Clinical trial NCT04114656
Conditions: Pain
Keywords: GSK3858279 Crossover study Pain assessment Placebo-controlled Intravenous
Sponsor: GlaxoSmithKline
Start date: 2019-10-15; Completion date: 2021-09-16
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will evaluate the mechanistic basis for the analgesic effects of GSK3858279 in humans by using a battery of experimental pain assessments in healthy participants. This will be placebo-controlled, three-period two-treatment crossover study. In each period, participants will receive either GSK3858279 or placebo in a 1:1 ratio. Only healthy male participants will be enrolled into the study. The duration of the study will be approximately 6 months.

Detailed description:

Arms: arm 1: All participants will receive a single dose of placebo in either one or two of the three study periods, as per the randomization schedule. arm 2: All participants will receive a single dose of GSK3858279 in either one or two of the three study periods, as per the randomization schedule.
Interventions: intervention 1: Placebo intervention 2: GSK3858279
Intervention descriptions: intervention 1: Placebo will be available as intravenous (IV) infusion of normal saline (0.9 percent \[%\] sodium chloride solution). intervention 2: GSK3858279 will be available as IV infusion and the dose level to be administered is 3 milligrams (mg) per kilogram (kg).

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Protocol 
 
Study ID:  209973 
 
Official Title of Study: A randomized, double-blind, placebo-controlled, three-period 
two-treatment incomplete-block crossover study to investigate the effects of intravenous 
GSK3858279 on a battery of evoked pain tests in healthy participants. 
 
EudraCT: 2019-002609-23 
 
Approval Date of Document: 25-MAY-2021 
 
 


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TITLE PAGE 
Protocol Title: A randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study to investigate the effects of intravenous 
GSK3858279 on a battery of evoked pain tests in healthy participants. 
Protocol Number: 209973/ Amendment 4 
Compound Number 
or Name: 
GSK3858279  
Study Phase: Phase 1  
Short Title: GSK3858279 vs PBO, Phase 1, Evoked Pain Tests, Pharmacokinetics and 
Target Engagement in healthy participants. 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s):  
EudraCT:  2019-002609-23 
Approval Date: 25-May-2021 
 
 
 
 
 
Copyright 2021 GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title: A randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study to investigate the effects of intravenous 
GSK3858279 on a battery of evoked pain tests in healthy participants. 
Protocol Number: 209973/ Amendment 4 
Compound Number 
or Name: 
GSK3858279  
 
 
 
 
 
Nicolas Wisniacki 
Vice President, Discovery Medicine,  
Clinical Pharmacology & Experimental Medicine. 
 
Date 
 
 
 
 
The signed page is a separate document. 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY. 
Document 
Date of Issue 
DNG Number 
Amendment 4 
25-MAY-2021 
TMF-13778634 
Amendment 3 
10-AUG-2020 
2020N405625_03 
Amendment 2 
11-FEB-2020 
2019N405625_02 
Amendment 1 
23-SEP-2019 
2019N405625_01 
Original Protocol 
25-JUL-2019 
2019N405625_00 
 
Amendment 4 25-MAY-21 
Overall Rationale for the Amendment:  
Amendment to the Interim Analysis sections. An interim analysis may be performed once 
the last UVB-MITT participant has completed their period 3 final day 15 PainCart 
assessments. Dependent on the results, the study could be stopped for futility. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis 
 
Section 4.1 
Overall Design 
 
Section 6.3.2. 
Blinding 
 
Section 9.5 
Interim Analysis 
 
 
Included the potential of performing an 
interim futility analysis when all UVB-MITT 
participants have been enrolled and 
completed their period 3, day 15 PainCart 
assessments. 
For futility and internal 
decision-making. A review of 
the primary PainCart 
endpoints, safety, 
demography, PK and TE will 
be conducted.  
Section 4.4 
Justification of 
dose and washout 
period  
Updates made to reflect emerging data from 
FTiH study  
Updated to reflect 
information present in the 
current IB  
Throughout 
Update 
to 
SARS-CoV-2 
mitigation 
measures 
To reflect update to site 
procedures 
Throughout  
IB, Interim Report and RAP reference and 
associated citations updated  
Updated to reflect the most 
current version of the 
documents  


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Section # and 
Name 
Description of Change 
Brief Rationale 
 Throughout  
Enrolment number amended from 30 
participants to ‘a maximum of 30’ 
participants 
To ensure consistency with 
language already included in 
Section 09: Statistical 
analysis 
 
 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY .......................................................................................... 8 
1.1. 
Synopsis ....................................................................................................... 8 
1.2. 
Schema ...................................................................................................... 11 
1.3. 
Schedule of Activities (SoA) ........................................................................ 12 
1.3.1. 
Screening and follow-up .............................................................. 12 
1.3.2. 
Study periods 1, 2, 3 and Early Withdrawal .................................. 14 
2. 
INTRODUCTION .................................................................................................... 17 
2.1. 
Study Rationale .......................................................................................... 17 
2.2. 
Background ................................................................................................ 17 
2.3. 
Benefit/Risk Assessment ............................................................................ 19 
2.3.1. 
Risk Assessment ......................................................................... 20 
2.3.2. 
Benefit Assessment ..................................................................... 30 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 30 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 30 
4. 
STUDY DESIGN .................................................................................................... 31 
4.1. 
Overall Design ............................................................................................ 31 
4.2. 
Number of Participants ............................................................................... 32 
4.3. 
Scientific Rationale for Study Design .......................................................... 33 
4.3.1. 
Participant Input into Design ........................................................ 33 
4.4. 
Justification for Dose and Washout Period .................................................. 33 
4.5. 
End of Study Definition ............................................................................... 34 
5. 
STUDY POPULATION ........................................................................................... 35 
5.1. 
Inclusion Criteria ......................................................................................... 35 
5.2. 
Exclusion Criteria ........................................................................................ 36 
5.3. 
Lifestyle Considerations .............................................................................. 39 
5.3.1. 
Meals and Dietary Restrictions .................................................... 39 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 39 
5.3.3. 
Activity ......................................................................................... 39 
5.3.4. 
Exposure to sunlight .................................................................... 40 
5.3.5. 
SARS-CoV-2 related restrictions .................................................. 40 
5.4. 
Screen Failures........................................................................................... 40 
5.4.1. 
Re-screening ............................................................................... 40 
5.4.2. 
Re-testing of Clinical Laboratory Values during Screening ........... 40 
6. 
STUDY INTERVENTION ........................................................................................ 41 
6.1. 
Study Intervention(s) Administered ............................................................. 41 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 42 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 42 
6.3.1. 
Randomization ............................................................................. 42 
6.3.2. 
Blinding ........................................................................................ 43 
6.4. 
Study Intervention Compliance ................................................................... 44 
6.5. 
Concomitant Therapy.................................................................................. 44 
6.5.1. 
Permitted Therapies .................................................................... 45 


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6.5.2. 
Prohibited Medications ................................................................. 45 
6.6. 
Dose Modification ....................................................................................... 46 
6.7. 
Intervention after the End of the Study ........................................................ 46 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 46 
7.1. 
Study Stopping Criteria ............................................................................... 46 
7.2. 
Discontinuation of Study Intervention .......................................................... 46 
7.2.1. 
Liver Chemistry Stopping Criteria ................................................ 47 
7.2.2. 
QTc Stopping Criteria .................................................................. 47 
7.2.3. 
SARS-CoV-2 related stopping criteria .......................................... 48 
7.3. 
Participant Discontinuation/Withdrawal from the Study ............................... 48 
7.4. 
Lost to Follow Up ........................................................................................ 49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 49 
8.1. 
Safety Assessments ................................................................................... 50 
8.1.1. 
Physical Examinations ................................................................. 50 
8.1.2. 
Vital Signs .................................................................................... 50 
8.1.3. 
Electrocardiograms ...................................................................... 51 
8.1.4. 
Clinical Safety Laboratory Assessments ...................................... 51 
8.1.5. 
Echocardiogram........................................................................... 51 
8.1.6. 
Skin Reactions ............................................................................. 51 
8.2. 
Adverse Events and Serious Adverse Events ............................................. 51 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 52 
8.2.2. 
Method of Detecting AEs and SAEs ............................................. 52 
8.2.3. 
Follow-up of AEs and SAEs ......................................................... 52 
8.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 53 
8.2.5. 
Pregnancy ................................................................................... 53 
8.3. 
Treatment of Overdose ............................................................................... 53 
8.4. 
Pharmacokinetics ....................................................................................... 54 
8.4.1. 
Pharmacokinetic Sample Analysis ............................................... 54 
8.5. 
Pharmacodynamics .................................................................................... 54 
8.5.1. 
Target Engagement ..................................................................... 55 
8.5.2. 
PainCart ...................................................................................... 55 
8.6. 
Genetics ..................................................................................................... 55 
8.7. 
Biomarkers ................................................................................................. 55 
8.8. 
Immunogenicity Assessments ..................................................................... 55 
8.9. 
Health Economics ....................................................................................... 55 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 56 
9.1. 
Statistical Hypotheses................................................................................. 56 
9.2. 
Sample Size Determination ........................................................................ 56 
9.2.1. 
Sample Size Sensitivity ................................................................ 56 
9.3. 
Populations for Analyses ............................................................................ 59 
9.4. 
Statistical Analyses ..................................................................................... 60 
9.4.1. 
General Considerations ............................................................... 60 
9.4.2. 
Primary Endpoint(s) ..................................................................... 60 
9.4.3. 
Secondary/Exploratory Endpoint(s).............................................. 60 
9.4.4. 
Other Safety Analyses ................................................................. 60 
9.4.5. 
Other Analyses ............................................................................ 60 
9.5. 
Interim Analyses ......................................................................................... 61 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 62 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 62 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 62 
10.1.2. 
Financial Disclosure ..................................................................... 62 
10.1.3. 
Informed Consent Process .......................................................... 63 
10.1.4. 
Data Protection ............................................................................ 63 
10.1.5. 
Committees Structure .................................................................. 64 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 64 
10.1.7. 
Data Quality Assurance ............................................................... 64 
10.1.8. 
Source Documents ...................................................................... 65 
10.1.9. 
Study and Site Start and Closure ................................................. 65 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 67 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 69 
10.3.1. 
Definition of AE ............................................................................ 69 
10.3.2. 
Definition of SAE .......................................................................... 70 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................... 71 
10.3.4. 
Reporting of SAE to GSK ............................................................. 73 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 74 
10.4.1. 
Contraception Guidance: ............................................................. 74 
10.4.2. 
Collection of Pregnancy Information: ........................................... 75 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 76 
10.6. 
Appendix 6: Abbreviations and Trademarks ................................................ 78 
10.7. 
Appendix 7: PainCart Details ...................................................................... 81 
10.7.1. 
Individual Assessments ............................................................... 81 
10.7.1.1. UVB model (Thermal pain, normal & UVB 
exposed skin) ............................................................. 81 
10.7.1.1.1. Thermal pain .......................................... 81 
10.7.1.2. Continuous assessment of pain .................................. 82 
10.7.1.3. Cold Pressor task (Cold pressor) ................................ 82 
10.7.1.4. Electrical stimulation task (Electrical stair) .................. 82 
10.7.1.5. Pressure stimulation task (Pressure pain) .................. 83 
10.7.2. 
PainCart Endpoints ...................................................................... 83 
10.7.3. 
Order of PainCart assessments ................................................... 83 
10.8. 
Appendix 8: Protocol Amendment History ................................................... 84 
11. REFERENCES ....................................................................................................... 89 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study to investigate the effects of intravenous 
GSK3858279 on a battery of evoked pain tests in healthy participants. 
Short Title: GSK3858279 vs PBO, Phase 1, Evoked Pain Tests, Pharmacokinetics and 
Target Engagement in healthy participants. 
Rationale: The purpose of the study is to elucidate the mechanistic basis for the 
analgesic effects of GSK3858279 in humans by using a battery of experimental pain 
assessments in healthy participants. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Primary 
To evaluate the effects of IV administration of 
GSK3858279 in Ultraviolet B (UVB) burn 
inflammatory test, cold pressor test and 
electrical pain test in the PainCart  
UVB heat pain detection (C) 
Cold pressor time to intolerable pain threshold 
(sec)  
Electrical pain tolerance threshold (mA) - 
single stimulus 
Safety 
Safety 
To evaluate the safety and tolerability of 
GSK3858279 following IV dosing 
Adverse Events (AE) and Serious Adverse 
Events (SAE).  
Clinical laboratory measurements, 12-lead 
electrocardiograms (ECG) and vital signs that 
are considered of potential clinical importance. 
Exploratory 
Exploratory 
To evaluate the pharmacokinetics (PK) of 
GSK3858279 following IV administration 
Serum PK concentrations and parameters 
including but not limited to: area under the 
concentration-time curve [AUC], maximum 
concentration [Cmax], tmax 
To evaluate the target engagement (TE) of 
Chemokine C-C motif ligand 17 (CCL17) by 
GSK3858279 following IV administration 
Free and total CCL17 levels in serum 
To evaluate the effects of IV administration of 
GSK3858279 in additional endpoints in UVB 
test, cold pressor test and electrical pain test in 
the PainCart 
Heat pain detection on normal skin (C) 
Cold pressor time to pain detection (sec)  
Electrical pain detection (mA) - single stimulus 
Electrical pain detection and tolerance 
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Objectives 
Endpoints 
For each test Area Under the Curve 
(AUC)/Area Above the Curve (AAC) and post-
test eVAS 
To evaluate the effects of IV administration of 
GSK3858279 in pressure pain test and 
Conditioned pain modulation (CPM) test of the 
PainCart 
Pressure pain (tolerance and detection) - KPa 
CPM - (detection and tolerance threshold) – 
mA 
For each test AUC/AAC and post-test eVAS 
To assess the potential for anti-GSK3858279 
antibody formation following IV dosing 
To include: incidence, titres, and, for samples 
with confirmed anti-drug antibodies (ADAs), 
neutralising activity 
 
Overall Design: 
This is a single-centre, randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study to investigate the effects of intravenous 
GSK3858279 on a battery of evoked pain tests in healthy participants. 
Disclosure Statement:  
This is a cross-over, basic science study with three study periods that is masking the 
participant and investigator. 
Number of Participants: 
A maximum of 30 healthy male participants will be enrolled into the study, such that at 
least approximately 24 participants complete dosing and critical assessments in all three 
study periods. 
 
An interim analysis may be performed once the last UVB-MITT participant has 
completed their period 3 final day 15 PainCart assessments. An interim analysis may also 
be performed once the final participant has completed their period 3 final day 15 PainCart 
assessments. 
 
For both UVB Heat Pain Detection and Cold Pressor time to intolerable pain threshold, 
the sample size is higher than that required for the Electrical Pain tolerance threshold test. 
Therefore, for the UVB-exposed population, from here on referred to as the UVB-MITT 
population, approximately 18 participants are required to be enrolled to ensure that 
approximately 15 participants complete all UVB tests of the PainCart assessment on 
irradiated skin in all three study periods.   
 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.  


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In each study period participants will receive either GSK3858279 or placebo in a 1:1 
ratio. During the trial, participants will receive both treatments, either two doses of 
GSK3858279 and one dose of placebo, or two doses of placebo and one dose of 
GSK3858279 with equal likelihood. The order of treatment assignments will be 
randomized. 
If participants prematurely discontinue the study, additional replacement participants may 
be randomized at the discretion of the Sponsor and in consultation with the Principal 
Investigator in order to ensure sufficient participants complete the study. Replacement 
participants will be assigned to the same treatment sequence as the participant they are 
replacing, at the discretion of the Sponsor and in consultation with the Principal 
Investigator. 
Intervention Groups and Duration: 
The study duration, including screening and follow-up will be approximately 6 months 
for all participants in the study: 
Screening 
Approximately 28 days prior to first dose. 
Number of 
Participants 
One Cohort of a maximum of 30 participants (N=30) 
Study (Treatment) 
Period(s) 
Will comprise of three study periods, investigating the difference 
between GSK3858279 (3mg/kg IV) and Placebo in the PainCart 
assessments. 
Each participant will be admitted to the unit either two days before 
dosing (Day-2, UVB-MITT participant) or one day before dosing (Day-1, 
non-UVB-MITT participant) on each study period. Participants will be 
dosed on Day 1 and discharged on Day 2 (except if, for medical 
reasons, participants need to stay longer). The participants will return for 
an outpatient visits on Day 7 (UVB-MITT participants only), Day 8 and 
Day 15. The participants will be contacted on Day 25 and asked about 
their general health.  
Washout Period 
Will be at least 4 weeks between doses for an individual participant. 
Follow-Up 
The participants will be contacted on Day 36 by telephone and asked 
about their general health. 
Approximately 56 days after the last study administration, a final follow-
up visit will occur. If warranted, additional follow-up visits may be 
scheduled.  
 
Data Monitoring or Other Committee:  
There will not be a data monitoring committee or any other committee on this study.  


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1.2. 
Schema 
Figure 1 
Study Design Schematic 
 
Figure 2 
Visit schematic 
 
Figure 3 
Study Period Details 
 
 
 
 


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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Screening and follow-up  
Procedure 
Screening  
(up to 28 days 
before Day 1) 
Follow-up 
check 
364 days 
post last 
dose 
Final 
follow-up 
564 days 
post-last 
dose 
Notes 
Part 1 
Part 2 
Out-patient visit 
X 
X 
 
X 
Optional in-clinic stay for 
participants at the discretion of 
investigator. 
Phone call 
 
 
X 
 
AE collection - may be 
out-patient visit at discretion of 
Investigator for additional 
checks 
Informed consent 
X 
 
 
 
 
Severe acute respiratory 
syndrome SARS-CoV-2 
PCR test or rapid antigen 
test 
X 
 
 
X 
 
Temperature check 
X 
X 
 
X 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
Recheck clinical status before 
randomization and/or 1st dose 
of study intervention. 
Demography 
X 
 
 
 
 
Full physical examination 
including height and 
weight. 
X 
 
 
 
Weight at screening is used 
for determination of dose 
Fitzpatrick Skin Type 
X 
 
 
 
Assessments for UVB-MITT 
population only 
Assessment to determine 
applying MED application 
Echocardiogram 
X 
 
 
 
 
Medical history (includes 
substance usage) 
X 
 
 
 
Substances: Drugs, Alcohol, 
tobacco and caffeine 
Current medical 
conditions 
X 
 
 
 
 
HIV, Hepatitis B and C 
X 
 
 
 
 
Haematology, clinical 
chemistry (include liver 
chemistries) and 
urinalysis 
X 
 
 
X 
Including Troponin-T (hs) 
NT-proBNP 
X 
 
 
X 
 
UrDrug, BrAlc 
X 
 
 
X 
 
12-lead ECG 
T 
 
 
X 
T = Triplicate 
X = Single 
Vital signs 
X 
 
 
X 
 


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Procedure 
Screening  
(up to 28 days 
before Day 1) 
Follow-up 
check 
364 days 
post last 
dose 
Final 
follow-up 
564 days 
post-last 
dose 
Notes 
Part 1 
Part 2 
PainCart training 
[X] 
[X] 
 
 
May be performed during 
either part 1 or part 2 (not 
both) 
Minimal Erythema Dose 
(MED) application 
X 
 
 
 
Assessments for UVB-MITT 
population only. Exposure to 
pre-determined 6 ascending 
doses of UVB radiation. 
MED application will be the 
final assessment on Part 1 of 
Screening and will only be 
completed after confirmation 
of eligibility from available 
results, e.g. lab data, 
echocardiogram results may 
not be available. 
 
MED assessment 
 
X 
 
 
Assessments for UVB-MITT 
population only. 24 hours ( 2 
hours) after UV exposure 
 
AE/SAE review 
X 
X 
X 
X 
 
• 
An echocardiogram performed within 3 months prior to first dosing is acceptable for 
enrolment into the study  
• 
MED determination performed within 6 weeks prior to first dosing is acceptable for 
enrolment into the study  


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1.3.2. 
Study periods 1, 2, 3 and Early Withdrawal 
When the following assessments are scheduled to be performed at the same time-point, the order will be as follows: 
ECG > vital signs > PK and PD sampling > PainCart 
Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
Out-patient visit 
 
 
 
 
X* 
X 
X 
 
X 
Optional in-clinic stay for participants at the discretion of 
investigator. 
*Day 7 is optional for those participants not receiving UVB. 
Admission in clinical unit 
X** 
 
 
 
 
 
 
 
 
Optional in-clinic stay for participants at the discretion of investigator 
** If subjects are not UVB-MITT participants, optional admission will 
be on Day-1 with Day-2 assessments completed on Day-1. 
Discharge from clinical 
unit 
 
 
 
X 
 
 
 
 
 
Except if, the participant needs to remain in the Unit longer for 
medical reasons. 
Phone Call 
 
 
 
 
 
 
 
X 
 
AE collection - may be out-patient visit at discretion of Investigator 
for additional checks 
Brief Physical 
Examination 
 
 
X 
X 
 
X 
X 
 
X 
 
Haematology, clinical 
chemistry (include liver 
chemistries) and 
urinalysis  
 
X 
X 
X 
 
X 
X 
 
X 
Troponin T to be assessed on Day -1, 8, 15 (and EW if needed). 
C3/C4 on Day -1 only 
UrDrug, BrAlc 
 
X 
 
 
X* 
 
X 
 
 
*for volunteers who do not receive UVB application, the Day 7 
Assessments may be performed on Day 8 prior to PainCart  
SARS-CoV-2 PCR test or 
rapid antigen test 
X** 
 
 
 
 
 
 
 
X 
 


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Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
12-lead ECG 
 
T 
X 
 
 
X 
X 
 
X 
Day 1: pre-dose (T), 0.5hr, 1hr post start of infusion. 
On other days a single measure taken prior to 1st PainCart 
assessment. 
T = Triplicate 
X = Single 
Vital signs (including 
temperature) 
X** 
X 
X 
X 
X-t 
X 
X 
 
X 
Day 1: pre-dose, 0.5hr, 1hr, 2hr post start of infusion. 
X-t: temperature assessment on Day 7 for UVB-MITT population 
only  
On other days a single measure taken prior to 1st PainCart 
assessment. 
Randomization 
 
 
X 
 
 
 
 
 
 
Study period 1 only 
Drug/placebo IV infusion 
 
 
X 
 
 
 
 
 
 
Continuous infusion over 1 hour 
PainCart 
 
 
X 
X 
 
X 
X 
 
 
Day 1 pre-dose performed twice (baseline) 
Day 1 performed at 1 and 3 hours post start of IV infusion. Other 
days performed twice ~2 hours apart at approximately the same 
time of day in each study period. 
Day 15 - heat pain detection assessment associated with UVB test 
performed on normal skin only. 
Participants not receiving UVB application will not undergo UVB 
heat pain detection test on irradiated skin.  All other paincart 
assessments including heat pain detection performed on normal 
skin will still be assessed. See Appendix 7 for details of testing 
UVB application 
 
X 
 
 
X 
 
 
 
 
UVB application (2 x MED) will be performed 24hr (2hr) prior to 
start of infusion on Day 1. 
UVB application (2 x MED) on Day 7 will be performed 24hr (2hr) 
prior to PainCart assessment on Day 8. 
UVB application only applies to those in the UVB-MITT population. 


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Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
AE review 
X** 
X 
================================→ 
X 
 
SAE review 
X** 
X 
================================→ 
X 
 
Concomitant medication 
review 
X** 
X 
================================→ 
X 
 
Blood samples for PK and 
PD 
 
 
X 
X 
 
X 
X 
 
X 
Day 1: pre-dose, 1hr, 3hr post-start of IV infusion. 
On other days samples taken prior to 1st PainCart assessment. 
Blood sample for 
immunogenicity 
 
 
X 
 
 
 
X 
 
X 
Day 1: pre-dose. 
Day 15: prior to 1st PainCart assessment. 
** If subjects are not UVB-MITT participants, optional admission will be on Day-1 with Day-2 SARS-CoV-2 test performed on Day-1. 
• 
The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic assessments may be 
altered during the course of the study based on newly available data to ensure appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic 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. 
• 
The planned study assessments on Day 7 (UVB-MITT population only), 8, 15 and 25 may be performed within a   24hr window. 
• 
A questionnaire related to COVID-19 is part of each visit and included in the AE review. 


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2. 
INTRODUCTION 
GSK3858279 is a high affinity, human immunoglobulin G2σ (IgG2σ) (Fc-silenced), first-
in-class, monoclonal antibody (mAb) in development for the treatment of pain associated 
with osteoarthritis with a view to expand to other chronic pain diseases (e.g. neuropathic 
pain). 
2.1. 
Study Rationale 
The purpose of the study is to elucidate the mechanistic basis for the analgesic effects of 
GSK3858279 in humans by using a battery of experimental pain assessments in healthy 
participants. Analgesia has been demonstrated in animal models of pain with tool anti-
CCL17 antibodies however the mechanistic basis for this effect seen in animal studies is 
not well understood and, as has been observed for other development assets, may not 
translate to humans. Clinical studies in pain patients can be challenging because of large 
placebo responses, and heterogeneity of pain mechanisms within a single disease. 
Performing the study in healthy participants in a controlled, validated battery of 
experimental pain tests assessing several pain mechanisms contrasted with historical data 
of analgesic drugs will inform on pain disease indications to progress. 
2.2. 
Background 
CCL17, previously known as thymus and activation regulated chemokine (TARC), is a 
member of the CC-family of chemokines that binds and signals through the G-protein 
coupled CC-chemokine receptor, CCR4 [Imai, 1996; Imai, 1997]. CCL17 is produced by 
numerous immune and non-immune cell types. CCR4 is predominantly expressed on Th2 
cells but is also present on other immune and non-immune cell types. 
GSK3858279 is a high affinity (Kd<1pM), human immunoglobulin G2σ (IgG2σ) (Fc-
silenced), first-in-class, monoclonal antibody (mAb), binding specifically to the 
chemokine CCL17. It functionally inhibits CCL17 activating the chemokine receptor 
CCR4, to prevent downstream consequences of CCR4 signalling. 
At the time of this protocol, GSK3858279 is being developed for treatment of 
osteoarthritis pain, however non-clinical data suggests an opportunity to treat other 
chronic pain conditions including neuropathic pain by targeting this pathway. Alleviating 
chronic pain is a major unmet need as current therapies (e.g. NSAIDs, opioids) have 
significant side effects and addiction liabilities that prevent their effective use in treating 
the patient's pain. 
Rationale for CCL17 neutralisation in OA pain has been generated in vivo pre-clinically 
in inflammatory and arthritis models. CCL17 has been recently identified as a peripheral 
mediator of inflammatory pain and can itself induce arthritis. Intraplantar injection of 
recombinant CCL17 resulted in pain in mice in a CCR4-dependent manner [see IB, 
GlaxoSmithKline Document Number RPS-CLIN-004032 
 


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whilst therapeutic dosing with anti-CCL17 surrogate mAb inhibited established 
inflammatory pain [in house data - see IB, GlaxoSmithKline Document Number RPS-
CLIN-004032 
 Absence of CCL17 ameliorated inflammatory pain in various murine arthritis models.  
In parallel, in a preclinical in vivo model of nerve injury that recapitulates the mechanical 
hypersensitivity and thermal allodynia presented by neuropathic pain patients, therapeutic 
dosing of anti-CCL17 surrogate mAb reverses pain [see IB, GlaxoSmithKline Document 
Number RPS-CLIN-004032 
Importantly, in contrast to inflammatory and arthritic models, chronic neuropathic pain 
and the rodent nerve injury models tested are largely insensitive to NSAID treatment. As 
such, the mechanism of action of analgesia induced by neutralisation of CCL17 is 
potentially applicable to neuropathic pain conditions considered refractory to NSAIDs. 
The opportunities to treat pain by targeting CCL17 in the context of a variety of 
conditions and aetiology needs to be explored clinically. 
The PainCart is an integrated, multi-modal pain task battery of tests designed to 
investigate the efficacy of analgesic compounds against several types of pain, including 
thermal, electrical, chemical and mechanical pain. The models applied in the PainCart 
have been tested for predictive validity and reliability and can be used repeatedly, 
quickly, in short succession in healthy participant studies and patient studies. 
The translation of findings from animals, through human pain models to patients (and 
back) is one of the greatest challenges in modern (pain) research. One major disadvantage 
of many human pain models is that they do not represent the pain aetiology or pain entity 
when they are translated to patients, i.e. they may mimic aspects of the clinical pain 
condition, but they cannot reflect the full multidimensionality of a disease. In addition, 
the main limitation of models of pain is the inability to replicate spontaneous pain, which 
is one of the main complaints of chronic pain patients and there are currently no human 
models available to measure this. This being said, experimental pain models may be used 
to mimic certain aspects of chronic pain condition such as sensitization of the peripheral 
or central pain processing (windup of nociceptors via repetitive electrical stimulation), or 
by inducing inflammatory pain responses, additional measures of central sensitization 
may be taken which portray aspects of neuropathic pain such as touch evoked allodynia 
and punctate hyperalgesia. By using a combination of methods, the different aspects of 
nociceptive processing may be teased out and provide mechanistic information to aid 
decision making. Human experimental pain models can be supportive in understanding 
the pain mechanisms by exploring the pain system under controlled settings 
[Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or 
chemical) can be applied to the skin, muscles, and viscera for a differentiated and 
comprehensive assessment of various pain pathways and mechanisms], the challenge is to 
match specific treatments to different pain-generating mechanisms.   
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK3838279 is provided in the Investigator’s Brochure (IB) [GlaxoSmithKline 
Document Number RPS-CLIN-004032] 


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In light of the global COVID-19 pandemic, all participants will be screened for COVID-
19 at the beginning of the study period and will be required to have a negative SARS-
Cov-2 test prior to commencing each study period. Please see further details for risk 
assessment and mitigation strategy below. 
2.3. 
Benefit/Risk Assessment 
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) GlaxoSmithKline Document Number RPS-CLIN-004032 
The risk assessment of GSK3858279 is based on the pre-clinical studies conducted to 
date and the ongoing First in Human (FiH) study 207804 – GlaxoSmithKline Document 
Number 2020N429762_00.  
Summaries of findings from these pre-clinical studies and the FiH study can be found in 
the IB [GlaxoSmithKline Document Number RPS-CLIN-004032] 
Details of these risks, as well as the risks associated with the procedures, and the 
proposed strategy to mitigate/monitor these risks are detailed in Section 2.3.1. 
In this study, safety will be monitored closely both by subjective reporting and by 
objective means, i.e. serial assessments of vital signs, clinical laboratory information and 
cardiac monitoring. The study will be run in a clinical unit with access to hospital 
facilities for the treatment of medical emergencies. Participants will remain monitored in 
the clinic for a minimum of 2 hours after completion of dosing in each study period and 
will only be discharged from the unit if the investigator deems it safe to do so. 
 


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP)  
Hypersensitivity, including 
injection site and infusion 
reactions 
The administration of any (human) mAb has the potential to induce 
local or systemic immunologic reactions, for example acute allergic 
reactions (type I) and immune complex disease (ICD) associated 
with the formation of anti-drug antibodies (ADA) (type III). 
 
Non-Clinical 
In a 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 of three animals (one female at 10 mg/kg/week and 
one male and one female at 100 mg/kg/week) as well as 
mesangioproliferative glomerulopathy in the kidney of the males at 
10 mg/kg/week or 100 mg/kg/week, which is consistent with ICD 
following the formation of ADA. Nonspecific injection site reactions 
caused by the subcutaneous (SC) 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.  
Animals are not predictive for ADA-mediated adverse reactions in 
humans, including infusion reactions, hypersensitivity reactions or 
Participant Selection: 
Participants with a history of sensitivity to the 
study medication, or a history of any drug or 
other allergy that, in the opinion of the 
investigator, contraindicates their participation, 
will not be permitted to enter the study. 
Participants with renal disorders will also be 
excluded. 
  
Participant monitoring: 
In Part A of FiH study (207804), participants 
remained in the inpatient facility for 48 hours 
post dosing to allow adequate monitoring by 
trained site personnel.  
In Part B of FiH (207804) and in this study 
(209973), participants will be monitored for a 
minimum of two hours post dosing. 
Emergency resuscitation facilities will also be 
available. 
Participants will be instructed in the Informed 
Consent Form (ICF) as to the signs and 
symptoms of hypersensitivity reactions and be 


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Potential Risk of Clinical 
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Summary of Data/Rationale for Risk 
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anaphylaxis [Kronenberg, 2017]. 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 
During Part A of the FiH study (207804) in healthy participants, 
there was neither a report of any relevant hypersensitivity reactions 
nor any clinically significant changes in urinalysis. 
instructed to seek immediate clinical care 
should they develop.  
 
Immunogenicity 
Monoclonal antibodies may induce ADAs, which have the potential 
to induce adverse reactions (mentioned above) or affect the PK and 
PD properties of the drug. GSK3858279 is a human antibody, with 
a lower potential for ADA formation than a chimeric antibody. 
 
Nonclinical 
In the nonclinical 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 titre of 
ADA in nonclinical studies are not predictive of the generation of 
ADAs in humans. 
Samples will be drawn at baseline and at 
regular intervals to test for immunogenicity, and 
participants will be monitored for any evidence 
of adverse reaction as detailed in the 
hypersensitivity section of this table. 
 
Clinical laboratory safety assessments are 
included in the study. Urine microscopy and 
laboratory quantification of proteinuria will be 
investigated following unexplained dipstick 
proteinuria or haematuria. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Clinical 
In Part A of the FiH study (207804) in healthy participants there 
was a low incidence of pre-existing ADA and for which titres were 
low. There was no pattern of increasing incidence or increasing 
titres of ADAs following escalation of the dose level of 
GSK3858279 (or placebo) and there was no apparent difference 
between 3 mg/kg IV vs. 3 mg/kg SC. 
Risk of Infection 
The intended pharmacologic effect of GSK3858279 may result in 
an increase in the frequency and/or severity of infection, as a result 
of potential changes in immune cell trafficking. 
Non-Clinical 
No specific studies have been conducted in nonclinical 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). The role of CCL17 in systemic anti-
pathogen responses is unclear. 
In pre-clinical studies, administration of the anti-CCL17 antibody 
(GSK3858279) for 13 weeks to monkeys did not result in 
modulation of the immune system as assessed by T-cell dependent 
antibody response, an assessment of humoral immunity, or of 
peripheral blood lymphocyte populations as assessed by flow 
cytometry (see IB for further details). In addition, we are not aware 
Participant Selection 
Participants with active or chronic infections or a 
history of recent or recurrent infections will not 
be included in the study – see Section 5.2. 
 
Participant Monitoring 
Participants will be monitored for infection. 
Participants will be instructed in the ICF as to 
the signs and symptoms of infection, and to 
contact the site personnel should they develop. 


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Potential Risk of Clinical 
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of any pre-clinical in vitro or in vivo data to suggest a potent 
immunosuppressive effect of CCL17 blockade. There is, however, 
no data available to our knowledge of the consequences of CCL17 
inhibition/ablation in pre-clinical viral infection models.  
 
Clinical 
During Part A of the FiH study (207804) in healthy participants, 
there were no reports of infection-related serious adverse events. 
Vaccination Reactions 
There is a theoretical risk that GSK3858279 could decrease an 
individual’s immune response to vaccines administered while on 
therapy or to allow symptoms to develop following the 
administration of live vaccines. 
 
Non-Clinical 
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.  
Participant selection and non-permitted 
medications: 
Attenuated live vaccines should not be 
administered to participants from 1 month prior 
to dosing of study medication and for five half-
lives after dosing of study medication. If 
indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered whilst 
receiving GSK3858279 based on an 
assessment of the benefit:risk (e.g. risk of 
decreased responsiveness). 
Cardiac Risks 
Non-Clinical 
In the 4-week study, review of the heart data (ECG, blood pressure, 
heart rate, organ weights and histopathology), in monkeys at doses 
up to 100 mg/kg/week IV and 30 mg/kg/week SC to n=2/sex/group, 
did not identify any changes compared to controls. 
In the 13-week study, higher heart weights were noted compared to 
controls, without any histopathological or functional (ECG, blood 
Participant Exclusion: 
Participants with a history of cardiac disease or 
cardiac abnormalities (including abnormal 
Troponin T and NT-proBNP) that, in the opinion 
of the investigator, would compromise cardiac 
safety will be excluded from the study.  


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pressure, heart rate) correlate. The heavier heart weights were not 
dose-related and generally did not show a consistent pattern of 
increased absolute weights, relative to body weight or brain weight. 
Refer to IB [GlaxoSmithKline Document Number RPS-CLIN-
004032] 
] for further details. 
In the 26-week study, a thorough evaluation to investigate the 
potential for cardiotoxicity which included ECG, echocardiogram, 
telemetry (blood pressure, heart rate), serum cardiac troponin I, 
NT-proBNP, heart weight and histopathology, did not identify any 
treatment-related effects on the heart following doses up to 100 
mg/kg/week SC. 
GSK3858279 did not bind to human heart in the tissue cross-
reactivity studies and there is no known pharmacological 
mechanism following administration of an anti-CCL17 which would 
lead to an increase in heart weight. Therefore, the potential effect 
on heart weights noted in the 13-week study in monkey was not 
reproducible following 26 weeks of chronic dosing in monkey and is 
not considered to be clinically significant. 
Clinical 
During Part A of the FiH study (207804) in healthy participants, 
none of the abnormal findings in the ECG parameters were judged 
to be clinically significant. 
 
Participant monitoring: 
Investigations during screening include ECG, 
echocardiogram and troponin T and NT-
proBNP. TroponinT and NT-proBNP will be 
monitored after dosing.  
Bleeding Risk 
CCR4, the receptor for CCL17 is expressed on platelets and both 
CCL17 and CCL22 activate platelets in vitro. A potential risk of 
impaired platelet activation and blood clotting exists with CCL17 
Participant exclusion and non-permitted 
medication 


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antagonism although at this stage this is theoretical; there are two 
conflicting reports describing the ability of anti-CCR4 antibodies, to 
either block CCL17/CCL22 -mediated platelet aggregation ex vivo 
[Gear, 2001] or to not block platelet function in vitro/ex vivo assays 
[Hagemann, 2014]. Clinical data with direct inhibitors of CCR4, 
such as mogamulizumab (approved in Japan for treatment of T cell 
lymphoma), are not associated with increased bleeding risk. 
 
Non-Clinical 
Although platelet function has not been specifically assessed non-
clinically; no effects on platelet counts or clotting times were 
observed in the monkey studies. Neither were there any reports of 
excessive bruising nor difficulties in clotting after blood sampling. 
Clinical 
There were no reports of any clinically significant bleeding events 
during Part A of the FiH study (207804) in healthy participants. 
Participants with a previous or current history of 
bleeding diathesis will be excluded. 
Use of anti-coagulants or anti-platelet agents 
will be prohibited. 
Skin Reactions 
Cutaneous adverse clinical effects have been observed in patients 
with T-cell lymphomas treated with mogamulizumab (anti-CCR4 
antibody) including Stevens-Johnson syndrome. This may reflect 
depletion of immune regulating cells called “Regulatory T cells” 
within the skin compartment predisposing to cutaneous 
inflammatory or autoimmune responses. Given that GSK3858279 
will only block CCL17, the alternative ligand, CCL22, should offer 
redundancy to maintain T cell migration. Relevant to this, CCL22 is 
highly expressed in skin blister fluid [Bouma, 2017].  
 
 
Participant Exclusion 
Participants with a history of drug-induced skin 
reactions and Stevens-Johnson Syndrome will 
be excluded. 
 
Participant Monitoring 
Clinically significant skin reactions will be 
reviewed by a dermatologist and, if appropriate, 
a skin biopsy will be requested for histological 
analysis. 


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Clinical 
There were no reports of any clinically significant skin reactions 
during Part A of the FiH study (207804) in healthy participants. 
Study Procedures 
Events related to UVB 
irradiation 
UV irradiation from sunlight is associated with an increased 
incidence of skin cancer. UV irradiation is made up of a spectrum of 
wavelengths with UVB being one of the risk factors for skin cancer. 
The range of wavelength of UVB used in this study (narrow band 
range 310-315 nm) is that used for phototherapy to treat skin 
conditions such as psoriasis. Literature review [Lee, 2005] indicate 
there was no increased risk of skin cancer in four studies 
specifically assessing the potential carcinogenic risk of narrow-
band UVB, however there is insufficient literature on the number of 
exposures and risk of long term development of skin cancer at the 
UVB wavelength to be administered in this study [Hearn, 2008].  
Participant exclusion 
Participants with pre-existing risk factor for skin 
cancer will be excluded (applicable for UVB-
MITT population only). 
 
Dose of UVB irradiation will be at 2 x MED. 
Events related to UVB test 
The UVB test may induce a post-inflammatory hyperpigmentation 
(PIH) in some cases [Siebenga, 2019]. Typically, at centres 
performing the UVB inflammatory test, 3xMED (Minimum Erythemal 
Dose) of UVB irradiation is applied to induce sensitisation, 
however, long-lasting PIH has been associated with 3xMED. 
Participant exclusion 
Participants with Fitzpatrick skin type IV, V or VI 
will be excluded (applicable for UVB-MITT 
population only). 
 
Dose of UV irradiation will be at 2 x MED. 
 
Participant Monitoring 
At the follow-up visit, participants will be 
assessed to monitor the possible occurrence of 
the hyperpigmentation. 
Participants will be informed in the ICF as to the 
risk of forming PIH at the UV irradiation sites. 


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Other 
SARS-CoV-2 
The current SARS-CoV-2 pandemic can pose a challenge to 
integrity of the trials, protection of participants’ rights, safety and 
wellbeing and the safety of clinical trial staff. Therefore, risk 
mitigation strategies will be put in place for this trial and will be 
evaluated on an ongoing basis for the duration of this trial, or until 
there is a consensus that the period of the SARS-CoV-2 outbreak 
in the Netherlands has passed. If the dynamics of the SARS-CoV-2 
outbreak change in such a way that the safety of the trial 
participants and clinical trial staff or integrity of the data collected 
during this clinical trial cannot be guaranteed the trial will be halted. 
 
GSK3858279 on COVID-19 disease 
CCL17 (and CCL22) are ligands for the CCR4 receptor. The CCR4 
receptor is predominantly expressed on Th2 cells, but is also 
present on some Th1 cells (Kara, 2014). CCL17 is thus likely to 
mainly be involved in extracellular infections (e.g. parasitic, 
extracellular bacteria and fungi), rather than intracellular infections 
(e.g. viral such as COVID-19) although we cannot rule out a role for 
CCL17 in viral infection. 
 
Based on the available information in the Investigators Brochure 
and outlined in the ‘risk on infection’ section in this table, above, 
there is currently no reason to believe that GSK3858279 could 1) 
increase the susceptibility of trial participants to the SARS-CoV-2 
virus, or 2) worsen or mask any COVID-19 signs, symptoms or 
complications. 
 
Participant selection and monitoring 
Healthy subjects in the current study fall in a low 
risk category for complications of COVID-19, the 
disease caused by the SARS-CoV-2 virus. To 
reduce the risk of SARS-CoV-2 infections 
among trial participants, measures and 
procedures based on the advice issued by GSK 
Global COVID Guidance, the Dutch Centre for 
Infectious Disease Control (RIVM) and COVID-
19 measures declared by the Dutch government 
will be adhered to as outlined in CHDR SOP 
GGECOVID. These would include but are not 
limited to counselling participants regarding the 
importance of infection control measures such 
as hand washing, reducing inter-personal 
contacts as much as possible and participant 
awareness of potential COVID-19 symptoms. 
 
Site trial staff in direct contact and/or within 1.5 
m distance of study subjects will receive 
additional protection via the use of Personal 
Protective Equipment (PPE) and disinfectants. 
Guidance for how participants should conduct 
themselves throughout the study in relation to 
COVID-19 restrictions are outlined in CHDR 
SOP GGECOVID 
 


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All trial subjects will be screened for SARS-
CoV-2 with a PCR or rapid antigen test:  
1) at screening visit Part 1 
2) prior to each admission at the clinical unit 
with at least one overnight stay (i.e. at Day-
2/Day-1); and  
3) in case of symptoms possibly related to 
COVID-19.   
4) at the final follow up visit. 
5) at times as specified in current COVID-19 
guidance of CHDR 
 
Healthy subjects may be excluded from the 
study if they test positive for SARS-CoV-2 from 
screening to the end of study treatments. In 
case of a positive SARS-Cov-2 antigen test 
result after first dose was administered, a 
SARS-CoV-2 PCR will be performed for 
confirmation. In case of discordant results, the 
PCR result is leading 
 
 
Participants >50 years will be excluded from the 
study. 
 
 
Protection of Trial Integrity 
Adherence to the protocol and CHDR SOP 
GGECOVID protects the integrity of the data 


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collected during this clinical trial, as well as 
participants’ data protection rights. 
 
COVID-19 Contingency Plan  
Any subject that presents with COVID-19-
related symptoms and/or has a positive SARS-
CoV-2 PCR or rapid antigen test will be 
excluded from (further) participation in the trial 
and will receive follow-up medical attention per 
CHDR SOP GGECOVID 
 
 


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2.3.2. 
Benefit Assessment 
There will be no direct benefit to the healthy participants participating in this clinical 
trial. By enrolling in this study, participants will be contributing to the process of 
developing new analgesic medications – a significant area of unmet medical need for 
patients intolerant or unresponsive to NSAID-related treatments. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into consideration the measures taken to minimize the risks to those participating 
in this study, the potential risks identified in association with GSK3858279 at the dose 
level to be administered and those associated with the PainCart assessments are 
considered minimal and are justified. 
 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Primary 
To evaluate the effects of IV administration 
of GSK3858279 in Ultraviolet B (UVB) burn 
inflammatory, cold pressor test and electrical 
pain test in the PainCart  
UVB heat pain detection (oC) 
Cold pressor time to intolerable pain threshold 
(sec)  
Electrical pain tolerance threshold (mA) - single 
stimulus 
Safety 
Safety 
To evaluate the safety and tolerability of 
GSK3858279 following IV dosing 
Adverse Events (AE) and Serious Adverse 
Events (SAE).  
Clinical laboratory measurements, 12-lead 
electrocardiograms (ECG) and vital signs that 
are considered of potential clinical importance. 
Exploratory 
Exploratory 
To evaluate the PK of GSK3858279 
following IV administration 
Serum PK concentrations and parameters 
including but not limited to: area under the 
concentration-time curve [AUC], maximum 
concentration [Cmax], tmax 
To evaluate the target engagement of 
CCL17 by GSK3858279 following IV 
administration 
Free and total CCL17 levels in serum 


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Objectives 
Endpoints 
To evaluate the effects of IV administration 
of GSK3858279 in additional endpoints in 
UVB test, cold pressor test and electrical 
pain test in the PainCart 
Heat pain detection on normal skin (C) 
Cold pressor time to pain detection (sec)  
Electrical pain detection (mA) - single stimulus 
Electrical pain detection and tolerance threshold 
(mA) - repeat stimulus 
For each test AUC/AAC and post-test eVAS 
To evaluate the effects of IV administration 
of GSK3858279 in pressure pain test and 
Conditioned modulatory pain (CPM) test in 
the PainCart 
Pressure pain (tolerance and detection) - KPa 
CPM - (tolerance and detection) – mA 
For each test AUC/AAC and post-test eVAS 
To assess the potential for anti-GSK3858279 
antibody formation following IV dosing 
To include: incidence, titres, and, for samples 
with confirmed anti-drug antibodies (ADAs), 
neutralising activity 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study will be a randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study in healthy participants to investigate the 
effects of IV GSK3858279 on evoked pain tests in the PainCart. The study will be 
performed in a single centre. 
In each period, participants will receive either GSK3858279 or placebo in a 1:1 ratio. 
During the trial, participants will receive both treatments, either two doses of 
GSK3858279 and one dose of placebo, or two doses of placebo and one dose of 
GSK3858279 with equal likelihood. The order of treatment assignments will be 
randomized. (see Section 6.3). 
A three period design has been chosen because there is a marked reduction in variability 
for estimating the direct and residual treatment effects in three-period designs compared 
to two-period designs even with a large proportion of missing values, the three-period 
design is far more efficient than the two-period design [Carriere, 1994]. 
 
The total duration of the study (from signing informed consent until final follow-up visit) 
for each participant will be approximately 6 months.  Study participation may be 
prolonged in the event the study is on-hold. Screening period will be a maximum of 28 
days prior to study procedures, each study period will be approximately 2 weeks with at 
least a 4-week wash-out period between dosing (i.e. Day 1) in each of the study periods, 
final follow-up visit will be at approximately 8 weeks after last dose. 


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Participants will arrive at the research unit either one or two days before dosing, for the 
non-UVB-MITT and UVB-MITT group respectively. After arrival, subjects will be tested 
for SARS-CoV-2. Urine will be screened for the presence of drugs and an alcohol breath 
test will be performed. For participants with a positive urine drug screen or alcohol breath 
test, the treatment occasion may be rescheduled at the discretion of the principal 
investigator and GSK medical monitor. UVB irradiation will be applied approximately 24 
hours before dosing in the UVB-MITT population only. ECG and vital signs will also be 
performed. 
Participants will be assigned to receive treatment and pain assessments during either 
morning or afternoon sessions. They will continue to receive treatment and pain 
assessments at approximately the same time of day throughout all three study periods. 
Meals will be served at the site scheduled times. Safety, PK, PD and PainCart 
assessments will be performed as outlined in the SoA. Baseline measurements for 
PainCart (2 baseline measurements) are conducted at each study period prior to dosing. 
Phone contact to assess the participant’s general health will be conducted as per the SoA, 
the investigator may invite the participant for a site visit at the investigator's discretion 
for additional follow-up, as required. 
An interim analysis to assess the PD PainCart (three primary endpoints) and safety may 
occur once the final UVB-MITT participant has completed their final (day 15) PainCart 
assessments in Period 3. Participant demographics, safety, PK and target engagement 
may also be assessed at this interim (see Section 9.5 for further information). 
An interim analysis to assess the PD PainCart (three primary endpoints) and safety may 
occur once the final participant has completed their final (day 15) PainCart assessments 
in Period 3. Participant demographics may also be assessed at this interim (see Section 
9.5 for further information). 
 
4.2. 
Number of Participants 
Thirty healthy male participants will be enrolled into the study, such that at least 
approximately 24 participants complete all activites with the exception of the UVB on 
irradiated skin assessments, in all three study periods. If participants prematurely 
discontinue the study, additional replacement participants may be randomized, in order to 
guarantee that sufficient participants complete all three study periods. Replacement 
participants will be assigned to the same treatment sequence as the participant that they 
are replacing, at the discretion of the Sponsor and in consultation with the Principal 
Investigator. 
Of the maximum thirty to be enrolled, approximately 18 healthy male participants are to 
be enrolled as part of the UVB population such that approximately 15 subjects complete 
the UVB heat pain detection test of the PainCart assessment on irradiated skin in all three 
study periods, in addition to the rest of the assessments. 


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4.3. 
Scientific Rationale for Study Design 
The models allow a mechanistic approach to investigation of new drugs for pain, assessed 
in a controlled environment and allowing investigation of PK / TE / PD correlations. A 
number of existing drugs approved for treatment of pain have been used to validate these 
models [Hay, 2016; Okkerse, 2017] and although there are a few instances where the 
drugs fail to elicit a predicted response, the refinement/ standardisation of the models has 
improved this or allowed in part an explanation behind these discrepancies. The models 
allow investigation of specific pain mechanisms in a quantitative way. 
This provides additional information on the translation from animal models to the 
patients and thus can potentially assist in designing further clinical trials in patients by 
selection of the best patient population. 
The PainCart performed in this study is an integrated, multi-modal pain task battery of 
tests designed to investigate the efficacy of analgesic compounds against several types of 
pain, including thermal, electrical and mechanical pain. The models applied in the 
PainCart have been tested for predictive validity and reliability and can be used 
repeatedly, quickly, in short succession in healthy participant and patient studies. 
The PainCart consists of the following tests (see Appendix 7 for further details): 
• UVB burn model of inflammation (primary hyperalgesia) 
• Cold pressor test (acute cold-induced ischaemic pain and conditioned pain 
modulation) 
• Electrical pain test of nociceptor activation 
• Pressure pain test of muscle nociception 
For both UVB Heat Pain Detection and Cold Pressor time to intolerable pain 
threshold, the sample size is higher than that required for the Electrical Pain Test. 
Therefore, for the UVB-MITT population approximately 18 participants are required 
to be enrolled to ensure that approximately 15 participants complete all UVB heat 
pain detection tests of the PainCart assessment on irradiated skin in all three study 
periods.   
4.3.1. 
Participant Input into Design 
This is a study run in healthy participants. No participant input was taken into the design 
of this study. 
4.4. 
Justification for Dose and Washout Period 
The dose level of 3mg/kg, the 2-week testing duration of each study period, the wash out 
period of at least 4 weeks, the IV route of administration and the post dose assessment 
times of Day 1, Day 2, Day 8 and Day 15 are selected for the PainCart study based on: 


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The dose by IV route is equivalent to the dose of 240mg SC proposed to be administered 
in an on-going repeat dose study in osteoarthritis patients (207804) and was administered 
in a healthy participant cohort in that study (3 mg/kg IV).Serum levels of total 
(complexed, free and partially complexed) GSK3858279 are below the lower limit of 
quantification (LLQ; 100 ng/mL) after 8 weeks following IV infusion at 3 mg/kg; based 
on data from a fully validated non-neutralising anti-idiotype capture (NNAIC) assay 
[GlaxoSmithKline Document Number 2020N429762_00]. 
• Unbound CCL17 levels in serum have returned to approximately 30% of baseline 
at 4 weeks post dose.   
o A simulation plan was designed in order to investigate whether the 
statistical modelling for the PainCart assessments could control the 
potential properties of carry over effect. The plan details simulating carry 
over by varying different levels of drug accumulation in to the subsequent 
period, and the number of days it took for the drug to be eliminated.  The 
results from the simulation showed even in the most extreme scenario 
(40% accumulation, 2 weeks reduction) the model was capable of 
extracting the treatment differences while controlling any potential carry 
over effects.  
o Given the statistical model chosen for analysis, and no increase in risk of 
safety, the washout period of at least 4 weeks is selected and still 
considered sufficient (data on file). 
• Target engagement (percentage reduction from baseline of free CCL17) is above 
90% within 24 hours of dosing IV and continues to 1-week post IV dose of 
3 mg/kg. TE falls to 75% after 2 weeks post dose IV. 
• tmax is at end of IV dose administration allowing PainCart testing to be scheduled 
at consistent fixed timepoints relative to dosing. 
4.5. 
End of Study Definition 
A participant is considered to have completed the study if he has completed all phases of 
the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
Participant must be 18 to 50 years of age inclusive, at the time of signing the informed 
consent.  
Type of Participant and Disease Characteristics 
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, vital signs and cardiac 
monitoring.  
Weight 
Body weight within 50–100 kg and body mass index (BMI) within the range 
18----30kg/m2 (inclusive). 
Sex 
Must be Male: 
Participants must agree to the following during the intervention period and for at least 90 
days after the last dose of study intervention:  
• 
Refrain from donating sperm. 
PLUS, either: 
• 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR: 
• 
Must agree to use contraception/barrier as detailed below: 
o Agree to use a male condom  
o And should also be advised of the benefit for a female partner to 
use a highly effective method of contraception (see Section 10.4, 
Appendix 4) as a condom may break or leak when having sexual 
intercourse with a woman of childbearing potential who is not 
currently pregnant. 


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Informed Consent 
Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History or presence of/significant history of or current cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study intervention or interfering with the 
interpretation of data 
2. Personal or family history of cardiomyopathy. 
3. Abnormal blood pressure as determined by the investigator. 
4. Symptomatic herpes zoster within 3 months prior to screening. 
5. Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, and TB testing: a positive (not indeterminate) QuantiFERON-TB Gold 
test. 
NOTE: The QuantiFERON-TB Gold 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. 
6. Significant allergies to humanized monoclonal antibodies. 
7. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear immunoglobulin A (IgA) dermatosis, 
toxic epidermal necrolysis, and exfoliative dermatitis) 
8. Lymphoma, leukaemia, or any malignancy. Those who are at risk of DNA repair 
diseases or any family history of DNA repair disease. 
9. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN). 
10. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
11. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
12. QTc >450 msec 
 NOTES: 


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• 
The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read. 
• 
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject will be QTcF. In other words, several 
different formulae cannot be used to calculate the QTc for an individual subject 
and then the lowest QTc value used to include or discontinue the subject from 
the trial. 
• 
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP). 
13. History of Stevens-Johnson Syndrome. 
14. Known immunodeficiency. 
15. Participants with an acute, re-current or chronic infection (e.g., osteomyelitis), who 
have been receiving treatment within three months prior to dosing or individuals with 
an active infection. 
16. Previous or current history of excessive bleeding or coagulation disorders. 
17. Previous history of hypertrophic or keloid scarring. 
18. Any current, clinically significant, known medical condition in particular any existing 
conditions that would affect sensitivity to cold (such as atherosclerosis, Raynaud’s 
disease, urticaria, hypothyroidism) or pain (such as disease that causes pain, 
hypesthesia, hyperalgesia, allodynia, paraesthesia, neuropathy). 
19. Participants indicating pain tests intolerable at screening Participants achieving 
tolerance at >80% of maximum input intensity for cold pressor and electrical pain 
tests are to be excluded.  If pressure pain test tolerance is >80% of maximum input 
intensity they may be enrolled as per PI judgement 
20. History or presence of post-inflammatory hyperpigmentation. Applicable for the 
participants in the UVB-MITT population only.  
21. Participants with Fitzpatrick skin type IV, V or VI. Applicable for the participants in 
the UVB-MITT population only.  
22. Any of the following on the proposed test area on the back: widespread acne, 
freckles, tattoos, birthmarks or scarring (investigator discretion may be used to 
determine if small areas may be avoided in the testing area on the back). Applicable 
for the participants in the UVB-MITT population only.  
23. A minimal erythema dose (MED) higher than 355 mJ/cm2 at screening. Applicable 
for the participants in the UVB-MITT population only.  
Prior/Concomitant Therapy 
24. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 7 days prior to  dosing until after follow-up visit. 


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25. Live vaccine(s) within 1 month prior to dosing or plans to receive such vaccines 
during the study. 
26. Treatment with biologic agents (such as monoclonal antibodies including marketed 
drugs) or immunosuppressants within 3 months or 5 half-lives (whichever is longer) 
prior to dosing. 
27. Treatment with anti-platelet or anti-coagulant agents within 7 days of dosing. 
28. Major surgery (as per investigator’s judgement) within 3 months prior to dosing. 
Prior/Concurrent Clinical Study Experience 
29. Participant has made a blood or plasma donation or has had a comparable blood loss 
(>450mL) within the last 3 months prior to the Screening Visit. Blood donation 
during the study is not permitted. 
30. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 
31. Current enrolment or past participation in any other clinical study involving an 
investigational study intervention within the last 3 months, 5-half-lives or twice the 
duration of the biological product before dosing in this current study.  
Diagnostic assessments 
32. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention. 
33. Presence of Hepatitis B core antibody (HbcAb) at screening or within 3 months prior 
to first dose of study intervention. 
34. Positive Hepatitis C antibody test result at screening or within 3 months prior to first 
dose of study intervention. 
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained 
35. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention. 
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing 
36. Abnormal clinically significant echocardiogram at screening, as assessed by the 
investigator. 
37. Cardiac troponin T or NT-proBNP levels out of normal range at screening. 
38. Positive pre-study drug/alcohol screen. 
39. Positive human immunodeficiency virus (HIV) antibody test. 
40. Regular use of known drugs of abuse. 
41. Estimated glomerular filtration rate (eGFR) of <90 mL/min/1.73 m2 or serum 
creatinine >1.5xULN or urine albumin:creatinine ratio of >300mg/g at screening. 


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42. Positive SARS-CoV-2 PCR or rapid antigen test at screening  Participants may be re-
screened once they present a negative SARS-CoV-2 PCR or rapid antigen test 
Other Exclusions 
43.  Subjects with known COVID-19 positive contacts in the past 14 days 
44. Regular alcohol consumption within 6 months prior to the study defined as:  
• 
an average weekly intake of >21 units for males. One unit is equivalent to 8 g of 
alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of spirits.  
45. Smoker, smoking history or use of tobacco- or nicotine-containing products (e.g. 
nicotine patches or vaporizing devices) within 6 months prior to screening. 
46. Sensitivity to heparin or heparin-induced thrombocytopenia. 
47. 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 
Poppy seed or foods containing poppy seeds are not permitted from 3 days before 
screening, dosing and until the end of the last study period. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants will not be allowed to have excessive caffeine consumption, defined as 
>800 mg per day from 7 days prior to the first dose of the study drug until 24 hours 
prior to dosing. Participants will abstain from caffeine-containing products for 24 
hours prior to each visit to the study unit. Caffeine quantities defined as: one cup of 
coffee contains 100 mg of caffeine; one cup of tea, or one glass of cola, or portion of 
chocolate (dark: 100 g, milk: 200 g) contains approximately 40 mg of caffeine; one 
bottle of Red Bull contains approximately 80 mg of caffeine. 
• 
Alcohol will not be allowed from at least 24 hours before each scheduled visit, and 
whilst in the study unit until discharge from the study unit. At other times throughout 
the study, participants should not consume more than 2 units of alcohol daily on 
average (one unit is 8 g of alcohol). Participants may undergo an alcohol breath test 
at the discretion of the investigator.  
• 
Participants will abstain from the use of tobacco- or nicotine-containing products 
(including e-cigarettes and patches) from the screening visit throughout the study 
until the final follow-up visit. 
5.3.3. 
Activity 
• 
Strenuous physical activity (e.g., heavy lifting, weight or fitness training) is not 
allowed from 48 hours prior to each study day (including screening) until discharge 
from the study unit. Light ambulatory activities (e.g. walking at normal pace) will be 


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permitted, with the level of activities kept as similar as possible on all days in the 
study unit.  
5.3.4. 
Exposure to sunlight 
Participants, who will form the UVB-MITT population, are asked not to expose their 
back to excessive sunlight or to sunbathe, including sun tanning in a sun booth and 
chemical spray tans, between screening and last study period Day 15. This restriction is 
not required for volunteers who do not receive the UVB application sessions. 
5.3.5. 
SARS-CoV-2 related restrictions 
Participants will be required to adhere to the measures and procedures outlined in CHDR 
SOP GGECOVID, based on the advice issued by the Dutch Centre for Infectious Disease 
Control (RIVM) and COVID-19 measures declared by the Dutch government, to reduce 
risk of  SARS-CoV-2 infections among trial participants and clinical site staff. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 
5.4.1. 
Re-screening 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once, including if a positive SARS-Cov-2 test results is obtained 
Rescreened participants should be assigned a new participant number. 
5.4.2. 
Re-testing of Clinical Laboratory Values during Screening 
If a participant fails any of the laboratory criteria, the test may be repeated once within 
the screening period. If the participant fails the laboratory criteria for a second time they 
will be considered a screen failure. The urine drug screen can only be repeated for a valid 
reason (e.g. false positive result due to medication use, poppy seed consumption). 
If a blood sample needs to be repeated due to sample handling problems, breakage or 
sample integrity, this is not considered a re-testing. Further details regarding the 
procedure for re-testing may be found in the Study Reference Manual (SRM).  
 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention or placebo intended to be 
administered to a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
ARM Name 
Active 
Placebo 
Intervention Name 
GSK3858279 
Placebo 
Type  
Biologic 
Placebo 
Dose Formulation  
Solution for injection.  
GSK3858279 is formulated 
in 0.79 mg/mL sodium 
acetate, 50 mg/mL Sorbitol, 
0.4 mg/mL polysorbate 20, 
glacial acetic acid 0.28 
mg/mL, water for injection, 
pH 5.0. GSK3858279 
contains no preservative. 
Solution for injection. 
Normal Saline (0.9% sodium 
chloride) 
Unit Dose Strength 
50 mg/mL. Each vial has an 
extractable volume of 3.0 
mL (150 mg per vial). 
0.9% w/v sodium chloride, 
placebo level variable. 
Dosage Levels 
3 mg/kg.  
Single dose, once per study 
period. 
Single dose, once per study 
period. 
Route of Administration 
IV Infusion 
IV Infusion 
Dosing Instructions 
GSK3858279 will be infused 
over 1 hour. GSK3858279 
can be diluted in normal 
saline prior to administration  
The appropriate volume of 
placebo will be infused over 1 
hour.  
Use 
Experimental 
Placebo-control 
IMP and NIMP 
IMP 
Placebo 
Sourcing 
Study medication is 
supplied by GSK. 
Provided locally by the trial 
site, subsidiary, or designee. 


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Packaging and Labelling 
Bulk supplies will be 
provided in a vial contained 
within a carton. Each vial 
and carton will be labelled 
as required per country 
requirement. Dispensed 
medication will be labelled 
as required per country 
requirement. 
Commercial presentation. 
Dispensed placebo will be 
labelled as required per 
country requirement. 
6.2. 
Preparation/Handling/Storage/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 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 investigator and 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.  
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
At Screening a unique Participant Number (case report form [CRF] 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 screening eligibility criteria will be randomized to a treatment 
group through RAMOS NG. The randomization is centrally controlled by RAMOS NG. 


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RAMOS NG will confirm the participants CRF number (Participant number) and provide 
the randomization number, where: 
• A randomization number will be assigned from a randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software. Once assigned, this number must not be reassigned to any other 
participant in the study. 
In each period participants will receive either GSK3858279 or placebo in a 1:1 ratio 
where the intervention codes are as follows: 
Intervention code 
Intervention Description 
A 
3 mg/kg IV GSK3858279 
P 
Placebo  
 
During the trial, participants will receive both treatments, either two doses of 
GSK3858279 and one dose of placebo, or two doses of placebo and one dose of 
GSK3858279 with equal likelihood, the order of treatment assignments will be 
randomized. The exact sequences will be blinded to the blinded investigator site staff and 
participants to prevent bias. Participants will be randomized to a specific sequence on 
Day 1 of the first study period. 
The randomization will be stratified based on whether the pain assessments will be 
performed in the morning or afternoon.    
6.3.2. 
Blinding 
This will be a double-blind study with respect to allocation of GSK3858279 or placebo to 
participants and the following will apply. 
• The investigator or treating physician may unblind a participant’s intervention 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study intervention is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
investigator. 
• 
The interactive voice response system (IVRS)/ interactive web recognition system 
(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 
safety must always be the first consideration in making such a 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 treatment 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 the source documentation and CRF, as applicable. 


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• If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
intervention assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study. 
• The date and reason for the unblinding must be fully documented in the CRF 
• 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 the CRF. The participant will be followed up for safety monitoring if 
treatment was received. 
• GSK’s Safety and Medical Governance (SMG) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that 
an expedited regulatory report be sent to one or more regulatory agencies, a copy 
of the report, identifying the participant’s intervention assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy. 
• There will be an unblinded site pharmacist to prepare the study intervention; 
however, they will not have contact with study participants.  
• There may be two interim analyses performed (see Section 9.5 for details). 
Unblinded data will be reviewed by members of the GSK3858279 team who do 
not have direct contact with the study site or participants.   
6.4. 
Study Intervention Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 
• 
Participants will receive study intervention at the clinical unit directly from the 
investigator or designee, under medical supervision, via IV 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. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 


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potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study.  
6.5.1. 
Permitted Therapies 
Paracetamol at doses of 3 grams/day, is permitted for use at any time during the study 
except those times referred to in Section 6.5.2. 
Ibuprofen at doses of 1.2 grams/day, is permitted for use at any time during the study 
except those times referred to in Section 6.5.2. 
6.5.2. 
Prohibited Medications 
The following restrictions apply from first dose up until the 8-week follow-up visit 
Medication  
Pre-dose restriction  
Other times 
Ibuprofen 
2 days 
For 2 days prior to admission 
to unit and PainCart 
assessment (applicable from 
screening and during study) 
Paracetamol 
2 days 
For 2 days prior to admission 
to unit and PainCart 
assessment (applicable from 
screening and during study) 
All other pain medication including 
topical 
1 month 
From screening to 8-week 
follow-up 
Live vaccine(s) 
1 month 
Throughout and for five half-
lives after last dose 
Biologic agents (monoclonal antibodies, 
therapeutic proteins) 
3 months or 5 half-
lives (whichever is 
the longer) 
Throughout 
Antiplatelet or anticoagulant agents 
7 days 
Throughout 
Immunosuppressants 
3 months or 5 half-
lives (whichever is 
the longer) 
Throughout 
Systemic corticosteroids 
(inhaled administration is allowed) 
Parenteral: 3 months 
Oral: 1 month 
Throughout  


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6.6. 
Dose Modification 
No modification of the dose-level is planned on the study. 
6.7. 
Intervention after the End of the Study 
GSK will not provide treatment after the end of the study. 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Study Stopping Criteria 
Recruitment will be halted by the sponsor if any of the following occur in participants 
receiving GSK3858279: 
• Two participants experience the same SAE that is considered related to 
GSK3858279 
• Two participants experience the same significant clinical or significant laboratory 
abnormality that may plausibly relate to GSK3858279 (according to the clinical 
judgement of the investigator)  
• Two participants present with unexplained and clinically significant muco-
cutaneous bleeding (according to the clinical judgement of the investigator and 
medical monitor) that is considered causally related to GSK3858279.  
Recruitment may be resumed after appropriate positive review of safety findings by the 
Principal Investigator and GSK Medical Monitor and following approval to restart the 
study from the regulatory agency and ethics committee. 
7.2. 
Discontinuation of Study Intervention 
A participant will be permanently withdrawn from study treatment if any of the following 
symptoms or abnormalities occur, and an investigation will be carried out as described 
below. After withdrawal of treatment (under these conditions), where possible 
participants should complete the Early Withdrawal visit and be followed up for safety 
monitoring. Study medications will be discontinued and the participant withdrawn from 
the study in the event of any of the following: 
 
• All serious infections 
• 
Severe or serious hypersensitivity reactions, including anaphylaxis   
• If the liver chemistry stopping criteria (Section 7.2.1) or QTc stopping criteria 
(Section 7.2.2) are met.   
• Other serious or severe adverse events, at the discretion of the Investigator, after 
consultation with the GSK Medical Monitor.   


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7.2.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm. 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  
• Study intervention will be discontinued for a participant if liver chemistry 
stopping criteria are met: 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious 
adverse event; ULN = upper limit of normal. 
Refer to Appendix 5 for required Liver Safety Actions and Follow up 
Assessments. 
7.2.2. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study intervention.   


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• 
QTcF > 500 msec, 
• 
Increase from baseline:  QTcF > 60 msec 
• 
In this study as QTcF is used for study eligibility, thus QTcF must be used for 
discontinuation decisions. 
• 
QTcF has been chosen for a participant’s eligibility, the same formula must 
continue to be used for that participant for all QTc data being collected for data 
analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.   
• 
If an ECG demonstrates a prolonged QTc, obtain 2 more ECGs over a brief period 
(see Section 8.1.3), and then use the averaged QTc values of the 3 ECGs to 
determine whether the subject should be discontinued from the study. 
• 
If a clinically significant finding is identified (including, but not limited to changes 
from baseline in QT interval corrected using Bazett’s formula [QTcB] or Fridericia’s 
formula [QTcF]) after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. 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. 
7.2.3. 
SARS-CoV-2 related stopping criteria 
If a participant develops COVID-19 like symptoms during the course of the study, 
procedures as specified in CHDR SOP GGECOVID will be followed.  
Withdrawal of participants from the study will be at the discretion of the Principal 
Investigator, but should first be discussed and agreed with the GSK Medical Monitor.  
Further dosing and study related procedures except those required for participant safety 
and well being should be paused until the discussion is complete. 
Participants that test positive for a SARS-CoV-2 infection after the first study dose are 
withdrawn from the study (after discussion with the GSK Medical Monitor and PI) will 
be replaced at the discretion of the Sponsor and in consultation with the Principal 
Investigator.  
Subjects with a SARS-CoV-2 infection will be followed-up according to SOP 
GGECOVID. 
7.3. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 


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• 
The participant will be permanently discontinued both from the study 
intervention and from the study at that time. 
• 
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, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
7.4. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
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. The investigator will maintain a screening 


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log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• 
The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.1.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded. 
• 
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. 
8.1.2. 
Vital Signs 
• 
Tympanic body temperature, pulse rate, respiratory rate, and blood pressure will 
be assessed. 
• 
Blood pressure and pulse measurements will be assessed supine with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available. 
• 
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). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 
blood pressure readings will be used in the analysis. 
 


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8.1.3. 
Electrocardiograms 
• 
Triplicate or single 12-lead ECG will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 7 for QTc 
withdrawal criteria and additional QTc readings that may be necessary. 
• 
At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. 
8.1.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents.  
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the study reference manual or local practice and 
the SoA.  
8.1.5. 
Echocardiogram 
A transthoracic echocardiogram will be performed at screening and repeated if clinically 
significant changes are observed at any time during the study treatment. Images will be 
obtained in standard views. 
8.1.6. 
Skin Reactions 
Skin reactions will be recorded as Adverse Events. The investigator will assess any skin 
reactions for their clinical significance and clinically significant skin reactions (as per 
investigator’s judgement) will be reviewed by a dermatologist and if appropriate a skin 
biopsy will be requested for histological analysis. Further technical details will be 
provided in the SRM. 
8.2. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 


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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7).  
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, 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. 
• 
All AEs will be collected from the start of study intervention until the follow-up 
visit at the time points specified in the SoA (Section 1.3). 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.2.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.  
8.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 


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defined in Section 7.4). Further information on follow-up procedures is given in 
Appendix 3. 
8.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
For all studies except those utilizing medical devices investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure will 
notify the IRB/IEC, if appropriate according to local requirements. 
8.2.5. 
Pregnancy 
• 
Sponsor will make an effort to collect details of all pregnancies in female partners of 
male participants, this will be collected after the start of study intervention and until 
28 weeks after the last dose. 
• 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.3. 
Treatment of Overdose 
For this study, any dose of GSK3858279 greater than the scheduled dose will be 
considered an overdose. GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 56 days post-last dose of 
study intervention). 


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Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
8.4. 
Pharmacokinetics 
Serum samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of GSK3858279 as specified in the SoA. On Day 1, each PK sample 
should be collected as close as possible to the planned time relative to the dose (i.e., time 
zero) administered to the participant on Day 1. The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring, if 
warranted and agreed upon between the investigator and the sponsor. 
Details on PK blood sample collection including processing, storage and shipping 
procures will be provided in the SRM. 
8.4.1. 
Pharmacokinetic Sample Analysis 
Serum (PK) analysis will be performed under the control of GSK Invitro/Invivo 
Translation (IVIVT).  Serum concentrations of GSK3858279 will be determined using 
approved bioanalytical methodology. The bioanalytical site will be detailed in the 
relevant sample processing documents (e.g. SRM) and raw data will be archived in the 
GSK R&D GLP archives. Drug concentration information that may unblind the study 
will not be reported to investigative sites or blinded personnel until the study has been 
unblinded. 
8.5. 
Pharmacodynamics 
Blood samples (approximately 3.5mL) will be collected from participants in this study to 
investigate target engagement, with respect to the data obtained from the PainCart. 
On Day 1, each PD sample should be collected as close as possible to the planned time 
relative to the dose (i.e., time zero) administered to the participant on Day 1. The actual 
date and time of each blood sample collection will be recorded. The timing of PD 
samples may be altered and/or PD samples may be obtained at additional time points to 
ensure thorough PD monitoring, if warranted and agreed upon between the investigator 
and the sponsor. The timing of sample collections may be adjusted based on emerging 
data or other new information for this study to ensure optimal evaluation of target 
engagement. Details of the processing, storage and shipping procedures for all samples 
are provided in the SRM. 
All samples will be retained for a maximum of 15 years after the last participant 
completes the study. 


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8.5.1. 
Target Engagement 
Serum samples for the evaluation of the free and total CCL17. CCL17 can be detected in 
circulation and is the biological target for GSK3858279. The intention is to examine the 
relationship between free and total CCL17 and the effect of administration of 
GSK3858279 on the free levels of CCL17 in the circulation. 
8.5.2. 
PainCart 
Nociceptive pain detection and tolerance thresholds can be measured using the PainCart. 
This is an integrated range of tests for measuring different modalities of nociception. The 
PainCart aims to assess as objectively as possible the levels of pain induced in human 
participants by a variety of potentially noxious stimuli. All measurements will be 
performed in a quiet room with ambient illumination and temperature. Per session, there 
will only be one subject in the same room. During nociceptive tasks, participants will be 
sitting comfortably in a designated chair, with knees supported. The order of the 
individual PainCart assessments will be identical for all participants and for all time-
points. See Appendix 7 for further details. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Biomarkers are not planned to be evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Serum samples (approximately 5 mL) will be collected from all treated participants at 
pre-dose and various time points post-dosing, see SoA. Testing will be performed using 
the typical tiered approach involving screening, confirmation and titration assays 
[EMEA, 2017; FDA, 2014], performed by Clinical Immunology, GlaxoSmithKline. If 
sera contain potential anti-GSK3858279 antibodies, they will be confirmed by immune-
competition using excess drug, followed by a titration assay. Results will include the 
incidence of immunogenicity, antibody specificity and titres. 
For each participant, immunogenicity results, including the incidence and titres, will be 
reported. 
8.9. 
Health Economics 
Health Economics parameters are not evaluated in this study. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The study will test the null hypothesis that there is no difference between GSK3858279 
and placebo versus the alternative hypothesis that GSK3858279 is superior from placebo 
on the endpoints described: UVB heat pain detection test, cold pressor time to intolerable 
pain threshold test and electrical pain tolerance threshold test in the PainCart scale. No 
Adjustment will be made for multiplicity.  
9.2. 
Sample Size Determination 
A maximum of 30 participants will be randomized into the study as per Section 6.3.1 
such that approximately 24 participants complete all three periods of the study (except 
UVB assessments on irradiated skin). Approximately18 subjects will undergo the UVB 
assessments on irradiated skin such that approximately 15 subjects complete the UVB 
assessments in all three periods. 
On each of the three endpoints, a positive conclusion will be declared if, given the data, 
there is at least 90% probability that the ratio vs placebo is better than 1 (no difference) 
and a negative conclusion will be declared if, given the data, there is less than 75% 
probability that the difference vs placebo is better than 1 (no difference). 
The coefficient of variation for each endpoint was estimated from Loudon, 2018; 
Okkerse, 2017; Siebenga, 2019; van Amerongen, 2018, and is shown in Table 1. 
Table 1 
Coefficient of Variability 
UVB heat pain detection (oC) 
Cold pressor time to intolerable 
pain threshold (sec)  
Electrical pain tolerance 
threshold (mA) 
3.7% 
25.6% 
19.1% 
 
With 24 completed participants using a three-period two-treatment incomplete-block 
crossover design, the probability of declaring a positive outcome on each endpoint where 
there is no improvement is fixed at 10% by definition (Type I Error). The operating 
characteristics of each endpoint is provided in Figure 4. 
9.2.1. 
Sample Size Sensitivity 
The impact of increases/decreases in the variability of each endpoint from the expected 
variability is demonstrated in Figure 4 and Figure 5. Subject drop out of 20% is 
accounted for in the sample size. Operating characteristics and probability of positive 
outcomes Figure 4 and Figure 5 are based on a sample size of 24 for Electrical pain 
tolerance and Cold pressor time to intolerable pain threshold, and sample size of 15 for 
UVB heat pain detection on irradiated skin. 


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Figure 4 
Operating Characteristics of Study Design. a: Electrical pain 
tolerance threshold (mA)  b: Cold pressor time to intolerable pain 
threshold (sec)  c: UVB heat pain detection (oC) 
 


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Figure 5 
Probability of positive conclusion based on different assumptions. 
a: Electrical pain tolerance threshold (mA) b: Cold pressor time to 
intolerable pain threshold (sec) : UVB heat pain detection (oC) 


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9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Screened  
• 
All participants who were screened for eligibility 
Randomized  
 
• 
All participants who were randomly assigned to treatment in 
the study. 
• 
This population will be based on the treatment the participant 
was randomized to. 
Enrolled 
• 
All participants who passed screening and entered the study. 
Included are: Run-in Failures; Randomized Participants. 
• 
Note screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into 
the study (Reserve, Not Used) are excluded from the Enrolled 
population as they did not enter the study. 
Safety 
• 
All randomized participants who received at least one dose of 
study treatment. 
• 
This population will be based on the treatment the subject 
actually received. 
Pharmacokinetic (PK) 
• All participants in the Safety population who had at least 1 
non-missing serum PK assessment. 
• 
Note: Non-quantifiable [NQ] values will be considered as non-
missing values 
Intent-To-Treat (ITT) 
• 
All randomized participants who received at least one dose of 
study treatment. 
• 
This population will be based on the treatment the subject was 
randomized to. 
• 
Any participants who receives a treatment randomization 
number will be considered to have been randomized. 
Modified Intent-to-Treat 
(MITT) 
• 
All randomized participants who received at least one dose of 
study treatment and completed at least one PainCart 
assessment in at least two study periods. 
• 
This population will be based on the treatment the subject was 
randomized to. 
• 
Any participants who receives a treatment randomization 
number will be considered to have been randomized. 
UVB-MITT (UVB) 
• 
Those in the MITT Population who also perform the UVB Heat 
Pain detection PainCart assessments on irradiated skin. 


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Population 
Description 
Completers 
• 
All randomized participants who receive at least one dose of 
study treatment in all three periods of the trial and completed 
all scheduled PainCart assessments. 
• 
This population will be based on the treatment the subject was 
randomized to. 
• 
Any participants who receives a treatment randomization 
number will be considered to have been randomized. 
 
9.4. 
Statistical Analyses 
The Reporting and Analysis Plan will be finalized prior to database release (DBR) and it 
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. 
9.4.1. 
General Considerations 
9.4.2. 
Primary Endpoint(s) 
The PainCart measures as described in Section 10.7.2 will be summarized descriptively 
by intervention. A Bayesian repeated measures model using non-informative priors for 
each parameter will be fitted to the change from baseline data using an unstructured 
covariance matrix and, covariates in the model will be detailed in the Reporting and 
Analysis Plan. Posterior probabilities will be determined and presented at each timepoint. 
9.4.3. 
Secondary/Exploratory Endpoint(s) 
Will be described in the Reporting and Analysis Plan. 
9.4.4. 
Other Safety Analyses 
All safety analyses will be performed on the Safety Population and will be presented in 
tabular and/or graphical format and summarised descriptively according to GSK's 
Integrated Data Standards Library standards.  
9.4.5. 
Other Analyses 
A post hoc analysis may be carried out to assess the relationship between the observed 
measures of efficacy and the individual PK exposure or target engagement. If data 
permits, direct  or indirect response models to link efficacy with PK or TE may be 
developed. PK and TE data may be integrated in the previous population PK/TE model 
developed from Part A of study 207804 (GlaxoSmithKline Document Number RPS-
CLIN-015095). 
 


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9.5. 
Interim Analyses 
Two interim analyses may occur during the conduct of the study: 
• An interim analysis may be performed once the final  UVB-MITT participant in 
period 3 has completed the day 15 assessments of the PainCart.  At the interim, 
PainCart, safety, demographics, PK and TE data will be reviewed by the Project 
Leader and selected members of the Project Team and CPEM Leadership.  
Dependent on the results observed in the cold pressor and electrical pain single 
stimulus tolerance endpoints, the study could be stopped for futility. A secondary 
objective for the interim may be to use the analysis for internal decision-making 
purposes. An interim analysis may be performed once the final participant in 
period 3 has completed the day 15 assessments of the PainCart. The interim 
analyses will be used for internal decision making only, no changes to the study 
can occur.  
 
Further details of the interim analyses will be provided in the interim charter. The 
Reporting and Analysis Plan will provide further infomration on the planned statistical 
analyses performed at the interim analyses. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• 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 Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• 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/EC 
• Notifying the IRB/IEC of SAE 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), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre.  
• 
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 re-consented 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 or the participant’s 
legally authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about the study intervention or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the the study 
intervention approved for medical use or approved for payment coverage.  
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. 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 tick box 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. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  


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• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.5. 
Committees Structure 
Not applicable. 
10.1.6. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Disclosure Policy. 
• 
GSK intends to make anonymized patient-level data from this trial 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 trial participants are used to maximum effect in the creation of 
knowledge and understanding 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan. 


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• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 30 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
• 
A retention period of 30 years instead of 25 years is used, as the long-term 
effects of GSK3858279 are still unknown and the to be included healthy 
volunteers could be of relatively young age; thus still with a long life-
expectancy 
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF 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 can be found in a study-specific 
source document agreement. 
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first healthy participant to be screened is considered the first act of recruitment and 
will be the study start date. 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
If the study is prematurely terminated or 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 suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by the 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. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
Blood Urea 
Nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin (direct is 
only measured if 
total >1xULN) 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium 
Alkaline 
phosphatase 
3Complement 
protein C3 and 
C4 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Breath alcohol test 
• Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 


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Laboratory 
Assessments 
Parameters 
• HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B core 
antibody [HbcAb] and hepatitis C virus antibody. 
• QuantiFERON testUrine albumin-creatinine ratio (UACR) 
• 
4SARS-CoV2 PCR or rapid antigen test 
The results of each test must be entered into the medical notes. 
Other 
Screening and 
Follow-Up 
Tests 
• Troponin-T (high sensitivity) 
• NT-proBNP 
NOTES: 
1. 
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 Appendix 5. All events of ALT 3 × upper limit of normal 
(ULN) and 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 as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
2. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
3. 
Complement protein C3 and C4 to be performed Day -1 only (as baseline). 
4. 
Combined throat and nasopharyngeal swab; qPCR will be performed by NMDL-LCPL. Approved rapid antigen 
tests may be used instead of PCR 
 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 


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10.3. 
Appendix 3: Adverse Events: 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 (haematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions 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 drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
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. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 


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Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and SAE 
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, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 


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• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
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. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
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. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her 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. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 


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• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.3.4. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting 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) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line 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 off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
Males must use the male condom or be long-term sexually abstinent as per Section 5.1 
and should be advised of the benefit for a female partner to use a highly effective method 
of contraception as outlined in Section 10.4.1. 
10.4.1. 
Contraception Guidance: 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methods 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 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methods 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 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
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 amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction) 


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10.4.2. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event aetiology.  
Phase 1 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) or 
international normalized ratio (INR)  >1.5, Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin  2xULN or INR 
>1.5 
• Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis as soon as possible, and at 
least within 7 days, post last dose4  
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 


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Liver Chemistry Stopping Criteria  
 
If ALT≥3xULN AND bilirubin < 2xULN and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, 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 
If ALT≥3xULN AND bilirubin  2xULN or 
INR >1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding 
week) James, 2009].  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT  3xULN and bilirubin  2xULN. 
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  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN 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 subjects receiving anticoagulants 
3. Includes: Hepatitis A immunoglobulin (gM) 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) and Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM 
 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. Pharmacokinetics of Acetaminophen-
Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 


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10.6. 
Appendix 6: Abbreviations and Trademarks 
Abbreviations 
AAC 
Area Above the concentration-time Curve 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the concentration-time Curve 
BCG 
Bacillus-Calmette-Guerin 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CCL17 
Chemokine C-C motif ligand 17 
CFR 
Code of Federal Regulation 
CHDR 
Centre for Human Drug Research 
CIOMS 
Council for International Organizations of Medical Sciences 
cm 
Centimetre 
Cmax  
Maximum Observed Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID 
Coronavirus Disease 
CPK 
Creatine Phosphokinase 
CPM 
Conditioned Pain Modulation 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTFG 
Clinical Trial Facilitation Group 
DBR 
Database Release 
DNIC 
Diffuse Noxious Inhibitory Control 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency  
eVAS 
Electronic Visual Analogue Scale 
FDA 
Food and Drug Administration 
FiH 
First in Human 
g 
Gram 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPLC 
High-Performance Liquid Chromatography 
Hz 
Hertz 


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IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgM 
Immunoglobulin G 
INR 
International Normalized Ratio 
IP  
Investigational Product 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IRB 
Institutional Review Board 
IUS 
Intrauterine Hormone-Releasing System 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Recognition System 
kg 
Kilogram 
KPa 
Kilopascal 
LAM 
Lactational Amenorrhoea Method 
LDH 
Lactate Dehydrogenase 
mA 
MilliAmp 
mAb 
Monoclonal Antibody 
MCH 
Mean Corpuscular Haemoglobin 
MCV 
Mean Corpuscular Volume 
MED 
Minimal Erythema Dose 
mg 
Milligram 
mJ 
Millijoule 
mL 
Milliliter  
MSDS 
Material Safety Data Sheet 
NIMP 
Non-Investigational Medicinal Product 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OA 
Osteoarthritis 
PBO 
Placebo 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPE 
Personal Protective Equipment  
QTc 
Electrocardiogram QT interval corrected for heart rate 
QTcB 
Electrocardiogram QT interval corrected for heart rate using Bazett’s formula 
QTcF 
Electrocardiogram QT interval corrected for heart rate using Fridericia’s 
formula 
PDT 
Pain Detection Threshold 
PTS 
Platform Technologies and Science 
PTT 
Pain Tolerance Threshold 
RAMOS NG 
Randomization and Medication Ordering System Next Generation 
RAP 
Reporting and Analysis Plan 
RBC 
Red Blood Cells 


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RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SARS-Cov-2 
Severe acute respiratory syndrome– Coronavirus-2 
SC 
Subcutaneous 
sec 
Seconds 
SGOT 
Serum Glutamic-Pyruvic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SMG 
Safety and Medical Governance 
SRM 
Study Reference Manual 
SoA 
Schedule of Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TARC 
Thymus and Activation Regulated Chemokine 
TB 
Tuberculosis 
TDAR 
T-cell Dependent Antibody Response 
TE 
Target Engagement 
tmax 
Time taken to Maximum Observed Drug Concentration 
TST 
Tuberculin Skin Test 
UACR 
Urine albumin-creatinine ratio 
UK 
United Kingdom 
ULN 
Upper Limit of Normal  
UV 
Ultraviolet 
UVB 
Ultraviolet B 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cells 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
RAMOS NG 
 
PainCart 
 
 
Q-sense 
 
QuantiFERON 
 
Spike2 software 


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10.7. 
Appendix 7: PainCart Details 
At the Centre for Human Drug Research (CHDR), nociceptive (pain) detection and 
tolerance thresholds can be measured using the PainCart. This is an integrated range of 
tests for measuring different modalities of nociception. The PainCart aims to assess as 
objectively as possible the levels of pain induced in human subjects by a variety of 
potentially noxious stimuli. All measurements will be performed in a quiet room with 
ambient illumination and temperature. Per session, there will only be one subject in the 
same room. During nociceptive tasks, subjects will be sitting in a designated chair, with 
knees supported. 
10.7.1. 
Individual Assessments 
10.7.1.1. 
UVB model (Thermal pain, normal & UVB exposed skin) 
UVB irradiation (TL01 [narrow-band], Philips) is applied at the screening visit in 
ascending doses (corresponding to different irradiation times) to 6 different 1 x 1 cm 
areas of skin on the back to determine the individual UVB dose that produces the first 
clearly discernible erythema (MED). The MED is assessed visually. See Table 3 for the 
dosing schedule per skin type (mJ/cm2). 
Two times the MED of UVB (assessed at screening) will be applied on the back, 24±2 
hours prior to the first pain tasks (the day prior to dosing on all 3 study periods and on 
day 7 of all study periods). The area of skin irradiated will be 30 x 30 mm. The procedure 
has been adapted from the methods of Bishop and colleagues [Bishop, 2009], and is 
according to CHDR SOP CCNUVB with the exception that assessment of MED will be 
performed at screening only. 
To assess inflammatory pain, thermal pain tests will be performed first on normal skin 
contralateral to the site of UVB irradiation, then on UVB irradiated skin. On Day 15 
thermal pain tests will only be performed on an area of normal skin on the back, not 
on skin earlier exposed to UVB 
Table 3 
UVB dose regimen per skin type (mJ/cm2). 
 
Skin Type 
Dose (mJ/cm2) 
I 
II 
III 
IV 
#1 
64 
126 
176 
234 
#2 
91 
177 
248 
330 
#3a 
128 
251 
351 
467 
#4 
181 
355 
496 
660 
#5 
256 
502 
702 
934 
#6 
362 
710 
993 
1321 
a - The mean MED according to Sayre et al. [Sayre, 1981]. 
 
10.7.1.1.1. Thermal pain 
Thermal pain detection and tolerance thresholds are determined using the Q-sense 
(Medoc, Israel), which controls a 30 x 30 mm thermode that is placed on the subjects 


T M F -1 3 7 7 8 6 3 4  
C O N FI D E N TI A L  
 
 
 
2 0 9 9 7 3  
 
8 2  
 
bac k. T he i nitial te m perat ure of t he t her m o d e will be 3 2° C a n d will i ncreas e b y 0. 5° C·s -1 
u ntil t he s u bject percei ves t he sti m ul us as pai nf ul ( Pai n Detecti o n T hres h ol d  [ P D T] - 
i n dicate d wit h p us hi n g a b utt o n o n a ha n d-hel d f ee d bac k c o ntr ol) or w he n a te m perat ur e 
of 5 0° C is reac h e d. T he a vera ge of a tri plicat e meas ure me nt will be use d t o deter mi ne 
pai n t hres h ol ds.  
1 0. 7. 1. 2.  
C o nti n u o u s a s s e s s m e nt of p ai n  
Pai n i nte nsit y will be me as ure d c o nti n u o usl y f or eac h of t he f oll o wi n g n o cice pti ve tas ks 
wit h s u bjects rati n g t heir pai n i n te nsit y usi n g a 1 0 0 % e V A S-sli der, wit h 0 a n d 1 0 0 
defi ne d as  
 a n d 
, res pecti vel y. E q ui p me nt is pr o gra m me d 
t o cease gi vi n g sti m uli if pai n i nte nsit y reac h es t he ma xi m u m p ossi ble sc ore. 
Alter nati vel y, all tas ks ha ve a ma xi m u m sa fet y li mit at w hic h t he tas ks a ut o maticall y 
st o ps. 
1 0. 7. 1. 3.  
C ol d Pr e s s or t a s k ( C ol d pr e s s or)  
T he met h o d of c ol d pr ess or pai n is base d o n t he m et h o ds descri be d b y E c k har dt a n d 
c ollea g ues a n d J o nes a n d c ollea g ues [Ec k har dt , 1 9 9 8; J o nes, 1 9 8 8]. S u bjects place t heir 
n o n -d o mi na nt ha n d i nt o a water b at h ( mi ni mal de pt h 2 0 0 m m) at 3 5 ± 0. 5 ° C f or 2 
mi n utes. At 1 mi n ute 4 5 sec o n ds a bl o o d pr ess ure c uff o n t he u p per -ar m will be i nflate d 
t o 2 0 m m H g bel o w resti n g diast olic press ure. At 2 mi n utes t he s u bject will t he n m o ve 
t heir ha n d fr o m t he w ar m water bat h, directl y placi n g t heir h a n d i nt o a si milar size d bat h 
at 1. 0 ± 0. 5 ° C. T he s u bjects will be i nstr ucte d t o i n dicate w he n p ai n detecti o n t hres h ol d 
is reac h e d (first c h a n ge i n se nsati o n fr o m c ol d n o n-pai nf ul t o pai nf ul) as w ell as t he 
i ncreas e i n pai n i nte nsit y, b y m o vi n g t he e V A S sli der. W he n pai n t olera n ce is reac h e d 
(se nsati o n is n o l o n ger t olera ble; e V A S sli der at 1 0 0 m m), or w he n a ti me li mit ( 1 2 0 s) is 
reac h e d, s u bjects are i nstr ucte d t o re m o v e t heir ha n d fr o m t he water, at w hi c h p oi nt t he 
bl o o d press ure c uff will deflate.  
1 0. 7. 1. 4.  
El e ctri c al sti m ul ati o n t a s k ( El e ctri c al st air)  
F or c uta n e o us ele ctrical pai n, t w o electr o d es ( A g -A g Cl) are place d o n cl ea n (scr u b be d) 
s ki n o verl yi n g t he left ti bial b o ne 1 0 0 m m distal fr o m t he ca u dal e n d of t he patella 
( mi d dle of t he first electr o de is place d 1 0 0 m m distal t he ca u dal e n d of t he patella a n d 
mi d dle of t he sec o n d el ectr o de 1 3 5 m m directl y u n der neat h t he first). Electrical 
resista nce b et wee n electr o des s h o ul d be less t ha n 2 k Ω.  
F or si n gle (stair) sti m ul us, eac h sti m ul us ( 1 0 -Hz teta nic p ulse wit h a d urati o n of 0. 2 ms) 
is c o ntr olle d b y a c o m p ut er-c o ntr olle d c o nsta nt c urre nt sti m ulat or. C urre nt i nte nsit y 
i ncreas es fr o m 0 m A i n ste ps of 0. 5 m A·s-1 ( c ut-off  5 0 m A). T he p ai n i nte nsit y after 
eac h sti m ulati o n is meas ure d usi n g t h e e V A S, u ntil pai n t olera nce le vel is reac h e d or a 
ma xi m u m of 5 0 m A is reac he d ( A da pte d fr o m t he met h o d of Ol ofse n a n d c ollea g u es) 
[Da ha n , 2 0 0 4; Ol ofse n , 2 0 0 5 ]. 
F or re peat e d ( b urst) sti m ul us, eac h si n gle sti m ul us is re peate d 5 ti mes wit h a fre q u e nc y of 
2 Hz. Pai n t hres h ol d is ta ke n as t he val u e ( m A) w here b y a s u bj ect i n dicates eit her: all 5 
sti m uli are pai nf ul, or t he trai n of 5 sti m uli starte d feeli n g n o n-pai nf ul b ut e n ds feeli n g 
C CI
C CI


T M F -1 3 7 7 8 6 3 4  
C O N FI D E N TI A L  
 
 
 
2 0 9 9 7 3  
 
8 3  
 
pai nf ul ( V A S > 0) ( A da pte d fr o m t he met h o d of Are n dt -Nielse n a n d c ollea g ues)  [Are n dt -
Nielse n , 2 0 0 7]. 
T o meas ure c o n diti o ne d p ai n m o d ul ati o n  ( C P M; f or merl y diff us e n o xi o us i n hi bit or y 
c o ntr ol [ D NI C]), t he si n gle sti m ul us will be re peate d wit hi n 5 mi n utes of t he e n d of t he 
c ol d press or tas k.  
1 0. 7. 1. 5.  
Pr e s s ur e sti m ul ati o n t a s k ( Pr e s s ur e p ai n)  
T his met h o d of press ure pai n i n d ucti o n has bee n s h o w n t o pri mar il y assess n ocice pti o n 
ge n erat e d fr o m t he m uscl e wit h mi ni mal c o ntri b uti o n b y c ut a ne o us n ocice pt ors a n d is 
base d o n met h o ds descri be d b y P olia ns kis a n d c ollea g ues [P olia ns kis , 2 0 0 1]; P olia ns kis , 
2 0 0 2] . Briefl y, a n 1 1 c m wi de t o ur ni q uet c uff ( V B M Me dizi ntec h ni k G m b H, S ulz, 
Ger ma n y) is pla ce d o ver t he gastr oc ne mi us m uscl e wit h a c o nsta nt pr ess ur e rate i ncrease 
of 0. 5 k Pa/s c o ntr olle d b y a n electr o -p ne u matic re g ulat or (I T V 1 0 3 0 -3 1 F 2 N 3 -Q, S M C 
C or p orati o n, T o k y o, J a pa n), P o wer 1 4 0 1 m kII a nal o g ue – t o-di gital c o n verter a n d S pi ke 2 
s oft ware ( C E D, Ca m bri d ge, U K). T h e s u bject sits c o mf orta bl y wit h t heir f o ot flat o n t he 
fl o or a n d rat es t heir pai n i nte nsit y usi n g t he e V A S, wit h 0 a n d 1 0 0 defi ne d as 
a n d
, res pecti vel y. T he p ne u matic press ure is i ncreas e d u ntil t he 
s u bject i n dicates t heir pai n t olera nce t hres h ol d, or a ma xi m u m press ure of 1 0 0  k Pa is 
ac hie ve d, at w hic h p oi nt t he de vice releas es press ure t o t he t o ur ni q uet.  
1 0. 7. 2.  
P ai n C art E n d p oi nt s  
A A C: Area a b o ve t he c ur ve fr o m e V A S, A U C = area u n der t he c ur ve fr o m e V A S, P D T = 
pai n detecti o n t hres h ol d, P T T = pai n t olera nce t hr es h ol d, (e) V A S = (electr o nic) vis ual 
a nal o g ue scale  
•  T her mal Pai n ( N or m al S ki n): P D T  
•  T her mal Pai n ( U V B s ki n): P D T  
•  C ol d Press or: P D T, P T T, A A C,  p ost -test V A S  
•  Electrical stair ( pre -c ol d press or): P D T, P T T, A U C, p ost -test V A S  
•  Electrical stair ( p ost -c ol d press or): P D T, P T T, A U C, p ost -testV A S  
•  Electrical b urst: P D T, P T T, A U C, p ost -test V A S  
•  Press ure Pai n: P D T, P T T, A U C, p ost -test V A S  
F or Pai n Cart ass ess me nts, baseli ne is defi ne d as t he a vera ge v al ue pri or t o d osi n g i n eac h 
sessi o n. 
1 0. 7. 3.  
Or d er of P ai n C art a s s e s s m e nt s  
Or der of Pai n Cart assess me nts will be as s pecifie d i n C H D R S O P  
C CI
C CI


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10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 3 10-AUG-2020 
Overall Rationale for the Amendment: Change to Analysis Populations.  Populations 
are now UVB-MITT who undergo all assessments and MITT population who do not 
receive UVB irradiation (and not perform UVB heat pain detection assessment on 
irradiated skin). In addition, changes to expand age range and amendment of certain 
exclusion criteria in order to reduce volunteer burden and aide recruitment. 
Risk Benefit Analysis has also been amended in protocol amendment 03 to reflect 
changes made to the study design and new safety guidance available. 
As a result of the worldwide pandemic of COVID-19, throughout the protocol there have 
been addition of SARS-Cov2 screening and mitigation strategies to ensure the safety of 
the study participants. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis 
Explanation of UVB-MITT population  
 
 
Clarification of visit days for UVB-MITT 
population 
This is to clarify that not all 
participants will be required 
to receive UVB irradiation 
This is to clarify how the visit 
days differ for the UVB-
MITT population 
Section 1.2 figure 
3 
Clarification of measurements for UVB-
MITT population  
This is to clarify which of the 
new analysis populations 
receive UVB irradiation and 
assessments 
Section 1.3.1 
Schedule of 
Activites 
Clarification of assessments for UVB-MITT 
Population 
 
 
This is to clarify which of the 
new analysis populations 
receive UVB irradiation and 
assessments 
Section 1.3.2 
Schedule of 
Activites 
Clarification of assessments for UVB-MITT 
Population 
 
 
Addition of Day -2 
This is to clarify which of the 
new analysis populations 
receive UVB irradiation and 
assessments 
This is to accommodate a 
COVID-19 test prior to UVB 
exposure 
Section 1.3.2 
Schedule of 
Activites 
Addition of an extra blood sample for PK 
and PD assessments 
This is to allow for a better 
estimate of Cmax and link to 
the target engagement 


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Section # and 
Name 
Description of Change 
Brief Rationale 
2.3.1 Risk 
Assessment 
Change to minimum monitoring time post-
dose 
 
Clarity that UVB irradiation and UVB test 
risk only applicable to UVB-MITT 
population 
Update to participant monitoring for 
potential risk ‘Hypersensitivity, including 
injection site and infusion reactions 
Update to summary of rationale for 
potential risk ‘risk fo infection’ 
To make consistent with 
other ongoing study 
(207804) with GSK3858279 
Change to Analysis 
populations  
 
Inclusion of additional 
information from ongoing 
First in human study.  
Clarification on 
immunosuppressive action 
of CCL17. 
4.2 Number of 
Participants 
Addition of analysis populations and detail 
minimum number to be enrolled into the 
UVB-MITT population 
Change to analysis 
populations 
4.3 Scientific 
Rationale for Study 
Design 
Clarification given for the number of 
volunteers needed for UVB-MITT 
Population 
Change to analysis 
populations 
4.4 Justification for 
Dose and Washout 
Update to GSK 3858279 limits of 
quantification and return to baseline 
(washout) 
New data available on file 
for GSK3858279 from study 
207804 
5.1 Inclusion 
Criteria 
1.Extending upper range of age to 50 years To make consistent with 
other ongoing study 
(207804) with GSK3858279 
5.2 Exclusion 
Criteria 
19.  Subjects failing PainCart assessments 
on exploratory endpoints (e.g. pressure 
pain) during screening visit may still be 
enrolled into study 
This is an exploratory 
measure 
5.2 Exclusion 
Criteria 
29- 22 criteria specifically for UVB-MITT 
population 
 
Change to analysis 
populations 
5.3.4 Exposure to 
sunlight 
Exposure to sunlight restriction lifted for 
MITT-Population 
Restriction only required for 
volunteers having UVB 
irradiation in UVB-MITT 
population 
7.2.2 QTc 
Stopping Criteria 
Clarification of QTc recording method  
This is to clarify wording on 
the number of replicate 
ECGs required to meet the 
stopping criteria  
8.1.3 
Electrocardiograms 
Amendment to ECG timings  
Reduced from 4 to 2 
minutes  
8.4.1 
Pharmacokinetcis 
Sample Analysis 
Amendment to name of the group 
completing PK sample analysis 
Group completing PK 
analysis have changed 
name 


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Section # and 
Name 
Description of Change 
Brief Rationale 
9,2 Sample Size 
Determination 
Addition of sample size determination for 
UVB-MITT Population  
Change to analysis 
populations 
9.3 Populations for 
analysis  
Addition of UVB-MITT and PK populations  
Change to analysis 
populations 
1.2 Schema,  
1.3 Schedule of 
events, 
2.2 Background 
2.3.1 Risk 
Mitigation 
4.1 Overall Design 
5.2 Exclusion 
criteria 
5.3 Lifestyle 
considerations 
5.4.1 Re-screening 
7.2 Discontinuation 
of Study 
Intervention 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
Addition of COVID-19 related measures 
Minimize risk of COVID-19 
pandemic effects on study 
and subject safety 
Throughout the 
document  
Minor changes to clarify meaning of 
existing text 
 
 
Amendment 2 11-FEB-2020 
Overall Rationale for the Amendment: Correction to certain exclusion criteria in order 
to streamline with the other related exclusion criteria. A minor correction to one of the  
objectives and endpoints, and washout period of few of the prohibited medications. 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 
Synopsis & 
3. 
Objectives 
and 
Endpoints 
Conditioned Modulation Pain (CPM) endpoint 
units corrected to “mA” from “seconds” 
Error in original protocol 
Table 1.3.2 
Footnote updated to clarify that the planned 
study assessments on day 25 may also be 
performed within a ± 24hr window 
Omitted in error from original 
protocol 
2.3.1 Risk 
Assessment 
In Vaccination reactions row, Mitigation 
Strategy column, text has been updated to 
Error in original protocol 


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Section # 
and Name 
Description of Change 
Brief Rationale 
reflect washout being effective before dosing 
and not screening for live vaccination 
5.2. 
Exclusion 
Criteria 
Exclusion criteria no. 24, 25, 26, 27 and 31 are 
updated to reflect that prescribed washout 
periods for over the counter medications, anti-
platelet therapies and investigational biologic 
agents, are till the dosing day in this study 
rather than screening.  
Error in original protocol 
6.5.2 
Prohibited 
Medications 
Clarification of Prohibited medication washout 
period applying to the dosing day rather than 
screening. 
Error in original protocol 
 
Amendment 1 23-SEP-2019 
Overall Rationale for the Amendment: Feedback from Scientific Review meeting and 
Ethics Committee following protocol finalisation. Updates to SoA, Table 2 and Appendix 
7 for clarity. 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1. and 3. 
Objectives 
and 
Endpoints 
Heat pain detection on normal skin 
associated with UVB test is added 
to list of endpoints 
Omitted in error from original protocol 
1.3. Schedule 
of Activities 
C3/C4. Note added to clarify 
performed on Day -1 
 
PainCart: Note added to specify 
thermal test associated with UVB 
test performed on normal skin Day 
15 
 
Study Visit: 24hr window for 
study visit on day 7,8 & 15 
 
An echocardiogram performed 
within 3 months prior to first 
dosing is acceptable for enrolment 
into the study  
 
MED determination performed 
within 6 weeks prior to first dosing 
is acceptable for enrolment into 
the study  
 
Day of test confirmed to ensure taken as 
baseline measure 
 
No UVB irradiation is performed for Day 
15 however testing on normal skin is to be 
performed on Day 15 
 
 
Flexibility for study scheduling 


TMF-13778634 
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Section # 
and Name 
Description of Change 
Brief Rationale 
5.3.2. 
Caffeine, 
Alcohol and 
Tobacco 
One unit of alcohol corrected to 8g 
of alcohol 
Error in original protocol 
9.3 
Populations 
for Analyses 
Included a new population 
“Modified Intent-to-Treat” (MITT) 
and amended the definition of the 
“Completers” population 
 
MITT is the primary PainCart population.  
Completers definition updated to reflect all 
PainCart assessments completed. 
9.4.5. Other 
Analyses 
10.1.7 Data 
Quality 
Assurance 
Study number (207804) added for 
clarity 
Study retention changed from 25 
to 30  years 
And sentence added  ‘A retention 
period of 30 years instead of 25 
years is used, as the long-term 
effects of GSK3858279 are still 
unknown and the to be included 
healthy volunteers could be of 
relatively young age; thus still with 
a long life-expectancy’ 
 
Omitted in error from original protocol 
 
Request to change to comply with Local 
competent authority guidelines and 
consistency with protocol 
 
10.1.9. Study 
and Site Start 
and Closure 
Reason for early closure of study 
'Discontinuation of further study 
intervention development' deleted. 
This is not a valid reason for early 
termination of study  
10.2. Protocol 
Required 
Safety 
Laboratory 
Assessments 
Footnote 3 updated to state C3/C4 
performed on Day -1 as baseline 
measure 
Day of test confirmed to ensure taken as 
baseline measure 
10.7.1.1 
UVB model 
(Thermal 
pain, normal 
& UVB 
exposed skin) 
Sentence added to specify thermal 
test associated with UVB test 
performed on area of normal skin 
of the back on Day 15 
No UVB irradiation is performed for Day 
15 however testing on normal skin is to be 
performed on Day 15 
10.7.3. Order 
of PainCart 
Assessments 
Added reference to SOP regarding 
order of assessments in PainCart  
Order of assessments is specified to 
ensure minimal carry over between 
assessments 
 
 
 


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11. 
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of single intravenous and subcutaneous doses of GSK3958279 in healthy participants. 
Effective Date 02-SEP-2020 


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GlaxoSmithKline Document Number RPS-CLIN-004032. GSK3858279 Investigator's 
Brochure Effective 26 FEB 2021. 
GlaxoSmithKline Document Number RPS-CLIN-015095. Reporting and Analysis Plan 
for the population pharmacokinetic and target engagement modelling of GSK3858279 in 
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OCT-2020. 
GSK Disclosure Policy: https://www.gsk.com/media/2946/disclosure-of-clinical-trial-
information-policy.pdf 
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patients treated with narrow-band ultraviolet B phototherapy. Br J Dermatol. 2008; 
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Regenass F. Comparative assessment of immune complex-mediated hypersensitivity 
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lessons for future studies. Regul Toxicol Pharmacol. 2017; 88: 125-137. 
Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the 
literature. Int J Dermatol. 2005; 44; 355-360. 
Loudon P, Siebenga P, Gorman D, Gore K, Dua P, van Amerongen G, Butt RP. 
Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 
in a battery of human evoked pain models. Br J Clin Pharmacol. 2018; 84(2); 301-309.  


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Okkerse P, van Amerongen G, de Kam ML, Stevens J, Butt RP, Gurrell R, Groeneveld 
GJ. The use of a battery of pain models to detect analgesic properties of compounds: a 
two-part four-way crossover study. Br J Clin Pharmacol. 2017; 83(5); 976-990. 
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analgesia: no sex differences detected in models of experimental pain. Anesthesiology. 
2005; 103; 130-9. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Pressure-pain function in desensitized 
and hypersensitized muscle and skin assessed by cuff algometry. J Pain. 2002; 3; 28-37. 
Polianskis R, Graven-Nielsen, T., Arendt-Nielsen, L. Computer-controlled pneumatic 
pressure algometry – a new technique for quantitative sensory testing. Eur J Pain. 2001; 
5; 267-277. 
Sayre RM, Desrochers DL, Wilson CJ, Marlowe E. Skin type, minimal erythema dose 
(MED), and sunlight acclimatization. Am Acad Dermatol. 1981; 5(4); 439-443. 
Siebenga PS, van Amerongen G, Klaassen ES, de Kam ML, Rissmann R, Groeneveld GJ. 
The ultraviolet B inflammation model: Postinflammatory hyperpigmentation and 
validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy 
subjects. Eur J Pain. 2019; 00; 1-10. 
Siebenga PS, van Amerongen G, Okkerse P, Denney WS, Dua P, Butt RP, Groeneveld, 
GJ. Reproducibility of a battery of human evoked pain models to detect pharmacological 
effects of analgesic drugs. Eur J Pain. 2019; 23(6); 1129-1140. 
Specht S, Frank JK, Alferink J, Dubben B, Layland LE, Denece G, Bain O, Förster I, 
Kirschning CJ, Martin C, Hoerauf A. CCL17 controls mast cells for the defense against 
filarial larval entry. J Immunol. 2011; 186(8); 4845-52. 
van Amerongen G, Siebeng, P, de Kam ML, Hay JL, Groeneveld GJ. Effect profile of 
paracetamol, Δ9-THC and promethazine using an evoked pain test battery in healthy 
subjects. Eur J Pain. 2018; 22(7); 1331-1342. 

SAP_001.pdf: 
 
 
 
 
Reporting and Analysis Plan  
 
Study ID:  209973 
 
Official Title of Study: Reporting and Analysis Plan for a randomized, double-blind, 
placebo-controlled, three-period two-treatment incomplete-block crossover study to 
investigate the effects of intravenous GSK3858279 on a battery of evoked pain tests in 
healthy participants. 
 
EudraCT: 2019-002609-23 
 
Approval Date of Document: 12-OCT-2021 
 
 


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 9 9 7 3  
 
1  
 
Di visi o n  
: W orl d wi de  De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
 
Title  
: Re p orti n g a n d A nal ysis Pla n f or a ra n d o mize d, d o u ble-
bli n d, place b o -c o ntr olle d, t hree-p eri o d t w o -treat me nt 
i nc o m plete-bl oc k cr oss o ver st u d y t o i n vesti gate t he effects 
of i ntra ve n o us G S K 3 8 5 8 2 7 9 o n a batter y of e v o ke d pai n 
tests i n healt h y partici pa nts. 
C o m p o u n d N u m ber  : G S K 3 8 5 8 2 7 9  
Effecti ve D ate  
: 0 8 -O C T -2 0 2 1  
 
Descri pti o n:  
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 0 9 9 7 3  
•  
T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of 
i nteri m a nal ys es a n d t he Statistical A nal ysis C o m plete ( S A C) a n d All A nal ysis 
C o m plete ( A A C) d eli vera bles. 
 
R A P A ut h or(s):  
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
Le a d  
0 1 -O C T -2 0 2 1  
E -Mail  
Pri nci pal Statisticia n  (Bi ostatistics ) 
C o -A ut h or  
2 2 -S E P -2 0 2 1  
E -Mail  
Ma na ger Q ua ntitati ve Cli nical P har mac ol o g y 
( C P M S) 
 
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d .
P P D
P P D


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 9 9 7 3  
 
2  
 
R A P Te a m R e vie w C o nfir m ati o n : 
Re vie wer  
D ate  
A p pr o v al 
Met h o d  
2 8 -S E P -2 0 2 1  
E -Mail  
Pri nci pal Pr o gra m mer/ A nal yst  ( Bi ostatistics) 
2 2 -S E P -2 0 2 1  
E -Mail  
Ma na ger, Cli nical P har m ac ol o g y ( C P M S)  
( CI L) 
2 0 -S E P -2 0 2 1  
E -Mail  
Disc o ver y Me di ci ne Scie ntist Ma na ger 
( Disc o ver y M e dici ne) 
( Safet y Lea d) 
( S E R M) 
2 9 -S E P -2 0 2 1  
E -Mail  
( Disc o ver y Me di ci ne 
Lea d)  
( Disc o ver y M e dici ne) 
2 0 -S E P -2 0 2 1  
E -Mail  
S & P  Li ne A p pr o v als : 
A p pr o ver  
A p pr o v al Met h o d  
e Si g nat ur e  
Statistics Lea der ( Bi ostatistics)  
e Si g nat ur e  
Pr o gra m mi n g Lea der  ( Bi ostatistics) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Version History ............................................................................................. 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
Changes from the planned statistical analysis specified in protocol amendment 4 
(2019N405625_04) are outlined in Table 1. ........................................................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Analyses ..................................................................................... 13 
3. 
PLANNED ANALYSES .......................................................................................... 14 
3.1. 
Interim Analyses ......................................................................................... 14 
3.2. 
Final Analyses ............................................................................................ 15 
4. 
ANALYSIS POPULATIONS ................................................................................... 16 
4.1. 
Protocol Deviations ..................................................................................... 17 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 18 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 18 
5.2. 
Baseline Definitions .................................................................................... 18 
5.3. 
Multicentre Studies ..................................................................................... 19 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 19 
5.4.1. 
Covariates and Other Strata ........................................................ 19 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 19 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 19 
6. 
STUDY POPULATION ANALYSES ....................................................................... 21 
6.1. 
Overview of Planned Study Population Analyses ........................................ 21 
7. 
PHARMACODYNAMIC ANALYSES....................................................................... 22 
7.1. 
Primary PainCart Analyses ......................................................................... 22 
7.1.1. 
Endpoint / Variables ..................................................................... 22 
7.1.2. 
Summary Measure ...................................................................... 22 
7.1.3. 
Population of Interest ................................................................... 22 
7.1.4. 
Strategy for Intercurrent (Post-Randomisation) Events ................ 22 
7.1.5. 
Statistical Analyses / Methods ..................................................... 23 
7.1.5.1. 
Statistical Methodology Specification .......................... 25 
7.1.5.1.1. 
UVB heat pain detection (Celsius) .......... 25 
7.1.5.1.2. 
Cold pressor time to intolerable 
pain & Electrical pain tolerance 
threshold – single stimulus...................... 26 
7.2. 
Exploratory PainCart Analyses ................................................................... 27 
7.2.1. 
Endpoint / Variables ..................................................................... 27 
7.2.2. 
Summary Measure ...................................................................... 27 
7.2.3. 
Population of Interest ................................................................... 27 


 
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7.2.4. 
Strategy for Intercurrent (Post-Randomisation) Events ................ 28 
7.2.5. 
Statistical Analyses / Methods ..................................................... 28 
7.2.5.1. 
Statistical Methodology Specification .......................... 30 
7.3. 
Serum Target Engagement Analyses ......................................................... 30 
7.3.1. 
Endpoint / Variables ..................................................................... 30 
7.3.1.1. 
Target Engagement Concentration Measures ............ 30 
7.3.1.2. 
Derived Target Engagement Parameters ................... 30 
7.3.2. 
Statistical Analyses / Methods ..................................................... 31 
7.4. 
Immunogenicity........................................................................................... 31 
7.4.1. 
Summary Measure ...................................................................... 31 
7.4.2. 
Population of Interest ................................................................... 31 
7.4.3. 
Statistical Analyses / Methods ..................................................... 31 
8. 
SAFETY ANALYSES ............................................................................................. 32 
8.1. 
Adverse Events Analyses ........................................................................... 32 
8.2. 
Clinical Laboratory Analyses ....................................................................... 32 
8.3. 
Other Safety Analyses ................................................................................ 33 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 35 
9.1. 
Drug Concentration Measures .................................................................... 35 
9.2. 
Derived Pharmacokinetic Parameters ......................................................... 35 
9.3. 
Population of Interest .................................................................................. 35 
9.4. 
Statistical Analyses / Methods .................................................................... 35 
10. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 36 
10.1. 
Statistical Analyses / Methods .................................................................... 36 
11. REFERENCES ....................................................................................................... 37 
12. APPENDICES ........................................................................................................ 38 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 38 
12.1.1. 
Exclusions from Per Protocol Population ..................................... 38 
12.2. 
Appendix 2: Schedule of Activities .............................................................. 39 
12.2.1. 
Protocol Defined Schedule of Events ........................................... 39 
12.2.1.1. Screening and Follow-Up ........................................... 39 
12.2.1.2. Study periods 1, 2, 3 and Early Withdrawal ................ 41 
12.3. 
Appendix 3: Assessment Windows ............................................................. 44 
12.3.1. 
General ........................................................................................ 44 
12.3.2. 
PainCart Assessment Window ..................................................... 44 
12.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 46 
12.4.1. 
Study Phases .............................................................................. 46 
12.4.1.1. Study Phases for Concomitant Medication ................. 46 
12.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 46 
12.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 47 
12.5.1. 
Reporting Process ....................................................................... 47 
12.5.2. 
Reporting Standards .................................................................... 47 
12.5.3. 
Reporting Standards for Pharmacokinetic .................................... 48 
12.5.4. 
Reporting Standards for Target Engagement ............................... 48 
12.6. 
Appendix 6: Derived and Transformed Data ............................................... 50 
12.6.1. 
General ........................................................................................ 50 


 
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12.6.2. 
Study Population .......................................................................... 50 
12.6.3. 
Pharmacodynamic ....................................................................... 52 
12.6.4. 
Safety .......................................................................................... 54 
12.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 56 
12.7.1. 
Premature Withdrawals ................................................................ 56 
12.7.2. 
Handling of Missing Data ............................................................. 56 
12.7.2.1. Handling of Missing and Partial Dates ........................ 56 
12.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 58 
12.8.1. 
Laboratory Values ........................................................................ 58 
12.8.2. 
ECG ............................................................................................. 59 
12.8.3. 
Vital Signs .................................................................................... 59 
12.9. 
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ...................... 60 
12.9.1. 
Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 60 
12.10. Appendix 10: Abbreviations & Trade Marks ................................................ 61 
12.10.1. Abbreviations ............................................................................... 61 
12.10.2. Trademarks ................................................................................. 62 
12.11. Appendix 11: List of Data Displays.............................................................. 63 
12.11.1. Data Display Numbering .............................................................. 63 
12.11.2. Mock Example Shell Referencing ................................................ 63 
12.11.3. Deliverables ................................................................................. 63 
12.11.4. Study Population Tables .............................................................. 64 
12.11.5. Pharmacodynamic Tables ........................................................... 66 
12.11.6. Pharmacodynamic Figures .......................................................... 71 
12.11.7. Safety Tables ............................................................................... 73 
12.11.8. Pharmacokinetic Tables ............................................................... 78 
12.11.9. Pharmacokinetic Figures ............................................................. 79 
12.11.10. Pharmacokinetic / Pharmacodynamic Tables .............................. 79 
12.11.11. Pharmacokinetic / Pharmacodynamic Figures ............................. 80 
12.11.12. ICH Listings ................................................................................. 81 
12.11.13. Non-ICH Listings .......................................................................... 84 
12.12. Appendix 12: Mock Shells ........................................................................... 85 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the interim analyses and the Clinical Study Report for Protocol 209973: 
Revision Chronology: 
2019N405625_00 
25-JUL-2019 
Original. 
2019N405625_01 
23-SEP-2019 
Feedback from Scientific Review meeting, and the 
Ethics Committee, following protocol finalisation. 
Updates to SoA, Table 2 and Appendix 7 for clarity. 
2019N405625_02 
11-FEB-2020 
Correction to certain exclusion criteria in order to 
streamline with the other related exclusion criteria. A 
minor correction to one of the objectives and endpoints, 
and washout period of few of the prohibited 
medications. 
2019N405625_03 
10-AUG-2020 
Change to Analysis Populations. Populations are now 
UVB-MITT who undergo all assessments and MITT 
population who do not receive UVB irradiation (and not 
perform UVB heat pain detection assessment on 
irradiated skin). In addition, changes to expand age 
range and amendment of certain exclusion criteria in 
order to reduce volunteer burden and aid recruitment. 
 
Risk Benefit Analysis has also been amended in 
protocol amendment 03 to reflect changes made to the 
study design and new safety guidance available. 
 
As a result of the worldwide pandemic of COVID-19, 
throughout the protocol there have been addition of 
SARS-Cov2 screening and mitigation strategies to 
ensure the safety of the study participants. 
2019N405625_04 
25-MAY-2021 
Amendment to the Interim Analysis sections. An interim 
analysis may be performed once the last UVB-MITT 
participant has completed their period 3 final day 15 
PainCart assessments. Dependent on the results, the 
study could be stopped for futility. 
1.1. 
Version History 
RAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which RAP 
is Based 
Change 
Rationale 
Original RAP 
01-July-2021 
TMF-13778634 
(25-May-2021) 
None 
Original Version 


 
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RAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which RAP 
is Based 
Change 
Rationale 
RAP 
Amendment 
1  
##-October-
2021 
 
TMF-13778634 
(25-May-2021) 
CPM Summary 
measure updated. 
Definition of Exposure 
updated. 
Reduced number of 
SAC displays. 
Removal of the 
Bayesian PainCart by 
Day sensitivity 
analyses. 
Inclusion of an All 
Analysis Complete 
(AAC) Milestone for 
exploratory endpoints. 
Display is not analysed on 
the log scale, ratio to 
baseline is not suitable so 
change from baseline will 
be the summary measure. 
The volume of infusion will 
be presented to calculate 
exposure to study drug, 
along with start and stop 
date/time as a single dose 
study. 
Study has been terminated 
due to not meeting the 
futility threshold. A reduced 
SAC has been 
incorporated. 
The reduced SAC includes 
the removal of the 
Bayesian PainCart by Day 
sensitivity analyses. Due to 
the complex modelling 
structure in PROC MCMC, 
the low number of subjects 
compared to the amount of 
parameters, and that 
summary statistics and 
figures will be able to 
demonstrate the Period 
and Day effects, the 
analyses were removed.  
The AAC milestone has 
been incorporated to allow 
time for the analysis of all 
TLFs and not jeopardise 
the upper quartile 
performance targets and to 
report out the primary 
endpoints and AEs in a 
timely manner (SAC). This 
is due to the study 
terminating early and 
reporting the study 4 
months ahead of the 
original SAC date. 
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the planned statistical analysis specified in protocol amendment 4 
(2019N405625_04) are outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
Section 9.3 Populations for 
Analyses 
Removed population “Completers” 
Included UVB-ITT and UVB-Safety 
populations 
The MITT and UVB-MITT is 
being utilised for the 
PainCart analyses instead. 
UVB-ITT and UVB-Safety 
populations will be used for 
UVB heat pain detection on 
irradiated skin summaries 
and safety displays. 
Section 9.1.1.2  
Update PK parameter table to 
include AUC(0-7) and tlast  
 
AUC(0-7) may be used to 
assess whether there is any 
relationship between PK 
exposure and UVB Heat Pain 
AAUC(1-8). 
tlast needs to be output when 
AUC(0-t) is derived as per 
SOP_314000. 
 
Section 7.3.1.2 
Remove AUC(0-t) from TE 
parameter table for total CCL17  
NCA will not be performed 
for total CCL17. TE 
parameters for total CCL17 
will be determined directly 
from the observed total 
CCL17 levels in serum. 
Section 12.11.11 
Add exploratory 
Pharmacokinetic/Pharmacodynamic 
Figures 
An exploratory graphical 
analysis will be performed to 
assess the relationship 
between primary endpoints 
of efficacy and PK exposure. 
Section 9.1. Statistical 
Hypotheses 
Removed references to hypothesis 
testing 
The analysis is being perform 
in the Bayesian framework 
which does not involve 
hypothesis testing. 
 
 


 
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2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To evaluate the effects of IV 
administration of GSK3858279 in 
Ultraviolet B (UVB) burn 
inflammatory, cold pressor test and 
electrical pain test in the PainCart 
• 
UVB heat pain detection (C) 
• 
Cold pressor time to intolerable pain threshold (secs)  
• 
Electrical pain tolerance threshold (mA) - single stimulus 
Safety Objectives 
Safety Endpoints 
• 
To evaluate the safety and 
tolerability of GSK3858279 following 
IV dosing 
• 
Adverse Events (AE) and Serious Adverse Events 
(SAE) 
• 
Clinical laboratory measurements, 12-lead 
electrocardiograms (ECG) and vital signs that are 
considered of potential clinical importance. 
Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate the pharmacokinetics 
(PK) of GSK3858279 following IV 
administration 
• 
Serum PK concentrations and parameters including but 
not limited to: area under the concentration-time curve 
[AUC], maximum concentration [Cmax], tmax  
• 
To evaluate the target engagement 
(TE) of CCL17 by GSK3858279 
following IV administration 
• 
Free and total CCL17 levels in serum 
• 
To evaluate the effects of IV 
administration of GSK3858279 in 
additional endpoints in UVB test, 
cold pressor test and electrical pain 
test in the PainCart 
• 
Heat pain detection on normal skin (C) 
• 
Cold pressor time to pain detection (secs)  
• 
Electrical pain detection (mA) - single stimulus 
• 
Electrical pain detection and tolerance threshold (mA) - 
repeat stimulus 
• 
For each test Area Under the Curve (AUC)/Area Above 
the Curve (AAC) and post-test eVAS 
• 
To evaluate the effects of IV 
administration of GSK3858279 in 
pressure pain test and Conditioned 
pain modulation (CPM) test of the 
PainCart 
• 
Pressure pain (tolerance and detection) - KPa 
• 
CPM - (detection and tolerance thresholds) – mA 
• 
For each test AUC/AAC and post-test eVAS 
• 
To assess the potential for anti-
GSK3858279 antibody formation 
following IV dosing 
• 
To include: incidence, titres, and, for samples with 
confirmed anti-drug antibodies (ADAs), neutralising 
activity 


 
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2.3. 
Study Design 
This study will be a randomized, double-blind, placebo-controlled, three-period two-
treatment incomplete-block crossover study in healthy participants to investigate the 
effects of IV GSK3858279 on evoked pain tests in the PainCart. The study will be 
performed in a single centre. 
In each period participants will receive either GSK3858279 or placebo in a 1:1 ratio. 
During the trial participants will receive both treatments, participants will receive either 
two doses of GSK3858279 and one dose of placebo, or two doses of placebo and one 
dose of GSK3858279 with equal likelihood, the order of treatment assignments will be 
randomised. 
The total duration of the study (from signing informed consent until final follow-up visit) 
for each participant will be approximately 6 months.  Study participation may be 
prolonged in the event the study is on-hold. Screening period will be a maximum of 28 
days prior to study procedures, each study period will be approximately 2 weeks with at 
least a 4-week wash-out period between dosing (i.e. Day 1) in each of the study periods, 
final follow-up visit will be at approximately 8 weeks after last dose. 
Participants will arrive at the research unit either one or two days before dosing, for the 
non-UVB-MITT and UVB-MITT group respectively. After arrival, subjects will be tested 
for SARS-CoV-2. Urine will be screened for the presence of drugs and an alcohol breath 
test will be performed. For participants with a positive urine drug screen or alcohol breath 
test, the treatment occasion may be rescheduled at the discretion of the principal 
investigator and GSK medical monitor. UVB irradiation will be applied approximately 24 
hours before dosing in the UVB-MITT population only. ECG and vital signs will also be 
performed. 
Participants will be assigned to receive treatment and pain assessments during either 
morning or afternoon sessions. They will continue to receive treatment and pain 
assessments at approximately the same time of day throughout all three study periods. 
Meals will be served at the site scheduled times. Safety, PK, PD and PainCart 
assessments will be performed as outlined in the SoA. Baseline measurements for 
PainCart (2 baseline measurements) are conducted at each study period prior to dosing. 
Phone contact to assess the participant’s general health will be conducted as per the SoA, 
the investigator may invite the participant for a site visit at the investigator's discretion 
for additional follow-up, as required. 


 
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Overview of Study Design and Key Features 
Figure 1 
Study Design Schematic 
 
Figure 2 
Visit schematic 
Figure 3 
Study Period Details 
 
Design 
Features 
• 
A screening visit can occur up to 28 days before study day 1. 
• 
A SARS-CoV-2 PCR test and temperature check will be performed at screening 
visit, prior to any other screening procedure. 
• 
Each study period lasts for approximately 4 weeks, with PainCart assessments 
occurring the first 2 weeks and wash out periods lasting approximately 4 weeks 
between treatment dosing in each period. 
• 
For each study period, UVB application (2 x MED) will be performed 24hr (2hr) 
prior to start of infusion on Day 1 and Day 7 (24hr (2hr) prior to start of PainCart 
assessment on Day 8, for those participants enrolled into the UVB group. The 
PainCart assessments are performed twice on Day 1 before start of infusion 
(baseline readings) and performed twice again on Day 1 at 1 and 3 hours post start 


 
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Overview of Study Design and Key Features 
of IV infusion. On days 2, 8 and 15, the PainCart assessment is performed twice, 
approximately 2 hours apart. On day 15 the UVB pain assessment will only be 
performed on normal skin, due to no UVB applied skin being applicable at that visit. 
The planned PainCart assessments on Day 2, 8 & 15 may be performed within a  
24hr window. 
• 
Participant replacements are permitted in the study.  
• 
A follow up phone call is scheduled on day 36 of study period 3 (approximately 6 
weeks post dose) and a final follow up out-patient visit scheduled on day 56 
(approximately 8 weeks post dose). 
• 
Participants will be stratified in to two strata based on whether they perform the 
PainCart assessments in the morning (AM) or the afternoon (PM). These strata will 
continue throughout the full duration of the study for the participant (e.g. if a 
participant performs their first PainCart assessment in the morning, they will 
perform their subsequent assessments in the morning too). 
Dosing 
• 
According to a participant’s randomisation schedule, the dosing are as follows: 
o 3 mg/kg IV GSK3858279, single dose 
o Placebo, single dose 
• 
All dosing occurs on Day 1 for each study period. 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 
GSK3858279 and placebo will be administered in a 1:1 ratio according to the 
randomisation schedule, in a blinded manner. 
• 
A three period, cross over design, with participants receiving either two doses of 
GSK3858279 and one dose of placebo, or two doses of placebo and one dose of 
GSK3858279 with equal likelihood. The order of treatment assignments will be 
randomized. 
• 
Approximately 30 healthy participants will be enrolled into the study, such that at 
least approximately 24 participants complete dosing and critical assessments in all 
three study periods. 
• 
For the UVB-exposed population, approximately 18 participants are required to be 
enrolled to ensure that approximately 15 participants complete all UVB tests of the 
PainCart assessment on irradiated skin in all three study periods 
 
Intervention code 
Intervention Description 
A 
3 mg/kg IV GSK3858279 
P 
Placebo  
 
 
Interim 
Analysis 
• 
Two interim analyses may be performed at the following timepoints: 
o The final UVB-MITT participant in period 3 has completed the day 15 
assessments of the PainCart tests. Dependent on the results observed, the 
study could be stopped for futility, based on pre-specified futility criteria. A 
secondary objective for the interim is to potentially use the analysis for internal 
decision-making purposes.  
o The final participant in period 3 has completed the day 15 assessments of the 
PainCart tests. The interim analyses will be used for internal decision making 
only, no changes to the study can occur. 


 
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2.4. 
Statistical Analyses 
The study will estimate the difference between GSK3858279 and placebo on the 
endpoints described: UVB heat pain detection test, cold pressor time to intolerable pain 
threshold test and electrical pain tolerance threshold test in the PainCart scale.  
All participants will receive GSK3858279 and placebo during their course on the study, 
depending on their randomisation schedule.  
The primary endpoints are: 
• Ratio to Baseline in UVB heat pain detection (Celsius) 
• Ratio to Baseline in cold pressor time to intolerable pain threshold (seconds) 
• Ratio to Baseline in electrical pain tolerance – single stimulus (mA) 
If ratio to baseline is not suitable due to the distribution of the parameters, change from 
baseline will be utilised instead.  


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
Two interim analyses of the primary endpoints to inform internal decision making may 
be conducted during the study. The interim analyses may occur when: 
• The final UVB-MITT participant (approx. 15 evaluable participants) to have 
completed the day 15 assessments of the PainCart assessments in study period 3 
(final study period).  
• The final randomised participant has completed the day 15 assessments of the 
PainCart assessments in study period 3 (final study period).  
The table below details the endpoints that will be analysed/summarised at the interim: 
Purpose of Interim 
Endpoints 
Interim Analysis 1 
(Futility) 
UVB heat pain detection (Celsius) 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Cold pressor time to intolerable pain threshold (seconds): 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Electrical pain tolerance – single stimulus (mA): 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Summary of Demographic Characteristics  
Summary of Derived Serum GSK3858279 Pharmacokinetic 
Parameters (non-transformed and log-transformed) 
Summary of Serum GSK3858279 Concentration-Time Data 
(ng/mL) 
Summary of Derived Free and Total CCL17 in Serum Target 
Engagement Parameters (non-transformed and log-
transformed) 


 
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Summary of Free & Total CCL17 in Serum Concentration-
Time Data (pg/mL). 
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Period (>=2 Subjects with the AE) 
IA 2 – Internal 
Decision-Making 
Purposes 
UVB heat pain detection (Celsius) 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Cold pressor time to intolerable pain threshold (seconds): 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Electrical pain tolerance – single stimulus (mA): 
• Absolute values (Summarised) 
• Change from baseline (Summarised) 
• Ratio to Baseline (Summarised) 
• AAUC of Ratio to Baseline (Analysed) 
Summary of Demographic Characteristics  
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Period 
Note: Ratio to baseline will only be produced if deemed suitable by the distribution of the 
parameters.  
Note: AAUC = Analysis Area Under Curve. Derivation of AAUC is described in Section 
12.6.3 Pharmacodynamic. 
The statistical methods of the analyses are described in Section  7.1, Section 7.2 and 
Section  7.3. 
The following functions will be unblinded to interim analysis data: Clinical Statistics, 
Clinical Programming and CPMS. Other members of GSK will be unblinded to group 
level summary data following the interim analyses (as documented in the Interim 
Charter). 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol. 


 
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2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG and RAMOS 
procedures. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study Population 
• 
Safety 
Enrolled 
• 
All participants who passed screening and entered the 
study.  
• 
Note screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study. 
• 
Study Population 
Randomized  
 
• 
All participants who were randomly assigned to 
treatment in the study. 
• 
This population will be based on the treatment 
sequence the participant was randomized to. 
• 
Study Population 
Safety 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment 
sequence the subject actually received. 
• 
Note: Participants who were not randomized but 
received at least one dose of study treatment should be 
included. 
• 
Safety 
• 
PK/PD 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety population who had at least 
1 non-missing serum PK assessment. 
• 
Note: Non-quantifiable [NQ] values will be considered 
as non-missing values 
• 
PK 
Intent-To-Treat 
(ITT) 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment 
sequence the subject was randomized to. 
• 
Any participants who receives a treatment 
randomization number will be considered to have been 
randomized. 
• 
PainCart 
• 
Study Population 
Modified Intent-
to-Treat (MITT) 
• 
All randomized participants who received at least one 
dose of study treatment and completed at least one 
PainCart assessment in at least two study periods. 
• 
This population will be based on the treatment 
sequence the subject was randomized to. 
• 
Any participants who receives a treatment 
randomization number will be considered to have been 
randomized. 
• 
PainCart 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
UVB Safety 
• 
Those in the Safety Population who also perform the 
UVB Heat Pain detection PainCart assessments on 
irradiated skin. 
• 
Safety (UVB 
Sensitivity) 
UVB Intent-to-
Treat (UVB-ITT) 
• 
Those in the ITT Population who also perform at least 
one UVB Heat Pain detection PainCart assessment on 
irradiated skin in at least one study period. 
• 
PainCart UVB heat 
pain irradiated skin 
endpoint - 
summary 
UVB Modified 
Intent-to-Treat 
(UVB-MITT) 
• 
Those in the MITT Population who also perform at least 
one UVB Heat Pain detection PainCart assessment on 
irradiated skin in at least two study periods. 
• 
PainCart UVB heat 
pain irradiated skin 
endpoint - analysis 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 
A populations exclusion meeting will be held before unblinding of the data. The meeting 
minutes and list of participants excluded from the populations mentioned in Section 4: 
Analysis Populations will be documented and uploaded to eTMF. A summary and listing 
of the participants excluded from certain populations will be created. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan Date: 05-Sept-2019, 
Version 1.0. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
A 
3 mg/kg IV GSK3858279 
GSK3858279 
2 
P 
Placebo 
Placebo 
1 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. GSK3858279 vs Placebo 
 
For treatment sequence displays: 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF 
A/P/P 
3 mg/kg IV GSK3858279 – Placebo – 
Placebo 
GSK3858279-Placebo-
Placebo 
2 
P/A/A 
Placebo – 3 mg/kg IV GSK3858279 – 
3 mg/kg IV GSK3858279 
Placebo- GSK3858279- 
GSK3858279 
1 
 
 
Total 
3 
 
 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. This study has three study periods, with each period having its own baseline which 
is the latest non-missing value prior to dosing in that period.  
For the PainCart test, two assessments are performed at each visit except for visit Day 1 
where two are performed prior to dose and two are performed after dose. The baseline 
value is defined as the mean of the two pre-dose assessments on Day 1 for each study 
period. If only one pre-dose assessment record is present on Day 1, then this value will be 
set as the baseline value.  
For the PainCart analyses, baseline will compose of two variables: 
• Subject level baseline = the mean of the three period baseline values for each subject. 
• Period level baseline = Subject level baseline – Period specific baseline value. 


 
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Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Screening 
Day -1 
Day 1 (Pre-Dose) 
Efficacy 
PainCart Assessments 
 
 
X 
Mean of Day 1 (Pre-
Dose) Assessments 
Safety 
Vital Signs 
 
 
X 
Day 1 (Pre-Dose) 
Haematology 
 
 
X 
Day 1 (Pre-Dose) 
Chemistry 
 
 
X 
Day 1 (Pre-Dose) 
ECG 
 
 
X 
Day 1(Pre-Dose) 
[Mean of triplicate 
measurements] 
Urinalysis 
 
 
X 
Day 1 (Pre-Dose) 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3. 
Multicentre Studies 
This is a single centre study. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses.  
Category 
Details 
Strata 
Time of Assessment (AM or PM) 
Covariates 
Baseline (of the analysis variable of interest), Study Period 
5.5. 
Multiple Comparisons and Multiplicity 
There are no planned adjustments for multiple comparisons or multiplicity. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
12.3 
Appendix 3: Assessment Windows 


 
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Section 
Component 
12.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.6 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Reporting Standards for Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the population specified in Appendix 11: 
List of Data Displays, unless otherwise specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications 
and exposure will be based on GSK Core Data Standards.   
Details of the planned displays are presented in Appendix 12: List of Data Displays. 


 
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7. 
PHARMACODYNAMIC ANALYSES 
7.1. 
Primary PainCart Analyses 
7.1.1. 
Endpoint / Variables 
The primary endpoints are 
• 
UVB heat pain detection (Celsius) 
• 
Cold pressor time to intolerable pain threshold (seconds) 
• 
Electrical pain tolerance threshold (mA) – single stimulus 
 
7.1.2. 
Summary Measure 
For each of the three endpoints, the Analysis Area Under the Curve (AAUC) of the Ratio 
to Baseline will be the primary summary measure. The PainCart assessments will be log 
transformed in order to calculate the log change from baseline result which will be used 
for the primary analysis, and back transformed to obtain the ratio to baseline result. As 
default, summaries of Change from Baseline will also be calculated. If modelling 
assumptions are invalidated, then the results will not be presented. Ratio to baseline and 
change from baseline will be measured at each day where the assessment was performed. 
The AAUC is calculated via the trapezoidal method and will be normalised. Further 
details are referenced in Section 12.6.3 Pharmacodynamic. 
7.1.3. 
Population of Interest  
The primary analyses will be based on the MITT population for the cold pressor time to 
intolerable pain and electrical pain tolerance endpoints, and on the UVB-MITT for the 
UVB heat pain detection endpoint, unless otherwise specified. 
7.1.4. 
Strategy for Intercurrent (Post-Randomisation) Events 
Intercurrent current events (ICE) are defined as: 
• Early withdrawal from study due to Covid-19 
• Early withdrawal from study not due to Covid-19 
• Use of prohibited medications 
• Early discontinuation of study drug 
• Use of COVID-19 vaccinations. 
The “Hypothetical” strategy will be applied to handle the “Early withdrawal from study 
due to Covid-19”, “Early withdrawal from study not due to Covid-19 and “Early 
discontinuation of study drug” in the analysis for all endpoints. For the “Early withdrawal 
from study due to Covid-19” ICE, this strategy attempts to estimate treatment effects had 
the Covid-19 ICE not occurred. With COVID-19, the likelihood of participants 
withdrawing from the study is increasing (e.g. closure of the site, participants advised not 


 
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to leave homes etc.) which makes the Hypothetical strategy reasonable. The “Use of 
prohibited medications” and “Use of COVID-19 vaccinations” ICEs will implement a 
“Treatment Policy” strategy. The strategy implies direct use of data irrespective of the 
occurrence of the intercurrent events. The “Treatment policy” strategy is the same as de 
facto type estimand. 
 
7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Table 2: Primary PainCart Analyses details which of the primary endpoints are to be 
analysed and/or summarised. 
 


 
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Table 2 
Primary PainCart Analyses 
Estimand 
Endpoint 
Summary* 
Primary Analysis – 
Bayesian AAUC 
Mixed ANCOVA 
Listing 
UVB Heat Pain 
Detection (UVB 
Skin) 
Yes 
Yes (AAUC 1-8 days) 
Yes (Inc. 
AAUC) 
Cold Pressor 
Tolerance 
Yes 
Yes (AAUC 1-15 days) 
Yes (Inc. 
AAUC and 
eVAS) 
Electrical pain – single 
stimulus (Pre-Cold 
Pressor) 
Tolerance 
Yes 
Yes (AAUC 1-15 days) 
Yes (Inc. 
AAUC and 
eVAS) 
*The summary will include summary statistics for the summary measures, AAUC and post-test eVAS scores. 
MMRM: Mixed Model Repeated Measures; ANCOVA: Analysis of Covariance; AAUC: Analysis Area Under Curve, BRM: Bayesian Repeated Measures 


 
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7.1.5.1. 
Statistical Methodology Specification 
7.1.5.1.1. UVB heat pain detection (Celsius) 
Endpoint / Variables 
• Ratio to baseline (or change from baseline) in UVB heat pain detection (Celsius) AAUC(1-8 
Days) 
• If ratio to baseline is deemed suitable due to the distribution of the parameters, the response 
will be log transformed. Any transformation of a response variable is also expected to be 
applied to the corresponding baseline variable. Final decisions on transformations will be 
based on the observed data and model diagnostics 
Model Specification 
The analysis will be performed on the AAUC (1-8 days) using a Bayesian Mixed Analysis of 
Covariance (ANCOVA) model.  
 
Refer to Section 12.6.3 Pharmacodynamic for the derivation of the AAUC via the trapezoidal 
method. 
 
Non-informative priors will be utilized for each model parameter as either a normal distribution 
with a mean = 0 and variance = 1e6 (very large variance), unless specified elsewhere. 
The prior for the variance covariance matrix will follow an inverse Wishart distribution. An inverse 
Wishart prior on the covariance matrix is chosen as it ensures sampling efficiency with PROC 
MCMC using the conjugate sampler to draw the unstructured covariance.  
 
The random seed to use has been calculated prior to unblinding. Section 12.6 details the seed 
to use for the analyses in this RAP. 
 
The mixed model ANCOVA will be fitted using Bayesian techniques with PROC MCMC using 
the following approach: 
 
• Assume equal variances across treatment arms and use a pooled estimate of residual 
variability. 
• Fit the following model: 
o M: Intercept + Treatment + Time of Assessment Stratum + Subject Level Baseline + 
Period Level Baseline + Study Period + Study Period*Period Level Baseline + 
Treatment*Study Period  
o Time of assessment stratum (AM, PM) may be removed from the model if model 
convergence issues arise. 
 
• For the model, use appropriate combinations of the model parameters (back transforming 
the combination if response variable is ratio to baseline) to obtain posterior distributions for 
the variables of interest. Binary flag variables can be used to evaluate the probability 
statements.  


 
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• The MCMC iterations are flagged if the posterior summary ratio > X, where X is various 
criteria.  
• The posterior probability is then calculated by summarising the number of flagged MCMC 
iterations / total number of MCMC iterations. 
Model Checking & Diagnostics 
• 
Refer to the relevant documentation (Bayesian Statistics Best Practice at GSK – Clinical 
Trials using Bayesian Inference). 
Model Results Presentation 
• The posterior ratio to baseline AAUC median for each treatment group will be presented 
along with the coefficient of variation (CV) (%) (calculated as √(exp(𝑠𝑑2) −1)) and/or 
95% credible intervals (CrI). The posterior treatment ratio to placebo, along with 
corresponding 95% Credible Intervals (CrI) and posterior probabilities that the true ratio is 
greater than 1 will be presented. 
• If the Ratio to Baseline is not suitable, the change from baseline AAUC in UVB heat pain 
detection will be compared between the treatment groups using a Bayesian mixed ANCOVA 
with the same model specification as above. All available post-baseline scheduled visits will 
be included in the analysis. Non-informative priors will be used for all modelling parameters. 
Wherever possible conjugate priors will be utilised. An unstructured covariance matrix will be 
used to model the within-subject error. 
 
7.1.5.1.2. Cold pressor time to intolerable pain & Electrical pain tolerance 
threshold – single stimulus 
Endpoint / Variables 
• Ratio to baseline in cold pressor time to intolerable pain threshold (seconds) (AAUC 1-15 
days) 
• Ratio to baseline in electrical pain tolerance threshold (mA) – single stimulus (AAUC 1-15 
days) 
• If ratio to baseline is deemed suitable due to the distribution of the parameters, the response 
will be log transformed. Any transformation of a response variable is also expected to be 
applied to the corresponding baseline variable. Final decisions on transformations will be 
based on the observed data and model diagnostics 
Model Specification 
• A Bayesian mixed ANCOVA model will be fitted to the ratio to baseline AAUC (1-15 days) 
for the electrical pain tolerance threshold endpoint and cold pressor time to intolerable pain 
endpoint, and used to estimate the ratio to placebo. 
• Refer to Section 7.1.5.1.1 Model Specification for more information 
Model Checking & Diagnostics 
• Refer to Section 7.1.5.1.1 Model Checking & Diagnostics for more information 


 
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Model Results Presentation 
• Refer to Section 7.1.5.1.1 Model Results Presentation for more information 
Interim Analysis 1 
• The first interim analysis may occur once the final UVB-MITT participant in period 3 has 
completed their day 15 assessments of the PainCart tests. 
• In addition to posterior probabilities, predictive probabilities of achieving the criteria of 
interest at the end of the study if we were to randomise and analyse an additional 12 
subjects will be estimated using a Bayesian Normal-Normal update. Vague priors for all 
modelling parameters will be used to compute the posterior distributions. 
• Further information is contained in the 209973 Interim Analysis Charter. 
 
7.2. 
Exploratory PainCart Analyses 
7.2.1. 
Endpoint / Variables 
The exploratory endpoints are: 
• Cold pressor time to pain detection threshold 
• Electrical pain detection threshold– single stimulus 
• Electrical pain tolerance threshold– repeat stimulus 
• Electrical pain detection threshold– repeat stimulus 
• Conditioned pain modulation (CPM) detection threshold 
• Conditioned pain modulation (CPM) tolerance threshold 
• Heat pain detection on normal skin 
• Pressure pain tolerance threshold  
• Pressure pain detection threshold  
7.2.2. 
Summary Measure 
For each of the exploratory PainCart endpoints apart from heat pain detection on normal 
skin, conditioned pain modulation and pressure pain thresholds, Ratio to Baseline will be 
the primary summary measure. As default, summaries of Change from Baseline will also 
be shown. For the conditioned pain modulation endpoint, the change from baseline will 
be the summary measure. If modelling assumptions are invalidated, then neither ratio 
to/change from baseline may be shown. For heat pain detection on normal skin and 
pressure pain thresholds only summary statistics (mean/geometric mean, SD/CV(%), 
Median, Min, Max) will be produced. Refer to Table 4 for further details. 
7.2.3. 
Population of Interest  
The exploratory analyses will be based on the MITT population, unless otherwise 
specified. 


 
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7.2.4. 
Strategy for Intercurrent (Post-Randomisation) Events 
Refer to Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events 
7.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 


 
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Table 3 
Exploratory PainCart Analyses 
Estimand 
Endpoint 
Summary* 
Analysis – Bayesian 
AAUC Mixed 
ANCOVA 
Listing 
Cold Pressor 
Detection 
Yes 
Yes 
Yes  
Electrical pain – single stimulus 
Detection 
Yes 
Yes  
Yes  
Electrical pain – repeat stimulus 
Detection 
Yes 
Yes  
Yes  
Tolerance 
Yes 
Yes  
Yes  
Conditioned pain modulation 
Detection 
Yes 
Yes  
Yes  
Tolerance 
Yes 
Yes  
Yes 
Heat Pain 
Detection (Normal Skin) 
Yes 
No 
Yes 
Pressure Pain 
Detection 
Yes 
No 
Yes 
Tolerance 
Yes 
No 
Yes 
*The summary will include summary statistics for the summary measures, AAUC and post-test eVAS scores. 
Note: ANCOVA analyses will be performed in the Bayesian framework only. 


 
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7.2.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• The endpoints will be analysed as detailed in Section 7.1.5.1. 
Model Specification 
• Refer to Section 7.1.5.1.2 Model Specification for more information 
Model Checking & Diagnostics 
• Refer to Section 7.1.5.1.2 Model Checking and Diagnostics for more information 
Model Results Presentation 
• Refer to Section 7.1.5.1.2 Model Results Presentation for more information 
 
7.3. 
Serum Target Engagement Analyses 
The Target Engagement analyses described below will be carried out for Free and Total 
CCL17 in Serum. The target engagement analyses will be based on the Safety population, 
unless otherwise specified. 
7.3.1. 
Endpoint / Variables 
7.3.1.1. 
Target Engagement Concentration Measures 
Refer to Appendix 5 Section 12.5.4 Reporting Standards for Target Engagement. 
7.3.1.2. 
Derived Target Engagement Parameters 
All calculations will be based on actual sampling times.  
Target engagement parameters listed below will be determined from the observed free 
CCL17 levels in serum. Additional parameters may be included as required. 
Parameter 
Parameter description 
Cmin 
• Minimum observed concentration 
• Determined directly from the concentration-time data 
tmin 
• Time to reach Cmin  
• Determined directly from the concentration-time data 
BL 
• Baseline (as defined in Section 5.2) 
Percentage 
reduction 
• Percentage of free CCL17 reduced by the presence of GSK3858279 
• Calculated by time point as: (BL-concentration)*100/BL 
Maximum 
Percentage 
reduction 
• Maximum Percentage of free CCL17 reduced by the presence of 
GSK3858279 
• Calculated as: (BL-Cmin)*100/BL 
NOTES: 
Additional parameters may be included as required. 


 
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Target engagement parameters listed below will be determined from the observed total 
CCL17 levels in serum. Additional parameters may be included as required. 
Parameter 
Parameter description 
Cmax 
• Maximum observed concentration 
• Determined directly from the concentration-time data 
tmax 
• Time to reach Cmax  
• Determined directly from the concentration-time data 
BL 
• Baseline (as defined in Section 5.2) 
Fold 
increase 
• Ratio of total CCL17 concentration to baseline 
• Calculated by time point as: Concentration/BL 
• Determined directly from the concentration-time data 
Maximum 
Fold 
increase 
• Ratio of maximum concentration of total CCL17 to baseline 
• Calculated as: Cmax/BL 
• Determined directly from the concentration-time data 
NOTES: 
Additional parameters may be included as required. 
7.3.2. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarised using descriptive statistics by treatment and study period, graphically 
presented (where appropriate) and listed. 
7.4. 
Immunogenicity 
7.4.1. 
Summary Measure 
The number and percentage of confirmed positive samples in each treatment group and 
period will be presented at each time assessed. 
7.4.2. 
Population of Interest  
The immunogenicity analyses will be based on the Safety population, unless otherwise 
specified. 
7.4.3. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.4.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 


 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
8.1. 
Adverse Events Analyses 
The definition of an AE is detailed in Appendix 3 of the protocol. Any reported skin 
reactions will be recorded as Adverse Events as mentioned in the protocol. 
Analyses of AEs will only include those events that are on-treatment as defined in 
Appendix 4: Study Phases and Treatment Emergent Adverse Events (Section 12.4). 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards.  
The details of the planned displays are provided in Appendix 12: List of Data Displays. 
8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations will be based on GSK Core Data Standards and will include: 
• Haematology laboratory tests  
• Chemistry laboratory tests 
• Urinalysis 
• Other screening tests 
Clinical laboratory analyses will include all assessments post-baseline. 
Details of the planned displays are presented in Appendix 11: List of Data Displays 
The laboratory assessments for each category are displayed below (Table 2 of the 
protocol):  
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 


 
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Laboratory 
Assessments 
Parameters 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium 
Alkaline 
phosphatase 
3Complement 
protein C3 and 
C4 
Routine 
Urinalysis2 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Breath alcohol test 
• Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
• HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B core 
antibody [HbcAb] and hepatitis C virus antibody) 
• QuantiFERON test 
• Urine albumin-creatinine ratio (UACR) 
The results of each test must be entered into the medical notes. 
Other screening 
and follow up 
tests 
• Troponin-T (high sensitivity) 
• NT-proBNP 
NOTES: 
1. 
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 Appendix 5 of the protocol. All events of ALT 3 × upper limit 
of normal (ULN) and 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 
as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
3. 
Complement protein C3 and C4 to be performed (as baseline). 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
8.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results will be based on GSK Core Data 
Standards, unless otherwise specified.  


 
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The non-laboratory safety test results include: 
• Vital Signs 
• ECGs 
 
The details of the planned displays are presented in Appendix 12: List of Data Displays. 


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3 
Reporting Standards for Pharmacokinetic). 
9.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations will be based on actual sampling times. 
Pharmacokinetic parameters listed below will be determined from the serum 
GSK3858279 concentration-time data, as data permits. Additional parameters may be 
included as required. 
Parameter 
Parameter Description 
AUC(0-t) 
• Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t))  
• 
Calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-7) 
• Area under the concentration-time curve from time zero (Day 1) to 7 days 
post-dose (Day 8) 
• Calculated using the linear trapezoidal rule for each incremental trapezoid 
and the log trapezoidal rule for each decremental trapezoid 
Cmax 
• Maximum observed concentration 
• 
Determined directly from the concentration-time data. 
tmax 
• Time to reach Cmax  
• Determined directly from the concentration-time data 
tlast 
• Time of occurrence of last quantifiable concentration 
• Determined directly from the concentration-time data 
NOTES: 
Additional parameters may be included as required. 
9.3. 
Population of Interest  
The pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified. 
9.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.2 will be 
summarised using descriptive statistics by study period, graphically presented (where 
appropriate) and listed. 


 
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10. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
The primary goal of this analysis is to characterize the pharmacokinetic / 
pharmacodynamic (PK/PD) relationship of GSK3858279 administered IV in healthy 
participants. 
The PK and TE data may also be integrated with ongoing and planned studies to develop 
a Population PK/TE model for GSK3858279. Details of this integrated analysis will be 
described in a separate PDAP. 
10.1. 
Statistical Analyses / Methods 
A summary of the planned PK/PD analyses is outlined below: 
• An exploratory graphical analysis will be performed to assess the relationship 
between observed measures of nociception and individual PK or TE data. If the 
exploratory graphical analysis suggests a relationship and data permits, direct or 
indirect response models may be developed and linked with the previous popPK/TE 
model to characterise the relationship between different modalities of nociception and 
PK or TE. Details of this analysis, if required, will be described in a separate SAP. 
• To support this analysis, a PK/PD dataset will be generated. The details for the 
dataset specifications are provided in Appendix 9: Pharmacokinetic / 
Pharmacodynamic Analyses. 
• S&P will deliver 6 PK/PD figures, as detailed in Section 12.11.11: Pharmacokinetic / 
Pharmacodynamic Figures as part of the AAC package.  


 
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11. 
REFERENCES 
Arendt-Nielsen L, Frokjaer JB, Staahl C, Graven-Nielsen T, Huggins JP, Smart TS, et al. 
Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth 
Pain Med. 2007; 32; 382-8. 
Bishop T, Ballard A, Holmes H, Young AR, McMahon SB. Ultraviolet-B induced 
inflammation of human skin: Characterisation and comparison with traditional models of 
hyperalgesia. Eur J Pain. 2009; 13; 524–532. 
Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous 
measurement and integrated analysis of analgesia and respiration after an intravenous 
morphine infusion. Anesthesiology. 2004; 101; 1201-9.  
Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M. Same incidence of 
adverse drug events after codeine administration irrespective of the genetically 
determined differences in morphine formation. Pain. 1998; 76; 27–33.  
GlaxoSmithKline Document Number 2019N405625_04. Study ID 209973: A 
randomized, double-blind, placebo-controlled, three-period two-treatment incomplete-
block crossover study to investigate the effects of intravenous GSK3858279 on a battery 
of evoked pain tests in healthy participants. 
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Pressure-pain function in desensitized 
and hypersensitized muscle and skin assessed by cuff algometry. J Pain. 2002; 3; 28-37. 
Polianskis R, Graven-Nielsen, T., Arendt-Nielsen, L. Computer-controlled pneumatic 
pressure algometry – a new technique for quantitative sensory testing. Eur J Pain. 2001; 
5; 267-277. 
 


 
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12. 
APPENDICES 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
The full list of protocol deviations collected on the eCRF is in the Protocol Deviation 
Management Plan (PDMP). Please refer to this document for current guidance.  
12.1.1. 
Exclusions from Per Protocol Population 
There is no Per Protocol population in this study. 
 


 
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12.2. 
Appendix 2: Schedule of Activities 
12.2.1. 
Protocol Defined Schedule of Events 
12.2.1.1. 
Screening and Follow-Up 
Procedure 
Screening  
(up to 28 days 
before Day 1) 
Follow-up 
check 
364 days 
post last 
dose 
Final 
follow-up 
564 days 
post-last 
dose 
Notes 
Part 1 
Part 2 
Out-patient visit 
X 
X 
 
X 
Optional in-clinic stay for 
participants at the discretion of 
investigator. 
Phone call 
 
 
X 
 
AE collection - may be 
out-patient visit at discretion of 
Investigator for additional 
checks 
Informed consent 
X 
 
 
 
 
Severe acute respiratory 
syndrome SARS-CoV-2 
PCR test 
X 
 
 
X 
 
Temperature check 
X 
X 
 
X 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
Recheck clinical status before 
randomization and/or 1st dose 
of study intervention. 
Demography 
X 
 
 
 
 
Full physical examination 
including height and 
weight. 
X 
 
 
 
Weight at screening is used 
for determination of dose 
Fitzpatrick Skin Type 
X 
 
 
 
Assessments for UVB-MITT 
population only 
Assessment to determine 
applying MED application 
Echocardiogram 
X 
 
 
 
 
Medical history (includes 
substance usage) 
X 
 
 
 
Substances: Drugs, Alcohol, 
tobacco and caffeine 
Current medical 
conditions 
X 
 
 
 
 
HIV, Hepatitis B and C 
X 
 
 
 
 
Haematology, clinical 
chemistry (include liver 
chemistries) and 
urinalysis 
X 
 
 
X 
Including Troponin-T (hs) 
NT-proBNP 
X 
 
 
X 
 
UrDrug, BrAlc 
X 
 
 
X 
 
12-lead ECG 
T 
 
 
X 
T = Triplicate 
X = Single 
Vital signs 
X 
 
 
X 
 


 
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Procedure 
Screening  
(up to 28 days 
before Day 1) 
Follow-up 
check 
364 days 
post last 
dose 
Final 
follow-up 
564 days 
post-last 
dose 
Notes 
Part 1 
Part 2 
PainCart training 
[X] 
[X] 
 
 
May be performed during 
either part 1 or part 2 (not 
both) 
Minimal Erythema Dose 
(MED) application 
X 
 
 
 
Assessments for UVB-MITT 
population only. Exposure to 
pre-determined 6 ascending 
doses of UVB radiation. 
MED application will be the 
final assessment on Part 1 of 
Screening and will only be 
completed after confirmation 
of eligibility from available 
results, e.g. lab data, 
echocardiogram results may 
not be available. 
 
MED assessment 
 
X 
 
 
Assessments for UVB-MITT 
population only. 24 hours (2 
hours) after UV exposure 
 
AE/SAE review 
X 
X 
X 
X 
 
• 
An echocardiogram performed within 3 months prior to first dosing is acceptable for 
enrolment into the study  
• 
MED determination performed within 6 weeks prior to first dosing is acceptable for 
enrolment into the study  


 
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12.2.1.2. 
Study periods 1, 2, 3 and Early Withdrawal 
When the following assessments are scheduled to be performed at the same time-point, the order will be as follows: 
ECG > vital signs > PK and PD sampling > PainCart 
Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
Out-patient visit 
 
 
 
 
X* 
X 
X 
 
X 
Optional in-clinic stay for participants at the discretion of 
investigator. 
*Day 7 is optional for those participants not receiving UVB. 
Admission in clinical unit 
X** 
 
 
 
 
 
 
 
 
Optional in-clinic stay for participants at the discretion of 
investigator. 
** If subjects are not UVB-MITT participants, optional admission will 
be on Day-1 with Day-2 completed on Day-1. 
Discharge from clinical 
unit 
 
 
 
X 
 
 
 
 
 
Except if, the participant needs to remain in the Unit longer for 
medical reasons. 
Phone Call 
 
 
 
 
 
 
 
X 
 
AE collection - may be out-patient visit at discretion of Investigator 
for additional checks 
Brief Physical 
Examination 
 
 
X 
X 
 
X 
X 
 
X 
 
Haematology, clinical 
chemistry (include liver 
chemistries) and 
urinalysis  
 
X 
X 
X 
 
X 
X 
 
X 
Troponin T to be assessed on Day -1, 8, 15 (and EW if needed). 
C3/C4 on Day -1 only 
UrDrug, BrAlc 
 
X 
 
 
X* 
 
X 
 
 
*for volunteers who do not receive UVB application, the Day 7 
Assessments may be performed on Day 8 prior to PainCart  
SARS-CoV-2 PCR test 
X** 
 
 
 
 
 
 
 
X 
 


 
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Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
12-lead ECG 
 
T 
X 
 
 
X 
X 
 
X 
Day 1: pre-dose (T), 0.5hr, 1hr post start of infusion. 
On other days a single measure taken prior to 1st PainCart 
assessment. 
T = Triplicate 
X = Single 
Vital signs (including 
temperature) 
X** 
X 
X 
X 
X-t 
X 
X 
 
X 
Day 1: pre-dose, 0.5hr, 1hr, 2hr post start of infusion. 
X-t: temperature assessment on Day 7 for UVB-MITT population 
only  
On other days a single measure taken prior to 1st PainCart 
assessment. 
Randomization 
 
 
X 
 
 
 
 
 
 
Study period 1 only 
Drug/placebo IV infusion 
 
 
X 
 
 
 
 
 
 
Continuous infusion over 1 hour 
PainCart 
 
 
X 
X 
 
X 
X 
 
 
Day 1 pre-dose performed twice (baseline) 
Day 1 performed at 1 and 3 hours post start of IV infusion. Other 
days performed twice ~2 hours apart at approximately the same 
time of day in each study period. 
Day 15 - heat pain detection assessment associated with UVB test 
performed on normal skin only. 
Participants not receiving UVB application will not undergo UVB 
heat pain detection test on irradiated skin.  All other PainCart 
assessments including heat pain detection performed on normal 
skin will still be assessed. See Appendix 7 of protocol for details of 
testing 
UVB application 
 
X 
 
 
X 
 
 
 
 
UVB application (2 x MED) will be performed 24hr (2hr) prior to 
start of infusion on Day 1. 
UVB application (2 x MED) on Day 7 will be performed 24hr (2hr) 
prior to PainCart assessment on Day 8. 
UVB application only applies to those in the UVB-MITT population. 


 
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Procedure 
Study periods 1, 2, 3 (Days) 
Early 
Withdrawal 
Notes 
 
-2 
–1 
1 
2 
7 
8 
15 
25 
 
Allowed visit windows are detailed in the Study Reference Manual 
(SRM) 
AE review 
X** 
X 
================================→ 
X 
 
SAE review 
X** 
X 
================================→ 
X 
 
Concomitant medication 
review 
X** 
X 
================================→ 
X 
 
Blood samples for PK and 
PD 
 
 
X 
X 
 
X 
X 
 
X 
Day 1: pre-dose, 1hr, 3hr post-start of IV infusion. 
On other days samples taken prior to 1st PainCart assessment. 
Blood sample for 
immunogenicity 
 
 
X 
 
 
 
X 
 
X 
Day 1: pre-dose. 
Day 15: prior to 1st PainCart assessment. 
** If subjects are not UVB-MITT participants, optional admission will be on Day-1 with Day-2 assessments completed on Day-1. 
 
• 
The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic assessments may be 
altered during the course of the study based on newly available data to ensure appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic 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. 
• 
The planned study assessments on Day 7 (UVB-MITT population only), 8, 15 and 25 may be performed within a  24hr window. 
• 
A questionnaire related to COVID-19 is part of each visit and included in the AE review. 


 
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12.3. 
Appendix 3: Assessment Windows 
12.3.1. 
General 
Clinic visits are scheduled to take place as specified in Appendix 2: Schedule of 
Activities. Measurements will be reported based on the visits they are assigned to in the 
study database without adjustment. Measurements outside visit windows will not be 
excluded from analyses and may constitute an important protocol deviation upon further 
review. 
If a circumstance should arise where multiple measurements have been collected and 
recorded against the same scheduled visit and timepoint, for which only one 
measurement should have been collected, then the first valid value will be used for that 
timepoint. 
12.3.2. 
PainCart Assessment Window 
During each study period, all participants will be assessed on the various PainCart tests 
for measuring different modalities of nociception. The PainCart assessments are 
performed multiple times during each study period and taken multiple times during each 
clinical visit.  
The following information in Table 4: PainCart Assessment Windows displays which 
PainCart assessments relate to which day, and how they are summarised at each visit. As 
a note, the AAUC analysis for the PainCart endpoints will utilise the individual 
assessments instead of the summarised daily assessments detailed below. 
Table 4 
PainCart Assessment Windows 
PainCart Assessment Windows 
Analysis Day 
Analysis Period 
Timepoint 
Summarised 
Baseline 
Day 1 (Randomisation, Pre-
Dose) 
Two assessments are performed 
pre-dosing. Baseline is defined as 
the mean value prior to dosing in 
each study period. If only one pre-
dose assessment record is present 
on Day 1, then this value will be set 
as the baseline value 
Day 1 
Day 1 (Randomisation, Post-
Dose) 
Two assessments are performed at 
1 and 3 hours post start of IV 
infusion. The analysis day value is 
defined as the mean value of the 
two assessments. If only one post-
dose assessment is performed on 
Day 1, then that value will be set as 
the analysis day value.. 


 
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PainCart Assessment Windows 
Analysis Day 
Analysis Period 
Timepoint 
Summarised 
Day 2, 8 and 15 
Day 2, 8 and 15 from day of 
randomisation 
Two assessments are performed at 
approximately 2 hours apart at 
roughly the same time of day in 
each study period. The analysis day 
value is defined as the mean value 
of the two assessments. If only one 
assessment is performed on the 
day, then that value will be set as 
the analysis day value. 
The planned PainCart assessments 
on day 2, 7 (MED application), 8 & 
15 may be performed within a  1- 
24hr window. 
 
Acceptable time windows around the nominal time points for other assessments will be 
included in the Study Reference Manual (SRM) and assessments performed within these 
time windows will not constitute a protocol deviation. 


 
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12.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
12.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the start date of the study treatment. 
Study Phase 
Definition 
Pre-Treatment  
Date/Time < Study Treatment Dose Date/Time (Period 1) 
On-Treatment 
Study Treatment Dose Date/Time (Period 1) ≤ Date/Time  
 
12.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 7 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
 
For period specific concomitant medications, Refer to Section 12.6.1 for period 
definitions 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
12.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If the AE is on-treatment, then the AE is treatment emergent. 
• 
Refer to Section 12.6.1 for period definitions. 
NOTES:  
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 


 
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12.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
12.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. R may be used for Stage 2 QC 
purposes. 
Reporting Area 
HARP Server 
: UK1SALX00175 
HARP Compound 
: arenv/arprod/gsk3858279/mid209973/ 
Analysis Datasets  
• 
Analysis datasets will be created according to Legacy GSK A&R dataset standards. 
Generation of RTF Files 
• 
RTF files will be generated for Interim SAC (if performing) and final SAC/AAC tables. 
12.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and/or figures. 
• 
All unscheduled visits will be included in listings and determination of PCIs. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 


 
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Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
12.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
VQD-GUI-000722 (6.0).  
Note: Concentration values will be imputed as per VQD-GUI-000722 (6.0). 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per VQD-GUI-000722 (6.0) for 
descriptive summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data 
specification detailed in Section 12.9.1 Pharmacokinetic/Pharmacodynamic 
Dataset Specification. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by CPMS 
The following PK parameters will be derived by CPMS:  
• 
AUC(0-t), AUC(0-7), Cmax, tmax and tlast. 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to SOP_314000. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to VQD-GUI-000722 (6.0). 
 
12.5.4. 
Reporting Standards for Target Engagement 
Target Engagement Concentration Data 
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per VQD-GUI-000722 (6.0) 
for descriptive summary statistics/analysis and summarized graphical 
displays only. NQ values for Free CCL17 will be set to ½ LLQ and 
subsequent valid concentrations will be retained. Median will be imputed 
for missing baseline values. LLQ value will be imputed for baseline values 
equal to zero. 


 
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Target Engagement Parameter Derivation 
TE Parameter to be 
Derived by CPMS 
• 
None 
 
TE Parameter to be 
Derived by 
Programmer 
The following TE parameters will be derived by programmer:  
• 
Cmin, tmin, BL, percentage reduction, maximum percentage reduction 
for free CCL17 
• 
Cmax, tmax, BL, fold increase, maximum fold increase for total CCL17 
Target Engagement Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to SOP_314000. 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to VQD-GUI-000722 (6.0). 
 
 


 
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12.6. 
Appendix 6: Derived and Transformed Data 
12.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Study Period 
• 
The start date of Period [1/2/3] is the dosing Day 1 date for that period. 
• 
The end date of Period [1/2] is the Day -1 date for the subsequent period. 
• 
The end date for Period 3 and Period[1/2] if no subsequent period follows, will be the final follow up 
visit date, or if applicable, study withdrawal date, whichever date is earlier. 
Study Day / Period Day 
• 
Study day is derived with respect to the very first dose date (Period 1): 
• 
Ref Date = Missing      → Study Day = Missing  
• 
Ref Date < Dose Date → Study Day = Ref Date – Dose Date 
• 
Ref Data ≥ Dose Date → Study Day = Ref Date – (Dose Date) + 1     
• 
Period day is derived with respect to the dose date during that period: 
• 
Ref Date = Missing                    → Period Day = Missing  
• 
Ref Date < Period Start Date     → Period Day = Ref Date – Period Dose Start Date     
• 
Ref Data ≥ Period Start Date     → Period Day = Ref Date – (Period Dose Start Date) + 1 
 
12.6.2. 
Study Population 
Extent of Exposure 
• 
This is a single dose per period study, the volume of infusion will be recorded, as will the start and 
stop date/time of infusion. 
• 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Date of Subsequent/Last Dose – (Date of First Dose) +1+ 18*5 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
Age 
• 
Birth date will be presented in listings as ‘YYYY’. 
• 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows: 
o Any subject with a missing day will have this imputed as day ‘15’. 
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• 
Calculated based on the screening date 
• 
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, 
the age of the participant will not be calculated and will remain missing. 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)2] 


 
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Race Category  
• 
The five high level Food and Drug Administration (FDA) race categories and designated Asian 
subcategories are: 
1. African American/African Heritage 
2. American Indian or Alaska Native 
3. Asian 
a) Central/South Asian Heritage 
b) Japanese/East Asian Heritage/South East Asian Heritage 
c) Mixed Asian Heritage (only required if data exists) 
4. Native Hawaiian or other Pacific Islander 
5. White 
• 
These categories and subcategories will be summarized along with all combinations of high level 
categories which exist in the data. All five of the high level race categories and the two Asian 
subcategories must appear on the display even if there are no participants in a particular category, 
but combinations that do not exist in the data do not need to be represented. Combinations will be 
represented as the concatenation of the high level category terms, e.g., “White & Asian.” The 
designated Asian subcategories will not be summarized as combinations with other categories. 
• 
In addition, the standard race categories collected per IDSL will be summarized along with 
categories for mixed race. The categories are:  
1. African American/African Heritage 
2. American Indian or Alaska Native 
3. Asian - Central/South Asian Heritage 
4. Asian – East Asian Heritage 
5. Asian – Japanese Heritage 
6. Asian – South East Asian Heritage 
7. Asian – Mixed Race 
8. Native Hawaiian or other Pacific Islander 
9. White – Arabic/North African Heritage 
10. White – White/Caucasian/European Heritage 
11. White – Mixed Race 
12. Mixed Race 
• 
“Asian – Mixed Race” is only used if more than one Asian category is selected, but no non-Asian 
races. Similarly, “White – Mixed Race” is only used if both of the White categories are selected, and 
no non-White races. If multiple races of different types are selected, then the overall “Mixed Race” 
category is used. 
• 
A participant will only be represented in a single category. A participant who selects a combination of 
races will be counted as “Asian – Mixed Race,” “White – Mixed Race,” or “Mixed Race,” but not in each 
of the constituent terms. Therefore, the counts will add up to the total number of participants with a 
response, and the percentages will add to 100%. 


 
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12.6.3. 
Pharmacodynamic 
 PainCart Assessments 
General 
• 
For PainCart assessments, baseline is defined as the mean value of the two assessments taken 
prior to dosing in each session (Day 1). 
 
• 
The following PainCart endpoints will be assessed utilising all available individual assessments 
recorded during the study periods (AAUC: Analysis area under the curve, PDT = pain detection 
threshold, PTT = pain tolerance threshold): 
 
• 
UVB Heat: PDT AAUC 
• 
Cold Pressor: PDT, PTT AAUC 
• 
Electrical stair (pre-cold pressor): PDT, PTT AAUC 
• 
Electrical burst: PDT, PTT, AAUC 
• 
Conditioned pain modulation (CPM): PDT, PTT AAUC 
 
• 
The following PainCart endpoints will be assessed at Baseline, Day 1, Day 2, Day 8 and Day 15 
(AAC: Area above the curve from eVAS, AUC = area under the curve from eVAS, PDT = pain 
detection threshold, PTT = pain tolerance threshold, (e)VAS = ((electronic) visual analogue scale): 
 
• 
UVB Heat Pain Detection – Normal Skin 
• 
Cold Pressor: PDT, PTT, post-test VAS 
• 
Electrical stair (pre-cold pressor): PDT, PTT, post-test VAS 
• 
Electrical stair (post-cold pressor): PDT, PTT, post-test VAS (for use in calculation for CPM) 
• 
Electrical burst: PDT, PTT, AUC, post-test VAS 
• 
Pressure Pain: PDT, PTT, AUC, post-test VAS 
 
• 
The UVB heat pain endpoint on irradiated skin will be assessed at all timepoints mentioned above 
except for Day 15. 
 
Conditioned Pain Modulation (CPM) 
• 
CPM is the activation of the pain-modulatory mechanism, as part of the descending endogenous 
analgesia system. The degree of CPM is assessed by comparing the electrical pain thresholds for 
the single stimulus paradigm before and after the cold pressor task. i.e. 
• 
CPM = Post-Cold Pressor electrical stair threshold – Pre-Cold electrical stair threshold 
Derivation of AAUC for PainCart Assessments  
• The following analysis AAUC’s for the PainCart assessments will be calculated as follows:  
 
Assessment 
AAUC’s 
Calculated 
Derivation Details 
Heat Pain Detection on 
UVB skin 
AAUC (1-8 Days) 
➢ Baseline = Day 1 (Pre-Dose) 


 
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 PainCart Assessments 
Cold Pressor Detection 
and Tolerance 
AAUC (1-15 Days) 
➢ Baseline = Day 1 (Pre-Dose) 
All other PainCart 
assessments 
AAUC (1-15 Days) 
➢ Baseline = Day 1 (Pre-Dose) 
 
• The weighted mean AAUC parameters will be derived by calculating the area under the 
curve (AUC) using the trapezoidal rule, and then dividing by the actual relevant time interval 
(i.e. tf - tl):   
𝑾𝒆𝒊𝒈𝒉𝒕𝒆𝒅 𝑴𝒆𝒂𝒏 𝑨𝑨𝑼𝑪(𝒕𝒇−𝒕𝒍) =
𝟏
𝟐∑
(𝒕𝒊+𝟏−𝒕𝒊)(𝒚𝒊+𝟏+ 𝒚𝒊)
𝑰−𝟏
𝒊=𝟏
𝒕𝒍−𝒕𝒇
 
 
      Where (example provided for UVB heat pain detection AUC(1-8 Days):   
• yi  = Value of endpoint at ith time point  
• ti  = The ith actual time point (days) for UVB heat pain detection: 
o t values will be calculated as the actual time recorded in the SAS dataset in the SAS 
datetime format. For baseline, the timepoint will be calculated as the midpoint of the 
two pre-dose assessments.   
• 
tf  = Actual time point of first non-missing obs 
• tl  = Actual time point of last non-missing obs 
• I  = Number of time points used in the AAUC calculation 
 
Seeds for PainCart Analyses – PROC MCMC  
• Seeds for all planned analyses were determined in advance using the following SAS code 
(analysis_seed.SAS) and documented within this RAP prior to unblinding: 
data temp; 
   do i = 1 to 15; 
    number=round(100000*ranuni(0),1); 
   output; 
  end; 
run; 
proc print; 
run; 
 
 
 
 
 
Endpoint 
Test 
Analysis 
Macro Seed 
Heat Pain 
Detection 
Mixed ANCOVA 
57743 


 
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 PainCart Assessments 
Cold Pressor 
Tolerance 
Mixed ANCOVA 
95933 
Detection 
Mixed ANCOVA 
55572 
Electrical Pain – single 
stimulus (Pre-cold pressor) 
Tolerance 
Mixed ANCOVA 
01749 
Detection 
Mixed ANCOVA 
19282 
Conditioned Pain Modulation 
(CPM) 
Detection 
Mixed ANCOVA 
46555 
Tolerance 
Mixed ANCOVA 
33042 
Electrical Pain – repeated 
stimulus 
Tolerance 
Mixed ANCOVA 
80088 
Detection 
Mixed ANCOVA 
73186 
 
12.6.4. 
Safety 
Adverse Events 
• 
Adverse events will be coded using the current MedDRA coding dictionary at the time of reporting 
providing a Preferred Term (PT) and a System Organ Class (SOC) for analysis and reporting. 
 
ECG Parameters 
RR Interval 
• 
IF RR interval (msec) is not provided directly, then RR can be derived as: 
[1] If QTcB is machine read & QTcF is not provided, then: 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value, THEN do not derive. 
Corrected QT Intervals 
• 
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fredericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements. 
• 
IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:  
               𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
                                                 𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
Worst Case Rules 
Worst case finding based on the interpretation and the clinical significance: 
• 
Count the participant as ‘ABNORMAL’ and ‘CLINICALLY SIGNIFCANT’, if any of the findings are 
‘ABNORMAL’ and ‘CLINICALLY SIGNIFCANT’ during the time period/Post-Baseline.   
• 
Else count the participant as ‘ABNORMAL’ and ‘NOT CLINICALLY SIGNIFCANT’, if any of the 
findings are ‘ABNORMAL’ and ‘NOT CLINICALLY SIGNIFCANT’ and none of the findings are 
‘ABNORMAL’ and ‘CLINICALLY SIGNIFCANT’ during the time period/Post-Baseline.  
• 
Else count the participant as ‘NORMAL’ if there is a finding of ‘NORMAL’ and none of the findings 
are ‘ABNORMAL during the time period/Post-Baseline.  
• 
Otherwise, do not count the participant during the time period/Post-Baseline, i.e. little n will reflect 
that the subject is not counted in the time period/Post-Baseline. 
 


 
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Laboratory Parameters 
o All BLQ values will be imputed with ½ LLOQ.  
o All ALQ values will be imputed with the ALQ + [smallest positive number with the same number 
of decimal places as the ALQ is reported with] 
o Values reported as < x are assumed to have an LLOQ of x. 
o Values reported as > x are assumed to have an ALQ of x. 


 
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12.7. 
Appendix 7: Reporting Standards for Missing Data 
12.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
A participant is considered to have completed the study if they have completed all 
phases and periods of the study including the last visit. 
• 
Withdrawn participants may be replaced (as detailed in Section 2.3) in the study in 
order to ensure sufficient participants complete the study. Replacement participants will 
be assigned to the same treatment sequence as the participant they are replacing, at 
the discretion of the Sponsor and in consultation with the Principal Investigator. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits. 
12.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
MMRM 
Analysis 
• 
All the available assessments taken at scheduled visits will be included in the 
repeated measures models in which missing data are not explicitly imputed but the 
correlation between visits for all participants is used to adjust the estimate of 
treatment effect considering any missing data. 
12.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 


 
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Element 
Reporting Detail 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
 


 
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12.8. 
Appendix 8: Values of Potential Clinical Importance 
12.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Haematocrit  
Ratio of 
1 
Male 
0.39 
0.54 
∆ from BL 
↓0.075 
>10% 
Haemoglobin  
g/L 
 
Male 
124 
180 
∆ from BL 
↓25 
>10% 
Lymphocytes  
x109/ L 
 
0.75 
4.5 
Neutrophil Count  
x109/ L 
 
1.5 
8.0 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count (WBC) 
x109/ L 
 
2.5 
15 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30 
 
Calcium 
mmol/L 
 
2.00 
2.75 
Creatinine 
 
µmol/L 
 
 
 
1.3 X ULN 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Total CO2 
mmol/L 
 
18 
32 
Creatinine kinase 
mg/dL 
 
 
>1.6 X ULN 
C-reactive protein 
mg/L 
 
 
≥3.0 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
IU/L 
High 
≥2xULN 
AST/SGOT  
IU/L 
High 
≥2xULN 
AlkPhos  
IU/L 
High 
≥2xULN 
T Bilirubin  
µmol/L 
High 
≥1.5xULN 
T. Bilirubin + ALT 
µmol/L 
High 
ALT≥3xULN AND bilirubin≥ 1.5xULN 
IU/L 
 


 
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12.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>500 
Absolute PR Interval 
msec 
<110 
>220  
Absolute QRS Interval 
msec 
<75 
>120 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
12.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
 


 
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12.9. 
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses 
An exploratory graphical analysis of the total drug on the primary endpoints of efficacy 
will be performed by generating the PK/PD plots as presented in Appendix 12. 
If the exploratory graphical analysis suggests a relationship and data permits, a 
PopPK/TE model may be developed from the final PK and TE data from the first-time in 
human study 207804 and may be fitted to the current data using the nonlinear mixed 
effects modelling software NONMEM. In this case, data relative to the primary measures 
of efficacy will be used to model the PD effect. Direct and indirect response models may 
be developed from all available PD data and linked with the PK/TE to characterise the 
relationship between different modalities of nociception and PK or TE.  
The appropriateness of the PopPK/PD model will be assessed by the OFV, successful 
convergence, covariance estimation, shrinkage, parameter uncertainty, standard GoF and 
simulation-based diagnostic plots e.g. VPC.   
The GoF plots may include, but are not limited to: 
• 
Population and individual predictions versus observations 
• 
Conditional weighted residuals versus population predictions and time 
If a VPC is a performed, this will be based on 1000 simulations with the model and the 
design structure of the observed data (i.e. dose level and time, time of PK/PD sampling 
and individual values of model covariates, if any). The median and the 10th and 90th will 
be compared to the observed data. 
If any PK/PD modelling is conducted, it will be reported in a separate CPMS modelling 
report, after reporting of this study. 
12.9.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
The dataset specification to support any PK/PD analysis will be provided as a separate 
document. 
The merging of PK, TE, PainCart, treatment, and demographic data together with the 
creation of the NONMEM-specific dataset will be performed by, or under the direct 
auspices of, Clinical Statistics & Programming, GlaxoSmithKline.  
This dataset programming will be conducted in a HARP environment using the currently 
supported version of SAS. 


 
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12.10. 
Appendix 10: Abbreviations & Trade Marks 
12.10.1. 
Abbreviations 
Abbreviation 
Description 
AAC 
All Analysis Complete  
AAUC 
Analysis Area Under the Curve 
ADAs 
Anti-Drug Antibodies 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
ANCOVA 
Analysis of Covariance 
A&R 
Analysis and Reporting  
 
AUC 
Area Under the Curve 
CDISC 
Clinical Data Interchange Standards Consortium 
CHDR 
Centre for Human Drug Research 
CI 
Confidence Interval 
CrI 
Credible Interval 
CPM 
Conditioned Pain Modulation 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
eVAS 
Electronic Visual Analogue Scale 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GoF 
Goodness-of-Fit 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
LS 
Least Squares 
mA 
Milliamp 
MCMC 
Markov Chain Monte Carlo 
MITT 
Modified Intent to Treat 


 
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Abbreviation 
Description 
MMRM 
Mixed Model Repeated Measures 
OFV 
Objective Function Value 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Posterior Probability 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDSP 
Study Data Standardization Plan 
SE 
Standard Error 
SEC 
Seconds 
SOP 
Standard Operation Procedure 
SP 
Study Period 
TA 
Therapeutic Area 
TE 
Target Engagement 
TFL 
Tables, Figures & Listings  
UVB 
Ultraviolet B 
12.10.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
NONMEM version 7.3 
 
 
PainCart 
 
 
R / RStudio 
 
 
SAS 
 
 
WinNonLin 
 
 


 
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12.11. 
Appendix 11: List of Data Displays 
12.11.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.01 to 1.17 
N/A 
Pharmacodynamic 
2.01 to 2.25 
2.01 to 2.09 
Safety 
3.01 to 3.24 
N/A 
Pharmacokinetic 
4.01 to 4.02 
4.01 to 4.03 
Pharmacokinetic / Pharmacodynamic 
N/A 
5.01 to 5.06 
Section 
Listings 
ICH Listings 
1 to 31 
Other Listings 
32 to 40 
 
12.11.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
 
POP_Tn 
 
Pharmacodynamic 
PD_Fn 
PD_Tn 
PD_Ln 
Safety 
 
 
 
Pharmacokinetic 
 
 
 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
 
 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
12.11.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
IA 1 SAC [X] 
Interim Analysis 1 Statistical Analysis Complete 
IA 2 SAC [X] 
Interim Analysis 2 Statistical Analysis Complete 
SAC [X] 
Final Statistical Analysis Complete 
AAC [X][2] 
Final All Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
2. 
The displays listed as Delivery AAC may be delivered for the SAC milestone depending on availability of the 
displays. 


 
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12.11.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.01. 
Randomised 
ES1xo 
 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record by Relationship to COVID-19 
Pandemic 
ICH E3, FDAAA, EudraCT 
Present by: Overall, Related to 
COVID-19, Not Related to COVID-19 
AAC [1] 
1.02. 
Screened 
ES6 
Summary of Screen Status and Reasons for Screen Failure 
Journal Requirements 
AAC [1] 
1.03. 
ITT 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment by Relationship to COVID-19 Pandemic 
ICH E3 
Present by: Overall, Related to 
COVID-19, Not Related to COVID-19 
AAC [1] 
1.04. 
ITT 
ES4 
Summary of Subject Disposition at Each Study Period 
ICH E3 
 
AAC [1] 
1.05. 
ITT 
ES11 
Summary of Outcome of Adverse Events Which Led to Study 
Withdrawal at Each Study Period 
EMA mandated clinical trial results 
registry 
AAC [1] 
1.06. 
ITT 
ES5 
Summary of Reason for Withdrawal at Each Period 
FDAAA, EMA 
Only if the withdrawal at each period is 
collected. 
AAC [1] 
1.07. 
ITT 
POP_T1 
Summary of Attendance at Each Day 
 
AAC [1] 
1.08. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
Relative to COVID-19 Pandemic Measures 
EudraCT/Clinical Operations 
Present Total column only. 
Present Overall, and by Before and 
After implementation of Pandemic 
Measures 
AAC [1] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviation 
1.09. 
ITT 
DV1 
Summary of Important Protocol Deviations by relationship to 
COVID-19 Pandemic 
ICH E3 
Present only Total column 
Present by: Overall, Related to 
COVID-19, Not Related to COVID-19 
AAC [1] 
Population Analysed 
1.10. 
Screened 
SP1 
Summary of Study Populations  
IDSL 
 
AAC [1] 
Demographic and Baseline Characteristics 
1.11. 
Randomised 
DM1xo 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
Programming Note: Include BMI 
summary 
Present by COVID-19 Pandemic 
Measures Subgroup: Overall, Before, 
After 
IA 1 [1], IA 2 
[2], AAC [3] 
1.12. 
Enrolled 
DM11xo 
Summary of Age Ranges 
EudraCT 
AAC [1] 
1.13. 
Randomised 
DM6xo 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
AAC [1] 
Medical Conditions  
1.14. 
Safety 
MH1 
Summary of Past Medical Conditions (Cardiovascular Risk 
Factors) 
ICH E3  
Present total column only, as per IDSL 
crossover recommendation. 
AAC [1] 
1.15. 
Safety 
MH1 
Summary of Current Medical Conditions (Cardiovascular Risk 
Factors) 
ICH E3  
Present total column only, as per IDSL 
crossover recommendation. 
AAC [1] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Prior and Concomitant Medications 
1.16. 
Safety 
CM8 
Summary of Prior Concomitant Medications 
ICH E3 
AAC [1] 
1.17. 
Safety 
CM8 
Summary of Concomitant Medications by Period 
ICH E3 
Present by period 
AAC [1] 
 
12.11.5. 
Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PainCart 
UVB Heat Detection Assessment 
2.01. 
UVB-ITT 
PD_T1 
Summary of UVB Heat Pain Detection (Celsius) on UVB Skin 
NVSCATCD=0015 and 
NVTESTCD=AF001 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. Day 15 
not recorded for UVB heat pain UVB 
skin assessments 
IA 1 [1], IA 2 
[2], SAC [3] 
2.02. 
UVB-MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-8 Days) in UVB Heat Pain Detection 
(Celsius*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
IA 1 [1], IA 2 
[2], SAC [3] 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.03. 
ITT 
PD_T1 
Summary of UVB Heat Pain Detection (Celsius) on Normal Skin 
NVSCATCD=0014 and 
NVTESTCD=AF001 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline.  
AAC [1] 
Cold Pressor Assessment 
2.04. 
ITT 
PD_T1 
Summary of Cold Pressor Time to Intolerable Pain Threshold 
(Seconds) 
NVSCATCD=0011 and 
NVTESTCD=AF004 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline.  
IA 1 [1], IA 2 
[2], SAC [3] 
2.05. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Cold Pressor Time to 
Intolerable Pain Threshold (Seconds*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
IA 1 [1], IA 2 
[2], SAC [3] 
2.06. 
ITT 
PD_T1 
Summary of Cold Pressor Time to Pain Detection Threshold 
(Seconds) 
NVSCATCD=0011 and 
NVTESTCD=AF003 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline.  
AAC [1] 
2.07. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline in Cold 
Pressor Time to Pain Detection Threshold (Seconds) – Area 
Under Curve 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Electrical Stimulation Assessment 
2.08. 
ITT 
PD_T1 
Summary of Electrical Pain Tolerance Threshold (mA) – Single 
Stimulus 
NVSCATCD=0013 and 
NVTESTCD=AF004 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline.  
IA 1 [1], IA 2 
[2], SAC [3] 
2.09. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Electrical Pain Tolerance 
Threshold – Single Stimulus (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
IA 1 [1], IA 2 
[2], SAC [3] 
2.10. 
ITT 
PD_T1 
Summary of Electrical Pain Detection Threshold (mA) – Single 
Stimulus 
NVSCATCD=0013 and 
NVTESTCD=AF003 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline.  
AAC [1] 
2.11. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Electrical Pain Detection 
Threshold – Single Stimulus (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 
2.12. 
ITT 
PD_T1 
Summary of Electrical Pain Tolerance Threshold (mA) – Repeat 
Stimulus 
NVSCATCD=0012 and 
NVTESTCD=AF004 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.13. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Electrical Pain Tolerance 
Threshold – Repeat Stimulus (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 
2.14. 
ITT 
PD_T1 
Summary of Electrical Pain Detection Threshold (mA) – Repeat 
Stimulus 
NVSCATCD=0012 and 
NVTESTCD=AF003 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 
2.15. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Electrical Pain Detection 
Threshold – Repeat Stimulus (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 
Conditioned Pain Modulation (CPM) 
2.16. 
ITT 
PD_T1 
Summary of Conditioned Pain Modulation Detection Threshold 
(mA) 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 
2.17. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Conditioned Pain 
Modulation Detection Threshold (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 
2.18. 
ITT 
PD_T1 
Summary of Conditioned Pain Modulation Tolerance Threshold 
(mA) 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.19. 
MITT 
PD_T3 
Bayesian Statistical Analysis of Ratio to Baseline Analysis Area 
Under the Curve (AAUC 1-15 Days) in Conditioned Pain 
Modulation Tolerance Threshold (mA*Day) 
Programming note: Include footnotes for 
the final model fitted, including priors 
used and interpretations of the direction 
of effect. 
AAC [1] 
Pressure Pain Assessment 
2.20. 
ITT 
PD_T1 
Summary of Pressure Pain Detection Threshold (kPa) 
NVSCATCD=0016 and 
NVTESTCD=AF003 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 
2.21. 
ITT 
PD_T1 
Summary of Pressure Pain Tolerance Threshold (kPa) 
NVSCATCD=0016 and 
NVTESTCD=AF004 
Programming Note: Repeat for 
Treatment: GSK3858279; Period: 2 and 
3. Geometric Mean and CV (%) 
Presented for Ratio to Baseline. 
AAC [1] 
Serum Concentration 
2.22. 
Safety 
PD_T5 
Summary of Free & Total CCL17 in Serum Concentration-Time 
Data (pg/mL) 
By treatment & study period. 
IA 1 [1], AAC 
[2] 
Target Engagement 
2.23. 
Safety 
PD_T7 
Summary of Derived Free and Total CCL17 in Serum Target 
Engagement Parameters (non-transformed and log-transformed) By treatment & study period. 
IA 1 [1], AAC 
[2] 
2.24. 
Safety 
PD_T7 
Summary of Derived Free and Total CCL17 in Serum Target 
Engagement Parameters - Percent Reduction and Fold Increase 
(non-transformed and log-transformed) 
By treatment & study period. Include 
a column Planned Time Point. 
IA 1 [1], AAC 
[2] 


 
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Pharmacodynamic: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Immunogenicity 
2.25. 
Safety 
IMM1 
Summary of Immunogenicity 
Present by Period. Drop Planned 
Time Column. Include a Total 
Column.  
Footnote: “Note: Percentage is 
calculated as (x/n)*100 where x = 
the number of subjects with a 
positive sample 
and n = the number of subjects for 
whom a sample was collected.” 
AAC [1] 
 
 
12.11.6. 
Pharmacodynamic Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PainCart 
2.01. 
UVB-MITT 
PD_F1 
Ratio to Baseline in UVB Heat Pain Detection 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 
2.02. 
MITT 
PD_F1 
Ratio to Baseline in Cold Pressor Time to Intolerable Pain 
Threshold 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 
2.03. 
MITT 
PD_F1 
Ratio to Baseline in Electrical Pain Tolerance Threshold – Single 
Stimulus 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 


 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.04. 
UVB-ITT 
PD_F1 
Individual Ratio to Baseline in UVB Heat Pain Detection 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 
2.05. 
ITT 
PD_F1 
Individual Ratio to Baseline in Cold Pressor Time to Intolerable 
Pain Threshold 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 
2.06. 
ITT 
PD_F1 
Individual Ratio to Baseline in Electrical Pain Tolerance 
Threshold – Single Stimulus 
Programming note: Include footnote on 
how the ratio to baseline was derived. 
State original unit of pain assessment. 
SAC [1] 
Target Engagement Concentrations 
2.07. 
Safety 
PK16A 
Individual Free & Total Serum CCL17 Concentration-Time Plots 
(Linear and Semi-log) 
IDSL. By participant, endpoint and 
treatment sequence  
Period is presented on the same plot, 
with linear and semi-logarithmic scale 
side by side 
AAC [1] 
2.08. 
Safety 
PK17 
Mean Free & Total Serum CCL17 Concentration-Time Plots 
(Linear and Semi-log) by Treatment 
IDSL. By endpoint and treatment 
sequence. 
Period is presented on the same plot, 
with linear and semi-logarithmic scale 
side by side. 
AAC [1] 
2.09. 
Safety 
PK18 
Median Free & Total Serum CCL17 Concentration-Time Plots 
(Linear and Semi-log) by Treatment 
IDSL. By endpoint and treatment 
sequence. 
Period is presented on the same plot, 
with linear and semi-logarithmic scale 
side by side. 
AAC [1] 
 
 


 
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12.11.7. 
Safety Tables 
Safety: Tables – All Safety Tables will be presented by Period unless stated otherwise. 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.01. 
Safety 
AE1xo 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Period 
ICH E3 
Present by Period 
Programming note: For interim analysis 
present AEs SOCs and PTs which have 
more than 2 subjects overall per period. 
i.e. at least two unique subjects in the 
Total column per period. 
Include footnote: Note: For interim, only 
AEs occurring in two or more subjects 
by period are reported. 
IA 1 [1], IA 2 [2], 
SAC [3] 
3.02. 
UVB-Safety 
AE1xo 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Period – UVB Participants Only 
ICH E3 
Present by Period 
SAC [1] 
3.03. 
Safety 
AE1xo 
Summary of All Adverse Events by System Organ Class and 
Preferred Term - Overall 
ICH E3 
Present Placebo, GSK3858279, Total 
Columns 
SAC [1] 
3.04. 
Safety 
AE5A 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity by Period 
ICH E3 
 
SAC [1] 
3.05. 
Safety 
AE1xo 
 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term by Period 
 
ICH E3 
SAC [1] 
3.06. 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity by Period 
ICH E3 
SAC [1] 
3.07. 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency by Period 
PLS Requirement 
 
SAC [1] 


 
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Safety: Tables – All Safety Tables will be presented by Period unless stated otherwise. 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.08. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) by Period 
FDAAA, EudraCT 
 
SAC [1] 
Serious and Other Significant Adverse Events 
3.09. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
by Period 
FDAAA, EudraCT 
Produce if more than 5 SAEs are 
reported. 
SAC [1] 
3.10. 
Safety 
AE3 
Summary of Serious Drug-Related Adverse Events by Overall 
Frequency by Period 
PLS Requirement 
 
SAC [1] 


 
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Safety: Tables – All Safety Tables will be presented by Period unless stated otherwise. 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Chemistry  
3.11. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline by Period 
ICH E3 
Present by Period 
AAC [1] 
3.12. 
Safety 
LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline by Period 
ICH E3 
Present by period 
 
AAC [1] 
Laboratory: Haematology 
3.13. 
 Safety 
LB1 
Summary of Haematology Changes from Baseline by Period 
ICH E3 
Present by Period 
 
AAC [1] 
3.14. 
Safety 
LB17 
Summary of Worst Case Haematology by PCI Criteria Post-
Baseline Relative to Baseline by Period 
ICH E3 
Present by Period 
AAC [1] 
Laboratory: Urinalysis 
3.15. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline by 
Period 
ICH E3 
Present by Period 
AAC [1] 
3.16. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline by Period 
ICH E3 
Present by Period 
AAC [1] 
ECG 
3.17. 
 Safety 
EG1 
Summary of ECG Findings by Period 
IDSL 
 
AAC [1] 
3.18. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category by Period 
IDSL 
 
AAC [1] 


 
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Safety: Tables – All Safety Tables will be presented by Period unless stated otherwise. 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.19. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Day by 
Period 
IDSL 
 
AAC [1] 
3.20. 
[Safety] 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category by Period 
IDSL 
 
AAC [1] 
Vital Signs 
3.21. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs by Period 
ICH E3 
 
AAC [1] 
3.22. 
Safety 
VS7 
Summary of Worst-Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline by Period 
IDSL 
AAC [1] 
Laboratory: Hepatobiliary (Liver) 
3.23. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting by 
Period 
IDSL 
Programming Note: Subjects should be 
recorded under the treatment they are 
receiving at the time the liver 
monitoring/stopping event is reported, 
or if the liver monitoring/stopping event 
was reported during a washout period, 
under the last study treatment received.   
Only produce if there is a liver event 
AAC [1] 


 
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Safety: Tables – All Safety Tables will be presented by Period unless stated otherwise. 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
COVID-19 
3.24. 
 Safety 
PAN1A 
Summary of COVID-19 Assessments for Subjects with 
Suspected, Probable or Confirmed COVID-19 Adverse Events 
by Period 
Present by Period. Treatment columns 
as: Placebo and GSK3858279 
COVID-19 recommended display 
AAC [1] 
 
 
 


 
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12.11.8. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic Concentrations 
4.01. 
PK 
PK01 
Summary of Serum GSK3858279 Concentration-Time Data 
(ng/mL) 
IDSL. Include 95% Confidence 
Interval for the mean. 
Present by period. 
IA[1], AAC [2] 
4.02. 
PK 
PK06 
Summary of Derived Serum GSK3858279 Pharmacokinetic 
Parameters (non-transformed and log-transformed) 
IDSL. Include Cmax, tmax, tlast, 
AUC(0-t), AUC(0-7). 
tmax and tlast should not be log-
transformed. 
Present by period 
IA 1 [1],  AAC 
[2] 
 


 
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12.11.9. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic Concentrations 
4.01. 
PK 
PK16A 
Individual Serum GSK3858279 Concentration-Time Plots 
(Linear and Semi-log) 
IDSL. By participant and treatment 
sequence.  
Legend by study period in the plot 
with linear and semi-logarithmic 
scale side by side. 
AAC [1] 
4.02. 
PK 
PK17 
Mean Serum GSK3858279 Concentration-Time Plots (Linear 
and Semi-log) 
IDSL. By Treatment sequence. 
Legend by study period in the plot 
with linear and semi-logarithmic 
scale side by side 
AAC [1] 
4.03. 
PK 
PK18 
Median Serum GSK3858279 Concentration-Time Plots (Linear 
and Semi-log) 
IDSL. By Treatment.sequence. 
Legend by study period in the plot 
with linear and semi-logarithmic 
scale side by side 
AAC [1] 
 
 
12.11.10. Pharmacokinetic / Pharmacodynamic Tables 
No PK/PD tables are currently detailed to be produced by S&P. 
 
If any PK/PD modelling analysis is conducted by CPMS, it will be reported in a separate CPMS modelling report, after reporting of this 
study. Any PK/PD Tables generated by CPMS will be included in the CPMS modelling report. 


 
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12.11.11. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.01 
PK 
PKPD_F1 
Individual UVB Heat Pain Detection Threshold AAUC(1-8) 
versus GSK3858279 AUC(0-7) Plot (Linear) by Period 
 
AAC [1] 
5.02 
PK 
PKPD_F1 
Individual Cold Pressor Time to Intolerable Pain Threshold 
AAUC(1-15) versus GSK3858279 AUC(0-t) Plot (Linear) by 
Period 
 
AAC [1] 
5.03 
PK 
PKPD_F1 
Individual Electrical pain (single stimulus) Pain Tolerance 
Threshold AAUC(1-15) versus GSK3858279 AUC(0-t) Plot 
(Linear) by Period 
 
AAC [1] 
5.04 
PK 
PKPD_F1 
Time Matched Individual UVB Heat Pain Detection 
Threshold (Celsius) versus GSK3858279 Serum 
Concentrations Plot (Linear) by Period 
Colour-coded per time point. Pre-
Dose, 1HR, 3HR, Day 2, Day 8, 
Day 15. Include a legend for 
Period. 
AAC [1] 
5.05 
PK 
PKPD_F1 
Time Matched Individual Cold Pressor Time to Intolerable Pain 
Threshold (Seconds) versus GSK3858279 Serum 
Concentrations Plot (Linear) by Period 
Colour-coded per time point. Pre-
Dose, 1HR, 3HR, Day 2, Day 8, 
Day 15. Include a legend for 
Period. 
AAC [1] 
5.06 
PK 
PKPD_F1 
Time Matched Individual Electrical pain (single stimulus) Pain 
Tolerance Threshold (Milliamps) versus GSK3858279 Serum 
Concentrations Plot (Linear) by Period 
Colour-coded per time point. Pre-
Dose, 1HR, 3HR, Day 2, Day 8, 
Day 15. Include a legend for 
Period. 
AAC [1] 
 
The figures listed in Section 12.11.11. will be produced by S&P.  


 
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If any PK/PD modelling analysis is conducted by CPMS, it will be reported in a separate CPMS modelling report, after reporting of this 
study. Any PK/PD figures generated by CPMS will be included in the CPMS modelling report.  
 
12.11.12. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
AAC [1] 
2.  
Screened 
ES9 
Listing of Subjects who were Rescreened 
 
AAC [1] 
3.  
Enrolled 
ES2xo 
Listing of Reasons for Study Withdrawal 
ICH E3 
AAC [1] 
4.  
ITT 
SD2xo 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
AAC [1] 
5.  
ITT 
BL2 
Listing of Subjects for Whom the Treatment Blind was Broken 
ICH E3 
 
AAC [1] 
6.  
ITT 
TA2 
Listing of Planned and Actual Treatments 
IDSL 
AAC [1] 
Protocol Deviations 
7.  
Enrolled 
DV2xo 
Listing of Important Protocol Deviations  
ICH E3 
AAC [1] 
8.  
Enrolled 
DV2xo 
Listing of Non-Important COVID-19 related Protocol Deviations 
COVID-19 recommended display 
AAC [1] 
9.  
Enrolled 
IE4 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
ICH E3 
AAC [1] 
Populations Analysed 
10.  
Enrolled 
SP3a 
Listing of Subjects Excluded from Any Population 
ICH E3 
 
AAC [1] 
Demographic and Baseline Characteristics 
11.  
ITT 
DM2xo 
Listing of Demographic Characteristics 
ICH E3 
AAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.  
ITT 
DM9xo 
Listing of Race 
ICH E3 
AAC [1] 
Prior and Concomitant Medications 
13.  
ITT 
CM10xo 
Listing of Current and Past Concomitant Medications 
IDSL 
AAC [1] 
Prior and Concomitant Medications 
14.  
ITT 
MH2xo 
Listing of Current and Past Medical Conditions 
IDSL 
AAC [1] 
Exposure 
15.  
ITT 
EX3xo 
Listing of Exposure Data 
ICH E3 
AAC [1] 
Adverse Events 
16.  
Safety 
AE8CPxo 
Listing of All Adverse Events 
ICH E3 
SAC [1] 
17.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC [1] 
18.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC [1] 
Serious and Other Significant Adverse Events 
19.  
Safety 
AE8CPxo 
Listing of Serious Adverse Events 
ICH E3 
Include column for Fatal/Non-Fatal 
SAC [1] 
20.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC [1] 
21.  
Safety 
AE8CPxo 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC [1] 
22.  
Safety 
AE8CPxo 
Listing of Other Significant Adverse Events 
ICH E3 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
All Laboratory 
23.  
Safety 
 
LB5xo 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
AAC [1] 
24.  
Safety 
LB5xo 
Listing of All Laboratory Data 
 
AAC [1] 
25.  
Safety 
UR2xo 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
AAC [1] 
26.  
Safety 
UR2xo 
Listing of All Urinalysis Data 
 
AAC [1] 
ECG 
27.  
Safety 
EG3xo 
Listing of ECG Values 
IDSL 
AAC [1] 
28.  
Safety 
EG5xo 
Listing of ECG Findings 
IDSL 
AAC [1] 
Vital Signs 
29.  
Safety 
VS4xo 
Listing of All Vital Signs 
IDSL 
AAC [1] 
Hepatobiliary (Liver) 
30.  
Safety 
MH2 
Listing of Medical Conditions for Participants with Liver 
Stopping Events 
IDSL (Conditional on liver event being 
seen) 
AAC [1] 
31.  
Safety 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events 
IDSL (Conditional on liver event being 
seen) 
AAC [1] 
 
 


 
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12.11.13. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PainCart Assessments 
32.  
ITT 
EFF_L1 
Listing of PainCart Assessments 
 
SAC [1] 
33.  
ITT 
EFF_L2 
Listing of PainCart Visual Analogue Scale Scores 
 
AAC [1] 
Pharmacokinetics 
34.  
Safety 
PK07xo 
Listing of Serum GSK3858279 Concentration-Time Data 
(ng/mL) 
 
AAC [1] 
35.  
Safety 
PK13xo 
Listing of Derived Serum GSK3858279 Pharmacokinetic 
Parameters 
 
AAC [1] 
Pharmacodynamics 
36.  
Safety 
PK07xo 
Listing of Free & Total CCL17 in Serum Concentration-Time 
Data (pg/mL) 
Include Percentage reduction / Fold 
Increase 
Present by Endpoint: Free CCL17, 
Total CCL17 
AAC [1] 
37.  
Safety 
PK13xo 
Listing of Derived Free CCL17 in Serum Target Engagement 
Parameters 
 
AAC [1] 
38.  
Safety 
PK13xo 
Listing of Derived Total CCL17 in Serum Target Engagement 
Parameters 
 
AAC [1] 
39.  
Safety 
IMM2 
Listing of Immunogenicity 
 
AAC [1] 
COVID-19 
40.  
Safety 
PAN7 
Listing of All Subjects with Visits and Assessments Impacted by 
COVID-19 Pandemic 
 
AAC [1] 


 
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12.12. 
Appendix 12: Mock Shells 
Data Display Specification will be made available on request  


Si g nat ure Pa ge f or  2 0 9 9 7 3 T M F- 1 4 0 4 6 9 4 3 v 1. 0
Si g nat ure Pa ge f or T M F- 1 4 0 4 6 9 4 3 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 0 8- Oct- 2 0 2 1 1 5: 4 1: 2 9 G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 1 2- Oct- 2 0 2 1 1 6: 5 1: 5 7 G M T + 0 0 0 0
P P D
P P D