Short-Form McGill Pain 
Questionnaire total score over time  
To further compare the efficacy of GSK3858279 
compared to placebo in pain relief in participants with 
DPNP 
• 
Change from baseline in the weekly average of 
average daily pain intensity over time, assessed on 
the NRS 
• 
Occurrence of ≥30% reduction from baseline in the 
weekly average of average daily pain intensity at 
Week 12, assessed on the NRS 
• 
Occurrence of ≥50% reduction from baseline in the 
weekly average of average daily pain intensity at 
Week 12, assessed on the NRS 
 

 
 
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Objective(s) 
Endpoint(s) 
Tertiary 
To determine the effect of GSK3858279 compared to 
placebo on various dimensions of pain and pain 
responder rate in participants with DPNP 
• 
Change from baseline in the weekly average of 
worst daily pain intensity over time, assessed on the 
NRS 
• 
Change from baseline in the weekly average of 
nighttime pain intensity over time, assessed on the 
NRS 
• 
Occurrence of ≥30% reduction from baseline in the 
weekly average of average daily pain intensity over 
time, assessed on the NRS 
• 
Occurrence of ≥50% reduction from baseline in the 
weekly average of average daily pain intensity over 
time, assessed on the NRS 
To determine participant’s impression of overall 
change and severity, as well as clinically meaningful 
within-patient change in patient reported outcome 
endpoints in participants with DPNP 
• 
Patient Global Impression of Change (PGIC) over 
time 
• 
Change from baseline in Patient Global Impression 
of Severity (PGIS) over time  
To determine the effect of GSK3858279 compared to 
placebo on rescue medication use in participants with 
DPNP 
• 
Usage of rescue medication (occurrence, number of 
days, amount taken) over time 
To determine the effect of GSK3858279 compared to 
placebo on exploratory biomarkers in whole blood in 
participants with DPNP 
• 
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 and 
immune cell activation markers, may be investigated 
• 
Whole blood transcriptomics (ribonucleic acid [RNA] 
sequencing) and epigenetics markers may also be 
explored 
To determine the effect of GSK3858279 compared to 
placebo on pain severity and pain interference in 
participants with DPNP 
• 
Change from baseline in Brief Pain Inventory Short 
Form (BPI-SF) pain severity and interference 
domains over time  
Additional Safety (Tertiary) 
To determine the safety of repeated doses of 
GSK3858279 compared to placebo in participants with 
DPNP 
• 
Change from baseline in laboratory parameters, vital 
signs and ECG 
To assess the potential for anti-GSK3858279 antibody 
formation (ADA and NAb) in participants with DPNP 
• 
Occurrence of ADA and NAb and titers of ADA for 
samples with confirmed ADA  
Additional PK/PD/TE/Biomarkers (Tertiary) 
To characterize the PK following repeated dosing of 
GSK3858279 in participants with DPNP over time 
 
• 
Serum PK concentrations of total GSK3858279 over 
time 
• 
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)) after the 1st, 4th and 8th dose  
To evaluate the CCL17 profile following repeat dosing 
of GSK3858279 in participants with DPNP over time 
• 
Total and free CCL17 levels in serum over time 
• 
Reduction (%) from baseline in free CCL17 over 
time 
To explore 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]) pain 
over time 

 
 
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3.1. 
Efficacy estimands 
Primary estimand for the primary efficacy objective 
Description 
Mean change from baseline at Week 12 in the weekly average of average daily pain intensity 
for GSK3858279 compared to placebo in adult participants with DPNP, 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 (60 mg/week or 360 mg/week) compared to placebo 
Endpoint 
Change from baseline in the weekly average of average daily pain intensity at Week 12, 
assessed on the NRS 
Population 
Adult participants with DPNP 
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation due to lack of efficacy or adverse events 
• 
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: occasional 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 in means between each GSK3858279 treatment arm and placebo 

 
 
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Two additional estimands will also be defined as follows: 
Additional estimand #1 for the primary efficacy objective  
Description 
Mean change from baseline at Week 12 in the weekly average of average daily pain intensity 
for GSK3858279 and placebo in adult participants with DPNP, 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 (60 mg/week or 360 mg/week) compared to placebo 
Endpoint 
Change from baseline in the weekly average of average daily pain intensity at Week 12, 
assessed on the NRS, in the absence of treatment discontinuations, use of prohibited pain 
medications, and allowed rescue medication  
Population 
Adult patients with DPNP 
Strategy for 
intercurrent 
events (ICEs) 
ICE: 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: 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: occasional use of 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 the weekly average of average daily pain intensity 
for GSK3858279 compared to placebo in adult participants with DPNP, 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 and allowed rescue medication.  
Treatment 
Condition 
GSK3858279 (60 mg/week or 360 mg/week) compared to placebo 
Endpoint 
Change from baseline in the weekly average of average daily pain intensity at Week 12, 
assessed on the NRS 
Population 
Adult participants with DPNP 
Strategy for 
intercurrent 
events (ICEs) 
ICE: study treatment discontinuation 
• 
Strategy: treatment policy; all data collected after the ICE will be included 

 
 
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Additional estimand #1 for the primary efficacy objective  
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 
Difference from placebo in mean change from baseline for each GSK3858279 treatment arm 
The attributes of the primary and additional estimands will be applied to the following 
continuous secondary efficacy endpoints, using the same strategies to address the same 
intercurrent events: 
• 
Change from baseline in the Short-Form McGill Pain Questionnaire total score over 
time 
• 
Change from baseline in the weekly average of average daily pain intensity over 
time, assessed on the NRS 
Primary and additional estimands for the binary secondary efficacy endpoints are 
described below: 
Estimand for the binary secondary efficacy endpoint 
Treatment Condition 
GSK3858279 (60 mg/week or 360 mg/week) compared to placebo 
Endpoints 
Occurrence of ≥30% reduction from baseline in the weekly average of average daily pain 
intensity at Week 12, assessed on the NRS 
Occurrence of ≥50% reduction from baseline in the weekly average of average daily pain 
intensity at Week 12, assessed on the NRS 
Population 
Adult participants with DPNP 
Strategy for 
intercurrent events 
(ICEs) (Primary 
estimand) 
 ICE: study treatment discontinuation due to lack of efficacy or adverse events 
• 
Strategy: composite; study treatment discontinuation is considered a negative 
outcome, and post-ICE assessments are set to non-responder 
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; use of prohibited pain medications is considered a negative 
outcome, and post-ICE assessments are set to non-responder 
ICE: occasional 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 

 
 
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Estimand for the binary secondary efficacy endpoint 
Strategy for 
intercurrent events 
(ICEs) 
(Additional estimand 
#1) 
ICE: 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: use of persistent prohibited pain therapy 
• 
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: occasional use of 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 used to derive the binary endpoint 
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 used to derive the binary endpoint 
Strategy for 
intercurrent events 
(ICEs) 
(Additional estimand 
#2) 
 
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 
Odds ratio  
3.2. 
Safety estimands 
Primary estimand for safety objectives  
Treatment 
Condition 
GSK3858279 (60 mg/week or 360 mg/week) compared to placebo 
Endpoints 
• 
Occurrence of Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special 
Interest (AESIs) 
• 
Occurrence of National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) grade ≥3 hematological/clinical chemistry abnormalities 
Population 
Adult participants with DPNP 
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 will be included 
Population-level 
summary 
• 
AEs, SAEs, AESIs, NCI-CTCAEs: number and % of participants with at least one event by 
Preferred Term for each treatment arm 

 
 
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4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a Phase 2, randomized, double-blind, parallel group, placebo-controlled study to 
evaluate the efficacy, safety, tolerability, PK and TE of GSK3858279 vs. placebo when 
administered with repeated weekly SC injections in approximately 240 enrolled 
participants with DPNP. The number of participants may be increased by approximately 
15% to ensure regional requirements for recruitment are met. 
Participants will undergo a screening visit, after which they will go into a washout period 
of all of their DPNP pain medications (if applicable), consisting of at least 3 days or 5 
half-lives, whichever is longer. This is followed by a further 7 days of run-in period to 
establish an accurate baseline; after which they will first be stratified based on region 
(Japan, China or the rest of the world) and an average of the average daily pain score at 
baseline (<7 or ≥7) and then randomized at 1:1:1 ratio to either GSK3858279 at 60 mg 
SC weekly or GSK3858279 at 360 mg SC weekly or placebo SC weekly within each 
stratum. 
Total study duration will be approximately 33 weeks. Screening will take place within 
6 weeks before randomization. Treatment period is up to 12 weeks. Primary endpoint is 
at Week 12 to determine the efficacy of GSK3858279 at 60 mg SC weekly and 
GSK3858279 at 360 mg SC weekly on pain compared to placebo in participants with 
DPNP. Participants will be followed for additional 15 weeks in the off-treatment 
follow‑up period. There will be 2 visits during the off-treatment follow-up period in 
addition to end-of-study visit at Week 27, where bloods for PK, TE and safety will be 
collected. Any rescue medication use will be reported by the participant on the electronic 
diary (eDiary) on a daily basis. 
An Interim Analysis for futility will be performed when approximately 30 participants in 
each treatment arm qualify for Week 12 assessment (by either attending the Week 12 
assessment or through missing data imputation strategy, for example in the case that a 
participant withdraws from the study). Further additional interim analyses may be 
considered to support internal decision-making and regulatory interactions. An internal 
data review committee (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. 

 
 
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4.2. 
Scientific rationale for study design 
The overall study design is well established to assess the efficacy of a novel therapeutic 
agent in participants with DPNP after they have been unable to sufficiently manage pain 
despite trying standard of care therapies. 
The double-blind, placebo-controlled, randomized study design is considered the gold 
standard for the safety and efficacy assessment of a new therapy in DPNP both by 
clinicians and regulatory authorities. 
The primary endpoint is change from baseline in the weekly average of average daily 
pain (ADP) intensity at Week 12, assessed on the Numeric Rating Scale (NRS). ADP on 
NRS is a validated clinical endpoint widely used in clinical studies of DPNP and is 
accepted by the regulatory agencies [European Medicines Agency, 2016]. It is a direct 
and simple way of measuring pain intensity with clear clinical relevance to participants. 
Pain intensity is the regulator requested key measure of efficacy of an analgesic drug and 
should always be reported. In long-term studies the weekly averages of the daily 
measurement compared to baseline, are commonly used as the primary efficacy variable. 
Change in ADP intensity is further supported by other endpoints such as the change from 
baseline in the Short-Form McGill Pain Questionnaire and change from baseline in Brief 
Pain Inventory Short Form (BPI-SF) questionnaire domains that will generate additional 
evidence to inform how a participant feels and functions. 
All participants will have a final follow-up visit 15 weeks after their last visit at Week 12 
(16 weeks after their last dose of study intervention at Week 11). This equates to a 
follow-up period over approximately 5× the apparent terminal elimination half-life for 
total GSK3858279. 
4.2.1. 
Participant input into design 
Feedback on study design was obtained during a participant engagement survey with 56 
participants based in Australia, South Africa, Spain, USA and UK in May 2022. The 
study was well-received overall, and the general design and requirements were 
acceptable. 
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 doses chosen (60 mg/week and 360 mg/week) allow an exploration of the dose-
exposure-response of GSK3858279 in DPNP as the doses are predicted to encompass a 
range of target engagement (reductions compared to baseline) of the chemokine, CCL17 
(Figure 2). 
GSK3858279 target engagement has been demonstrated in both healthy and OA of the 
knee participants. Following single IV (0.1-10 mg/kg) and SC (3 mg/kg) administrations, 

 
 
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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 CCL17 (as measured by a semi-quantitative method) were maintained 
over 8 weeks on repeat weekly dosing (240 mg) to participants with moderate to severe 
OA of the knee (207804, Part B). 
In participants with moderate to severe OA of the knee the 240 mg/week dose 
demonstrated efficacy on daily average pain (as measured by NRS score). The Phase 1b 
study (207804, Part B) provides the only prior clinical information on the impact of 
functional inhibition of CCL17. 
The doses (60 mg/week and 360 mg/week) have been selected based on an integration of 
model predicted target engagement (reductions from baseline in free CCL17) and free 
concentration-time data [GSK Document Number TMF-14616324]. The target-mediated 
drug disposition (TMDD) model uses the Quasi Steady State (QSS) approximation and is 
fitted to total GSK3858279 and total CCL17 data from studies 207804 and 209973 [GSK 
Document Number TMF-14616324]. 
The integrated analysis predicts almost complete target engagement (reductions in 
CCL17 compared to baseline of ≥89%) over the entire dosing interval following the 
highest dose selected for this study, 360 mg/week (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 dose of 360 mg SC weekly. 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 1a healthy volunteer study provides a 
margin over both Cmax (~5.8-fold) and AUC (~2.2-fold) following repeat weekly dosing 
at 360 mg SC. As there is no rationale for a population effect, translation to DPNP has 
been assumed. 
The lower dose (60 mg/week) is predicted to result in smaller (maximum and trough) 
CCL17 reductions (Figure 2). Therefore, the selected 6-fold dose range (60 - 360 
mg/week) allows for an exploration of the efficacy, safety, and tolerability of 
GSK3858279 across a range of reductions in target levels and aligns with good practices 
on understanding efficacy, safety, and tolerability across a wide dose range in Phase 2. 
This will facilitate selection of dose(s) in Phase 3. 

 
 
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Figure 2 
Model Predicted Reductions (median and 95% CI of the prediction) 
in free CCL17 following weekly SC dosing with GSK3858279 (60 mg 
or 360 mg) over 12 weeks [GSK Document Number TMF-14616324]. 
 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the off-treatment phase (Week 27 visit). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 

 
 
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5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1. 18-75 years of age inclusive, at the time of signing the informed consent. 
Country-specific requirement: South Korea. Participants from South Korea are 
required to be aged at least 19 years or greater for entry into the study.  
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Type I or Type II diabetes with painful, distal, symmetrical, sensory-motor 
neuropathy attributed to diabetes, of at least 6 months duration; 
a. 
Pain must have begun in bilateral distal lower limbs. 
b. Pain is not related to underlying infection or trauma. 
c. 
Diagnosis confirmed by a positive Douleur Neuropathique 4 [DN4] 
questionnaire at screening. 
d. Levels of glycosylated hemoglobin A1c (HbA1c) less than 97 mmol/mol 
(<11%). 
3. On a stable anti-diabetic medication regimen (unchanged dose over the last 30 
days for diabetes) prior to screening. Adjustment of insulin dose is acceptable, 
however, resumption of insulin treatment is not allowed since 30 days prior to 
screening. 
4. No recent unplanned (i.e. within the previous 6 months) hospitalizations due to 
non-compliance or uncontrolled diabetes 
5. At screening (Visit 1 a), a pain score ≥4 and ≤9 by the 11-point NRS (0-10) for 
average daily pain intensity over the past 24. 
6. 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). Pain scores must be recorded on at least 6 out of 7 days and should not 
be highly variable (standard deviation ≤1.5). The Investigator will receive 
confirmation of eligibility if all daily pain score 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 6.9.3 for details.  
7. Documented history of insufficient pain relief from, or inability to tolerate, or 
contraindication to at least one line of current standard of care therapy, e.g. 
antidepressants (tricyclic antidepressants [TCAs], selective serotonin reuptake 
inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), 
antiepileptic (anticonvulsant) drugs. 

 
 
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8. 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 
9. BMI within the range of 18 to 40 kg/m2 (inclusive). 
SEX 
10. Male or Female participant; 
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) as defined in Section 
10.4 
OR 
− 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. non-compliance, recently initiated) in relationship to 
the first dose of study intervention. 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention. See Section 8.3.5. 
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5. 
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. 
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. 
INFORMED CONSENT 
11. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 

 
 
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5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. History 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. Participant has current painful peripheral neuropathy due to a cause other than 
diabetes (e.g. pernicious anemia, hypothyroidism, post-herpetic neuralgia). 
3. Participant has any lower extremity amputation. 
4. Participant has a current or previous foot ulcer within the past 3 months as 
described by medical history and/or medical examination. 
5. Participants who have complications of diseases that are considered to affect the 
assessment of DPNP. For example, nerve diseases with pain other than DPNP 
(cervical spondylosis, carpal tunnel syndrome, spinal canal stenosis, and post-
herpetic pain), pain diseases other than nerve diseases (collagen diseases, gout, 
chronic obstructive arteriosclerosis, and arthritis), and other pain at the site of 
evaluation (skin diseases and traumatic injury). 
6. Current immunodeficiency diseases including but not limited to acquired 
immunodeficiency disorder or immunoglobulin deficiency. 
7. History of infected joint prosthesis, chronic leg ulcers, permanent in-dwelling 
catheters, chronic sinusitis, recurrent chest infections or recurrent urinary tract 
infections. 
8. Symptomatic herpes zoster within 3 months prior to screening. 
9. Current or previous active Mycobacterium tuberculosis infection regardless of 
treatment. 
10. 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. 

 
 
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• 
If the participant has had recent close contact with persons who have active TB 
and did not receive satisfactory anti-tuberculosis treatment prior to first dose of 
study intervention, they will not be eligible. 
11. History of significant allergies to monoclonal antibodies. 
12. 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 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 participant as not suitable to participate 
in the study. 
13. History or evidence of 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). 
14. 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. 
15. Liver 
− Alanine Aminotransferase (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%). 
− Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
16.  Hematological laboratory values at screening 
− White Blood Cell (WBC) count <3.0×109/L. 
− Hemoglobin <10.0 g/dL. 
− Platelet count <125×109/L. 
17. Myocardial infarction or unstable angina, or cerebrovascular event within 6 
months prior to screening. 
18. Unstable or life-threatening cardiac arrhythmia requiring intervention within 3 
months prior to screening. 
19. New York Heart Association (NYHA) Class III or IV heart failure. 
20. 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. 

 
 
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21. Evidence of significant renal insufficiency, indicated by an estimated creatinine 
clearance <45 mL/min/1.73 m2 at screening. 
22. Planned surgical procedure over the duration of the study. 
23. Major surgery (as per Investigator’s judgment) within 3 months prior to first dose 
of study intervention. 
24. Participants with a recurrent or chronic infection (e.g. osteomyelitis), who have 
been receiving treatment within 3 months prior to first dose of study intervention 
or individuals with an active infection at screening or Day 1 visit. 
PRIOR/CONCOMITANT THERAPY 
25. Use of any analgesic medication is prohibited, including those used for DPNP 
such as gabapentanoids, tricyclic antidepressants, SNRIs, 
anticonvulsants/antiepileptics, SSRIs (except for well-controlled 
depression/anxiety), NSAIDs (except for acetylsalicylic acid used for 
cardiovascular prophylaxis), opioids (including tapentadol), topical analgesics 
(including transdermal patches), capsaicin products, mexiletine, 
dextromethorphan, tramadol, cannabinoids and ketamine until completion of the 
Week 12 visit. These medications must be washed out for at least 3 days or 5 half-
lives, whichever is longer, prior to the study's first daily pain assessment (start of 
run-in period). Before washout a tapered withdrawal can be conducted as deemed 
clinically necessary to local guidance with the Investigator’s supervision. 
26. Immunomodulators, including: 
− Corticosteroids (parenteral within 3 months prior to first dose of study 
intervention; oral within 1 month prior to first dose of study intervention); 
− Biologic agents (such as monoclonal antibodies including marketed drugs) 
within 3 months or 5 half-lives (whichever is longer) prior to first dose of study 
intervention; 
− Non-biologic agents (e.g. methotrexate, azathioprine, JAK-inhibitors) within 4 
weeks or 5 half-lives (whichever is longer) prior to first dose of study 
intervention; 
are prohibited during the study. 
27. Received live or live attenuated vaccine(s) within 30 days prior to first dose of 
study intervention or plans to receive such vaccines during the study. 
28. Use of pain interventions as per Section 6.9.1.4 within 4 weeks of screening. 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
29. Current enrollment or past participation in a clinical study of an IMP within the 
last 30 days or 5 half-lives (whichever is longer) of signing ICF. 
30. Exposure to more than 4 new Investigational Medicinal Products within 12 
months prior to first dose of study intervention, or any previous exposure to 
GSK3858279. 

 
 
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31. 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). 
32. Participants who cannot be contacted by phone in an emergency. 
33. 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. 
DIAGNOSTIC ASSESSMENTS 
34. Positive human immunodeficiency virus (HIV) antibody test. 
35. Has a positive test for hepatitis B virus (HBV) defined as either: 
− positive for hepatitis B surface antigen (HBsAg) OR 
− 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 8.3.6 for 
hepatitis B reactivation monitoring. 
Country-specific requirements for participants from sites in Japan only: additionally, 
positive for hepatitis B surface antibody (HBsAb) AND positive for HBV DNA. 
36. 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. 
37. Positive hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention. 
38. Active or suspected COVID-19 infection. 
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 before they can enroll 
into the study. 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 test 
14 days after symptoms resolution prior to first dose of study intervention. 
39. A positive drug screen 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 prior to first dose of study intervention. 

 
 
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OTHER EXCLUSIONS 
40. Pregnant (as confirmed by serum pregnancy test) or lactating, or women planning 
to become pregnant or initiating breastfeeding. 
41. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse 
or dependence within a year prior to first dose of study intervention. 
42. 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. 
5.3. 
Lifestyle considerations 
5.3.1. 
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. Details are 
provided as per the SoA. 
5.3.2. 
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. 
5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. 
5.3.4. 
Other restrictions 
Not applicable. 
5.4. 
Screen failures 
A screen failure occurs when a participant who consents 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, protocol deviations and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failures) 
may be rescreened once. A further re-screening for administrative reasons can be 
approved at the discretion of the Medical Monitor. Rescreened participants are required 

 
 
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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 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. 
6.1. 
Study intervention(s) administered 
Study intervention SC injections should be administered weekly, preferably on the same 
day each week. Each participant across all the treatment arms will receive 3 injections at 
each visit. 
The SC injections should be administered to the abdomen or thigh. The same site 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 3 injections 
should be administered in the same area (quadrant for abdomen, lower or upper half of a 
thigh) 2-3 cm 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. 
The IMP injection site should be different from the insulin injection site, if applicable. 
A window of ± 2 days is acceptable between weekly doses (except for Visits 2) and a 
minimum gap of 5 days between each dose, for no more than 2 consecutive dosing visits. 
Participants should return to their 7-day dosing schedule as soon as possible thereafter. 
The SC 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 post-injection during 
the first two dosing visits. Safety monitoring will include monitoring for systemic 
hypersensitivity and local ISRs. 
All participants are to receive a weekly dose of GSK3858279 60 mg SC or GSK3858279 
360 mg SC or placebo irrespective of weight. 
The doses of GSK3858279 for injection will be prepared at the investigational site by 
unblinded authorized site staff, from the stock solution provided. 

 
 
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Table 4 
Study intervention(s) administered 
Intervention Label 
GSK3858279 
Placebo 
Rescue Medication 
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) 
Paracetamol/Acetaminophen 
Type 
Biologic 
Placebo 
Drug 
Dosage form 
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 grey/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 
Route of administration  
and duration 
SC Injection, 12 
weeks 
SC Injection, 12 
weeks 
Oral 
Dosage Level(s) 
60 mg/week and 360 
mg/week. 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 
 
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. 

 
 
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Intervention Label 
GSK3858279 
Placebo 
Rescue Medication 
Packaging and 
Labelling 
Study intervention will 
be provided in a 
single-use vial 
contained within a 
carton. 
Each single-use vial 
and carton will be 
labelled as required 
per country 
requirement. 
 
Dispensed 
medication will be 
labelled 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 
labelled as required 
per country 
requirement. 
 
Dispensed medication will be labelled 
as required per country requirement. 
Table 5 
Study arm(s) 
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. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled 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 guidance and information for the final disposition of unused study intervention 
are provided in the Pharmacy Manual. 
Arm Title 
GSK3858279 
GSK3858279 
Placebo 
Arm Type 
Experimental 
Experimental 
Placebo 
Regimen number 
N/A as parallel group study 
N/A as parallel group study 
N/A as parallel group study 
Arm Description 
 
Participants will receive 
GSK3858279 (SC) 60 mg 
once per week for 12 
weeks 
Participants will receive 
GSK3858279 (SC) 360 mg 
once per week for 12 
weeks 
Participants will receive 
Placebo (SC) once per 
week for 12 weeks 

 
 
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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 site 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 will be 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 randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the login information and directions for the IWRS 
will be provided to each site. Administration of study intervention is summarized in the 
SoA. 
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 
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 according to region (Japan, China or the rest of the 
world) and an average of the average daily pain score at baseline (<7 or ≥7), and 
randomized in a ratio of 1:1:1 to receive GSK3858279 60 mg SC weekly or 360 mg 
SC weekly or placebo SC weekly within each stratum. 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 labelled with 
yellow ‘blinding tape’ to mask any visual differences of the liquid between 

 
 
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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 eCRF. 
• 
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 eCRF. The participant will be followed up for safety monitoring if 
treatment was received. 
• 
GSK’s Global Safety staff may unblind the intervention assignment for any 
participant with an SAE. If the SAE requires that an expedited safety 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. 
• 
Unblinded site 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 
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• 
Primary reporting will take place after the target number of participants have 
completed their Week 12 (or Early Withdrawal) visit. GSK staff who have direct 
contact with sites will remain blinded to individual subject allocation until the end-
of-study. 
6.5. 
Study intervention compliance 
The 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. 
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 source documents and in the eCRF. 

 
 
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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. 
Concomitant treatments 
Medications prohibited or restricted prior to the study, during the treatment period and/or 
during the off-treatment follow-up period of the study are listed below, along with any 
period of exclusion which must be applied. 
Whether the participant will need to discontinue IMP, possibly temporarily, will depend 
on the nature of the prohibited medicine and the risk to participant’s safety by continuing 
IMP. 
The Investigator should discuss any such situation with the Medical Monitor and 
certainly in any situation where a new immunomodulator has been commenced whilst the 
participant is in the study and receiving IMP. 
Should a participant breach the prohibited medicines rules, regardless, the participant 
should be strongly encouraged to remain in the study. 
6.9.1.1. 
Immunomodulators 
Immunomodulators must have been discontinued prior to first dose of study intervention 
and must not be used throughout the study. 
• 
Corticosteroids: parenteral within 3 months prior to first dose of study intervention; 
oral within 1 month prior to first dose of study intervention. Inhaled, intranasal, otic, 
and ophthalmic corticosteroids can be used at any time throughout the study. Topical 
steroids applied on sites other than the DPNP disease area are also allowed. 
• 
Biologic agents (such as monoclonal antibodies including marketed drugs) within 3 
months or 5 half-lives (whichever is longer) prior to first dose of study intervention. 
• 
Non-biologic agents (e.g. methotrexate, azathioprine, JAK-inhibitors) within 4 
weeks or 5 half-lives (whichever is longer) prior to first dose of study intervention. 

 
 
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6.9.1.2. 
Analgesics 
Use of any analgesic medication is prohibited, including those used for DPNP such as 
gabapentanoids, tricyclic antidepressants, SNRIs, anticonvulsants/antiepileptics, SSRIs 
(except for well-controlled depression/anxiety), NSAIDs (except for acetylsalicylic acid 
used for cardiovascular prophylaxis), opioids (including tapentadol), topical analgesics 
(including transdermal patches), capsaicin products, mexiletine, dextromethorphan, 
tramadol, cannabinoids and ketamine until completion of the Week 12 visit. These 
medications must be washed out for at least 3 days or 5 half-lives, whichever is longer, 
prior to the study's first daily pain assessment (start of run-in period). Before washout a 
tapered withdrawal can be conducted as deemed clinically necessary to local guidance 
with the Investigator’s supervision. 
Occasional and limited use of an NSAID (including selective COX-2 inhibitors) is 
permitted only for non-DPNP related pain or self-limiting conditions. However it should 
be avoided within 24 hours of a study visit or during the last 2 weeks of the treatment 
period prior to the Week 12 visit. The use of NSAIDs should be restricted to a maximum 
of 3 days during each 4-week interval. 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. 
For non-pain related co-morbid conditions, participants will be allowed to take 
throughout the study the following medications. The dose must be stable for at least 4 
weeks prior to screening and will remain stable throughout the study (PRN [as needed] 
use is not allowed): 
• 
A benzodiazepine, zolpidem, diphenhydramine or related drugs for insomnia. 
• 
A selective serotonin reuptake inhibitor (SSRI) for well-controlled 
depression/anxiety. 
• 
Oral aspirin (≤325 mg/day) for cardiovascular prophylaxis. 
6.9.1.3. 
Diabetic therapy 
Participants must be on a stable anti-diabetic medication regimen (unchanged dose over 
the last 30 days for diabetes) prior to screening. Adjustment of insulin dose is acceptable, 
however, resumption of insulin treatment is not allowed since 30 days prior to screening. 
Participants should remain on the same anti-diabetic medications over the course of the 
study, unless there is a medical need to adjust anti-diabetic medications. 

 
 
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6.9.1.4. 
Prohibited concomitant pain interventions 
Concomitant use of the following interventions must be discontinued 4 weeks prior to 
screening and is prohibited until completion of the Week 12 visit: 
• 
Laser therapy 
• 
Acupuncture therapy 
• 
Nerve blocks 
• 
Spinal cord stimulation 
• 
Electrical stimulation therapy 
• 
Other forms of pain reduction interventions that might confound protocol 
assessments 
6.9.2. 
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 prior to entering them into the study (refer to American 
Diabetic Association recommendations where no local guidelines are available 
[Professional Practice Committee; 12, 2022]), 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 first dose of 
study intervention and are prohibited throughout the study. 
6.9.3. 
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 
within 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 1b 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. 

 
 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Permanent discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of the 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 will be requested to remain in the study and 
complete the planned visits and assessments for the treatment period (up to the Week 12 
visit) per SoA in Section 1.3 (except for the weekly SC IMP injections and post-dose  
[24-72 hours or 96-120 hours] PK/TE sample collection), with a final follow-up visit  
(Visit 20) 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 Discontinuation/Withdrawal 
visit, preferably 1 week from the last dose received (applicable during the treatment 
period) or as soon as possible after the participant’s decision has been communicated to 
the site staff (applicable during the off-treatment phase), and a final follow-up visit (Visit 
20) approximately 16 weeks from the last dose received. The final follow-up visit will 
assess all the items per the SoA for the Week 27 visit. Participants should be requested to 
complete average daily pain, worst daily pain, nighttime pain NRS scoring and 
Paracetamol/Acetaminophen intake Diary up to the final follow-up visit (Visit 20). 
A participant will be permanently discontinued from study intervention (but may 
continue to be followed in the study) if any of the following criteria are met: 
• 
Pregnancy 
• 
Serious hypersensitivity reactions assessed as related to study intervention 
• 
Active TB infection 
• 
Liver chemistry, renal function, hematological abnormality, ECG parameters 
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 
• 
Other serious or severe adverse events, at the discretion of the Investigator, after 
consultation with the GSK Medical Monitor 

 
 
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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. 
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. 

 
 
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Phase 2 Liver chemistry stopping criteria and increased monitoring algorithm 
 
ALT = Alanine Transaminase; INR = International Normalized Ratio; SAE = Serious Adverse Event; ULN = Upper Limit 
of Normal; Tbili = Total bilirubin 
Refer to Appendix 6 (Section 10.6) for required liver safety actions and follow-up 
assessments. 

 
 
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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 QTcF 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. 
• 
Absolute QTcF ≥500 msec 
• 
Absolute QTcF <320 msec (clinically significant QTcF shortening) 
• 
Increase from baseline in QTcF of >60 msec 
• 
Prolongation in repeated ECG interval measurements of PR or QRS of >40 msec 
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 IMP doses 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 <8.0 g/dL 
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. 

 
 
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7.1.6. 
Temporary discontinuation 
• 
Serious and opportunistic infections or suspected TB; 
If a serious or opportunistic infection or suspected TB develops, temporarily 
discontinue IMP 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 treatment period (up to the Week 12 visit) with a final follow-up visit 
approximately 16 weeks from the last dose received. 
• 
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 the participant will be requested to complete the treatment period (up to 
the Week 12 visit) with a final follow-up visit 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. 

 
 
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7.2. 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioral, or compliance reasons. Investigators will attempt to contact 
participants who do not return for scheduled visits or follow-up. 
At the time of discontinuing from the study, if possible, an Early Discontinuation/ 
Withdrawal visit should be conducted, preferably 1 week from the last dose received 
(applicable during the treatment period) or as soon as possible after the participant’s 
decision has been communicated to the site staff (applicable during the off-treatment 
phase), and a final follow-up visit (Visit 20) approximately 16 weeks from the last dose 
received as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
All data and samples collected up to and including the date of withdrawal/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 source 
documents 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 
Specify 
Study Terminated by Sponsor 
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other, specify 
Other 
Specify 
Death 
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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: 
1. 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. 
2. 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. 
3. Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. Adherence to the study design requirements, 
including those specified in the SoA, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Participants who have signed ICF 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. 

 
 
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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 medical record and the 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/vaccination history 
Obtain the participant’s medical/vaccination history by interviewing the participant and 
review of the participant’s medical record. Record any pre-existing conditions, signs 
and/or symptoms present prior to study start in the eCRF. 
8.2. 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
Participants will be provided with the eDiary (Clario, a third-party vendor) on which to 
record all their patient reported outcomes including Paracetamol/Acetaminophen use. 
Training on how to use the device and on how to accurately report pain will be provided 
at the run-in visit (by Clario and WCG respectively, third-party vendors) with the 
accurate pain reporting training being repeated at the Week 8 visit. eDiary support will be 
available throughout the trial. 
8.2.1. 
Average Daily Pain NRS 
Brief Pain Inventory item 5 is a single item designed to capture information on the self-
reported average pain intensity 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. 
Worst Daily Pain NRS 
Brief Pain Inventory item 3 is a single item designed to capture information on the self- 
reported worst pain intensity 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. 

 
 
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8.2.3. 
Nighttime Pain NRS 
Nighttime pain NRS is a single item designed to capture information on the self-reported 
pain intensity. Participants will be asked to rate their pain intensity between the time they 
went to bed and the time they woke up. Participants will be asked to mark their pain 
intensity in the morning, using the NRS, on an 11-point scale (0-10), with 0 = no pain, 
and 10 = pain as bad as you can imagine. 
8.2.4. 
Brief Pain Inventory Short Form (BPI-SF) 
The BPI-SF allows participants to rate the severity of their pain and the degree to which 
that pain interfered with multiple and common dimensions of feeling and function. The 
BPI assesses pain severity by measuring pain at its ‘worst’, ‘least’, ‘average’, and ‘now’. 
Furthermore, the BPI measures how much pain has interfered with seven daily activities, 
including general activity, walking, work, mood, enjoyment of life, relations with others 
and sleep. 
The BPI pain interference score is scored as the mean of the seven interference items. This 
mean can be used if at least four of seven items have been completed on a given 
administration. 
8.2.5. 
Patient Global Impression of Change (PGIC) 
The PGIC is a single item scale that allows participants to rate the change in the disease 
state from baseline to specified time points during the study. It provides the participant’s 
impression of overall change. It is used as an anchor in analyses to evaluate threshold of 
clinically meaningful within-patient score change and may be used for additional validation 
analyses. 
8.2.6. 
Patient Global Impression of Severity (PGIS) 
The PGIS is a single item scale that allows participants to rate the overall severity in the 
disease state. It measures static, current state patient global impression of overall disease 
severity. It is used as an anchor in analyses to evaluate threshold of clinically meaningful 
within-patient change and may be used for additional validation analyses. 
8.2.7. 
McGill Pain Questionnaire Short Form 2 (SF-MPQ-2) 
The McGill pain questionnaire Short Form 2 is a 22-item questionnaire, which has been 
developed and validated to evaluate multi-dimensional pain over time. The questionnaire 
consists of 22 descriptors that are rated on an intensity scale from 0 = none to 10 = worse 
possible [Dworkin, 2009]. 

 
 
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8.2.8. 
Glycated Hemoglobin (HbA1c) 
Given the potential exacerbation of DPNP with extremes of glycemic control, HbA1c will 
be collected during treatment and follow-up periods in order to explore any relationship 
with efficacy assessments. 
8.3. 
Safety assessments 
Planned time points 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 (1a). 
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 the 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 in the off-treatment phase as specified in the SoA, vital signs may be 
collected and recorded by a HHS professional. 
8.3.3. 
Electrocardiograms 
12-lead ECG 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). 

 
 
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Triplicate tracings will be obtained at baseline visit (Day 1). The three 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 tracings at baseline.  
Single ECG tracing will be obtained at all other visits as outlined in the SoA (see 
Section 1.3) 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 ECG 
parameters withdrawal criteria. 
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
3
 
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 Laboratory 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. 
• 
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 (see Section 10.3.1 and 
Section 10.3.2 ). 
• 
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. 
• 
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 and reference ranges 
will also be recorded in the eCRF for SAEs. 
8.3.5. 
Pregnancy testing 
A serum pregnancy test must be performed for all female participants of childbearing 
potential at screening Visit 1a. 
A urine or serum pregnancy test must be performed for all female participants of 
childbearing potential 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. 
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 
per the SoA during study intervention period for all women of childbearing potential 
(WOCBP). If a urine pregnancy test is positive or cannot be confirmed as negative (e.g. 
an ambiguous result) a serum pregnancy test is required. In such case, the IMP should be 
withheld until a negative serum pregnancy test result is available. The participant must 
permanently discontinue the IMP if the serum pregnancy result is positive. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure (refer to Section 1.3 for details). 
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulations, to establish the absence of pregnancy at 
any time during the WOCBP’s participation in the study. 

 
 
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8.3.6. 
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 monitoring assessments for 
hepatitis B during the trial as follows: 
• 
ALT, AST, HBsAg and HBV DNA will be tested at Week 4 (Visit 7), Week 8 (Visit 
12) and Week 12 (Visit 17) and then at end of study, Week 27 (Visit 20) 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. 
• 
Additional monitoring requirements for participants at Japan sites only [See 
Appendix 8 (Section 10.8)]: 
− 
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. 
− In addition to the hepatitis B reactivation monitoring timepoints above, 
monitoring will also be tested at Week 16 (Visit 18) and Week 20 (Visit 19).  
8.4. 
Safety monitoring and Data Review Committees 
Participant safety will be continuously monitored in a blinded manner by the Medical 
Monitor and a 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. 

 
 
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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. 
− Study enrolment and dosing will be paused AND 
− The IDMC will review the unblinded safety data and make a recommendation to: 
− Resume enrolment 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 enrolment and dosing without any study modification, this will be 
implemented immediately. 
• 
Two or more SAEs in separate participants reported in the same active treatment arm 
(same dose level) that are considered attributable by the Investigator or GSK safety 
group to GSK3858279. 
− Study enrolment will continue and dosing will not be paused AND 
− 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. 
Furthermore, an iDRC 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 or study 
(see Section 7). This includes events reported by the participant (or, when appropriate, by 
a caregiver, surrogate, or the participant’s legally authorized representative). 

 
 
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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 final 
follow-up visit at the time points 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 eCRF, 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. 
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 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 non-serious AESIs (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. 

 
 
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8.5.4. 
AESI 
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 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. 
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 Section 10.3.5.3. 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review, 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 
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Table 6 
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 AEs Report 
24 hours* 
electronic AEs 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 post 
intervention 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 the female partner’s pregnancy of a male participant. 
• 
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 female 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 6 for reporting timeframes. 
• 
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the sponsor as described in 
Section 8.5.1. While the Investigator is not obligated to actively seek this 
information in former female 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. 

 
 
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8.5.7. 
Cardiovascular and death events 
For any cardiovascular events detailed in Appendix 3 (Section 10.3) 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, and pregnancies 
Table 7 
Contact information for reporting SAEs, AESIs, and pregnancies 
AESI = Adverse event of special interest; GSK = GlaxoSmithKline Biologicals SA; SAE = Serious adverse event. 
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. 
Dispensation of participant card should be documented in source documents. 
8.6. 
Pharmacokinetics 
Blood samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of total GSK3858279 at the time points indicated in the SoA and used to 
characterize the PK of GSK3858279 in DPNP participants. The actual date and time of 
each blood sample collection and dose administration will be recorded. 
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure optimal PK monitoring. Each PK sample should be 
collected as close as possible to the planned time relative to the dose administered to the 
Study contact for questions regarding SAEs, AESIs, and pregnancies: 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs, AESIs, and pregnancies: 
Available 24/24 hours and 7/7 days 
uk.gsk-rd-gcsp-ctsm-admin@gsk.com  

 
 
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participant on dosing days. Details on PK blood sample collection including processing, 
storage and shipping procedures are provided in the Central Laboratory Manual. 
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. 
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 (e.g. CLW). Drug concentration information that may unblind the study will 
not be reported to investigational 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 the analyses for TE (Section 8.8), 
biomarkers (Section 8.10) and immunogenicity assessments (Section 8.11). 
8.8. 
Target (CCL17) concentrations 
Blood samples of approximately 3.5 mL will be collected from participants in this study 
to investigate target engagement at the time points specified in the SoA. The actual date 
and time of each blood sample collection and dose administration will be recorded. The 
timing of TE samples may be altered and/or TE samples may be obtained at additional 
time points to ensure optimal TE monitoring. Each TE sample should be collected as 
close as possible to the planned time relative to the dose administered to the participant 
on dosing days. 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 investigational sites or blinded 
personnel until the study has been unblinded. 

 
 
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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 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 Central Laboratory Manual. 
If allowed by country regulation/ethics, genetic sampling may be conducted remotely by  
a HSS professional. 
8.10. 
Biomarkers 
Serum and whole blood samples will be collected to determine the effect of GSK3858279 
on peripheral exploratory biomarkers in participants with DPNP. 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. 
Collected 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 of biomarker and/or other responses to 
GSK3858279. Further research and analysis will only be conducted in countries where 
permitted by local regulations and guidelines. 
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 
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Analysis of serum proteins 
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 immune cell activation markers. Proteomic analysis of a 
large panel of serum proteins may 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. 
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 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. 
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 or medical resource utilization and health economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) 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 
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9.1. 
Statistical hypotheses/comparisons 
The primary objective of this study is to estimate the difference in means between 
GSK3858279 60 mg SC and placebo and GSK3858279 360 mg SC and placebo, in 
change from baseline in the weekly average of average daily pain intensity at Week 12, 
assessed on the NRS, in adult participants with DPNP, where persistent use of prohibited 
pain therapy and study treatment discontinuations due to lack of efficacy or AEs 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%. 
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 hierarchical closed testing procedure will be used 
with 360 mg weekly evaluated first in the hierarchy. 
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 randomized) 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 analyzed according to the study 
intervention they actually received 
• 
Safety 

 
 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
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 
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 analyzed according to the study 
intervention they actually received 
• 
PK 
9.4. 
Statistical analyses 
9.4.1. 
General considerations/definitions 
The primary study analysis and reporting will be conducted when the planned target 
sample size of approximately 240 randomized participants have completed their Week 12 
(or Early Withdrawal) study visit. An end-of-study analysis will take place when a target 
sample size of approximately 240 randomized participants have completed the study 
(including the off-treatment follow-up period). Recruitment may continue to include 
additional participants and may be increased by approximately 15% 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 analyzed and reported separately. 
Unless otherwise stated, baseline will be defined as the latest assessment prior to first 
dose of study intervention. 
The number of participants with each intercurrent event will be summarized by treatment 
group. 
For all analyses, treatment effects will be presented as GSK3858279 60 mg SC weekly 
vs. placebo and GSK3858279 360 mg SC weekly vs. placebo. 
Summary statistics for each treatment arm, time point, and efficacy endpoint will be 
presented. 
For the cases that repeated measurement model is employed to analyze the data, an 
unstructured correlation matrix will be considered to account for multi-collinearity of 
repeated measurements data. 
Non-informative priors will be used for the Bayesian analyses. 

 
 
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For the primary estimand, persistent use of prohibited pain therapy or treatment 
discontinuations due to lack of efficacy or AEs 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. 
9.4.2. 
Primary endpoint(s)/estimand(s) 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-
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. 
A Bayesian repeated measurement linear mixed model will be fitted to the change from 
baseline response including region, baseline assessment, week (categorical) and treatment 
as fixed effects as well as interactions for baseline-by-week and treatment-by-week. The 
difference from placebo at Week 12 from this model 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. 
9.4.3. 
Secondary endpoint(s)/estimand(s) analysis 
9.4.3.1. 
Safety analysis 
The strategy for handling ICEs is described in Section 3.2. 
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. 

 
 
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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. 
Laboratory data, immunogenicity data, ECG and vital signs will be presented in tabular 
and/or graphical format and summarized descriptively according to GSK standards at 
each time point. No imputations will be performed for the reporting of safety. 
9.4.3.2. 
Efficacy analysis 
Details of the estimands for secondary efficacy endpoints are described in Section 3.1. 
The change from baseline in Short-Form McGill Pain Questionnaire total score will be 
analyzed using a Bayesian repeated measures mixed model including region, baseline 
assessment, week (categorical) and treatment as fixed effects as well as interactions for 
baseline-by-week and treatment-by-week. The difference from placebo at each time point 
from this model will be summarized as Mean and 95% equal-tail credible interval of the 
posterior distribution. 
The Bayesian repeated measures model used for the analysis of the primary endpoint will 
also be used to estimate the change from baseline in the weekly average of average daily 
pain intensity over time. The difference from placebo at each time point from this model 
will be summarized as Mean and 95% equal-tail credible interval of the posterior 
distribution. 
The occurrence of ≥30% reduction from baseline in the weekly average of average daily 
pain intensity at Week 12, assessed on the NRS, will be analyzed using a Bayesian 
logistic model including region, baseline assessment and treatment as fixed effects and a 
binary variable (with 1 if ≥30% reduction from baseline and 0 otherwise) as response. 
The odds ratio and 95% credible interval of the posterior distribution will be presented. 
To analyze the occurrence of ≥50% reduction from baseline in the weekly average of 
average daily pain intensity at Week 12, assessed on the NRS, the same approach will be 
used. 
9.4.3.3. 
Pharmacokinetic (PK) 
PK (Cmax, tmax, Ctau, Cavg and AUC(0-tau)) will be predicted using a model-based 
analysis. Details of the planned analyses will be provided in the SAP. Any deviations 
from the planned analyses will be described in an SAP addendum or justified in the final 
Clinical Study Report. 
PK, TE, demographic and efficacy data may be integrated with other ongoing or 
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9.4.4. 
Tertiary endpoints 
Planned analyses of tertiary/exploratory endpoints will be described in the SAP. 
9.5. 
Interim analysis 
Prior to the primary study analysis, one interim analysis is planned. 
An interim analysis for overall study futility data is planned when approximately 30 
participants in each arm (approximately 90 total) qualify for a Week 12 efficacy 
assessment, either by attending the Week 12 visit or through data imputation strategy. 
Additional data (including safety and PK/TE) may also be reviewed. 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. The potential outcome of this interim is either continue 
or stop the study. The non-binding futility rule will be prospectively specified in the 
interim analysis charter. 
An iDRC will be appointed for this study to review the interim analysis data in an 
unblinded manner (see Section 10.1.6). Specific details regarding all interim analyses will 
be outlined in the iDRC charter, along with the outline of how the iDRC will ensure data 
integrity and appropriate quality control of data prior to making decisions and an outline 
of the committee membership. 
Additional administrative interim may occur, e.g. in order to inform internal decision-
making or support regulatory interactions. No change to the study is planned as a result of 
these additional interim analyses. Full details of all interim analyses including the timing 
and reason for the interim analysis will be prospectively outlined in the iDRC Charter. 
9.6. 
Sample size determination 
Approximately 240 participants will first be stratified based on region (Japan, China or 
the rest of the world) and an average of the average daily pain score at baseline (<7 or ≥7) 
and then randomized in a 1:1:1 ratio to GSK3858279 60 mg SC weekly, GSK3858279 
360 mg SC weekly and placebo SC weekly within each stratum. The recruitment may 
continue beyond this by approximately 15% to ensure regional requirements are met. The 
probability of achieving various criteria of interest given various sample sizes was 
assessed, conditional on different true values for the treatment difference. The results are 
summarized in Table 8, and are not conditional on the planned interim analysis. Based on 
these results, a sample size of 80 participants per arm is considered sufficient. 
For these calculations, the population standard deviation for the change from baseline is 
assumed to be 2.2 for each treatment arm. [Rauck, 2013], reported a standard deviation of 
2.2 for change in NRS Pain through Week 16. Similarly, [Campbell, 2012], reported a 
standard deviation of 2.1 for change in NRS Pain at Week 16. 
The same standard deviation (i.e. 2.1) was reported in an unpublished clinical trial by 
Laurenza and his team [Laurenza, 2013]. 

 
 
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Table 8 
Probability of meeting various criteria of interest, conditional on 
different true treatment differences, standard deviations and sample 
sizes. 
 
Probability of meeting criterion given  
true treatment difference (Δ) 
Criterion of 
Interest 
N 
per 
arm 
Assumed 
SD 
Δ = 
-1.2 
Δ = 
-1 
Δ = 
-0.8 
Δ = 
-0.6 
Δ = 
0 
Observed 
difference 
vs. placebo 
required  
Posterior 
probability (true 
difference from 
placebo <-0.6) 
>70% 
70 
2.2 
86% 
71% 
51% 
30% 
2% 
-0.795 
2.7 
79% 
64% 
47% 
30% 
3% 
-0.839 
80 
2.2 
89% 
73% 
52% 
30% 
1% 
-0.782 
2.7 
81% 
66% 
48% 
30% 
3% 
-0.823 
90 
2.2 
90% 
76% 
53% 
30% 
<1% 
-0.772 
2.7 
83% 
68% 
49% 
30% 
2% 
-0.811 
100 
2.2 
92% 
78% 
55% 
30% 
<1% 
-0.763 
2.7 
85% 
70% 
50% 
30% 
2% 
-0.800 
Posterior 
probability (true 
difference from 
placebo <-0.7) 
>70% 
70 
2.2 
79% 
61% 
40% 
21% 
<1% 
-0.895 
2.7 
72% 
55% 
38% 
23% 
2% 
-0.939 
80 
2.2 
82% 
63% 
41% 
21% 
<1% 
-0.882 
2.7 
74% 
57% 
39% 
22% 
2% 
-0.924 
90 
2.2 
84% 
65% 
41% 
20% 
<1% 
-0.872 
2.7 
76% 
59% 
39% 
22% 
1% 
-0.911 
100 
2.2 
86% 
67% 
42% 
20% 
<1% 
-0.863 
2.7 
78% 
60% 
40% 
21% 
1% 
-0.900 

 
 
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Probability of meeting criterion given  
true treatment difference (Δ) 
Criterion of 
Interest 
N 
per 
arm 
Assumed 
SD 
Δ = 
-1.2 
Δ = 
-1 
Δ = 
-0.8 
Δ = 
-0.6 
Δ = 
0 
Observed 
difference 
vs. placebo 
required  
Posterior 
probability (true 
difference from 
placebo <-0.8) 
>70% 
70 
2.2 
71% 
51% 
30% 
14% 
<1% 
-0.995 
2.7 
64% 
47% 
30% 
17% 
1% 
-1.040 
80 
2.2 
73% 
52% 
30% 
14% 
<1% 
-0.982 
2.7 
66% 
48% 
30% 
16% 
<1% 
-1.024 
90 
2.2 
76% 
53% 
30% 
13% 
<1% 
-0.972 
2.7 
68% 
49% 
30% 
15% 
<1% 
-1.011 
100 
2.2 
78% 
55% 
30% 
12% 
<1% 
-0.963 
2.7 
70% 
50% 
30% 
15% 
<1% 
-1.000 
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: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines. 
− Applicable ICH GCP guidelines. 
− Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, IB, IDFU, and/or 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 (CTIS will be 
used in EU as per the requirements). 
• 
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• 
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
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• 
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. 
10.1.3. 
Informed consent process 
• 
The Investigator or his/her representative will explain the nature of the study, 
including the risk and benefits, to the participant 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, privacy and 
data protect requirements, where applicable, and the IRB/IEC or study centre. 
• 
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 written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
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. 

 
 
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• 
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 personal 
information such as date of birth, sex of the baby will be collected as part of safety 
follow-up. Consent for the baby may be obtained from the participant and/or their 
partner as per local regulations. 
• 
If female 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 Personal Information such as last menstrual period and/or year 
of birth or the PI such as date of birth and/or sex of their baby as part of safety 
follow-up. 
10.1.4. 
Recruitment strategy 
Feedback from patients with DPNP 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 enrol 
from their own patients and networks. 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, the sponsor will develop several items designed to help the potential 
participant understand the study including for example, a SoA table to represent the visit 
tests and procedures, an informed consent flow chart to help site staff walk patients 
through the ICF, a 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. 

 
 
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• 
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 his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• 
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. 
• 
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. 
Committees structure 
A Safety Review Team (SRT) is in place for each GSK product. It comprises 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 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 is included in the iDRC charter. 
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, is 
detailed in the IDMC charter. 

 
 
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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. 
• 
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 electronically (e.g. laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• 
QTLs will be 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. 

 
 
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• 
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 non-compliance 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. 
• 
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 a minimum period of 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. 
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 

 
 
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reader). The non-exhaustive list of documents shared to inform the central reader 
may include, discharge summaries, 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. 
10.1.10. 
Study and site start and closure 
First Act of Recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date) at a country-level. 
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. 

 
 
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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. 
10.2. 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 9 will be performed by the central laboratory apart from urine 
pregnancy and dipstick urinalysis tests, and T-SPOT TB test (with prior Sponsor’s 
approval) if applicable. 
NOTE: 
• 
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. 
• 
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. 

 
 
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Table 9 
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 
Glucose 
(non-fasting) 
Creatine 
Phosphokinase 
(CPK) 
Alkaline Phosphatase 
Albumin 
Blood Urea 
Nitrogen 
(BUN) 
BUN/creatinine ratio 
Gamma Glutamyl 
Transpeptidase 
(GGT) 
Creatinine 
Estimated Creatinine Clearance/ 
glomerular filtration rate 
(CKD-EPI3) 
Other labs 
Lipid Panel, fasting (LDL [direct], 
HDL, total cholesterol, triglycerides) 
HbA1c 
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, 
leukocyte by dipstick performed locally 
• 
Urine sample must be sent to the central laboratory for samples on Day 1 and 
Week 12. For all other visit the urine sample may be sent to the central laboratory 
for further testing based on Investigator assessment, if required 
• 
Urine Protein Creatinine Ration (UPCR) and Urine Albumin Creatinine Ration 
(UACR) at Day 1 and Week 12  
Pregnancy testing 
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for WOCBP)4 

 
 
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Laboratory 
Assessments 
Parameters 
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 sites in Japan only: hepatitis B surface antibody (HBsAb) and 
hepatitis B virus DNA (HBV DNA). 
NOTES: 
1. Hematological abnormality stopping criteria: White Blood Cell Count (WBC) <2.0×109/L; Platelets count 
<100×109/L; Hemoglobin <8 g/dL. 
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 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 sites in Japan, 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. 
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). 

 
 
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• 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. 
• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, admission for routine examination). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. Pre-existing diseases 
will be recorded in the medical history section of the eCRF. 
• Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 

 
 
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10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 
one or more of the criteria listed: 
a. 
Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are 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 
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 international normalized ratio (INR) >1.5 must be reported as an SAE. 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 

 
 
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− 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 cardiovascular events 
Cardiovascular events (CV) definition 
Investigators will be required to fill out the specific CV event page of the eCRF 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. 
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. 

 
 
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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 an 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 adverse event 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 adverse event 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 adverse event 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. 
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. 

 
 
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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 non-serious 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, SAE or AESI 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. 
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 non-serious AESIs (as defined in Section 8.5.4), will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up. 
Other non-serious AEs must be followed until they are resolved or until the participant is 
lost to follow-up. 
Follow-up during the study: 
AEs/SAEs/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 
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Follow-up of pregnancies: 
Pregnant participants or 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 AEs 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 Section 10.3.6. 
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 
8.5.8). 
10.3.6. 
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 of awareness. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to the Medical Monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
non-serious AEs, pregnancy exposure, related to any GSK product that is not part of 
the study design, they will report these events to GSK or to the concerned CA via the 
national spontaneous reporting system. These will be classified as spontaneous 
Individual Case Safety Reports (ICSRs). 

 
 
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• 
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, 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. 
10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Women 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: 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. 

 
 
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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. 
Women 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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 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 
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10.4.2. 
Contraception guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency  
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
Intrauterine Device (IUD) 
Intrauterine hormone-releasing System (IUS)c 
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 WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview 
Highly effective methodsb that are user dependent  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
a. 
Contraceptive use 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, a blood sample will be collected for DNA analysis after the participant 
agrees and signs the optional genetic ICF. 
DNA samples will be used for research related to GSK3858279 or DPNP 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 DPNP continues but no longer than 15 years after the last participant’s 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 5× ULN 
ALT Increase 
ALT 3× ULN persists for >4 weeks 
Bilirubin1, 2 
ALT 3× ULN and total bilirubin 2× ULN (>35% direct bilirubin) 
INR2 
ALT 3× ULN and INR >1.5 
Cannot 
Monitor 
ALT 3× ULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT 3× 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) 
• Viral hepatitis serology4 
• Obtain INR and recheck 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 
2× ULN 
• Obtain complete blood count with 
differential to assess eosinophilia 

 
 
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Liver chemistry stopping criteria  
MONITORING: 
If ALT 3× ULN AND total bilirubin 
2× 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 <2× 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 
• 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 
• 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 3× ULN AND total bilirubin 2× 
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 
• 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) 

 
 
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Liver chemistry stopping criteria  
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 3× 
ULN and total bilirubin 2× 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 3× ULN and total bilirubin 2× ULN (>35% direct bilirubin) or ALT 3× 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 in the eCRF. 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 <3× 
ULN and bilirubin <2× ULN and INR ≤1.5, 
monitor participants twice monthly until liver 
chemistry tests resolve or return to within 
baseline 
10.7. 
Appendix 7: Important study assessment details & study-
specific equipment 
10.7.1. 
Douleur Neuropathique 4 (DN4) questionnaire 
The DN4 is a physician administered questionnaire that was developed and validated for 
identifying participants with neuropathic pain [Spallone, 2012]. The DN4 score is 
calculated by counting the number of positive responses to each of the 10 items on the 
questionnaire, which include burning, painful cold, electric shocks, tingling, pins and 
needles, numbness, itching hypoesthesia to touch, hypoesthesia to prick and brushing.  
A diagnosis of neuropathic pain is made by a score of ≥4. 

 
 
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10.8. 
Appendix 8: Country-specific requirements 
France specific requirement: 
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. 
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 source documents/ 
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 ICF. Subjects not completing the study for 
whatever reason could be compensated generally on a pro rata basis. 
2. Concerning the «Study governance considerations» 
In section “Regulatory and ethical considerations, including the informed consent 
process” of study protocol 
a. 
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. 
b. Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
French Patient Informed Consent Form is in duplicate (triplicate for minor subject). 
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 his/her 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 his/her establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him/her 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 

 
 
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Investigator(s), the number of sites involved in his/her 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. 
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 
number, subject 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). 
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 him/her, a right of access, of rectification, erasure and of opposition with GSK in 
accordance with the legal provisions. 
5. Investigational Medicinal Product accountability, reconciliation, and destruction 
In specific situations where institutional practices dictate that the site disposes of and/or 
destroys IMP prior to allowing the “monitor” to verify and document IMP accountability, 
the following applies: 
“During the conduct of the study, Investigational Medicinal Product (IMP) will be 
destroyed by the Institution prior to a GSK “monitor” conducting final IMP 
accountability. Institution agrees that such destruction will comply with Institution’s 
Investigational Medicinal Product accountability procedures and will provide GSK with 
IMP accountability logs and supporting documentation to verify adherence to ‘Bonnes 
Pratiques Cliniques’ (decision dated on the 24th of November 2006)”. 

 
 
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Japan specific requirement: 
For evidence of an active or past hepatitis B infection participants from sites in 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 16 (Visit 18) and Week 20 (Visit 19) in 
participants from sites in Japan. 
Chronic Kidney Disease Epidemiology Collaboration equation will be used for 
calculating and reporting eGFR. For participants from sites in Japan, the Japanese 
coefficient (0.813) modified CKD-EPI will be used for calculating and reporting eGFR. 
South Korea specific requirement: 
Participants from South Korea are required to be aged at least 19 years or greater for 
entry into the study. 
10.9. 
Appendix 9: Protocol amendment history 
Amendment 1 (24 July 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. 
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 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 10: 
Male participant contraceptive 
requirements added.  
Added following a regulatory 
agency request 
5.2 Exclusion criteria 
Added: Exclusion criterion 16: 
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  
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. 

 
 
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Section # and title 
Description of change 
Brief rationale 
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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