Conditions: Arthritis, Rheumatoid
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 48
Healthy volunteers: yes

Brief summary:
This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also intends to understand the effect of GSK3358699 on systemic markers of inflammation following low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been carefully designed to explore the in vivo biology of the target and the potential for the study drug to become a transformative medicine for subjects in multiple immuno-inflammatory disease indications.

Detailed description:
Subjects who are enrolled in the dose escalation treatment Periods of Part A may choose to only take part in the dose escalation treatment Periods 1-3, or may choose to also take part in the challenge Treatment Period (Period 4). If a subject chooses to participate in the dose escalation treatment Periods 1-3 only, or does not (at screening) meet the eligibility criteria specific to challenges (treatment Period 4), a new subject will be recruited for treatment Period 4 only and will be regarded as a replacement subject. The study will be conducted in three Parts. Total duration for participation will be approximately 19 weeks for subjects taking part in all three dose escalation treatment Periods and 23 weeks if a subject takes part in all four treatment Periods of Part A. For replacement subjects only taking part in the challenge treatment Period (Period 4), approximate study duration will be 10 weeks. Total duration for participation will be approximately 9 weeks for Part B and 12 weeks for Part C. The study will be conducted in up to 80 subjects.

Arms:
arm 1: Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589). arm 2: Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter\^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589). arm 3: Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654 (NCT03306589). arm 4: Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout Period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter\^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654 (NCT03306589). arm 5: The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fasted condition in TP1 followed by fed condition in TP2. This cohort intended to evaluate the effect of food. arm 6: The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fed condition in TP1 followed by fasted condition in TP2. This cohort intended to evaluate the effect of food. arm 7: The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter\^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin). arm 8: The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter\^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).

Interventions: intervention 1: Placebo intervention 2: GSK3358699 intervention 3: GM-CSF intervention 4: LPS intervention 5: Cantharidin
Intervention descriptions: intervention 1: Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily intervention 2: GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (3 to 45 mg), in Part A, B and Part C once daily. intervention 3: The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter\^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C intervention 4: LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C. intervention 5: This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A randomised, double-blind (sponsor open), placebo-controlled, three 
part study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 
single (in both fed and fasted states) or repeat doses of GSK3358699 in healthy male 
participants. 
Protocol Number: 207546/ Amendment 4
Short Title: First-time-in-Human Study to evaluate safety, tolerability, pharmacokinetics
and pharmacodynamics of single (in both fed and fasted states) or repeat doses of 
GSK3358699.
Compound Number:
GSK3358699
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 number: 2017-003997-15
Approval Date: 11-DEC-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
11-DEC-2018
Amendment 3
29-MAY-2018
Amendment 2
21-MAR-2018
Amendment 1
25-JAN-2018
Original Protocol
30-NOV-2017
Amendment 4:  11-DEC-2018
Overall Rationale for the Amendment:
Four asymptomatic, non-serious, non-severe and self-limiting cardiac arrhythmias were 
observed in the study. A temporary dosing hold was implemented during Cohort 4 (Part 
C) to allow sufficient time for safety panel review of these events.  As described in this 
protocol amendment, Part C of the study will commence from Cohort 5 with an 
additional cohort added to provide four full planned cohorts (Cohorts 5-8).
Additionally, the randomization ratio has been changed to 1:1 (Active:Placebo) in Part C, 
to provide a balanced comparison between subjects on active and placebo.  Furthermore, 
the Part C study design has been modified to remove the in vivo challenges from Cohorts 
5, 6 and 7 to limit unnecessary exposure of participants receiving placebo to 
immunological challenge, and to attenuate study duration and complexity.
Exclusion criteria have been revised to exclude individuals who may be at higher natural 
risk of cardiac arrhythmias. 
An interim analysis following Cohort 7 has also been included to allow formal readout of 
data obtained up to that point whilst Cohort 8 (which are primarily experimental 
endpoints) is still ongoing.
In addition, further administrative clarifications have been made.
The specific revisions are summarised below:


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Section # and Name
Description of Change
Brief Rationale
Sponsor Signatory 
page
Change of Sponsor Signatory to 
Nicolas Wisniacki.
Sponsor Signatory has changed.
Synopsis and Section 
5.1; Overall Design 
Added ‘is planned to’ to final sentence 
regarding Part C and amended 
number of cohorts.
Increased flexible wording; change in 
study design.
Synopsis; Number of 
participants
Table updated to reflect new cohorts 
and number of participants required 
for each.
Text added to state that Part C 
participants may take part in a later 
Part C cohort if they fulfil all eligibility 
criteria.
Last paragraph updated to include 
revisions to participant numbers for 
additional cohorts and added text on 
alternative dosing regimens including 
for challenges.
Change in study design / 
randomisation requirements.
Increased flexibility.
Increased flexibility.
Synopsis; Treatment 
Groups and Duration 
Part A
Text revised to confirm blister harvest 
timepoint of 48h post-induction and 
confirm LPS dose of 0.75 ng/kg.
Blister harvest timepoint and LPS dose 
was confirmed during Part A after 
completion of enabling study 207654.
Synopsis; Treatment 
Groups and Duration 
Part B, and Section 
5.1.2 Part B Food 
Effect
Added text ‘dose level chosen for Part 
B will be within the range already 
evaluated….’
Clarification in line with Part A and C 
wording.
Synopsis; Treatment 
Groups and Duration 
Part C
Schematic updated with revised 
cohort information.
Text updated to describe Cohorts 5-7, 
where there are now no in vivo
challenges, separately from Cohorts 4 
and 8.
Change in study design.
Change in study design / 
randomisation requirements.
Part B SoA
12h sample timepoint for S4 removed 
and notes updated to reflect changes 
to sampling requirements
Updated based on emerging data
Part B and C SoAs
Additional notes added for 
haematology, coagulation, clinical 
chemistry and urinalysis.
Gamma-glutamyl transferase and 
creatine kinase added at selected 
timepoints.
Note added to Drug / Alcohol test and 
Blood sampling for systemic PK rows 
to allow ad-hoc testing in the event of 
a cardiac arrhythmia.
Clarification.
Additional monitoring
Additional monitoring
Part C SoAs 
Section 2.3 and Section 2.3.1 now 
contain new SoA tables covering 
Change in study design.


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Section # and Name
Description of Change
Brief Rationale
assessments required for Cohorts 5-7 
with no in vivo challenges.
Section 2.4, Section 2.4.1, Section
2.4.2 and Section 2.4.3 SoA tables 
are the previous challenge tables but 
now only apply to Cohorts 4 and 8.  
Some study assessments have also 
been updated. 
Some study assessments were altered 
during the course of Part A based on 
newly available data and documented 
via File Note and in the SRM.  They 
are now being incorporated into 
Protocol Amendment 4. 
Section 3.3. Benefit / 
Risk Assessment
Text inserted to capture potential risk, 
given NSVTs observed during study to 
date.
Included to transparently capture 
clincal observations to date.
Section 3.3.1 Risk 
Assessment
LPS text in mitigation strategy 
amended to confirm LPS dose.
Text inserted to capture potential risk, 
given NSVTs observed during study to 
date.
LPS dose was confirmed during Part A 
after completion of enabling study 
207654.
Included to transparently capture 
clincal observations to date.
Section 4 Objectives 
and Endpoints
Deleted exploratory endpoint for 
inflammatory markers following LPS 
challenge / ex-vivo incubation
Relates to E2c sampling in SoA table 
which has now been removed based 
on emerging data.
Section 5.1.1.2 Part A 
LPS or GM-CSF 
challenge
LPS text amended to confirm LPS 
dose.
Blister harvest timepoint and LPS dose 
was confirmed during Part A after 
completion of enabling study 207654.
Section 5.1.3 Part C 
Study Design
Schematic updated with revised 
cohort information.
Separate sub-sections created and 
updated to describe Cohorts 5-7, 
where there are now no in vivo
challenges, separately from Cohorts 4 
and 8 as follows:
Section 5.1.3.1 Part C Multiple 
Ascending Doses Cohort 4 added 
(refers to Section 5.1.3.3 for further 
details on study design as for Cohort 
8).
Section 5.1.3.2 Part C Multiple 
Ascending Doses Cohorts 5, 6 and 7 
added.
Section 5.1.3.3 Part C Repeat Dosing 
Followed by LPS or GM-CSF 
Challenge with Cantharidin-Induced 
Blisters Cohort 4 and 8 updated to 
revise detail of Cohorts and number of
participants.
Change in study design.
Change in study design / 
randomisation requirements.
This section was previously Section 
5.1.3 and the study design is 
fundamentally the same as was 
described in that section for the 
challenge cohorts.
Section 5.2 Number 
of Participants
Table updated to reflect new cohorts 
and number of participants required 
Change in study design / 
randomisation requirements.


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Section # and Name
Description of Change
Brief Rationale
for each.
Text added to first paragraph under 
the table to state that Part C 
participants may take part in a later 
Part C cohort if they fulfil all eligibility 
criteria.
Second paragraph below table 
updated to include revisions to 
participant numbers for additional 
cohorts and added text on alternative 
dosing regimens including for 
challenges.
Increased flexibility.
Increased flexible wording.
Section 5.4 Scientific 
Rationale for Study 
Design
Updated 3rd bullet to state that ‘In Part 
C it is planned that five cohorts…’ 
Added reference to Cohorts 4 and 8 
for Part C challenge cohorts.
Changed Part C challenge 
administration time from ‘will be 
administered at a timepoint of low 
systemic….’ to ‘may be administered 
at a timepoint of low systemic….’
Bullet on rationale for exclusion of 
females from the study revised.
Increased flexible wording and change 
in study design.
Clarification in relation to revised study 
design.
Increased flexible wording around 
timing of Part C challenge admin in the 
event that emerging data suggests 
different admin timepoints may be 
optimal.
The embryo-foetal toxicology studies 
referred to in the previous version of 
the protocol have now been completed.
Section 5.5.1 Part A 
Dose Justification
LPS text amended to confirm LPS 
dose.
LPS dose was confirmed during Part A 
after completion of enabling study 
207654.
Section 5.5.3 Part C 
Dose Justification
Updated to revise number of cohorts 
to five and add flexibility in number of 
days dosing for Cohort 8.
LPS text amended to confirm LPS 
dose.
Text deleted on additional cohorts, 
alternative dosing schedules etc and 
Section 7.2 referenced instead.
Change in study design.
LPS dose was confirmed during Part A 
after completion of enabling study 
207654.
Reduction of repetition; dose / 
treatment related modifications that 
could be required are detailed in 
Section 7.2.
Section 6.1 Inclusion 
Criteria
Inclusion #1 age range split out for 
each study Part.
Increased clarity.
Section 6.2 Exclusion 
Criteria
Exclusion criteria modified (cardiac 
disease deleted from Exclusion #1, 
Exclusions #4 and #5 (new 
numbering) added / updated, 
In line with overall rationale for 
amendment.


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Section # and Name
Description of Change
Brief Rationale
Exclusions #7, #8 and #9 (new 
numbering) added.
Exclusion #3 updated to remove 
reference to fair / dark skin.
Exclusion #24 (new numbering) 
amended to fasted glucose ≥7.0
Implications discussed with participant 
rather than being an exclusion. 
In line with requirement for screening 
samples to be fasted.
Section 6.3.1 Meals 
and Dietary 
Restrictions
Part C Day 1 post-dose fast amended 
to 4 hours
To make consistent with Day 14.
Section 7.1 
Treatment 
Administration Table 
5
LPS text amended to confirm LPS 
dose.
LPS dose was confirmed during Part A 
after completion of enabling study 
207654.
Section 7.2 Dose 
Modification
Section updated to describe in greater 
detail the possible dose / challenge 
related modifications that could 
potentially be required based on 
emerging data.
Increase clarity / flexible wording.
Section 7.3 Method of 
Treatment 
Assignment Part C
Text for 5:2 randomisation ratio 
clarified as being for Cohort 4.  Text 
for Cohort 8 1:1 randomisation ratio 
added.
Change in study design.
Section 7.4 Blinding
Added that certain analytical lab staff 
at site can be unblinded
To reduce analytical burden at site for 
the monocyte isolation process with
increased number of placebo 
intracellular PK samples which would 
not subsequently be analysed by GSK.
Section 8.1.6 
Individual Safety 
Stopping Criteria
New criteria added.
Additional safety measure in line with 
overall rationale for amendment.
Section 9.4.2 Body 
Weight
Text revised to add specific Cohort 
numbers 4 and 8 and that body weight 
will be measured on day prior to
challenge (as opposed to Day 13).
Clarification on Cohorts as this body 
weight assessment is for dose 
calculation of challenges and therefore 
does not apply to non-challenge 
cohorts 5-7.  Removed reference to 
Day 13 for added flexibility in the event 
that fewer than 14 days dosing is 
required in Cohort 8.
Section 9.4.4 Vital 
Signs
Detail on blood pressure and pulse 
split out for Cohorts 5-7 separately 
from Cohorts 4 and 8.
Day 14 measurements in Cohorts 4 
and 8 are more intensive due to 
monitoring requirements post-
challenges.  Less intensity required for 
Cohorts 5-7. 
Section 9.4.5 
Electrocardiograms
‘or other exclusionary criteria’ added 
to the end of third bullet on Holter 
monitoring. 
To broaden this text to encompass 
other criteria that may apply.
Section 9.4.7
Additional bullet included to state that 
a PK sample and drugs of abuse test 
Additional monitoring in line with 
overall rationale for the amendment.


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Section # and Name
Description of Change
Brief Rationale
should be taken if a cardiac 
arrhythmia occurs
Section 9.6.1 Ex-vivo 
PD sample [S4]
Text revised to remove reference to 
‘TruCulture null’ tubes and add 
reference to ‘GSK3358699 LPS’ 
tubes.
Emerging data indicates that a positive 
control sample is anticipated to be of 
more value than null samples.
Section 9.8.1.1 
Cellular activation 
markers blood 
sample [E2b]
Heading text updated to add ‘all 
cohorts in Part C’
Clarification 
Section 9.8.1.2 
Circulating 
inflammatory 
biomarkers blood 
sample [E2a]
Heading text updated to add
“challenge cohorts only”.
Clarification as this sample no longer 
applies to non-challenge cohorts 5-7.
Section 9.8.1.3 Ex-
vivo LPS stimulation 
blood sample [E2c]
Section deleted.
Emerging data demonstrated that this 
sample would be of little value.
Section 9.8.1.3 Gene 
array panels
New section number now that LPS 
sample E2c is deleted. Heading text 
updated to add “challenge cohorts 
only”.
Clarification as this sample no longer 
applies to non-challenge cohorts 5-7.
Section 10.2.1 
Sample size 
assumptions Part C
Updated to detail and split out 
participant numbers and 
randomisation ratios for Cohort 4, 
Cohorts 5-7 and Cohort 8.
Text deleted on additional cohorts, 
alternative dosing / randomisation 
schedules etc and Section 7.2 
referenced instead.
Change to study design.
Reduction of repetition; dose / 
treatment related modifications that 
could be required are detailed in
Section 7.2.
Section 10.4.4 Interim 
Analyses
Text revised to include a formal 
interim analysis after Cohort 7, in the 
event that Cohort 8 is required.
To allow reporting on Part A, Part B 
and Cohorts 5-7 in Part C for primary 
and secondary study objectives whilst 
exploratory evaluation is ongoing.
Section 12.2 
Appendix 2: Clinical 
Laboratory Tests
Gamma-glutamyl transferase and 
Creatine kinase added to laboratory 
assessments table
Additional monitoring
Section 12.3 
Appendix 3; Dose 
Escalation Committee
Reference to Cohort 8 added.
Change to study design.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................13
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................21
2.1.
Part A General Schedule of Activities .........................................................21
2.1.1.
Part A Period 4 Schedule of Activities..........................................26
2.1.1.1.
Part A Period 4 Detailed SoA for LPS 
Challenge and Biomarker Sampling ...........................29
2.1.1.2.
Part A Period 4 Detailed SoA for GM-CSF 
challenge and Biomarker Sampling ............................30
2.2.
Part B Food Effect Schedule of Activities....................................................31
2.3.
Part C General Schedule of Activities Cohorts 5-7 (no challenges).............34
2.3.1.
Part C Day 14 Detailed SoA for PK and PD / Biomarker 
Sampling Cohorts 5-7 (no challenges).........................................37
2.4.
Part C General Schedule of Activities Cohorts 4 and 8 (with 
challenges) .................................................................................................38
2.4.1.
Part C Day 14 Detailed SoA for Challenge Administration 
and PK Sampling Cohorts 4 and 8 (with challenges) ...................42
2.4.2.
Part C Day 14 Detailed SoA for LPS Challenge and 
Biomarker Sampling Cohorts 4 and 8 (with challenges)...............43
2.4.3.
Part C Day 14 Detailed SoA for GM-CSF Challenge and 
Biomarker Sampling Cohorts 4 and 8 (with challenges)...............44
3.
INTRODUCTION....................................................................................................46
3.1.
Study Rationale ..........................................................................................46
3.2.
Background ................................................................................................47
3.3.
Benefit/Risk Assessment ............................................................................47
3.3.1.
Risk Assessment .........................................................................49
3.3.2.
Benefit Assessment.....................................................................59
3.3.3.
Overall Benefit:Risk Conclusion...................................................59
4.
OBJECTIVES AND ENDPOINTS...........................................................................59
5.
STUDY DESIGN ....................................................................................................61
5.1.
Overall Design ............................................................................................61
5.1.1.
Part A ..........................................................................................61
5.1.1.1.
Part A Single Ascending Doses – Cohort 1 and 
Cohort 2: ....................................................................61
5.1.1.2.
Part A LPS or GM-CSF challenge with 
cantharidin-induced blisters – Cohort 1 and 
Cohort 2: ....................................................................63
5.1.1.3.
Part A Dose Escalation / Challenge Total 
Duration:.....................................................................64
5.1.2.
Part B Food Effect - Cohort 3.......................................................65
5.1.3.
Part C ..........................................................................................65
5.1.3.1.
Part C Multiple Ascending Doses Cohort 4.................66
5.1.3.2.
Part C Multiple Ascending Doses Cohorts 5, 6 
and 7 ..........................................................................66


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5.1.3.3.
Part C Repeat Dosing Followed by LPS or GM-
CSF Challenge with Cantharidin-Induced 
Blisters Cohort 4 and 8...............................................67
5.2.
Number of Participants ...............................................................................69
5.3.
Participant and Study Completion...............................................................70
5.4.
Scientific Rationale for Study Design ..........................................................70
5.5.
Dose Justification........................................................................................73
5.5.1.
Part A ..........................................................................................73
5.5.2.
Part B ..........................................................................................74
5.5.3.
Part C ..........................................................................................74
5.5.4.
Human PK and PK/PD predictions...............................................75
6.
STUDY POPULATION...........................................................................................77
6.1.
Inclusion Criteria.........................................................................................77
6.2.
Exclusion Criteria........................................................................................78
6.3.
Lifestyle Restrictions...................................................................................81
6.3.1.
Meals and Dietary Restrictions ....................................................81
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................82
6.3.3.
Activity .........................................................................................82
6.4.
Screen Failures...........................................................................................83
7.
TREATMENTS.......................................................................................................83
7.1.
Treatments Administered............................................................................84
7.2.
Dose Modification .......................................................................................86
7.3.
Method of Treatment Assignment ...............................................................87
7.4.
Blinding.......................................................................................................89
7.5.
Preparation/Handling/Storage/Accountability..............................................89
7.5.1.
GSK3358699...............................................................................90
7.5.2.
Cantharidin ..................................................................................90
7.5.3.
LPS..............................................................................................91
7.5.4.
GM-CSF ......................................................................................91
7.6.
Treatment Compliance................................................................................91
7.7.
Concomitant Therapy..................................................................................92
7.8.
Treatment after the End of the Study ..........................................................92
8.
DISCONTINUATION CRITERIA.............................................................................92
8.1.
Discontinuation of Study Treatment ............................................................92
8.1.1.
Liver Chemistry Stopping Criteria ................................................92
8.1.2.
QTc Stopping Criteria ..................................................................93
8.1.3.
Haematological Stopping Criteria.................................................93
8.1.4.
Lipid Stopping Criteria..................................................................94
8.1.5.
Gastrointestinal Stopping Criteria ................................................94
8.1.6.
Individual Safety Stopping Criteria ...............................................94
8.1.7.
Dose Adjustment/Stopping Pharmacokinetic Criteria ...................94
8.1.8.
Dose Adjustment/Stopping Pharmacodynamic Criteria................95
8.1.9.
Dose Escalation / Study Progression Stopping Safety 
Criteria.........................................................................................95
8.1.10.
Rechallenge.................................................................................96
8.1.10.1.
Study Treatment Restart or Rechallenge....................96
8.2.
Withdrawal from the Study..........................................................................96
8.3.
Lost to Follow Up........................................................................................96


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9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................97
9.1.
Efficacy Assessments.................................................................................97
9.2.
Adverse Events...........................................................................................97
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................97
9.2.2.
Method of Detecting AEs and SAEs.............................................98
9.2.3.
Follow-up of AEs and SAEs.........................................................98
9.2.4.
Regulatory Reporting Requirements for SAEs .............................98
9.2.5.
Pregnancy ...................................................................................99
9.3.
Treatment of Overdose...............................................................................99
9.3.1.
GSK3358699...............................................................................99
9.3.2.
Cantharidin ..................................................................................99
9.3.3.
LPS............................................................................................100
9.3.4.
GM-CSF ....................................................................................100
9.4.
Safety Assessments .................................................................................100
9.4.1.
Physical Examinations...............................................................101
9.4.2.
Body Weight ..............................................................................101
9.4.3.
Assessment of blister sites ........................................................101
9.4.4.
Vital Signs..................................................................................101
9.4.5.
Electrocardiograms....................................................................102
9.4.6.
Cardiac Telemetry .....................................................................102
9.4.7.
Clinical Safety Laboratory Assessments ....................................103
9.4.8.
Participant Diary Card................................................................103
9.5.
Pharmacokinetics .....................................................................................103
9.5.1.
Blood sample collection and analysis.........................................103
9.5.2.
Urine Sample Collection and Analysis .......................................104
9.6.
Pharmacodynamics ..................................................................................104
9.6.1.
Ex vivo PD sample.....................................................................104
9.6.2.
Circulating inflammatory biomarkers / proteins ..........................105
9.6.3.
Gene array panel.......................................................................105
9.7.
Genetics ...................................................................................................105
9.8.
Biomarkers ...............................................................................................105
9.8.1.
Biomarkers in blood...................................................................106
9.8.1.1.
Cellular activation markers blood sample (all 
cohorts in Part C) .....................................................106
9.8.1.2.
Circulating inflammatory biomarkers blood 
sample (challenge cohorts only) ...............................106
9.8.1.3.
Gene array panels (challenge cohorts only) .............106
9.8.2.
Biomarkers in blisters.................................................................106
9.8.2.1.
Cellular blister sample ..............................................106
9.8.2.2.
Soluble blister sample ..............................................106
9.8.3.
RNA Expression Research of a Subset of RNA Species............107
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics................................................................................................107
10. STATISTICAL CONSIDERATIONS......................................................................107
10.1.
Hypotheses...............................................................................................107
10.2.
Sample Size Determination ......................................................................107
10.2.1.
Sample size assumptions ..........................................................107
10.3.
Populations for Analyses ..........................................................................108
10.4.
Statistical Analyses...................................................................................109
10.4.1.
Safety Analyses.........................................................................109


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10.4.2.
Pharmacokinetic Analyses.........................................................109
10.4.3.
Other Analyses ..........................................................................110
10.4.4.
Interim Analyses ........................................................................110
11. REFERENCES.....................................................................................................112
12. APPENDICES......................................................................................................115
12.1.
Appendix 1: Abbreviations and Trademarks..............................................115
12.2.
Appendix 2: Clinical Laboratory Tests.......................................................118
12.3.
Appendix 3: Study Governance Considerations........................................120
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................125
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................130
12.6.
Appendix 6: Genetics................................................................................132
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................134
12.8.
Appendix 8: Protocol Amendment History.................................................136


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1.
SYNOPSIS
Protocol Title: A randomised, double-blind (sponsor open), placebo-controlled, three 
part study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 
single (in both fed and fasted states) or repeat doses of GSK3358699 in healthy male 
participants.
Short Title: First-time-in-Human Study to evaluate safety, tolerability, pharmacokinetics 
and pharmacodynamics of single (in both fed and fasted states) or repeat doses of 
GSK3358699.
Rationale:
This first time in human (FTIH) study intends to identify doses of GSK3358699 that are 
well tolerated whilst delivering a robust pharmacodynamic response.  As such, the study 
will involve the first administration of GSK3358699 to humans and will evaluate the 
safety, tolerability, pharmacokinetic and pharmacodynamic profile of single (in both fed 
and fasted states) and multiple ascending doses of GSK3358699 in healthy male 
participants within a pre-defined and controlled pharmacodynamic and pharmacokinetic 
range.  Further, this study will seek to understand the effect of GSK3358699 on systemic 
markers of inflammation following low dose in vivo Lipopolysaccharide (LPS) or 
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local 
inflammation in cantharidin-induced blisters as exploratory objectives.  This 
experimental approach has been carefully designed to explore and inform the potential 
for GSK3358699 to become a transformative medicine for patients in multiple immuno-
inflammatory disease indications.
Objectives and Endpoints:
Objectives
Endpoints
Primary
[P1] To evaluate the safety and tolerability 
of single and repeat oral doses of 
GSK3358699 in healthy male participants.
Adverse event (AE) reporting.
Laboratory safety data (clinical chemistry, 
haematology, urinalysis).
Vital signs (blood pressure, heart rate, body 
temperature).
12 lead electrocardiograms (ECGs)
Secondary
[S1] To evaluate the systemic 
pharmacokinetic (PK) profile following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.

Plasma concentrations of GSK3358699 plus 
derived PK parameters.
[S2] To evaluate the systemic PK profile of 
the acid metabolite, GSK3206944 following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.
Plasma concentrations of GSK3206944 plus 
derived PK parameters.


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Objectives
Endpoints
[S3] To evaluate the intracellular PK profile 
of GSK3206944 in target cells following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.

Monocyte intracellular quantification of 
GSK3206944.
[S4] To understand the extent of target 
engagement (TE) after ex vivo LPS 
challenge following single and repeat oral 
doses of GSK3358699 in healthy male 
participants.

Plasma concentrations of monocyte 
chemoattractant protein (MCP)-1, interleukin 
(IL)-6 and tumour necrosis factor (TNF) in 
blood stimulated ex vivo with LPS over time.
[S5] To assess the effect of food on the PK 
and pharmacodynamics (PD) of 
GSK3358699 and GSK3206944 following 
single doses in healthy male participants.
Plasma concentrations of GSK3358699 and 
GSK3206944 plus derived PK parameters.
Monocyte intracellular quantification of 
GSK3206944.

Plasma concentrations of MCP-1, IL-6 and 
TNF in blood stimulated ex vivo with LPS 
over time.
P1: Primary Objective 1 – Safety
S1: Secondary Objective 1 – GSK3358699 systemic PK
S2: Secondary Objective 2 - GSK3206944 systemic PK
S3: Secondary Objective 3 - GSK3206944 intracellular PK
S4: Secondary Objective 4 - TE
S5: Secondary Objective 5 – Effect of food on PK and PD
Overall Design:
This study will be a randomised, double-blind (sponsor open), placebo-controlled, three 
part study of oral administration of GSK3358699 in healthy male participants.  Part A 
will be a single ascending dose crossover design in two interlocking cohorts of 
participants (Cohorts 1 and 2).  Part B will be a single-dose, open-label two-way
crossover study with GSK3358699 administered under fed and fasted conditions in a 
further cohort of participants (Cohort 3).  Part C is planned to be a repeat dose design in  
5 sequential cohorts of participants (Cohorts 4-8). 
Number of Participants:
The number of participants and the required number of evaluable participants are outlined 
below:


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Part
Participants per cohort
Evaluable 
participant 
number per 
cohort
Evaluable participant 
definition
A
(Cohorts 
1-2)
9 (6:3 GSK3358699 : 
Placebo)
6
Complete both screening 
and all their planned 
treatment Periods.
B
(Cohort 3)
6 (all receive 
GSK3358699)
5
Complete both screening 
and both treatment 
Periods.
C
(Cohort 4)
14 (10:4 GSK3358699 : 
Placebo)
9
Complete both screening 
and the 14 day treatment 
Period and subsequent 
48 h assessment Period.
C 
(Cohorts 
5-7)
18 (9:9 GSK3358699 : 
Placebo)
12
Complete both screening 
and the 14 day treatment 
Period and subsequent 
48 h assessment Period.
C
(Cohort 8)
20 (10:10 GSK3358699 : 
Placebo)
14
Complete both screening 
and the 14 day treatment 
Period and subsequent 
48 h assessment Period.
Participants who are randomized into a particular part of the study can be enrolled in 
another part of the study, as well as be enrolled in a later cohort of the same part of the 
study in Part C, if they still fulfil all eligibility criteria (which means that participants 
having received LPS challenge in Part A will not be eligible to participate in another part 
of the study).
Additional participants/cohorts may be enrolled in Part A or Part C to allow for 
evaluation of additional dose levels or alternative regimens, including for challenges. No 
more than 9 additional participants will be included as part of a new cohort in Part A and 
no more than 20 additional participants will be allowed as part of a new cohort in Part C 
(ie in addition to Cohort 4-8 participants).
Treatment Groups and Duration:
All participants in Part A, Part B and Part C of the study will attend a screening visit 
within 35 days prior to their first dose (with the exception of Cohort 8 where the 
screening visit will be within 45 days prior to their first dose) and a follow up visit within 
7-14 days of their last dose.  A second follow up visit will also be conducted 
approximately 5 weeks after the last dose for those participants in cohorts where 
challenges and blisters are being administered.


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Part A: Single Ascending Doses and LPS / GM-CSF/ cantharidin blister challenges
(Cohorts 1 and 2)
Part A Schematic: Planned Doses
In the Part A single dose escalation phase (treatment Periods 1-3), there will be two 
interlocking cohorts (Cohorts 1 and 2) each with 9 healthy participants. Each participant 
will receive a maximum of 2 single ascending oral doses of GSK3358699, and 1 placebo
dose. At each dose level, GSK3358699 and placebo will be administered in a 2:1 ratio 
within each Period, according to the randomisation schedule, in a blinded manner. Up to 
a maximum of 6 dose levels will be studied in total in Part A with planned doses of 
between 1 mg and 45 mg GSK3358699.  
Participants who are enrolled in the dose escalation treatment Periods of Part A may 
choose to only take part in the dose escalation treatment Periods 1-3, or may choose to 
also take part in the challenge treatment period (Period 4). If a participant chooses to 
participate in the dose escalation treatment Periods 1-3 only, or does not (at screening)
meet the eligibility criteria specific to challenges (treatment Period 4), a new participant 
will be recruited for treatment Period 4 only and will be regarded as a replacement 
subject.
During each treatment Period, participants in an individual cohort will be admitted to the 
clinical unit on Day -1 and will remain there until completion of all assessments on Day 3 
(at approximately 48 hours post-dose). 
Upon conclusion of the dose escalation phase of Part A, an additional dosing Period 
(treatment Period 4) will be included.  Eligible participants in both cohorts will attend the 
clinic for outpatient visits on Day -10 (3 days) to have control blisters induced on the
forearm (0.2% cantharidin) and will have a blister sample taken at approximately 48hrs 
post blister induction. Participants in Cohort 1 will be administered intravenous (IV) in 
vivo LPS challenge at a dose of 0.75 ng/kg following treatment with GSK3358699 or 
placebo and will then have blisters induced on the forearm (0.2% cantharidin).  Similarly, 
participants in Cohort 2 will be administered 60 g/m2 IV in vivo GM-CSF challenge 


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following treatment with GSK3358699 or placebo and will then have blisters induced on 
the forearm (0.2% cantharidin). 
Of the nine participants within each cohort, six will receive GSK3358699 and three will 
receive placebo in treatment Period 4, as per the randomisation schedule.  The doses of 
LPS and GM-CSF to be administered to participants have been defined as part of an 
ongoing clinical enabling study (Study ID 207654) and will be administered around the 
time of the GSK3358699 systemic maximum concentration (Cmax) defined from data 
gathered in treatment Periods 1-3.  The dose levels of GSK3358699 administered to 
either cohort in Period 4 will be identical and will be decided by the dose escalation 
committee (DEC). This will be a single dose of GSK3358699 that is within the range 
investigated in treatment Periods 1-3 of Part A. 
The duration of treatment Period 4 from Day -1 onwards and the implementation of 
sentinel dosing will be the same as for each of the treatment Periods 1-3.  
There will be a minimum 14 days between each dosing in Cohort 1 and Cohort 2, and 
therefore a minimum 28 day washout period between the start of dosing, (ie dosing of 
sentinel participants) in each treatment Period for a particular cohort (including between 
Periods 3 and 4).  
The total duration of this part of the study for each participant, including screening and 
follow-up, is approximately 19 weeks for participants taking part in all three dose 
escalation treatment Periods and 23 weeks if a participant takes part in all four treatment 
Periods. For replacement participants only taking part in the challenge treatment Period 
(Period 4), approximate study duration is 10 weeks.
Part B Food Effect (Cohort 3)
Part B Schematic
In Part B there will be one cohort of 6 participants (Cohort 3), taking part in a two-way 
crossover study.  Each participant will receive a single oral dose of GSK3358699 under 
fed conditions in one of the two treatment Periods and under fasted conditions in the 
other treatment Period. The dose level chosen for Part B will be a dose level within the 


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range already evaluated in the dose escalation part of the study (Part A) and one in which, 
based on in silico modelling, the maximum exposure will not be exceeded following 
either fed or fasted administration. The decision on the dose level of GSK3358699 to be 
administered in Part B will be made by the DEC.  
During each treatment Period participants will be admitted to the clinical unit on Day -1 
and will remain there until completion of all assessments on Day 3 (at approximately 48 
hours post-dose).
There will be a minimum of 14 days between each dose.  The total duration of this part of 
the study for each participant, including screening and follow-up, is approximately 9 
weeks.
Part B will only be conducted after completion of the dose escalation phase of Part A and 
may be conducted in parallel with Part C.
Part C: Multiple Ascending Doses (Cohorts 4-8)
Part C Schematic
In Part C of the study there are 5 planned cohorts (Cohorts 4-8).  Each cohort will take 
part in one repeat dose treatment Period with up to 14 days of once-daily dosing.
Cohort 4
Cohort 4 of the study is comprised of 14 participants, taking part in one repeat dose 
treatment Period, and randomised in a 5:2 ratio to receive either GSK3358699 or placebo, 
according to the randomisation schedule, once daily from Day 1 to Day 14.  Participants 
will attend the clinic for outpatient visits on Day -10 (3 days) to have control blisters 


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induced on the forearm (0.2% cantharidin) and will have blister samples taken at 
approximately 48 hours post-blister induction.
On the final day of dosing either an IV in vivo LPS challenge, at a dose of 0.75 ng/kg or a 
60 g/m2 GM-CSF IV infusion challenge will be administered followed by blister 
induction as described for Part A Period 4. 
Half the participants will be randomised to receive cantharidin induced blisters with the 
LPS challenge and half will receive the cantharidin induced blisters with the GM-CSF 
challenge.  In Cohort 4, of the 7 participants receiving each challenge, 5 will be 
randomised to receive GSK3358699 and 2 to receive placebo at the start of the cohort.  
The total duration of the study for each participant in Cohort 4, including screening and 
follow-up, is approximately 12 weeks.
Cohorts 5-7
Cohorts 5-7 will each comprise of 18 healthy male participants.  Each cohort will take 
part in one repeat dose treatment Period.  The participants will be randomised in a 1:1 
ratio to receive either GSK3358699 or placebo, according to the randomisation schedule, 
once daily from Day 1 to Day 14 inclusive.
All participants will be admitted to the clinical unit on the day prior to dosing (Day -1) 
and will remain in the Unit until after the 48 hour assessments following the Day 14 
GSK3358699 / placebo dose administration have been completed (Day 16). Participants 
will then be discharged from the unit.
The total duration of the multiple ascending dose phase of Part C for each participant in 
Cohorts 5-7 , including screening and follow-up, is approximately 10 weeks.
Cohort 8
Upon conclusion of the multiple ascending dose phase of Part C (Cohorts 5 – 7), an 
additional Cohort (Cohort 8) is planned to be included.  This cohort will be comprised of 
20 participants, taking part in one repeat dose treatment period.  Participants will be 
randomised in a 1:1 ratio to receive GSK3358699 or placebo once daily for up to 14 
days.  The actual duration of dosing will be decided by the DEC and will not exceed 14 
consecutive days.  
Participants will attend the clinic for outpatient visits on Day -10 (3 days) to have 
control blisters induced on the forearm (0.2% cantharidin) and will have blister samples
taken at approximately 48 hours post-blister induction.
On the final day of dosing either an IV in vivo LPS challenge, at a dose of 0.75 ng/kg or a 
60 g/m2 GM-CSF IV infusion challenge will be administered followed by blister 
induction as described for Part A Period 4.
Half the participants will be randomised to receive cantharidin induced blisters with the 
LPS challenge and half will receive the cantharidin induced blisters with the GM-CSF 


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challenge.  In Cohort 8, of the 10 participants receiving each challenge, it is planned that 
5 will be randomised to receive GSK3358699 and 5 to receive placebo.
The randomisation ratio of active to placebo for Cohort 8 and any subsequent additional 
cohorts may be altered by the DEC based on all available safety, PK and PD data 
following the conclusion of Cohort 7.
Data from Part A of this study and from Cohorts 4 - 7 in Part C will be used to confirm 
the decision to include challenges in Part C Cohort 8.  The decision will be made by the 
DEC.
The total duration of the study for each participant in Cohort 8, including screening and 
follow-up, is approximately 14 weeks.
In all cohorts, participants will be admitted to the clinical unit on the day prior to dosing 
(Day -1) and will remain in the Unit until after the 48 hour assessments following the 
final day of GSK3358699 / placebo dosing and challenge administrations have been 
completed.
The actual doses of GSK3358699 to be administered in Part A or Part C may be adjusted 
based on review of the safety, tolerability, PK and PD data from prior dose levels by the 
DEC. These dose adjustments may involve either an increase or a decrease in the planned 
dose.  Safety, PK and PD stopping criteria will be strictly applied. Doses investigated in 
Part B or Part C will not exceed the magnitude of those investigated in Part A.
The dosing schedule may also be adjusted to expand a cohort to further evaluate safety, 
PK or PD findings at a given GSK3358699 dose level, or to add cohorts to evaluate 
additional dose levels or a change in the dosing regimen to less than or more than once 
daily.  Dosing may also be halted before all planned dose levels have been completed if 
stopping criteria have been met or if a review of the data determines that evaluation of 
further dose levels is not necessary to meet study objectives. 
In addition, decisions relating to the challenge agent administrations may be altered 
during the course of the study based on newly available data.  This may include decisions 
to alter the timing of the LPS or GM-CSF challenge agent administration, or to evaluate 
more than one challenge agent administration timing. The evaluation of alternative LPS 
or GM-CSF challenge timings may involve inclusion in earlier cohorts, or expansion or 
addition of cohorts. Additionally it may be decided to include the blister induction and 
blister fluid harvest in cohorts prior to Cohort 8.  It may also be decided that fewer than 
14 days dosing is required in the challenge cohort.
.


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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Part A General Schedule of Activities
Procedure
Screening (up to 35 Days prior to 
Day 1)
Treatment Period 1-3
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose)
Follow-up 2  (5 weeks after last 
dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
The 2nd follow up visit is only required for 
those participants where challenges are 
being administered and blisters induced i.e. 
treatment period 4
General
Informed consent
X
See separate Period 4 Schedule of Activities
Inclusion and exclusion criteria
X
X
Day -1 assessment is to recheck eligibility 
against medical conditions, prior 
therapy etc, but not against Day -1 clinical 
chemistry and haematology results (see 
Section 9.4.7). 
Demography
X
Medical/medication/drug/
alcohol history 
X
X
Includes substance usage and family 
history of premature cardiovascular (CV) 
disease and current medical conditions.
Admission to unit for in-patient stay
X
Discharge from Unit following in-
patient stay
X
Outpatient visit
X
X
X


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Procedure
Screening (up to 35 Days prior to 
Day 1)
Treatment Period 1-3
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose)
Follow-up 2  (5 weeks after last 
dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
The 2nd follow up visit is only required for 
those participants where challenges are 
being administered and blisters induced i.e. 
treatment period 4
Safety Assessments including laboratory tests
Full Physical Exam
X
See separate Period 4 Schedule of Activities
Brief Physical Exam
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Blood pressure (BP), heart rate (HR), 
temperature, respiratory rate.  See Section 
9.4.4 for details on triplicate and single 
measurement timepoints.
12-Lead ECGs
X
X
X
X
X
X
X
X
X
X
12 Lead ECGs will be performed in 
triplicate at screening, Day-1, Day 1 pre-
dose, Day 2 and Day 3. Single ECGs will 
be performed at other time points and if any 
cardiac symptoms are experienced. ECGs 
to be performed prior to blood draws and 
dosing where these fall at the same 
nominal time. 
Telemetry
<=================================================>
from 1 h pre-dose to 24 h post-dose
Holter monitoring (24 hours)
X
If a participant is rescreened the Holter will 
not need to be repeated.
HIV, Hep B, Hep C
X
Haematology
X
X
X
X
X
X
Fasted screening samples. 24 and 48 hour 
samples will be taken prior to participants 
receiving breakfast
Coagulation
X
X
X
X
X
Fasted screening samples. 24 and 48 hour 
samples will be taken prior to participants 
receiving breakfast


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Procedure
Screening (up to 35 Days prior to 
Day 1)
Treatment Period 1-3
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose)
Follow-up 2  (5 weeks after last 
dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
The 2nd follow up visit is only required for 
those participants where challenges are 
being administered and blisters induced i.e. 
treatment period 4
Clinical Chemistry
X
X
X
X
X
X
Fasted screening samples. 24 and 48 hour 
samples will be taken prior to participants 
Urinalysis
X
X
X
X
X
X
Fasted screening samples. 24 and 48 hour 
samples will be taken prior to participants 
receiving breakfast
Drug / Alcohol Test
X
X
Urine Cotinine
X
X
Visual forearm check (cosmetic 
assessment or blister healing where 
appropriate)
X
X
X
X
Visual forearm checks are only required if 
participant is scheduled to take part in
treatment period 4. Details of checks: 

Screening check prior to first 
treatment period (cosmetic 
assessment)

Day -1 check in treatment 
Period 3 only. Between Day -1 
and Day 2 (ie 48 hour window)
(cosmetic assessment) 

Period 4 (cosmetic assessment 
and blister healing).  For further 
detail on time points in Period 4 
see Section 2.1.1.

Follow-up visits 1 and 2 (blister 
healing)


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Procedure
Screening (up to 35 Days prior to 
Day 1)
Treatment Period 1-3
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose)
Follow-up 2  (5 weeks after last 
dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
The 2nd follow up visit is only required for 
those participants where challenges are 
being administered and blisters induced i.e. 
treatment period 4
AE / SAE review
SAEs collected from signing of informed consent form until the final follow up visit; AEs collected continuously 
from time of first dose until the final follow up visit
Concomitant Medication Review
Monitored from first dose until the end of the final treatment Period
Treatment Administration
Study Drug / Placebo Administration
X
See Period 4 SoA


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Procedure
Screening (up to 35 Days prior to 
Day 1)
Treatment Period 1-3
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose)
Follow-up 2  (5 weeks after last 
dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
The 2nd follow up visit is only required for 
those participants where challenges are 
being administered and blisters induced i.e. 
treatment period 4
Pharmacokinetics, Pharmacodynamics and Genetics Samples
Blood sampling for systemic PK [S1] 
and [S2]
X
X
X
X
X
X
X
X
X
X
X
See separate Period 4 Schedule of Activities
Blood sampling for intracellular PK
[S3]
X
X
X
X
X
Blood sample for ex vivo PD assay
[S4]
X
X
X
X
X
X
X
X
Six samples (3 LPS and 3 null) are required 
on Day -1:  to be taken (LPS and null) at 
approximately 13:00, 17:00 and 20:00. Day 
1: Two pre-dose samples (LPS and null) to 
be taken at approximately 08:00.
Blood sample for circulating proteins 
[E1a]
X
X
X
X
X
Blood sample for gene panel [E1b]
X
X
X
X
X
Blood sample for companion 
diagnostic development
X
Sample to be taken on Day -1 in treatment 
Period 1 only.
Genetics sample for CES genotyping 
and optional genetic research [E5]
X
Sample to be taken on Day -1 in treatment 
Period 1 only.
Urine sample for metabolite analysis 
[E4]
X
<============================================>
Pre-dose sample, immediately prior to 
dosing participants will be instructed to void 
their bladder into a collection container.  
Following dosing participants will be 
instructed to collect all urine voided for a 0-
24 hour collection.


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2.1.1.
Part A Period 4 Schedule of Activities
Procedure
Treatment Period 4
Notes
Day -10 (3 days)
24-48h following 
Day -10 visit
Day -1
Day 1
Day 2
Day 3
If participants only take part in treatment Period 4 they will 
undergo screening assessments prior to this treatment Period 
as detailed in Section 2.1.
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
3 h
4 h
6h
8 h
12 h
24 h
48 h
General
Admission to unit for in-
patient stay
X
Discharge from Unit 
following in-patient stay
X
Outpatient visit
X
X
For baseline blister induction and sampling; see Section 
2.1.1.1 and Section 2.1.1.2. The baseline blister samples 
collected will be repeated if > 4 months elapses between the 
baseline blister and the challenge treatment Period (eg if a 
reserve in the study is not dosed and is subsequently 
rescreened for a later cohort).
Safety Assessments including laboratory tests
Brief Physical Exam
X
X
Vital signs
X
X
See Section 2.1.1.1 and Section 2.1.1.2 for vital signs measurements in 
relation to challenges
BP, HR, temperature, respiratory rate.
Body weight
X
Body weight will be measured on Day -1 to calculate doses for 
challenges.
12-Lead ECGs
X
X
X
X
X
X
X
X
12 lead ECGs will be performed in triplicate at Day -1, pre-
dose Day 1, Day 2 and Day 3.  Single ECGs will be performed 
at other time points and if any cardiac symptoms are 
experienced.  ECGs to be performed prior to any blood draws 
or dosing scheduled for the same nominal time point.


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Procedure
Treatment Period 4
Notes
Day -10 (3 days)
24-48h following 
Day -10 visit
Day -1
Day 1
Day 2
Day 3
If participants only take part in treatment Period 4 they will 
undergo screening assessments prior to this treatment Period 
as detailed in Section 2.1.
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
3 h
4 h
6h
8 h
12 h
24 h
48 h
Telemetry
<======================================================>
From 1 h pre-dose to 24 h post-dose. For participants 
receiving the LPS-challenge, telemetry must be performed for 
a minimum of 12 hours post-LPS or until their telemetry shows 
no clinically significant findings for 4 hours (whichever is 
longer).
Haematology
X
X
X
X
24 and 48 hour samples will be taken prior to participants 
receiving breakfast
Coagulation
X
X
X
24 and 48 hour samples will be taken prior to participants 
receiving breakfast
Clinical Chemistry
X
X
X
X
24 and 48 hour samples will be taken prior to participants 
receiving breakfast
Urinalysis
X
X
X
X
24 and 48 hour samples will be taken prior to participants 
receiving breakfast
Drug / Alcohol Test
X
Urine Cotinine
X
Visual forearm check 
(including cosmetic 
assessment)
X
X
See Section 2.1.1.1 and Section 2.1.1.2 for visual forearm checks in 
relation to challenges
AE / SAE review
SAEs collected from signing of informed consent form; AEs collected continuously from time 
of first dose
Concomitant 
Medication Review
Monitored from first dose until the end of the final treatment Period


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Procedure
Treatment Period 4
Notes
Day -10 (3 days)
24-48h following 
Day -10 visit
Day -1
Day 1
Day 2
Day 3
If participants only take part in treatment Period 4 they will 
undergo screening assessments prior to this treatment Period 
as detailed in Section 2.1.
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
3 h
4 h
6h
8 h
12 h
24 h
48 h
Treatment  / agent administration and PK sampling
Study Drug / Placebo 
Administration
X
In vivo LPS Challenge
<==========>
LPS administration to be performed at GSK3358699 systemic 
Cmax; anticipated to be between 0.5-2hrs post GSK3358699 
dose.
OR in vivo GM-CSF 
Challenge
<===================>
GM-CSF administration to be performed at GSK3358699 
systemic Cmax; GM-CSF will be administered as an infusion 
over 2 hours and the start of the infusion is anticipated to be 
between 0.5-2hrs post GSK3358699 dose. 
Blood sampling for 
systemic PK [S1] and
[S2]
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for 
intracellular PK [S3]
X
X
Cantharidin application 
and PD sampling
See Section 2.1.1.1 and Section 2.1.1.2


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2.1.1.1.
Part A Period 4 Detailed SoA for LPS Challenge and Biomarker Sampling
Procedure
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Day -1
Day 1 - pre-dose and all post-dose times below are in relation to 
the administration time of LPS not GSK3358699 administration
Day 2
Day 3
Notes
Pre-dose
0 h
20 mins
1 h
2 h
3h
4 h
6h
8 h
12 h
24 h
48 h
LPS challenge administration
X
See Section 2.1.1 for timing of LPS administration in 
relation to GSK3358699 / placebo dose.
Visual forearm check (including 
blister healing and cosmetic 
assessment)
X
X
X
X
X
Pre-cantharidin check to be within three hours prior to 
cantharidin application.
Cantharidin application
X
X
Day – 10: to be applied in the morning. Day 1: to be 
applied 20 minutes post LPS challenge.
Intravenous hydration with normal 
Saline at a rate of 250 mL / hr
<=========================================>
From 4 hours prior to LPS challenge administration 
until 8 hours after LPS challenge administration.
Vital Signs
X
X
<==========================================>
X
X
BP, HR, temp, respiratory rate.   Pre-dose vital signs 
to be taken pre-LPS challenge administration then 
post-LPS challenge as follows: every half hour for the 
first 4 hours, hourly until 12 hours, then 6- 8 hourly 
until discharge. Frequency can be increased if 
symptomatic.
Blood sample for circulating 
inflammatory biomarkers [E2a]
X
X
X
X
X
X
X
Blood sample for cellular activation 
markers [E2b]
X
X
X
X
Blood sample in TruCulture tube for 
inflammatory markers [E2c]
X
X
Pre-dose and 6 hours post LPS challenge: Null and 
LPS tubes at both time points.
Blood sample for gene panel [E2d]
X
X
X
X
X
Blister sample for biomarkers, blister 
volume and cell counts [E3]
X
X
Sample to be taken approx 24-48 hours post blister 
induction (time point being defined as part of ongoing 
enabling study).


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2.1.1.2.
Part A Period 4 Detailed SoA for GM-CSF challenge and Biomarker Sampling
Procedure
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Day -1
Day 1 - pre-dose and all post-dose times below are in relation to the start time
of the GM-CSF infusion not GSK3358699 administration
Day 2
Day 3
Notes
Pre-dose
0 h
1 h
2 h
2.3 h
3 h
4 h
5h
6 h
8 h
12 h
24 h
48 h
GM-CSF challenge administration
<===========>
See Section 2.1.1 for timing of the start of 
the GM-CSF infusion in relation to 
GSK3358699 / placebo dose. GM-CSF 
will be administered as an infusion over 2 
hours.
Visual forearm check (including blister 
healing and cosmetic assessment)
X
X
X
X
X
Pre-cantharidin check to be within three 
hours prior to cantharidin application.
Cantharidin application
X
X
Day – 10: to be applied in the morning. 
Day 1: 2 hours and 20 minutes after the 
start of the GM-CSF challenge.
Vital Signs
X
X
<===================================================>
X
X
BP, HR, temp, respiratory rate.   Pre-dose 
vital signs to be taken pre-GM-CSF 
challenge administration then post-GM-
CSF challenge as follows: every half hour 
for the first 4 hours, hourly until 8 hours, 
then 6- 8 hourly until discharge. 
Frequency can be increased if 
symptomatic.
Blood sample for circulating 
inflammatory biomarkers [E2a]
X
X
X
X
X
X
X
X
X
Blood sample for cellular activation 
markers [E2b]
X
X
X
X
X
X
Blood sample for gene panel [E2d]
X
X
X
X
X
Blister sample for biomarkers, blister 
volume and cell counts [E3]
X
X
Sample to be taken approx 24-48 hours 
post blister induction (time point being 
defined as part of ongoing enabling 
study).


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2.2.
Part B Food Effect Schedule of Activities
Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Periods 1 and 2
Follow-up 1 (7-14 days post-
last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
General
Informed consent
X
Inclusion and exclusion criteria
X
X
Day -1 assessment is to recheck eligibility against 
medical conditions, prior therapy etc, but not 
against Day -1 clinical chemistry and haematology 
results (see Section 9.4.7).  
Demography
X
Medical/medication/drug/alcohol 
history 
X
X
Includes substance usage and family history of 
premature CV disease and current medical 
conditions.
Admission to unit for in-patient stay
X
Discharge from Unit following in-
patient stay
X
Outpatient visit
X
X
Safety Assessments including laboratory tests
Full Physical Exam
X
Brief Physical Exam
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
BP, HR, temperature, respiratory rate.  


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Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Periods 1 and 2
Follow-up 1 (7-14 days post-
last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
12-Lead ECGs
X
X
X
X
X
X
X
X
X
X
12 Lead ECGs will be performed in triplicate at 
screening, Day-1, pre-dose Day 1, Day 2 and Day 
3.  Single ECGs will be performed at other time 
points and if any cardiac symptoms are 
experienced.  ECGs to be performed prior to any 
blood draws or dosing scheduled for the same 
nominal time point.
Telemetry
<================================================>
From 1 h pre-dose to 24 h post-dose.
Holter monitoring (24 hours)
X
If a participant is rescreened the Holter will not 
need to be repeated.
HIV, Hep B, Hep C
X
Haematology
X
X
X
X
X
X
Fasted screening samples. Follow-up visit 
samples do not require fasting.
Coagulation
X
X
X
X
X
Fasted screening samples. Follow-up visit 
samples do not require fasting.
Clinical Chemistry
X
X
X
X
X
X
Fasted screening samples. Follow-up visit 
samples do not require fasting.  Gamma-Glutamyl 
Transferase (GGT) and creatine kinase (CK) to be 
included at screening, Day-1 and follow up only.
Urinalysis
X
X
X
X
X
X
Fasted screening samples. Follow-up visit 
samples do not require fasting
Drug / Alcohol Test
X
X
Ad-hoc testing to be performed in the event of any 
cardiac arrhythmias, as close as possible to the 
time of occurrence
Urine Cotinine
X
X
AE / SAE review
SAEs collected from signing of informed consent form until the final follow up visit; AEs collected 
continuously from time of first dose until the final follow up visit.
Concomitant Medication Review
Monitored from first dose until the end of the final treatment Period


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Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Periods 1 and 2
Follow-up 1 (7-14 days post-
last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Pre-dose
0 h
15 mins
30 mins
1 h
2 h
4 h
6 h
8 h
12 h
24 h
48 h
Treatment administration
High Fat Breakfast
X
Participants will receive a high fat breakfast prior 
to dosing in one of the two treatment Periods only. 
See Section 6.3.1 for further details.
Study Drug Administration
X
Pharmacokinetics, Pharmacodynamics and Genetics Sample
Blood sampling for systemic PK 
[S1] and [S2]
X
X
X
X
X
X
X
X
X
X
X
Ad-hoc sample to be taken in the event of any 
cardiac arrhythmias, as close as possible to the 
time of occurrence
Blood sampling for intracellular PK
[S3]
X
X
X
X
X
Blood sample for ex vivo PD assay
[S4]
X
X
X
X
X
X
X
In total six samples (3 LPS and 3 LPS + 
GSK3358699) are required on Day -1:  to be taken 
(LPS and null) at approximately 13:00, 17:00 and 
20:00. Day 1: Two pre-dose samples (LPS and 
LPS + GSK3358699) to be taken at approximately 
08:00.  All sample timepoints pre- and post-dose 
require 1 LPS and 1 LPS + GSK3358699 sample.
Blood sample for potential 
companion diagnostic development
X
Sample to be taken on Day -1 in treatment Period 
1 only.
Blood sample for CES genotyping 
and optional genetic research [E5]
X
Sample to be taken on Day -1 in treatment Period 
1 only.


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2.3.
Part C General Schedule of Activities Cohorts 5-7 (no challenges)
Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
General
Informed consent
X
Inclusion and exclusion criteria
X
X
Day -1 assessment is to recheck eligibility against medical 
conditions, prior therapy etc, but not against Day -1 clinical 
chemistry and haematology results (see Section 9.4.7).  
Demography
X
Medical/medication/
drug/alcohol history 
X
X
Includes substance usage and family history of premature CV 
disease and current medical conditions.
Admission to unit for in-patient 
stay
X
Discharge from Unit following in-
patient stay
X
Outpatient visit
X
X
Safety Assessments including laboratory tests
Full Physical Exam
X
Brief Physical Exam
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
BP, HR, temperature, respiratory rate. See Section 2.3.1 for time 
points on Day 13, 14, 15 and 16. Measurements will be performed 
pre-dose on other dosing days.
12-Lead ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead ECGs will be performed in triplicate at screening, Day-1, 
pre-dose Day 1, Day 4, Day 8, Day 14 and Day 16.  Single ECGs 
will be performed at other time points and if any cardiac 
symptoms are experienced.  ECGs to be performed prior to any 
blood draws or dosing scheduled for the same nominal time point.  


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Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Telemetry
X
X
X
X
Continuous cardiac telemetry on each designated day from 1hr 
pre-dose until 24 h post-dose, and on other days if QTcF 
>450msec. 
Holter monitoring (24 hours)
X
If a participant is rescreened the Holter will not need to be 
repeated.
HIV, Hep B, Hep C
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on Day 
1, 2, 4, 8, 12 and 13. See Section 2.3.1 for haematology time 
points on Day 14, 15 and 16. Follow-up visit samples do not 
require fasting.
Coagulation
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on Day -
1, 4 and 8. See Section 2.3.1 for further details of Day 14 sample 
timings.   Follow-up visit samples do not require fasting
Fasting lipids and glucose
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on each 
day.  Both fasting lipids and glucose will be tested from same 
sample. Follow-up visit samples do not require fasting
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on each 
day. Follow-up visit samples do not require fasting. GGT and CK 
to be included at screening, Day-1 and follow up only
Urinalysis
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on each 
day. Follow-up visit samples do not require fasting
Drug / Alcohol Test
X
X
Ad-hoc testing to be performed in the event of any cardiac 
arrhythmias, as close as possible to the time of occurrence
Urine Cotinine
X
X
AE / SAE review
SAEs collected from signing of informed consent form until the final follow up visit; AEs 
collected continuously from time of first dose until the final follow up visit.
Concomitant Medication Review
Monitored continuously from first dose until the end of the treatment period
Treatment  / agent administration
Study Drug Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Once-daily in the morning on Days 1-14 inclusive.
Pharmacokinetics, Pharmacodynamics and Genetics Sample


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Procedure
Screening (up to 35 Days 
prior to Day 1)
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Blood sampling for systemic PK 
[S1] and [S2]
X
X
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 15mins, 30mins, 1h, 
2h, 4h, 6h, 8h, 12h and 24h post-dose, Pre-dose samples Days 
4, 8 and 12. See Section 2.3.1 for Day 14, 15 and 16 sample 
timings. Ad-hoc sample to be taken in the event of any cardiac 
arrhythmias, as close as possible to the time of occurrence
Blood sampling for intracellular 
PK [S3]
X
X
X
X
X
X
X
On Day 1 samples will be taken at 1h, 4h and 8h post-dose. Pre-
dose samples Days 4, 8 and 12. See Section 2.3.1 for Day 14, 
15 and 16 sample timings.
Blood sample for ex vivo PD 
assay [S4]
X
X
X
X
X
X
X
X
X
Day -1 samples to be taken at approximately 13:00, 17:00 and 
20:00. Day 1 and Day 14 pre-dose samples to be taken at 
approximately 08:00. Day 1 post-dose samples to be taken at 1h, 
4h and 8h post-dose. Samples to be taken pre-dose Days 2, 4, 8 
and 12. See Section 2.3.1 for Day 14, 15 and 16 sample timings. 
All sample timepoints pre- and post-dose require 1 LPS and 1 
LPS + GSK3358699 sample. 
Blood sample for circulating 
proteins [E1a]
X
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 2h, 4h and 8h post-
dose. Samples to be taken pre-dose Day 2, 4, 8 and 12. See 
Section 2.3.1 for Day 14 and 15 sample timings.
Blood sample for gene panel 
[E1b]
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 2h and 4h post-
dose. Samples to be taken pre-dose Days  4, 8 and 12. See 
Section 2.3.1 for Day 14 and 15 sample timings.
Blood sample for cellular 
activation markers [E2b]
X
X
X
X
X
Pre-dose samples Days 1, 4, 8 and 12. See Section 2.3.1 for 
Day 14 sample timings.
Blood sample for potential 
companion diagnostic 
development
X
Blood sample for CES
genotyping and optional genetic 
research [E5]
X
Urine sample for metabolite 
analysis [E4]
X
X
X
X
A 0-24 urine collection will be made on Day 1 and Day 14.  In 
each case, for the pre-dose sample, immediately prior to dosing 
participants will be instructed to void their bladder into a 
collection container.  Following dosing participants will be 
instructed to collect all urine voided for a 0-24 hour collection.


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2.3.1.
Part C Day 14 Detailed SoA for PK and PD / Biomarker Sampling Cohorts 5-7 (no challenges)
Procedure
Day 13
Day 14.
Day 15
Day 16
Notes
Pre-dose
0 h
15 mins 
30 mins 
1 h
2 h
4 h
6h
8 h
12 h
24 h
48 h
Treatment  / agent administration and PK sampling
Study Drug / Placebo 
Administration
X
Vital Signs
X
X
X
X
X
Haematology
X
X
X
X
Coagulation
X
Blood sampling for systemic 
PK [S1] and [S2]
X
X
X
X
X
X
X
X
X
X
X
Ad-hoc sample to be taken in the event of any cardiac arrhythmias, as 
close as possible to the time of occurrence
Blood sampling for 
intracellular PK [S3]
X
X
X
X
X
Blood sample for ex vivo PD 
assay [S4]
X
X
X
X
X
X
Blood sample for circulating 
proteins [E1a]
X
X
X
X
X
Blood sample for gene panel 
[E1b]
X
X
X
X
Blood sample for cellular 
activation markers [E2b]
X
X


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2.4.
Part C General Schedule of Activities Cohorts 4 and 8 (with challenges)
Procedure
Screening (up to 45 Days 
prior to Day 1)
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Follow-up 2 (5 weeks 
after last dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
The 2nd follow up visit is only required for those participants 
where challenges are being administered and blisters induced
General
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Day -1 assessment is to recheck eligibility against medical 
conditions, prior therapy etc, but not against Day -1 clinical 
chemistry and haematology results (see Section 9.4.7).  
Demography
X
Medical/medication/
drug/alcohol history 
X
X
Includes substance usage and family history of premature CV 
disease and current medical conditions.
Admission to unit for 
in-patient stay
X
Discharge from Unit 
following in-patient 
stay
X
Outpatient visit
X
X
X
X
X
Safety Assessments including laboratory tests
Full Physical Exam
X
Brief Physical Exam
X
X
X
Body Weight
X
X
Body weight will be measured on Day 13 to calculate doses for 
challenges.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
BP, HR, temperature, respiratory rate. See Section 2.4.2 and 
Section 2.4.3 for time points on Day 13, 14, 15 and 16. 
Measurements will be performed pre-dose on other dosing 
days.
12-Lead ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead ECGs will be performed in triplicate at screening, Day-
1, pre-dose Day 1, Day 4, Day 8, Day 14 and Day 16.  Single 
ECGs will be performed at other time points and if any cardiac 
symptoms are experienced.  ECGs to be performed prior to any 
blood draws or dosing scheduled for the same nominal time 


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Procedure
Screening (up to 45 Days 
prior to Day 1)
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Follow-up 2 (5 weeks 
after last dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
The 2nd follow up visit is only required for those participants 
where challenges are being administered and blisters induced
point.  
Telemetry
X
X
X
X
Continuous cardiac telemetry on each designated day from 1hr 
pre-dose until 24 h post-dose, and on other days if QTcF 
>450msec. For participants receiving the LPS-challenge, the 
Day 14 telemetry must be performed for a minimum of 12hrs 
post-LPS or until their telemetry shows no clinically significant 
findings for 4 hours (whichever is longer).
Holter monitoring 
(24 hours)
X
If a participant is rescreened the Holter will not need to be 
repeated.
HIV, Hep B, Hep C
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on 
Day 1, 2, 4, 8, 12 and 13. See Section 2.4.2 and Section 2.4.3
for haematology time points on Day 14, 15 and 16. Follow-up 
visit samples do not require fasting.
Coagulation
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on 
Day -1, 4, 8 and 13. See Section 2.4.2 for further details of Day 
14 sample timings. Day 13 and Day 14 samples are only 
performed for subjects receiving LPS. Follow-up visit samples 
do not require fasting
Fasting lipids and 
glucose
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on 
each day.  Both fasting lipids and glucose will be tested from 
same sample. Follow-up visit samples do not require fasting
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on 
each day. Follow-up visit samples do not require fasting GGT 
and CK to be included at screening, Day-1 and follow up only.
Urinalysis
X
X
X
X
X
X
X
X
X
Fasted screening samples. Sample to be taken pre-dose on 
each day. Follow-up visit samples do not require fasting
Drug / Alcohol Test
X
X
Ad-hoc testing to be performed in the event of any cardiac 
arrhythmias, as close as possible to the time of occurrence
Urine Cotinine
X
X


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Procedure
Screening (up to 45 Days 
prior to Day 1)
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Follow-up 2 (5 weeks 
after last dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
The 2nd follow up visit is only required for those participants 
where challenges are being administered and blisters induced
Visual forearm 
check (including 
blister healing and 
cosmetic 
assessment)
X
X
X
X
X
X
X
X
X
Pre-cantharidin check to be within three hours prior to 
cantharidin application. See Section 2.4.2 and Section 2.4.3 for 
further details of timing of forearm checks on Day 13, 14, 15 
and 16 in relation to challenges.
AE / SAE review
SAEs collected from signing of informed consent form until the final follow up visit; AEs collected continuously 
from time of first dose until the final follow up visit.
Concomitant 
Medication Review
Monitored continuously from first dose until the end of the treatment 
period
Treatment  / agent administration
Study Drug 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Once-daily in the morning on Days 1-14 inclusive.
Cantharidin 
application
X
X
Day – 10: to be applied in the morning. See Section 2.4.2 and 
Section 2.4.3 for further details on Day 14 blister timings.
In vivo LPS or GM-
CSF Challenge
X
See Section 2.4.1 for further details.
Pharmacokinetics, Pharmacodynamics and Genetics Sample
Blood sampling for 
systemic PK [S1] 
and [S2]
X
X
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 15mins, 30mins, 
1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose, Pre-dose samples 
Days 4, 8 and 12. See Section 2.4.1 for Day 14, 15 and 16
sample timings. Ad-hoc sample to be taken in the event of any 
cardiac arrhythmias, as close as possible to the time of 
occurrence
Blood sampling for 
intracellular PK [S3]
X
X
X
X
X
X
X
X
On Day 1 and Day 13 samples will be taken at 1h, 4h and 8h 
post-dose. Pre-dose samples Days 4, 8 and 12.  See Section 
2.4.1 for Day 14, 15 and 16 sample timings.
Blood sample for ex 
vivo PD assay [S4]
X
X
X
X
X
X
X
X
X
Day -1 samples to be taken at approximately 13:00, 17:00 and 
20:00. Day 1 and Day 14 pre-dose samples to be taken at 
approximately 08:00. Day 1 and Day 13 post-dose samples to 
be taken at 1h, 4h and 8h post-dose. Samples to be taken pre-
dose Days 2, 4, 8 and 12. See Section 2.4.1 for Day 14 and 15
sample timings. All sample timepoints pre- and post-dose 
require 1 LPS and 1 LPS + GSK3358699 sample.
Blood sample for 
X
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 2h, 4h and 8h 


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Procedure
Screening (up to 45 Days 
prior to Day 1)
Day -10 (3 days)
24-48 hours following 
Day -10 visit
Treatment Period
Follow-up 1 (7-14 days 
post-last dose)
Follow-up 2 (5 weeks 
after last dose 3 days)
Notes
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
The 2nd follow up visit is only required for those participants 
where challenges are being administered and blisters induced
circulating proteins 
[E1a]
post-dose. Samples to be taken pre-dose Day 2, 4, 8 and 12. 
See Section 2.4.1 for Day 14 and 15 sample timings.
Blood sample for 
gene panel 
[E1b/E2d]
X
X
X
X
X
X
On Day 1 samples will be taken at pre-dose, 2h and 4h post-
dose. Samples to be taken pre-dose Days  4, 8 and 12. See 
Section 2.4.1, Section 2.4.2 and Section 2.4.3 for Day 14 and 
15 sample timings for E2d.
Blood sample for 
circulating 
inflammatory 
biomarkers [E2a]
X
X
X
See Section 2.4.2 and Section 2.4.3 for sample timings.
Blood sample for 
cellular activation 
markers [E2b]
X
X
X
X
X
X
X
Pre-dose samples Days 1, 4, 8 and 12. See Section 2.4.2 and 
Section 2.4.3 for Day 14, 15 and 16 sample timings.
Blister sample for 
biomarkers, blister 
volume and cell 
counts [E3]
X
X
Blisters harvested approx 48 h post cantharidin application  See 
Section 2.4.2 and Section 2.4.3 for further detail on Day 16
sample timings.
Blood sample for 
potential companion 
diagnostic 
development
X
Blood sample for 
CES genotyping 
and optional genetic 
research [E5]
X
Urine sample for 
metabolite analysis 
[E4]
X
X
X
X
A 0-24 urine collection will be made on Day 1 and Day 14.  In 
each case, for the pre-dose sample, immediately prior to dosing 
participants will be instructed to void their bladder into a 
collection container.  Following dosing participants will be 
instructed to collect all urine voided for a 0-24 hour collection.


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2.4.1.
Part C Day 14 Detailed SoA for Challenge Administration and PK Sampling Cohorts 4 and 8 (with 
challenges)
Procedure
Day 13
Day 14 - pre-dose and all post-dose times below are in 
relation to the administration time of GSK3358699.
Day 15
Day 16
Notes
Pre-dose
0 h
15 mins 
30 mins 
1 h
2 h
4 h
6h
8 h
12 h
24 h
48 h
Treatment  / agent administration and PK sampling
Study Drug / Placebo 
Administration
X
In vivo LPS Challenge
< ======================= >
LPS administration may  be performed at low systemic GSK3358699 
concs when intracellular levels of GSK3206944 are high; the decision on 
the timepoint will be based on emerging data and will be no more than 
24hrs after dosing on Day 14.
OR in vivo GM-CSF Challenge
< =========================== >
GM-CSF administration may be performed at low systemic GSK3358699 
concs when intracellular levels of GSK3206944 are high; the decision on 
the timepoint will be based on emerging data. GM-CSF will be 
administered as an infusion over 2 hours and the start of the infusion will 
be no more than 24hrs after dosing on Day 14. 
Blood sampling for systemic PK 
[S1] and [S2]
X
X
X
X
X
X
X
X
X
X
X
Ad-hoc sample to be taken in the event of any cardiac arrhythmias, as 
close as possible to the time of occurrence
Blood sampling for intracellular 
PK [S3]
X
X
X
X
X
X
Pre-challenge samples. To be collected only until the start of challenge 
administration
Blood sample for ex vivo PD 
assay [S4]
X
X
X
X
X
X
Pre-challenge samples. To be collected only until the start of challenge 
administration. 
Blood sample for circulating 
proteins [E1a]
X
X
X
X
X
Pre-challenge samples. To be collected only until the start of challenge 
administration.
Blood sample for gene panel 
[E1b]
X
X
X
X
X
Pre-challenge samples. To be collected only until the start of challenge 
administration.
Cantharidin application and PD 
sampling
See Section 2.4.2 and Section 2.4.3


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2.4.2.
Part C Day 14 Detailed SoA for LPS Challenge and Biomarker Sampling Cohorts 4 and 8 (with challenges)
Procedure
Day 13
Day 14 - pre-dose and all post-dose times below are in relation to 
the administration time of LPS not GSK3358699 administration
Day 15
Day 16
Notes
Pre-dose
0 h
20 mins
1 h
2 h
3 h
4 h
6h
8 h
12 h
24 h
48 h
LPS challenge administration
X
See Section 2.4.1 for timing of LPS administration in relation to 
GSK3358699 / placebo dose.
Visual forearm check (including 
blister healing and cosmetic 
assessment)
X
X
X
X
Pre-cantharidin check to be within three hours prior to cantharidin 
application.
Cantharidin application
X
To be applied 20 minutes post LPS challenge.
Intravenous hydration with 
normal Saline at a rate of 250 
mL / hr
<=========================================>
From 4 hours prior to LPS challenge administration until 8 hours after 
LPS challenge administration.
Vital Signs
X
X
<=========================================>
X
X
BP, HR, temperature, respiratory rate.   Pre-dose vital signs to be 
taken pre-LPS challenge administration then post-LPS challenge as 
follows: every half hour for the first 4 hours, hourly until 12 hours, then 
6- 8 hourly until discharge. Frequency can be increased if 
symptomatic.
Haematology
X
X
X
X
X
Coagulation
X
X
Blood sample for circulating 
inflammatory biomarkers [E2a]
X
X
X
X
X
X
X
Blood sample for cellular 
activation markers [E2b]
X
X
X
X
X
Blood sample for gene panel 
[E2d]
X
X
X
X
X
Blister sample for biomarkers, 
blister volume and cell counts 
[E3]
X
Blisters harvested approx 48 h post cantharidin application.


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2.4.3.
Part C Day 14 Detailed SoA for GM-CSF Challenge and Biomarker Sampling Cohorts 4 and 8 (with 
challenges)
Procedure
Day 13
Day 14 - pre-dose and all post-dose times below are in relation to the start
time of the GM-CSF infusion not GSK3358699 administration
Day 15
Day 16
Notes
Pre-dose
0 h
1 h
2 h
2h 20mins
3 h
4 h
5h
6 h
8 h
12 h
24 h
48 h
GM-CSF challenge 
administration
<==========>
See Section 2.4.1 for timing of the start of the GM-CSF infusion in 
relation to GSK3358699 / placebo dose. GM-CSF will be 
administered as an infusion over 2 hours.
Visual forearm check (including 
blister healing and cosmetic 
assessment)
X
X
X
X
Pre-cantharidin check to be within three hours prior to cantharidin 
application.
Cantharidin application
X
2 hours and 20 minutes after the start of the GM-CSF challenge.
Vital Signs
X
X
<================================================>
X
X
BP, HR, temperature, respiratory rate.   Pre-dose vital signs to be 
taken pre-GM-CSF challenge administration then post-GM-CSF 
challenge as follows: every half hour for the first 4 hours, hourly until 
8 hours, then 6- 8 hourly until discharge. Frequency can be 
increased if symptomatic.
Haematology
X
X
X
X
X
Blood sample for circulating 
inflammatory biomarkers [E2a]
X
X
X
X
X
X
X
X
Blood sample for cellular 
activation markers [E2b]
X
X
X
X
X
X
Blood sample for gene panel 
[E2d]
X
X
X
X
X
Blister sample for biomarkers, 
blister volume and cell counts 
[E3]
X
Blisters harvested approx 48 h post cantharidin application.


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
The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered 
during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments 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 Institutional Review Board / Independent 
Ethics Committee (IRB/IEC) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the Informed 
Consent (ICF).

Acceptable time windows around the nominal time points for specific 
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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3.
INTRODUCTION
GSK3358699 is a targeted inhibitor of the bromodomain and extra-terminal domain 
(BET) family of epigenetic reader proteins [Ferri et al 2016, Chung et al 2012, 
Filippakopoulos et al 2014].  Recent literature reports have demonstrated that inhibitors 
of this protein family profoundly affect many of the pro-inflammatory molecular and 
cellular mechanisms which underpin a multitude of immuno-inflammatory diseases
[Nicodeme et al 2010, Mele et al 2013, Klein et al 2016].  To date, however, the clinical 
evaluation of panBET inhibitors such as GSK525762 [Mirguet et al 2013] has centred on 
oncology, with no reports citing the use of this pharmacology outside malignant 
neoplastic diseases [Jung et al 2015, Belkina et al 2012, Yu et al 2015, Dawson et al 
2012]. With a view to further exploring the potential of BET family inhibition in human 
disease, GlaxoSmithKline (GSK) is developing GSK3358699, a mononuclear myeloid 
targeted BET inhibitor. Based on pre-clinical work to date GSK3358699 has the 
potential to effect positive outcomes in myeloid-centric diseases with unmet need;
including but not limited to rheumatoid arthritis (RA), psoriasis, fibrotic liver disease and 
inflammatory bowel disease (IBD), with the potential to provide an improved safety 
profile compared to other panBET inhibitors [GlaxoSmithKline Document Number 
2017N333959_00].
In contrast to conventional inhibitors of the BET proteins and unique within this target 
class, GSK3358699 encompasses within its chemical structure an Esterase Sensitive 
Motif (ESM) [Needham et al 2011]. This cell targeting technology enables preferential 
delivery of the BET pharmacology to cells expressing human carboxyesterase-1 (CES-1), 
thereby limiting less desirable systemic effects. These target cells are primarily those of 
the mononuclear-myeloid lineage, including monocytes, macrophages and dendritic cells, 
but also include hepatocytes.
More specifically, GSK3358699 is selectively hydrolysed by the esterase CES-1 in target 
cells to form a pharmacologically active carboxylic acid, GSK3206944.  Like 
GSK3358699, this acid metabolite is a potent BET inhibitor, which, because of its 
charged nature, is selectively retained in high local concentrations within mononuclear 
myeloid cells.  
Targeting inflammatory cells that are sensitive to BET inhibition and play a key role in 
many inflammatory diseases [Chan et al 2015] should reduce non-target side effects 
leading to a wider therapeutic window relative to conventional non-targeted BET 
inhibitors. As a result, GSK3358699 has the potential to become a novel and important 
therapeutic modality for the treatment of inflammatory and fibrotic disorders.
3.1.
Study Rationale
This first time in human (FTIH) study intends to identify doses of GSK3358699 that are 
well tolerated whilst delivering a robust pharmacodynamic response.  As such, the study 
will evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD)
profile of single (in both fed and fasted states) and multiple ascending doses of 
GSK3358699 in healthy male participants within a pre-defined and controlled 
pharmacodynamic and pharmacokinetic range for each cohort.  Compound exposures 


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investigated as part of this study will not intentionally exceed pre-defined PK and PD 
stopping criteria as highlighted in Section 8.
Further, this study will seek to understand the effect of GSK3358699 on systemic 
markers of inflammation following low dose in vivo lipopolysaccharide (LPS) or 
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local 
inflammation in cantharidin-induced blisters.  This experimental approach has been 
carefully designed to explore the in vivo biology of the target and to inform potential 
immuno-inflammatory indications where GSK3358699 could provide substantial efficacy 
to address unmet clinical need.
3.2.
Background
Pre-clinically, BET inhibitors have demonstrated profound anti-inflammatory and anti-
fibrotic effects, driven by their ability to regulate gene expression at an epigenetic level.  
Indeed, non-targeted BET inhibitors have been shown to interact in vitro with multiple 
cellular effectors of disease and are efficacious in a range of animal models of disease
[Nadeem et al 2015, Meng et al 2014, Cheung et al 2017].  As the first targeted BET 
inhibitor, GSK3358699 has exhibited potent immuno-modulatory effects in vitro, for 
example in human whole blood assays stimulated with LPS or GM-CSF, as well as in 
samples from rheumatoid arthritis patients.  Further to this, GSK3358699, when 
investigated in a mouse model of arthritis, effectively inhibited joint inflammation and 
bone erosion, and abrogated cytokine production in an acute LPS challenge in 
cynomolgus monkeys. A detailed description of the chemistry, pharmacology and safety 
of GSK3358699 is provided in the Investigator’s Brochure (IB) [GlaxoSmithKline 
Document Number 2017N333959_00].
3.3.
Benefit/Risk Assessment
There is no direct benefit to the participants taking part in this study.  
The risk assessment of GSK3358699 is based on the pre-clinical studies conducted to 
date. Summaries of findings from these pre-clinical studies can be found in the IB. 
Details of these risks, as well as the risks associated with the challenge agents, and the 
proposed strategy to mitigate/monitor these risks are detailed in Section 3.3.1. For 
transparency, emerging clinical data from this study on NSVTs is also included as a 
potential risk, although causality with GSK3358699 has not been established and similar 
findings were not observed preclinically.
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 immediate access to 
hospital facilities for the treatment of medical emergencies.  Participants will remain 
monitored in the clinic for the duration of each treatment Period and will only be 
discharged from the unit at the end of each treatment Period if the investigator deems it 
safe to do so.


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More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events may be found in the Participant Information Leaflet 
for GM-CSF and cantharidin and in previous literature for LPS [Fullerton et al 2016].


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
Investigational Medicinal Product (IMP) GSK3358699
Lipid elevations
Non-adverse increased triglyceride was evident in female 
monkeys given ≥ 1 mg/kg/day. Higher triglyceride and/or 
cholesterol concentrations were also seen in rats given ≥10 
mg/kg/day.  The effects on triglycerides in monkeys and 
rats and the no observed effect level (NOEL) for rats are 
below the maximum predicted human exposure (AUC) at 
45 mg.  
Participant Selection / Monitoring / Stopping criteria:
Specific eligibility and withdrawal criteria (see Section 6.2
and Section 8).
The protocol includes laboratory assessments for 
triglycerides. Fasting lipids will additionally be monitored 
during part C (repeat dosing) of the study.
Relevant lipid data from the current and any previous cohort 
will be considered as part of dose escalation decisions.
Coagulation
Non-adverse increases in anticoagulant (prothrombin time 
(PT) and activated partial thromboplastin time (APTT)) and 
procoagulant (fibrinogen) factors were evident in rats at ≥ 
10 mg/kg/day and in individual monkeys given ≥ 10 
mg/kg/day in a dose ranging study for 15 days. No changes 
in PT or APTT were seen in monkeys given GSK3358699 
for 6 weeks. The effects on fibrinogen and the NOEL for 
clotting times in rat are below the maximum predicted 
human exposure (AUC) at 45 mg.  
Participant Selection / Monitoring / Stopping criteria:
Specific eligibility criteria based on history of prior 
thrombotic or bleeding disease (see Section 6.2).
The protocol includes evaluation of clotting parameters to 
assess potential changes in fibrinogen, PT and APTT.
Relevant coagulation and thrombotic safety data from the 
current and any previous cohort will be considered as part 
of dose escalation decisions.
Kidney function
Non-adverse increased urinary glucose concentration was 
seen in female monkeys and rats given ≥10 mg/kg/day. 
Other clinical pathology that may be related to perturbations 
in kidney function were seen in monkeys or rats. Monkeys
given ≥3 mg/kg/day for 6 weeks had decreased plasma 
albumin; rats given ≥10 mg/kg/day for 6 weeks had 
decreased urinary volume, lower urinary total protein and 
protein concentrations, variable changes in plasma 
creatinine concentration and urea, higher glucose and 
phosphorus concentrations and slightly lower sodium, 
Participant Selection / Monitoring/ Stopping Criteria:
Specific eligibility - criteria (see Section 6.2).
The protocol includes laboratory assessments for renal 
function, electrolytes, fasting glucose, as well as urinary 
glucose assessment.
Relevant renal and glycaemic safety data from the current 
and any previous cohort will be considered as part of dose 
escalation decisions.


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
potassium and chloride concentrations.  
No histological changes were seen in the kidneys of 
monkeys given GSK3358699. Tubular dilatation and higher 
kidney weight was evident at the non-tolerated 100 
mg/kg/day dose in male rats. 
Some of the urinary effects in rats are evident below the 
maximum predicted human exposure (AUC) at 45 mg and
the NOEL in monkeys at or below parity to the maximum 
predicted human exposure (AUC) at 45 mg.
Gastrointestinal (GI)
Gastrointestinal toxicity was observed following repeat oral 
dosing in rats and cynomolgus monkeys at ≥100 and ≥10 
mg/kg/day, respectively. In rats and monkeys there is an 
approximately 6-fold margin from the maximum predicted 
human exposure (AUC) at 45 mg to the no observed 
adverse effect limit (NOAEL) for gastrointestinal effects in 
the 6 week studies. No gastrointestinal effects were 
observed in the predicted clinical range up to a maximum of 
45 mg.
Clinical presentation included body weight reductions and/or 
loose feces, emesis and reduced food consumption and 
were dose limiting at ≥100 mg/kg in rats and 30 mg/kg in 
monkeys.  
Effects in monkeys dosed for 6 weeks were limited to non-
adverse slight erosion, oedema, haemorrhage and 
inflammatory cell infiltrate in the stomach of a single animal 
given 10 mg/kg/day. Similar findings, extending to the 
intestines, were seen in a different study where monkeys 
were dosed at ≥10 mg/kg for up to 15 days. Effects seen at 
30 mg/kg/day for up to 15 days were of greater severity, 
extended to the intestines and contributed to the morbidity 
of a single animal. Effects in rats dosed up to 6 weeks 
included atrophy and ulceration and were considered 
adverse. 
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 area under the 
concentration – time curve (AUC) of 255 ng/ml.h, systemic 
maximum concentration (Cmax)42 ng/ml which are the 
predicted AUC and Cmax at 45 mg once daily (QD).
Participant Selection / Monitoring / Stopping Criteria:
Specific eligibility and withdrawal criteria (see Section 6.2
and Section 8) are included.
Participant monitoring will be based on prior clinical 
experience with inhibitors from this target class, Medical 
history, physical examination and AE reporting will be used 
to monitor for toxicity in the GI tract. Supportive therapy will 
be provided as per standard medical practice. In the event 
of clinically significant toxicity, the participant will be 
withdrawn and supportive therapy provided according to 
standard medical practice. 
Relevant GI safety data from the current and any previous 
cohort will be considered as part of dose escalation 
decisions.


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
QTc prolongation 
QTc prolongation was observed in cynomolgus monkeys 
following single and repeat doses of ≥ 10 mg/kg, up to a 
maximum of 38 msec increase (16% change from 
pretreatment), but importantly, no arrhythmias were 
observed. There is a 3 fold margin and approximate parity
to the maximum predicted human exposure (free Cmax and 
AUC respectively) at 45 mg to the NOEL for QTc 
prolongation in monkeys. 
The QTc prolongation was not induced by direct inhibition 
of hERG binding with a > 164 fold from the hERG binding
inhibitory concentration (IC)50 (89.97 µM) to the 
GSK3358699 free maximum plasma concentration (Cmax) at 
10 mg/kg in monkeys.
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 AUC of 255 ng/ml.h, 
Cmax 42 ng/ml which are the predicted AUC and Cmax at 45
mg QD.
Participant Selection/ Monitoring / Stopping Criteria:
Specific eligibility and withdrawal criteria (see Section 6.2
and Section 8).
The protocol includes cardiac monitoring (12 lead ECGs 
and telemetry) of participants at each dose level 
investigated. 
Relevant cardiovascular safety data from the current and 
any previous cohort will be considered as part of dose 
escalation decisions.
Phototoxicity
The ultraviolet (UV)/visible (VIS) spectrum for GSK3358699 
showed absorbance in the region of concern which indicate 
a potential for a human phototoxicity risk. 
Participant Selection / Monitoring:
Participants will be advised not to sunbathe or use sunbeds 
and to wear suitable clothing that minimises exposed areas
of skin and to use a broad spectrum UVA/UVB sunscreen 
and lip balm (SPF ≥ 30) on exposed areas when outdoors. 
In addition, participants should wear sunglasses that filter 
UVA and UVB rays.  
These protections are recommended from day-1 for a 
minimum of 5 half-lives after GSK3358699 discontinuation.
Specific eligibility criteria (see Section 6.2)
Physical examination and AE reporting will be used to 
identify and assess phototoxicity.
Relevant safety data from the current and any previous 
cohort will be considered as part of dose escalation 
decisions.


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Mitigation Strategy
Testicular 
No testicular findings were observed in monkeys dosed up 
to 6 weeks at the maximum tolerated dose of 10 mg/kg/day. 
In the rat, testicular findings (sperm retention and/or 
minimal to slight germ cell degeneration, tubular 
vacuolation and multinucleate germ cells) were evident at
non-tolerated doses of ≥100 mg/kg/day with an 8-fold 
margin from the maximum predicted human exposure 
(AUC) at 45 mg to the NOAEL for testicular effects.  
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 AUC of 255 ng/ml.h, 
Cmax 42 ng/ml which are the predicted AUC and Cmax at 45
mg QD.
Participant Selection / Monitoring:
AE reporting will be used to identify and assess any signs 
and symptoms related to testicular safety.
Appropriate contraceptive measures for participants is 
included in Section 6.1 and Section 12.5.
Relevant safety data from the current and any previous 
cohort will be considered as part of dose escalation 
decisions.  
Aneugenicity
GSK3358699 has been determined to be an aneugen with 
a 7.-fold margin to the maximum predicted human exposure 
(Cmax) at 45 mg to the NOEL for aneugenicity in rats. 
GSK3359699 is derived from a series of benzimidazoles. 
Benzimidazoles as a class are known aneugens and the 
rodent carcinogenicity data and clinical exposure data for 
benzimidazoles indicates that there is no evidence for 
translation of the observed aneuploidy in to a carcinogenic 
risk for humans.
Dose Selection:
Doses administered as part of this study will not intentionally 
exceed the GSK3358699 AUC of 255 ng/ml.h, Cmax 42 
ng/ml which are the predicted AUC and Cmax at 45 mg QD.
Haematologic
Variable changes in red blood cell parameters were noted 
at non-tolerated doses in both rats and monkeys. At 
tolerated doses, no hematological changes were seen in 
monkey and increased red cell distribution width (RDW), 
reticulocytes and/or MCV were seen in rats. 
No microscopic changes were observed in the 
hematopoietic and lymphoid organs of monkeys and those 
evident in rats given ≥ 100 mg/kg/day were considered 
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 AUC of 255 ng/ml.h, 
Cmax 42 ng/ml which are the predicted AUC and Cmax at 45
mg QD.
Participant Selection / Monitoring / Stopping Criteria:
Specific eligibility and withdrawal criteria (see Section 6.2


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
non-adverse. Further details are in the IB Section 2.
Decreases in platelet count were not observed preclinically 
with GSK3358699 but have been observed with panBET 
inhibitors in the clinic.
and Section 8).
The protocol includes laboratory haematological 
assessments.
Relevant haematological safety data from the current and 
any previous cohort will be considered as part of dose 
escalation decisions.
Hepatic
Findings in the liver of monkeys dosed for 6 weeks 
consisted of non-adverse centrilobular vacuolation in a 
single animal given 10 mg/kg/day. Cytoplasmic rarefaction, 
hepatocellular hypertrophy and microvesicular vacuolation 
were seen in dose ranging monkey study. Non-adverse 
effects were also seen in rats given 100 mg/kg/day for 6 
weeks and included cytoplasmic vacuolation, cytoplasmic 
basophilia and decreased inflammatory infiltration. 
Clinical pathology changes potentially related to the liver 
findings include higher alkaline phosphatase (ALP) and 
aspartate aminotransferase (AST) activities in rats given 
100 mg/kg/day. Increases in total bilirubin was also evident 
in rats given 100 mg/kg/day. There was no evidence of 
hepatobiliary damage in any toxicology studies conducted 
with GSK3358699.
There is approximate parity and a 7- fold margin from the 
maximum predicted human exposure (AUC) at 45 mg to the 
NOEL for liver effects in monkeys and rats respectively.
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 AUC of 255 ng/ml.h, 
Cmax 42 ng/ml which are the predicted AUC and Cmax at 45
mg QD.
Participant Selection / Monitoring / Stopping Criteria:
Specific eligibility and withdrawal criteria (see Section 6.2
and Section 8).
The protocol includes laboratory liver chemistry 
assessments.
Relevant liver safety data from the current and any previous 
cohort will be considered as part of dose escalation 
decisions.
Non-sustained ventricular tachycardia (NSVT)
Four cases of asymptomatic, non-serious, non-severe and 
self-limiting NSVT were observed in this study (207546); 2 
in Part A and 2 in Part C. There was a lack of correlation 
between measured GSK3358699 systemic concentrations 
and the NSVTs. Similar findings were not observed 
preclinically.
Participant Selection / Monitoring / Stopping criteria:
Specific eligibility criteria (see Section 6.2).
Additional withdrawal criterion based on investigator and 
medical monitor judgement (see Section 8.1.6.).
The protocol includes cardiac screening and monitoring (12 
lead ECGs and telemetry) of participants at each dose level 


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
investigated.
Randomisation ratio in Part C has been changed to 1:1 
(GSK3358699:placebo) 
Relevant cardiovascular safety data from the current and any 
previous cohort will be considered as part of dose escalation 
decisions.


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
Haemodynamic
An increase in heart rate (increased by up to 46 beats per 
minute (bpm)) was observed after 13 doses of a non-
tolerated 30 mg/kg/day dose in a single cynomolgus 
monkey with a 16 fold margin to the NOEL (free Cmax). 
No abnormalities were observed histologically in the hearts 
of rats or monkeys given GSK3358699 for up to 6 weeks.
Dose Selection:
Doses administered as part of this study will not 
intentionally exceed the GSK3358699 AUC of 255 ng/ml.h, 
Cmax 42 ng/ml which are the predicted AUC and Cmax at 45 
mg QD.
Participant Monitoring:
The protocol includes cardiac monitoring (vital signs, 12 
lead ECGs and telemetry) of participants at each dose level 
investigated. 
Relevant cardiovascular safety data from the current and 
any previous cohort will be considered as part of dose 
escalation decisions.
Drug-Drug Interactions (DDIs)
GSK3358699 is a weak metabolism dependent inhibitor of 
Cytochrome P450 3A4 (CYP3A4) hence there is a risk of 
inhibiting CYP3A4 substrate con-meds resulting in clinically 
relevant DDIs.
Study Design:
GSK3358699 will not be administered with any other drug 
or known CYP3A4 substrate as part of this FTIH protocol. 
Human PK data generated as part of this study will be used 
with in vitro data to inform the DDI risk associated with 
GSK3358699 and future clinical mitigation strategies.


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Summary of Data / Rationale for Risk 
Mitigation Strategy
Low-dose LPS, GM-CSF and cantharidin are established models in healthy volunteer studies and are expected to be well tolerated.  The information on the challenge agents in this 
section is provided in the interest of full disclosure of all potential risks
Intravenous LPS Challenge Agent
Immune response leading to influenza – like 
symptoms.
Previous studies have shown that single intravenous doses 
of 0.5 ng/kg (6 EU/ng) has been well tolerated in healthy 
male participants, however literature reports of 2 ng/kg (10 
EU/ng) and above are very poorly tolerated and elicit 
considerable symptoms.
Observed adverse events were of mild severity and self-
limiting without therapeutic intervention.
LPS will be used at a concentration of 0.75 ng/kg.  A low, 
single dose of LPS is planned which means that systemic 
exposure will be limited.
The participants will be dosed with LPS in a Medicines and 
Healthcare Products Regulatory Agency (MHRA) accredited 
clinical research unit and will have regular monitoring of vital 
signs post dose.
Participants will receive telemetry for a minimum of 12 hours 
post-LPS dose or until their telemetry shows no clinically 
significant findings for 4 hours (whichever is longer).
Participants will be prehydrated with intravenous fluids prior 
to LPS challenge, and intravenous fluid hydration will 
continue following the challenge.  Normal saline will be 
infused at a rate of 250ml/hr for 4 hours prior to LPS dosing 
and 8 hours subsequently.
Participants with previous history of frequent vasovagal 
syncope will be excluded from the study
Participants with previous experimental exposure to IV LPS 
will be excluded.


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Intravenous GM-CSF Challenge Agent
Risk of respiratory, hepatic, renal and 
cardiovascular symptoms in addition to fluid 
retention.
If used at high doses, GM-CSF administration might result 
in increased risk of respiratory, hepatic, renal and 
cardiovascular symptoms in addition to fluid retention; fluid 
retention findings were observed in patients with cancer in 
receipt of chemotherapy.
Observed adverse events were of mild severity and self-
limiting without therapeutic intervention.
GM-CSF will be used at a dose of 60 µg/m2 that has 
previously been safely explored in a GSK sponsored study 
conducted in healthy male participants (207654).  A low, 
single dose of GM-CSF is planned which means that 
systemic exposure will be limited. 
Individuals with prior incidence of respiratory or 
cardiovascular diseases or pre-existing renal or hepatic 
dysfunction will be excluded from the study. In addition, we 
will use telemetry for a minimum of 6 hours following 
dosing, or until normal for 4 hours (whichever is longer).
Use of healthy volunteers is a mitigation for the fluid 
retention finding.  In addition, a lower, single dose of GM-
CSF is planned which means that the AUC and Cmax will be 
lower than in the patients in which this was observed.
Topical Cantharidin Challenge Agent
Irritation, burning or toxicity.
Cantharidin is a corrosive chemical substance which when 
used inappropriately may cause skin irritation, burning or 
toxicity.
Cantharidin has been used clinically to treat warts and 
extensively in a clinical setting in experimental medicine 
studies to chemically induce blisters. 
Cantharidin will be used at a known concentration lower 
than has been safely explored in GSK sponsored studies 
conducted in patients and healthy participants, (ie reduced 
in this study from 0.7% to 0.2 %).
Participants with a history of lymphangitis and/or 
lymphoedema or any participant who has undergone 
surgery resulting in loss of tissue associated with lymphoid 
drainage (e.g. certain breast surgery procedures) are 
excluded.
Participants will be advised to wear loose clothing at the site 
of blistering to minimise hyperaesthesia and discomfort that 
may occur.


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Potential Risk of Clinical Significance
Summary of Data / Rationale for Risk 
Mitigation Strategy
For immediate relief of any discomfort, paracetamol, at 
doses of 2 grams/day will be given to the participant, 
unless, in the opinion of the investigator and sponsor, the 
medication will interfere with the study.
Participants with history of keloids, skin allergy, 
hypersensitivity, or contact dermatitis, including previous 
reactions to dressings to be used in this study or any 
chronic skin disorder (e.g. psoriasis, atopic dermatitis, 
vitiligo) excepting isolated lesions remote from intended site 
of application of cantharidin are excluded. Appropriate skin 
care to avoid dyspigmentation and hypertrophic scar will be 
implemented.
To minimize the risk of infection, appropriate clean 
procedures will be followed.  Participants will be instructed 
to visually inspect blister sites on a daily basis and are 
informed what signs of inflammation/infection to watch for 
and contact the investigator with any concerns.
Cantharidin will not be dispensed to participants and all 
applications will be done at the research centre by suitably 
trained personnel.


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3.3.2.
Benefit Assessment
There will be no direct benefit to the healthy participants in this trial.  However, the 
information obtained from this study will critically inform the conduct of future clinical 
studies to develop new therapies in immuno-inflammation indications in areas of unmet 
medical need. 
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with GSK3358699, LPS, GM-CSF 
and cantharidin at the doses to be administered are considered minimal and are justified.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
[P1] To evaluate the safety and tolerability 
of single and repeat oral doses of 
GSK3358699 in healthy male participants.
AE reporting.
Laboratory safety data (clinical chemistry, 
haematology, urinalysis).
Vital signs (blood pressure, heart rate, body 
temperature).
12 lead ECGs.
Secondary
[S1] To evaluate the systemic 
pharmacokinetic (PK) profile following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.

Plasma concentrations of GSK3358699 plus 
derived PK parameters.
[S2] To evaluate the systemic PK profile of 
the acid metabolite, GSK3206944 following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.
Plasma concentrations of GSK3206944 plus 
derived PK parameters.
[S3] To evaluate the intracellular PK profile 
of GSK3206944 in target cells following 
single and repeat oral doses of 
GSK3358699 in healthy male participants.

Monocyte intracellular quantification of 
GSK3206944.
[S4] To understand the extent of target 
engagement (TE) after ex vivo LPS 
challenge following single and repeat oral 
doses of GSK3358699 in healthy male 
participants.

Plasma concentrations of monocyte 
chemoattractant protein (MCP)-1, interleukin 
(IL)-6 and tumour necrosis factor (TNF) in 
blood stimulated ex vivo with LPS over time.
[S5] To assess the effect of food on the PK 
and PD of GSK3358699 and GSK3206944
following single doses in healthy male 
participants.
Plasma concentrations of GSK3358699 and 
GSK3206944 plus derived PK parameters.
Monocyte intracellular quantification of 
GSK3206944.


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Objectives
Endpoints

Plasma concentrations of MCP-1, IL-6 and 
TNF in blood stimulated ex vivo with LPS 
over time.
Exploratory
[E1] To investigate effects on basal 
production of biomarkers of target 
engagement following single and repeat 
oral doses of GSK3358699 in healthy male 
participants.
Time course of circulating leukocyte numbers 
and circulating proteins; may include but is not 
limited to MCP-1, IL-12p40 and matrix 
metallopeptidase (MMP)-9.  
Gene panel using participant whole blood.
[E2] To investigate effects on inflammatory 
biomarkers after low dose in vivo LPS or 
GM-CSF challenge following single and 
repeat oral doses of GSK3358699 in 
healthy male participants.
Time course of circulating soluble 
inflammatory biomarkers; may include but is 
not limited to IL-1β, IL-6, IL-8, TNF, MCP-1, 
GM-CSF, C-reactive protein (CRP). 
Time course of leukocyte numbers and 
cellular activation markers may include, but 
not limited to expression of cluster of 
differentiation (CD) molecules CD16, CD86, 
CD80, CD163, CD206, CD83, CD40, CD209, 
Human Leukocyte Antigen – antigen D 
Related (HLA-DR) in circulating leukocytes.
Gene panel using participant whole blood.
[E3] To investigate effects on chemotaxis 
and inflammatory mediators in cantharidin-
induced blisters following single and repeat 
oral doses of GSK3358699 in healthy male 
participants.
Soluble inflammatory biomarkers in skin 
blisters; may include but is not limited to IL-
1β, IL-6, IL-8, TNF, MCP-1, GM-CSF. Blister 
volumes and differential cell counts; cellular 
activation markers that may include, but not 
limited to expression of CD16, CD86, CD80, 
CD163, CD206, CD83, CD40, CD209, HLA-
DR in blister leukocytes.
[E4] To collect residual plasma following 
GSK3358699 & GSK3206944 analysis, and 
urine samples, for analysis of metabolites of 
GSK3358699
Metabolites of GSK3358699 in plasma and 
urine.  These analyses will be run and 
reported under a separate protocol.
[E5] To explore the impact of CES genetic 
variation on PK and PD parameters of 
GSK3358699 and GSK3206944.

Genotype results using participant whole 
blood.


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P1: Primary Objective 1 – Safety
S1: Secondary Objective 1 – GSK3358699 systemic PK
S2: Secondary Objective 2 - GSK3206944 systemic PK
S3: Secondary Objective 3 - GSK3206944 intracellular PK
S4: Secondary Objective 4 - TE
S5: Secondary Objective 5 – Effect of food on PK and PD
E1: Exploratory Objective 1 – Effect on basal production of biomarkers of TE
E2: Exploratory Objective 2 – Effects on inflammatory biomarkers after low dose in vivo LPS or GM-CSF challenge
E3: Exploratory Objective 3 – Biomarkers in blisters
E4: Exploratory Objective 4 – PK metabolite analysis
E5: Exploratory Objective 5 – CES genetic variation
5.
STUDY DESIGN
5.1.
Overall Design
This study will be a randomised, double-blind (sponsor open), placebo-controlled, three
part study of oral administration of GSK3358699 in healthy male participants.  Part A 
will be a single ascending dose crossover design in two interlocking cohorts of 
participants (Cohorts 1 and 2). Part B will be a single dose, open-label two-way crossover 
study with GSK3358699 administered under fed and fasted conditions in a further cohort 
of participants (Cohort 3).  Part C is planned to be a repeat dose design in 5 sequential
cohorts of participants (Cohorts 4-8). 
All participants in Part A, Part B and Part C of the study will attend a screening visit 
within 35 days prior to their first dose (with the exception of Cohort 8 where the 
screening visit will be within 45 days prior to their first dose) and a follow up visit within 
7-14 days of their last dose.  A second follow up visit will also be conducted 
approximately 5 weeks after the last dose for those participants in cohorts where 
challenges and blisters are being administered.  If warranted, additional follow-up visits 
may be scheduled. 
5.1.1.
Part A
5.1.1.1.
Part A Single Ascending Doses – Cohort 1 and Cohort 2:
In the Part A dose escalation phase (treatment Periods 1-3), there will be two interlocking 
cohorts (Cohorts 1 and 2) each with 9 healthy participants.  Each participant will receive 
a maximum of 2 single ascending oral doses of GSK3358699 and 1 placebo dose. At 
each dose level, GSK3358699 and placebo will be administered in a 2:1 ratio, within 
each Period, according to the randomisation schedule, in a blinded manner.  Up to a 
maximum of 6 dose levels will be studied in total in Part A as illustrated in Figure 1
below.


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Figure 1
Part A Schematic Planned Single Ascending Doses and LPS / GM-
CSF challenges
Participants who are enrolled in the dose escalation treatment Periods of Part A may 
choose to only take part in the dose escalation treatment Periods 1-3, or may choose to 
also take part in the challenge treatment Period (Period 4) as detailed in Section 5.1.1.2. 
If a participant chooses to participate in the dose escalation treatment Periods 1-3 only, or 
does not (at screening) meet the eligibility criteria specific to challenges (treatment 
Period 4), a new participant will be recruited for treatment Period 4 only and will be 
regarded as a replacement subject.
During each treatment Period, participants in an individual cohort will be admitted to the 
clinical unit on Day -1 and will remain there until completion of all assessments on Day 3
(at approximately 48 hours post-dose).  Participants will then be discharged from the unit.
Staggering of the first two participants (sentinel dosing) will be implemented in each
cohort in each treatment Period for this single dose phase. No participant will be a 
sentinel participant more than once. On Day 1, one of the two participants will receive 
the active dose and the other will receive placebo.  Assuming adequate safety from these 
two participants over approximately 48 hrs post-dose, the remaining participants in the 
cohort can then be dosed from the morning of Day 2.
Data will be reviewed between each treatment Period, and hence dose level, and there 
will be a minimum 14 days between the start of dosing, (ie dosing of sentinel 
participants) in Cohort 1 and Cohort 2 in each treatment Period. The decision to proceed 
to the next dose level of GSK3358699 will be made at a Dose Escalation Committee 
(DEC) meeting based on:

assessment of safety, measurable plasma GSK3358699 PK concentrations and 
derived PK parameters and TE data obtained in a minimum of 6 participants (a 
minimum of 48 hours post-dose) in the most recently dosed group of subjects.  
Individual safety data (AEs, laboratory safety tests, ECGs and vital signs) will be 
reviewed. 


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
evaluation of all available safety, tolerability, PK, and PD data accumulated from 
preceding dose levels.
Safety stopping criteria will be strictly applied, precise details of these criteria can be 
found in Section 8. In addition, specific PK and PD stopping criteria will apply to this 
FTIH study:

Dose escalation will be halted if the mean cohort exposure exceeds or is predicted 
to exceed a GSK3358699 Cmax of 42 ng/ml or a total daily GSK3358699 AUC of 
255 ng/ml.h, which are the predicted exposures of the planned maximum dose of 
45 mg.  

Individuals in each cohort will be monitored throughout the study.  If 2 or more
participants in a given cohort at the same dose level exceed Cmax of 42 ng/ml or 
total daily AUC of 255 ng/ml.h, dose escalation will be halted. 

Based on the PD of GSK3358699, dose escalation will be halted if mean target 
engagement within a cohort, as measured by MCP-1 and TNF inhibition in 
participant blood stimulated ex vivo with LPS, exceeds or is predicted to exceed
the desired profile: maintenance of ≥ 90% MCP-1 and TNF inhibition for a 
minimum of 12 hours post dose relative to baseline.

Additionally, if the PD effect of GSK3358699 appears to have become saturated 
over the course of 2 consecutive dose levels, dose escalation will be halted.
Furthermore, throughout all parts of the study, either a population PK model or the results 
of a non-compartmental analysis will be used to help inform the choice of the next dose 
level as part of dose escalation discussions.  For either approach, it is planned that the 
95th percentile for the predicted total daily AUC values will not exceed 1/3 of the mean 
AUC observed at the cynomolgus monkey NOAEL and the 95th percentile of the 
predicted Cmax will not exceed 1/3 of the mean Cmax observed at the cynomolgus monkey 
NOAEL.
Further details of the DEC remit are provided in Section 12.3 and in the Dose Escalation
Plan (DEP). This plan outlines how the study team will ensure data integrity used in dose 
selection decisions by performing clinical data review and appropriate quality control of 
data prior to making dose selection decisions, as well as outlining the responsibilities of 
the investigators and site staff for reporting safety data, participation during dose 
escalation meetings, and confirmation that the data used for dose escalation are accurate 
and complete.
Further information on dose decisions / modifications is provided in Section 7.2.
5.1.1.2.
Part A LPS or GM-CSF challenge with cantharidin-induced blisters –
Cohort 1 and Cohort 2:
Upon conclusion of the dose escalation phase of Part A, an additional dosing Period
(treatment Period 4) will be included.  Eligible participants in both cohorts will attend the 
clinic for outpatient visits, on Day -10 (3 days) to have control blisters induced on the 


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forearm (0.2% cantharidin), and will have a blister sample taken at approximately 48hrs 
post-blister induction. Participants in Cohort 1 will be administered an IV in vivo LPS 
challenge at a dose of 0.75 ng/kg following treatment with GSK3358699 or placebo and 
will then have blisters induced on the forearm (0.2% cantharidin) approximately 20 
minutes after the challenge.  Similarly, participants in Cohort 2 will be administered 60
g/m2 in vivo GM-CSF challenge as an IV infusion following treatment with 
GSK3358699 or placebo and will then have blisters induced on the forearm (using 0.2% 
cantharidin) approximately 20 minutes after the end of the GM-CSF infusion. Of the nine 
participants within each cohort, six will receive GSK3358699 and three will receive 
placebo in treatment Period 4, as per the randomisation schedule.
The duration of treatment Period 4 from Day -1 onwards and the implementation of 
sentinel dosing will be the same as for each of treatment Periods 1-3.  The dose levels of 
GSK3358699 administered to either cohort in treatment Period 4 will be identical and 
will be decided by the DEC.
The doses of LPS and GM-CSF to be administered to participants have been defined as 
part of a clinical enabling study [GlaxoSmithKline Document Number 2016N309726_01
Study ID 207654] and will be administered at the GSK3358699 systemic Cmax defined 
from data gathered in treatment Periods 1-3.  The dose levels of GSK3358699 
administered to either cohort in treatment Period 4 will be identical. This will be a single 
dose of GSK3358699 that is within the range investigated in treatment Periods 1-3 of Part 
A and the decision on the dose level will be made by the DEC based on all available 
safety, tolerability, PK and PD data from treatment Periods 1-3.
The in vivo challenges included in treatment Period 4 will act as a pre-determinant to 
their inclusion in Part C.  That is, if GSK3358699 treatment does not robustly inhibit 
production of inflammatory mediators and leukocyte activation following either low dose 
in vivo LPS or GM-CSF challenges and blisters in Part A, the same challenge will not be 
investigated in Part C.  Inclusion of challenges in Part C will be decided once all the data 
has been generated from treatment Period 4 in Part A, and the criteria will be specific for 
each challenge.  Inclusion of the challenges in Part C will be based on inhibition of 
multiple inflammatory biomarkers which may include, but are not limited to, TNF, IL-6, 
MCP-1 and CRP for the LPS challenge, leukocyte activation markers, thymus and 
activation regulated chemokine (TARC) and Macrophage-Derived Chemokine (MDC)
for the GM-CSF challenge, and leukocyte counts, interferon gamma-induced protein-10 
(IP-10), MMP-9, transforming growth factor (TGF)-β and leukocyte activation markers 
for the cantharidin-induced blisters.  
5.1.1.3.
Part A Dose Escalation / Challenge Total Duration:
There will be a minimum of 14 days between each dosing in Cohort 1 and Cohort 2 to 
ensure that appropriate dose decisions can be made during the dose escalation phase.  
This results in a minimum 28 day washout Period between dosing in each treatment
Period for a particular cohort (including between treatment Periods 3 and 4).
The total duration of this part of the study for each participant, including screening and 
follow-up, is approximately 19 weeks for participants taking part in all three dose 
escalation treatment Periods and 23 weeks if a participant takes part in all four treatment 


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Periods. For replacement participants only taking part in the challenge treatment Period 
(treatment Period 4), approximate study duration is 10 weeks.
5.1.2.
Part B Food Effect - Cohort 3
In Part B there will be one cohort of 6 participants (Cohort 3), taking part in a two-way 
crossover study as per the schematic in Figure 2.  Each participant will receive a single 
oral dose of GSK3358699 under fed conditions in one of the two treatment Periods and 
under fasted conditions in the other treatment Period, according to the randomisation
schedule. 
Part B will only be conducted after completion of the dose escalation phase of Part A and 
may be conducted in parallel with Part C.
Figure 2
Part B Food Effect - Cohort 3
The dose level chosen for Part B will be a dose level within the range already evaluated 
in the dose escalation part of the study (Part A) and one in which, based on in silico
modelling, the maximum exposure is estimated to not exceed the maximum threshold 
allowed in this protocol (see Section 7.2). following either fed or fasted administration.
The decision on the dose level of GSK3358699 to be administered in Part B will be made 
by the DEC.
During each treatment Period participants will be admitted to the clinical unit on Day -1 
and will remain there until completion of all assessments on Day 3 (at approximately 48 
hours post-dose).  Participants will then be discharged from the unit.
There will be a minimum of 14 days between each dose.
The total duration of this part of the study for each participant, including screening and 
follow-up, is approximately 9 weeks.
5.1.3.
Part C
Part C of this study intends to investigate doses of GSK3358699 which deliver a robust 
pharmacodynamic response with adequate safety/tolerability and does not intend to dose 
escalate beyond the PK and PD stopping criteria detailed in Section 8.


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Figure 3
Part C Schematic
5.1.3.1.
Part C Multiple Ascending Doses Cohort 4
Cohort 4 of the study is comprised of 14 participants, taking part in one repeat dose 
treatment Period as illustrated in Figure 3, and randomised in a 5:2 ratio to receive either 
GSK3358699 or placebo, according to the randomisation schedule, once daily from Day 
1 to Day 14 (note that Cohort 4 was started but not completed due to the temporary halt).  
See Section 5.1.3.3. for study design.
5.1.3.2.
Part C Multiple Ascending Doses Cohorts 5, 6 and 7
In the multiple ascending dose phase of Part C there are 3 cohorts planned (Cohorts 5-7), 
each with 18 healthy male participants.  Each cohort will take part in one repeat dose 
treatment Period as illustrated in Figure 3. The participants will be randomised in a 1:1 
ratio to receive either GSK3358699 or placebo, according to the randomisation schedule, 
once daily from Day 1 to Day 14 inclusive.
All participants will be admitted to the clinical unit on the day prior to dosing (Day -1) 
and will remain in the Unit until after the 48 hour assessments following the Day 14 
GSK3358699 / placebo dose administration have been completed (Day 16). Participants 
will then be discharged from the unit.
Staggering of the first two participants (sentinel dosing) will be implemented for each 
cohort where a new GSK3358699 dose regimen is being tested. On Day 1, one of the two 
participants will receive the active dose and the other will receive placebo.  Assuming 
adequate safety from these two participants after the first 48 hours of dosing, the 


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remaining participants in the cohort can then be dosed.  If a sentinel subject withdraws 
after the first 48 hours, the remainder of the cohort can still be dosed.
The decision on the dose level of GSK3358699 to be administered in Cohort 5 will be 
made at a DEC meeting based on all available safety, tolerability, PK, PD and TE data 
accumulated from Part A of the study, Part C Cohort 4, and the dose modification / 
stopping criteria detailed in Section 7.2 and Section 8.
The decision on the dose level of GSK3358699 for the next repeat dose cohort (Cohort 6 
onwards) will be made at a DEC meeting following completion of a minimum 14 days 
dosing in no fewer than 12 participants in the current repeat dose cohort and will be based 
on:

assessment of all available safety, tolerability, PK, PD and TE data accumulated 
from Part A of the study. 

assessment of safety, plasma GSK3358699 PK concentrations and TE data 
obtained in a minimum of 12 participants in the most recently dosed group of 
subjects.  Individual safety data (AEs, laboratory safety tests, ECGs and vital 
signs) will be reviewed. 

evaluation of all available safety, tolerability, PK, PD and TE data accumulated 
from the previous repeat dose cohorts.  
As part of this decision making process, the DEC may decide to escalate or de-escalate 
the dose. Safety, PK and PD stopping criteria will be strictly applied as in Part A of the 
study.  Details of these criteria can be found in Section 8.
Further information on dose decisions / modifications is provided in Section 7.2.
The total duration of the multiple ascending dose phase of Part C, including screening 
and follow-up, is approximately 10 weeks for each participant in Cohorts 5 - 7.
5.1.3.3.
Part C Repeat Dosing Followed by LPS or GM-CSF Challenge with 
Cantharidin-Induced Blisters Cohort 4 and 8
Upon conclusion of the multiple ascending dose phase of Part C (Cohorts 5 – 7), an 
additional Cohort (Cohort 8) is planned to be included (Figure 3).  This cohort will be 
comprised of 20 participants, taking part in one repeat dose treatment period.
Participants will be randomised in a 1:1 ratio to receive GSK3358699 or placebo once 
daily for up to 14 days. The actual duration of dosing will be decided by the DEC and 
will not exceed 14 consecutive days.  
Participants will attend the clinic for outpatient visits, on Day -10 (3 days), to have 
control blisters induced on the forearm (0.2% cantharidin) and will have a blister sample 
taken at a timepoint at approximately 48 hours post-blister induction.


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On the final day of dosing, an IV in vivo LPS challenge at a dose of 0.75 ng/kg or a 60 
g/m2 GM-CSF challenge as an IV infusion will be administered as per the timepoints 
detailed in the SoA (Section 2.4.1), followed by blister induction (as described in Section 
5.1.1.2 Part A, treatment Period 4).
Half the participants will be randomised to receive the LPS challenge and half will 
receive the GM-CSF challenge.  In Cohort 4, of the 7 participants receiving each 
challenge, 5 will be randomised to receive GSK3358699 and 2 to receive placebo at the 
start of the cohort. In Cohort 8, of the 10 participants receiving each challenge, it is 
planned that 5 will be randomised to receive GSK3358699 and 5 to receive placebo.
The randomisation ratio of active to placebo for Cohort 8 and any subsequent additional 
cohorts may be altered by the DEC based on all available safety, PK and PD data 
following the conclusion of Cohort 7.
Data from Part A of this study and from Cohorts 4 - 7 in Part C will be used to confirm 
the decision for inclusion of the challenges in Part C Cohort 8. The decision will be made 
by the DEC.
All participants will be admitted to the clinical unit on the day prior to dosing (Day -1) 
and will remain in the Unit until after the 48 hour assessments following the final day of 
GSK3358699 / placebo dosing and challenge administration have been completed.
Participants will then be discharged from the unit.
Staggering of the first two participants (sentinel dosing) will be implemented. On Day 1, 
one of the two participants will receive the active dose and the other will receive placebo.  
Assuming adequate safety from these two participants after the first 48 hours of dosing, 
the remaining participants in the cohort can then be dosed.  If a sentinel subject 
withdraws after the first 48 hours, the remainder of the cohort can still be dosed and the 
challenges administered. The staggering of the participants will be such that the post-
challenge safety data from previous participants can be reviewed prior to further 
participants receiving challenges. The decision to administer a challenge to a participant 
will be based on that individual’s safety profile as well as continuous review of 
safety/tolerability of the challenges. 
The decision on the dose level of GSK3358699 to be administered in Cohort 4 will be 
made at a DEC meeting based on all available safety, tolerability, PK, PD and TE data 
accumulated from Part A of the study and the dose modification / stopping criteria 
detailed in Section 7.2 and Section 8.
The decision on the dose level of GSK3358699 to be administered in Cohort 8 will be 
made at a DEC meeting based on all available safety, tolerability, PK, PD and TE data 
accumulated from Part A of the study, the previous Part C cohorts, and the dose 
modification / stopping criteria detailed in Section 7.2 and Section 8.
As part of this decision making process, the DEC may decide to escalate or de-escalate 
the dose. Safety, PK and PD stopping criteria will be strictly applied as in Part A of the 
study.  Details of these criteria can be found in Section 8.


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Further information on dose decisions / modifications is provided in Section 7.2.  This 
includes any potential changes to the randomisation and administration and timing of 
challenge agents, as well as any changes related to the dose levels or dosing regimen of 
GSK3358699. 
The total duration of Part C of the study, including screening and follow-up, is 
approximately 12 weeks for participants in Cohort 4 and approximately 14 weeks for 
participants in Cohort 8.  
5.2.
Number of Participants
The number of healthy male participants and the required number of evaluable 
participants are outlined in Table 1.
Table 1
Number of Participants
Part
Participants per cohort
Evaluable 
participant 
number
per cohort
Evaluable participant 
definition
A
(Cohorts 1-2)
9 (6:3 GSK3358699 : Placebo)
6
Complete both 
screening and all their 
planned treatment 
Periods.
B
(Cohort 3)
6 (all receive GSK3358699)
5
Complete both 
screening and both 
treatment Periods.
C
(Cohort 4)
14 (10:4 GSK3358699 : 
Placebo)
9
Complete both 
screening and the 14 
day treatment Period 
and subsequent 48 h 
assessment Period.
C (Cohorts 
5-7)
18 (9:9 GSK3358699 : Placebo)
12
Complete both 
screening and the 14 
day treatment Period 
and subsequent 48 h 
assessment Period
C
(Cohort 8)
20 (10:10 GSK3358699 : 
Placebo)
14
Complete both 
screening and the 14 
day treatment Period 
and subsequent 48 h 
assessment Period.


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Participants who are randomized into a particular part of the study can be enrolled in 
another part of the study, as well as be enrolled in a later cohort of the same part of the 
study in Part C, if they still fulfil all eligibility criteria (which means that participants 
having received LPS challenge in Part A will not be eligible to participate in another part 
of the study).  
Additional participants/cohorts may be enrolled in Part A or Part C to allow for 
evaluation of additional dose levels or alternative regimens, including for challenges, as 
detailed in Section 7.2. No more than 9 additional participants will be included as part of 
a new cohort in Part A and no more than 20 additional participants will be allowed as part 
of a new cohort in Part C (ie in addition to Cohort 4-8 participants).
If participants prematurely discontinue the study during Part A, additional replacement 
participants may be recruited and assigned to the same treatment sequence, starting from 
the next planned dosing Period following the premature discontinuation, at the discretion 
of the Sponsor in consultation with the investigator.
If a participant chooses to participate in, or is eligible for, the dose escalation treatment 
Periods only in Part A as described in Section 5.1.1.1, a new participant will be recruited 
for the challenge treatment period (treatment Period 4) only and will be regarded as a 
replacement subject, assigned to the same treatment sequence. This will occur at the 
discretion of the Sponsor in consultation with the investigator.  
If participants prematurely discontinue the study during Part B, additional replacement 
participants may be recruited and assigned to the same treatment sequence, starting from 
the beginning of the first treatment Period, at the discretion of the Sponsor in consultation 
with the investigator.
If participants prematurely discontinue the study during Part C, additional replacement 
participants may be recruited and assigned to the same treatment sequence, starting at the 
beginning of the treatment Period, at the discretion of the Sponsor in consultation with 
the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he has completed all study 
visits, including the follow up visits, for which he was eligible or to which he consented.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study will be the first administration of GSK3358699 in human participants. The 
primary purpose of the current study is to characterise the safety and tolerability of 
GSK3358699 in healthy male participants within a pre-defined and controlled PK and PD 
range.  The study will additionally seek to understand the secondary and exploratory 
endpoints highlighted in Section 4.  Specific scientific considerations which contribute to 
the study design include:


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
In Part A, this study employs an interlocking crossover design to allow more 
accurate extrapolation of PK and PD data within participants at different dose 
levels.  In addition, this design minimises participant numbers across the single 
ascending dose (SAD) part of the study and allows for a minimum 28 day 
washout Period between doses for a particular cohort. To maximise the safety, PK 
and PD ‘within-participant’ information gathered during the dose escalation 
period, which will adequately inform dosing in treatment Period 4 and in Parts B 
and C of the study, the flexibility of participation in Part A has been enhanced to 
facilitate subject recruitment and retention.  

In Part B, the effect of food will be investigated.  An early understanding of any 
effect of food on exposure or PD will improve dose selection in future clinical 
studies with GSK3358699. Data from Part B is not intended to inform the 
conduct of Part C of the present study.

In Part C, it is planned that five repeat dose cohorts will be administered multiple 
doses of GSK3358699 or placebo.  As part of this, investigations into the dose 
response will be made.

According to a Physiologically Based Pharmacokinetic (PBPK) model established 
pre-clinically, GSK3358699 is predicted to have a short systemic half-life of 
approximately 3 hours.  However, the intracellular pharmacokinetics of 
GSK3206944 are less readily predicted.  The study will therefore include 
intracellular quantification of GSK3206944 in all three parts.
To further investigate the potential use of GSK3358699 in immuno-inflammatory 
diseases, in vivo inflammatory challenges (blisters, LPS and GM-CSF) will be 
administered in both Part A (treatment Period 4 only) and Part C (Cohorts 4 and 8) of the 
study, should data support this. GSK3358699 modulates multiple pro-inflammatory 
pathways in vitro [GlaxoSmithKline Document Number 2017N333959_00], and
therefore has potential utility across a broad range of diseases.  With this in mind,
cantharidin-induced blisters, LPS and GM-CSF challenges have been specifically 
selected as inflammatory challenges that are representative of the immune response 
encountered across a range of inflammatory conditions including fibrosis and RA.
Inclusion of these challenges will illuminate which of these disease-relevant mechanisms 
GSK3358699 modulates most efficiently in an in vivo setting.
In Part A, these challenges will be administered at GSK3358699 Cmax. In Part C the 
challenges may be administered at a time-point of low systemic GSK3358699 
concentration, but high intracellular GSK3206944 concentrations.  Taken together, this 
data may inform on systemic versus intracellular compound exposure as a key driver of 
PD response following pro-inflammatory in vivo challenges.  A summary and rationale 
for the challenges to be used as part of this study is below:

Ex vivo LPS challenge – GSK3358699 has shown concentration dependent 
inhibition of cytokine production in LPS stimulated blood in vitro.  Ex vivo LPS 
challenge of blood from participants dosed with GSK3358699 is a minimally 
invasive high throughput method through which to investigate target engagement.


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
In vivo LPS challenge - Human in vivo LPS challenges have been used as a 
methodology to induce systemic inflammation and produce many of the 
immunological (changes in leukocyte numbers and induction of inflammatory 
mediators and cellular activation markers) and physical signs of acute and chronic 
disease.  The human LPS model of systemic inflammation has been applied to 
clinical pharmacology studies to assess therapeutic interventions for analgesics, 
asthma, effective adjuvants, sepsis, trauma, Type-2 diabetes, Alzheimer’s disease 
and others [Fullerton et al 2016].  This study will investigate the effect of 
GSK3358699 on LPS-induced inflammation as measured by the phenotype of 
peripheral leukocytes and the production of inflammatory mediators and acute 
phase proteins over time.  

In vivo GM-CSF challenge - GM-CSF has a broad range of activities across innate 
and adaptive immune cells and is recognised as a key mediator in a number of 
inflammatory diseases, such as arthritis, multiple sclerosis, colitis, pain and 
interstitial lung disease [Wicks et al 2016].  Leukine (Sargramostim) given 
intravenously results in a systemic GM-CSF challenge that mobilises neutrophils, 
eosinophils and monocytes from the bone marrow.  A GM-CSF dose of 5 μg/kg
(equivalent to intravenous infusion of 60 µg/m2), administered subcutaneously, is 
associated with a measurable leukocyte response but is well tolerated based on the 
literature [Gianni et al 1990, Lieschke et al 1989]. 1.5μg/kg dose infused 
intravenously over 2 hours provides the same exposure (AUC) due to the 
increased bioavailability and higher Cmax concentrations (Cebon et al 1990). This 
study will investigate the effect of GSK3358699 on GM-CSF induced 
inflammation as measured by leukocyte numbers, soluble inflammatory 
mediators, as well as cellular activation markers on leukocytes, particularly 
monocytes, over a defined time course.  

Chemically induced skin blisters - Cantharidin is a vesicant (an agent that causes 
blisters) and a strong inhibitor of protein phosphatases type 1 and 2A [Honkanen
et al 1993], used clinically for the treatment of warts and molluscum contagiosum.  
Following contact with the skin, it is absorbed into the epidermis and activates 
proteases leading to intra-epidermal blistering [Bertaux et al 1988].  Blistering is 
limited to the suprabasal epidermis and lesions heal without scarring.  Skin blister 
induction by cantharidin has been utilised in clinical pharmacology for more than 
50 years as a model of acute inflammation, and provides methodology to 
investigate leukocyte trafficking, cellular activation states and detection of 
plethora of inflammatory mediators, including pro-fibrotic mediators, in the 
blister fluid.  The combination of blisters with systemic inflammation (induced by 
LPS or GM-CSF) provides a unique methodology to detect the effects of systemic 
inflammation on local inflammation.  This study will investigate the effect of 
GSK3358699 on cantharidin induced blisters in the presence of systemic 
inflammation, as measured by leukocyte numbers, cellular activation markers and 
soluble inflammatory mediators associated with autoimmune and fibrotic 
diseases.  
This study will be conducted in healthy male participants for the following reasons:


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Patients with immuno-inflammatory diseases may have existing co-morbidities or 
be taking medications that may confound the interpretation of data for
GSK3358699.
It is yet to be determined whether patients would derive benefit from a short 
duration of dosing of GSK3358699; however, taking part in this study may stop 
them receiving other required treatments.
Females are excluded from this study as the potential benefits do not outweigh the 
risks, particularly to women of child bearing potential and additionally, the use of 
challenge agents is not as well characterised in females.
The pre-clinical testicular toxicology findings show that there is a sufficient safety 
margin to allow the inclusion of males, including males of reproductive potential, 
in this study.
This study includes a placebo component to allow for a valid evaluation of AEs
attributable to treatment versus those independent of treatment and to serve as valid 
controls for the PD assessments.
5.5.
Dose Justification
This study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics 
of single (in the fed (Part B) and fasted state, Part A and B) and multiple (Part C) doses of 
GSK3358699 in healthy volunteers. Target engagement will be determined by the extent 
of MCP-1 inhibition following ex vivo LPS stimulation of participant blood.  This PD end 
point will form a central parameter to be considered along with PK, safety and 
tolerability during dose escalation decisions.  Additional endpoints such as TNF and IL-6 
inhibition will also be considered.
5.5.1.
Part A
The planned doses of GSK3358699 for Part A are shown in Table 2 and have been 
selected on the basis of the TE expected at the correspondent model predicted human PK 
exposures.
A dose of 1 mg resulting in a maximum MCP-1 target engagement below 10% has been 
selected as the starting dose.  This dose is below the minimum anticipated biological 
effect level (MABEL) for GSK3358699, which is considered to be 3 mg QD, based on 
anticipated levels of target engagement at that dose. Human PK/PD predictions together 
with a description of PD assays are described further below.  The 1 mg dose is below the 
maximal recommended starting dose based on Food and Drug Administration (FDA)
Guidance for Industry Estimating Maximum Safe Starting Dose in Initial Clinical Trial 
for Therapeutics in Adult Healthy Volunteers [U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), 2005].  Using the multiplication method, this includes a safety factor of greater 
than 200-fold based on the cynomolgus monkey NOAEL (10 mg/kg) which equates to a
Human Equivalent Dose (HED) of 227 mg for a 70 kg human.


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Table 2
Planned GSK3358699 doses
Planned 
dose
(mg)
Max TE
(%)
Cmax
(ng/ml)
AUC
(ng/ml h)
Monkey Gender-averaged 
NOAEL fold cover
Rat Gender-averaged 
NOAEL fold cover
Cmax
AUC
Cmax
AUC
1
9
1
6
612
275
1473
316
3
32
3
17
205
92
493
105
10
72
9
57
61
28
148
32
20
87
19
113
31
14
74
16
35
94
32
199
18
8
42
9
45
95
42
255
14
6
33
7
The current knowledge of pan-BET inhibitors suggests that a short duration, high level of 
target engagement is associated with a clinical reduction in inflammatory biomarkers.
Based on this, PK/PD modelling, where the PK was described by a compartment model 
and the PK/PD relationship by a maximum effect possible (Emax) model, suggests
efficacy could be achieved at 35 to 45 mg QD, a dose giving 90% target engagement for 
4 h. 
The dose of GM-CSF to be administered to participants in treatment Period 4 of Part A 
will be 60 g/m2.  The dose of LPS to be administered to participants in treatment Period 
4 of Part A will be 0.75 ng/kg.  The dose of cantharidin will be a standard dose as 
detailed in Section 7.1, and used in the enabling study 207654 [GlaxoSmithKline 
Document Number 2016N309726_01].  This dose represents a substantial reduction in 
exposure compared to that recommended for therapeutic use; it is the dose that will be 
used for all blister induction in this study.
A solution formulation will be used for doses of < 10 mg GSK3358699, and a capsule 
formulation for higher doses.  Currently, there is no indication as to the taste or 
palatability of GSK3358699 administered as a solution.  For this reason, participants 
receiving GSK3358699 or placebo as a solution in water (in any part of this study) may 
also need to consume a flavoured sweet (for example a hard boiled sweet) prior to or 
immediately following dosing, provided this does not interfere with ongoing monitoring 
or study procedures. The need for ongoing taste masking will be determined by the DEC.
5.5.2.
Part B
The dose level of GSK3358699 selected to be administered with or without a high fat 
meal in Part B will have been previously investigated in Part A of the study and will have 
demonstrated adequate exposure, safety and tolerability to support its inclusion in the 
food effect investigation.  The dose of GSK3358699 administered will be decided by the 
dose escalation committee.
5.5.3.
Part C
Five dosing cohorts are planned for Part C.  Once-daily dosing (QD) of GSK3358699 is 
planned for 14 consecutive days in Cohorts 4 – 7 and for up to 14 consecutive days in 
Cohort 8. The selection of appropriate doses will be performed upon consideration of 


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available safety and tolerability, PK and PD data from Part A and/or any preceding repeat 
dose cohorts in Part C.
The dose of GM-CSF to be administered to participants in Part C will be 60 g/m2. The 
dose of LPS to be administered to participants in Part C will be 0.75 ng/kg. 
Administration of the challenge agents will be on Day 14 in Cohort 4 and is planned to be 
on the final day of dosing in Cohort 8; the time point will be based on an estimate of the 
intracellular acid kinetics determined in the preceeding cohorts of the study and will be 
no more than 24 h after dosing with GSK3358699 or placebo on that day.
Based on emerging data, the DEC may decide to modify the dosing frequency to less than 
once daily or more than once daily, as well as make other modifications as detailed in 
Section 7.2.
5.5.4.
Human PK and PK/PD predictions
The PK of GSK3358699 in humans has been predicted by PBPK modelling using 
software Gastroplus. The human PBPK model was based on scaling of the monkey 
parameters, hepatic and renal clearance, except for the human acid metabolite
(GSK3206944) liver clearance which was based on scaling of the dog in vivo liver 
clearance. Based on this model a compartment model was built for selecting doses and 
predicting exposures (see Section 5.5.1).
LPS-induced MCP-1 inhibition is considered a robust measurement of BET protein target 
engagement. Human predicted MCP-1 inhibition levels (Figure 5) were based on results 
from in vitro human whole blood assay (LPS stimulated) data which provided an 
estimated pIC50 of 8.13, which translates to a plasma IC50 of 4.8 ng/ml and a plasma IC90
of 22.9 ng/ml (Hill slope=1.4).
As shown in Figure 4, Figure 5 and Table 2, the doses of GSK3358699 to be explored as 
part of the FTIH study have been carefully modelled to ensure a controlled dose 
escalation, such that the Brd4 BD1 IC50 (25 ng/ml) is only exceeded at small multiples 
and only at the highest doses proposed.  Brd4 BD1 is one of the two bromodomains 
present in the Brd4 protein and is used here as a comparative indicator of systemic 
bromodomain inhibition.  Non-targeted bromodomain inhibitors have classically relied 
on sustained systemic concentrations over and above the Brd4 BD1 IC90 to drive anti-
inflammatory and anti-proliferative effects.  Given the targeted nature of GSK3358699 
and in contrast to prior clinical investigations with panBET inhibitors, GSK3358699 
Brd4 BD1 IC90 (128 ng/ml) will not be exceeded systemically at any dose planned.
Importantly, the potency advantage derived from the ESM ensures that even at these 
comparatively low levels of systemic BET inhibition, MCP-1 inhibition is expected to be 
essentially complete at doses greater than 20 mg GSK3358699 QD (Figure 5 and Table 
2).  Based on this modelling, the current anticipated GSK3358699 dose levels are 
considered appropriate to the objectives of this FTIH investigation.


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Figure 4
GSK3358699 Predicted Human PK Profile


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Figure 5
Human predicted MCP-1 inhibition levels (ex vivo LPS stimulation)
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant age range:
a.
Part A (Cohort 1 and 2, no LPS or GM-CSF administration, ie if choosing 
not to take part in Treatment Period 4); participants enrolled into the study 
must be 18 to 65 years of age inclusive at the time of signing the informed 
consent form.
b. Part A (Cohort 1 and 2, LPS or GM-CSF administration); participants 
enrolled into the study, must be 18 to 55 years of age inclusive, at the time of 
signing the informed consent.


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c.
Part B (Cohort 3, no LPS or GM-CSF administration); participants enrolled 
into the study must be 18 to 65 years of age inclusive, at the time of signing 
the informed consent.
d. Part C (Cohorts 5 to 7, no LPS or GM-CSF administration); participants 
enrolled into the study must be 18 to 65 years of age inclusive at the time of 
signing the informed consent form.
e.
Part C (Cohort 8, LPS or GM-CSF administration) - Participants enrolled 
into the study must be 18 to 55 years of age inclusive at the time of signing 
the informed consent form.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring. 
Weight
3.
Body weight 50 kg and body mass index (BMI) within the range 18.5-35.0 kg/m2
(inclusive).
Sex
4.
Male
a. Male participants:
Where relevant (see Section 12.5) male participants must agree to use contraception 
as detailed in Section 12.5 during the treatment Period and for at least 91 days, after 
the last dose of study treatment and refrain from donating sperm during this Period.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF).
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Current or chronic history of:
pancreatitis.
diabetes mellitus or impaired glucose tolerance.
gastrointestinal disease.
liver disease, or known hepatic or biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones).


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anaphylaxis, and /or anaphylactoid (resembling anaphylaxis) reactions [Sampson
et al 2006].
renal disease where clinically significant (minor abnormalities may be permitted 
base on discussion between investigator and medical monitor).
respiratory disease or conditions including but not limited to asthma, chronic 
obstructive pulmonary disease (COPD), and bronchiectasis and any current 
respiratory infection (childhood asthma is not an exclusion criterion).
sensitivity or severe allergic responses to any of the challenge agents or 
cantharidin, or components thereof or a history of drug or other allergy that, in the 
opinion of the Investigator or GSK Medical Monitor, contraindicates their 
participation.
frequent vasovagal syncope.
surgery requiring general anaesthetic or significant trauma in 3 months leading to 
study enrolment.
relevant skin conditions (e.g. recent history of eczema or recurrent eczema,
keloid, skin allergies, psoriasis, atopic dermatitis, and vitiligo) which in the 
opinion of the investigator could pose safety issues or cause interference with 
study procedures. 
sepsis.
coagulation disorders.
peripheral oedema, lymphangitis, lymphoedema, pleural or pericardial effusion.
haemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder.
2.
History of malignancies e.g. recurrent basal cell carcinoma, haematological 
malignancy.
3. For participants receiving cantharadin: Presence on either forearm of tattoos, naevi, 
hypertrophic scars, keloids, hyper– or hypo- pigmentation that may, in the opinion of 
the Investigator, interfere with study assessments. Participants with excessive hair or 
any skin abnormalities that may, in the opinion of the Investigator, interfere with 
study assessments.  
4.
History of cardiac disease e.g. congenital heart disease, valvular heart disease, 
ischemic heart disease, clinically significant atrial or ventricular arrhythmias, QTc 
prolongation, or cardiac arrest.
5.
Family history of premature cardiovascular disease, long QT syndrome or sudden 
death.
6. QTcF > 450 msec, based on averaged QTcF values of triplicate ECGs obtained over a 
brief recording Period. 
NOTES:

The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF) machine-read or manually over-read.


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
For purposes of data analysis QTcF will be used as specified in the Reporting 
and Analysis Plan (RAP).
7.
Any clinically relevant abnormality on the screening ECG.
8.
Non-sustained ventricular tachycardia (NSVT) – defined as ventricular triplet or 
longer), or more than 30 Ventricular Premature Depolarisation (VPD)/hour on 
screening Holter.
9.
Has any condition that, in the opinion of the investigator, would make participation 
not be in the best interest (eg, compromise the well-being) of the subject or that 
could prevent, limit, or confound the protocol-specified assessments.
Prior/Concomitant Therapy
10. Unable or unwilling to refrain 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 potential enzyme inducer) or 5 half-lives (whichever is longer) before 
the start of study treatment until completion of the follow-up visit.  Paracetamol, at 
doses of 2 grams/day, is permitted for use any time during the study except as 
detailed in Section 7.7.  Other concomitant medication may be considered on a case-
by-case basis by the investigator in consultation with the Medical Monitor.
Prior/Concurrent Clinical Study Experience
11. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer) or currently in a study of an 
investigational device.
12. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
13. Previous exposure to intravenous LPS in a clinical research setting.
Diagnostic assessments at screening
14. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN). 
15. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
17. A positive pre-study drug/alcohol screen. 
18. A positive test for human immunodeficiency virus (HIV) antibody.
19. Persistent clinically significant abnormal CRP levels at screening.
20. Persistent clinically significant abnormal white cell count (WCC) levels at screening 
(if clinically significant abnormality is detected, WCC can be retested as clinically 
indicated).


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21. Platelets < 150 x 109/L.
22. Fasted Triglycerides >3.4 mmol/L.
23. Fasted Total cholesterol >7.7 mmol/L.
24. Fasted glucose ≥7.0 mmol/L
25. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months prior to screening.
Other Exclusions
26. History of regular alcohol consumption within 6 months of the study defined as: 

an average weekly intake of >14 units.  One unit is equivalent to 8 g of alcohol: 
a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of 
spirits. 
27. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period.
28. Unable to comply with precautions to minimise phototoxicity risk.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

In Part A dose escalation and challenge treatment Periods, participants will fast from 
approximately midnight on the day prior to GSK3358699 / placebo dosing and will
remain fasted until 4 hours post-dose (with the exception of the flavoured sweet used 
to mask the taste of the GSK3358699 solution formulation).  Water will be allowed 
as desired except for one hour before and one hour after study treatment 
administration (with the exception of the water administered with the study 
treatment). At all other times whilst participants are in the unit they will receive 
standardised meals scheduled at the same time in each treatment Period of the study.  
After breakfast on Day 2 the timing of the meals is at the unit’s discretion.

In Part B when participants are administered GSK3358699 under fasted conditions, 
they will follow the same fasting requirements as those described for Part A of the 
study.  When the participants are administered GSK3358699 with food, they will fast 
from approximately midnight on the day prior to dosing and will receive the standard 
FDA high fat, high calorie meal 30 minutes prior to GSK3358699 dosing.  
Participants will eat this meal in 30 minutes or less.  Dose administration will occur 
approximately 30 minutes after the start of meal consumption.  Participants will not 
receive any further food until 4 hours post-dose. Water will be allowed as desired 
except for one hour before and after study treatment administration (with the 
exception of the water administered with the study treatment).  At all other times 
whilst participants are in the unit they will receive standardised meals scheduled at 
the same time in each treatment Period of the study.  After breakfast on Day 2 the 
timing of the meals is at the unit’s discretion.

In Part C, on Days 2-13, participants will fast from midnight prior to each 
GSK3358699 / placebo dosing and will remain fasted until 2 hours post-dose (with 


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the exception of the flavoured sweet used to mask the taste of the GSK3358699 
solution formulation). On Day 1 and Day 14 (ie the days on which full PK profiling 
is conducted) participants will fast from approximately midnight on the day prior to 
GSK3358699 / placebo dosing and will remain fasted until 4 hours post-dose. Water 
will be allowed as desired except for one hour before and after study treatment 
administration on each dosing day (with the exception of the water administered with 
the study treatment). At all other times whilst participants are in the unit they will 
receive standardised meals.  The timing of the meals is at the unit’s discretion.

Participants will refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, from 7 days before the start of study treatment until after the final 
dose.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final sample in each 
treatment Period.

During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final sample in each treatment
Period. 

Only non-smokers are allowed to participate in this study, therefore use of tobacco 
products will not be allowed during the study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, walking, watching television, reading).  

Those participants who have blisters induced in Part A or Part C should avoid:

Strenuous exercise to the upper limbs whilst blister is present.

Getting the blister dressing wet during bathing.

Topical application of any creams to the forearms during the treatment Period 
where blisters are induced, from 24 hours prior to the start of the treatment
Period until the blisters have healed.

From 24 hours prior to each dose of study treatment and until discharge at the end of 
each treatment Period, participants will wear suitable clothing to minimise exposed 
areas of skin and will use a broad spectrum UVA/UVB sunscreen and lip balm (SPF 
≥ 30) on exposed areas when outdoors (note exception for blister treatment Period). 
In addition, participants should wear sunglasses that filter UVA and UVB rays.  

Participants must not sunbathe or use sun-beds from 24 hours prior to each dose of 
study treatment and until discharge at the end of each treatment Period. 


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6.4.
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, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened.  Participants can be re-screened only on approval of the GSK Medical 
Monitor and only once. Re-screening is allowed when a participant failed 
inclusion/exclusion criteria or some other screening condition initially, but the 
Investigator believes there is a reasonable probability that the participant would be 
eligible if re-screened. In the event of out-of-range results of safety tests, the tests may be 
repeated once within the screening window without this being considered a rescreen.  If a 
retest result is again outside the reference range and considered clinically significant by 
the investigator and GSK medical monitor, the participant will be considered a screen 
failure.  
Individuals who meet the eligibility criteria and are reserve participants who are 
subsequently not required for that cohort may also be rescreened for later cohorts.
If a subject is re-screened within the same cohort then they will retain the same subject 
number. If a subject is re-screened for a new cohort then they will be assigned a subject 
number within the numbering range for that cohort. All previously collected data will be 
automatically updated with the new number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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7.1.
Treatments Administered
Table 3
Investigational Product and Placebo to match
Study 
Treatment 
name
GSK3358699
Placebo
Formulation 
description
Solution of API in 
water for injection
(0.2 mg/mL)
API filled capsule
Water for injection
Microcrystalline 
Cellulose filled capsule
Dosage form
Oral solution
Capsules
Oral solution
Capsules
Unit dose 
strength (Part 
A)
From 1 mg up to 
10 mg*
From 10 mg to 
70 mg**
N/A
N/A
Unit dose 
strength (Part 
B)
To be confirmed (TBC) 
following Part A
TBC following Part A; 
minimum unit dose 
strength will be 3 
mg*, maximum unit 
dose strength will be 
70 mg**
N/A
N/A
Unit dose 
strength (Part 
C)
TBC following Part A
TBC following Part A; 
minimum unit dose 
strength will be 3 
mg*, maximum unit 
dose strength will be 
70 mg**
N/A
N/A
Route of 
administration 
Oral
Oral
Oral
Oral
Dosing 
Instructions
Required volume of 
0.2 mg/mL aqueous 
solution to be 
swallowed.  Following 
the solution 
administration a further
100mL of water will be 
added to the same 
vessel from which the 
treatment solution was 
administered and
swallowed.
One capsule to be 
swallowed with 
240mL of water. 
Required volume of
water to be swallowed 
Following the initial 
water administration a 
further 100mL of water 
will be added to the 
same vessel from 
which the treatment 
solution was 
administered and 
swallowed.
One capsule to be 
swallowed with 240mL 
of water.
Physical 
description
Clear colourless 
solution
Orange size 0 
capsules
Clear colourless 
solution
Orange size 0 
capsules
Packaging and 
Labelling
The study treatment and excipients will be provided in bulk in labelled bags within a labelled keg. 
The label will detail product description, lot number, expiry date, storage conditions and quantity.
Manufacturer
GSK to provide bulk GSK3358699 active pharmaceutical ingredient (API), placebo excipient, 
capsule shells to clinical site. Clinical site to manufacture the products extemporaneously according 
to a manufacturing batch record.
* It is planned that doses of 3 mg and above will be administered as a capsule formulation in Part B and Part C of the 
study, however the solution formulation dose strength range of 1 mg up to 10 mg will be retained for flexibility. 
** Dose strengths up to 45 mg are planned for this study but higher doses may be required if predicted PK is not 
achieved with planned doses.
The formulation, method of preparation and dosing instructions will be same as for each 
part of the study.


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The planned doses of GSK3358699 for Periods 1-3 of Part A are as detailed in Section 
5.5 and in Table 4. The planned doses may be adjusted as detailed in Section 7.2.
Table 4
Example Illustration of Planned Treatments for Dose Escalation in 
Part A. 
Treatment Period 1
Treatment Period 2
Treatment Period 3
Cohort 1
N=3
P
10 mg
35 mg
N=3
1 mg
P
35 mg
N=3
1 mg
10mg
P
Cohort 2
N=3
P
20 mg
45 mg
N=3
3 mg
P
45 mg
N=3
3 mg
20 mg
P
P= Placebo
1-45 mg = GSK3358699
The GSK3358699 dose for the challenge agent treatment Period 4 will be confirmed 
following completion of the dose escalation treatment Periods 1-3.  The GSK3358699 
dose for Part B, and the first cohort in Part C will be confirmed following completion of 
the dose escalation and challenge treatment Periods in Part A.  Doses for subsequent 
cohorts in Part C will be confirmed following completion of the previous Part C cohort at 
the prior dose level as further detailed in Section 5.5 and Section 7.2.  
Table 5
Challenge Agents
Study 
Treatment 
Name:
Cantharone 
(Cantharidin)
LPS
GM-CSF
Intravenous 
Hydration with saline 
solution (for LPS 
only)
Dosage 
formulation:
Liquid (mixture)
Ether (42.8 % W/V), 
Acetone (36.0 % V/V), 
Alcohol (14.2 % W/V),
Camphor (1.2 % W/V), 
Cantharidin (0.7 % W/V) 
Balance (5.1%W/V) 
mixture of pyroxylin and 
castor oil
LPS is lyophilized 
in a 1 microgram 
vial, formulated in 
1% lactose and 
0.1% PEG6000.
The vial of lyophilized 
LEUKINE contains 250 
mcg (1.4 × 106 IU/vial) 
sargramostim. The 
reconstituted 
lyophilized LEUKINE 
vial also contain 40 
mg/mL mannitol, USP; 
10 mg/mL sucrose, NF; 
and 1.2 mg/mL 
tromethamine, USP, as 
excipients.
0.9% Sodium Chloride 
IV bags.
Unit dose 
strength(s)/Dos
age level(s):
0.7% cantharidin liquid
which will be diluted with 
acetone to 0.2%
0.75 ng/kg
(activity 6 EU/ng)
60g / m2
1L
Route of 
Administration 
Topical
IV
IV infusion
IV
Dosing 
instructions:
Apply 5 μl of 0.2 % 
Cantharidin solution 
(diluted in acetone) 
directly onto skin in area 
of ~ 1 cm2.
IV injection of 
0.75 ng/kg body 
weight 
formulated as 
suspension in 
normal saline.
Dose calculated by 
calculating body 
surface area to give IV 
infusion dose given 
over approximately 2 
hours.
Administer 
intravenously at a rate 
of 250 mL/hr for 4 
hours prior to dosing 
with LPS and 8 hours 
after dosing with LPS.


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Study 
Treatment 
Name:
Cantharone 
(Cantharidin)
LPS
GM-CSF
Intravenous 
Hydration with saline 
solution (for LPS 
only)
Manufacturer
Dormer Laboratories 
Inc. ADDRESS: 91 
Kelfield St. # 5 Rexdale
Ontario Canada M9W 
5A3
http://www.dormer.ca/P
DF/CanRegMSDS.pdf
List Biological 
Laboratories, INC
540 Division 
Street, 
Campbell
California 95008-
6906
USA
www.listlabs.com
Leukine is a registered 
trademark licensed to 
Genzyme Corporation.
Manufactured by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
US License No. 1752
© April 2013 sanofi-
aventis U.S. LLC
Phone:
Baxter Inc.
Caxton Way
Thetford
IP24 3SE
Information regarding the dose of the cantharidin, LPS and GM-CSF challenge agents to 
be administered in Part A treatment Period 4, and Part C (Cohorts 4 and 8), of the study is 
described in Section 5.5.
7.2.
Dose Modification
Details of all the planned dose levels of GSK3358699, the LPS and GM-CSF challenge 
agents, and cantharidin are provided in Section 5.5 and Section 7.1. The actual doses of 
GSK3358699 to be administered in either Part A or Part C may be adjusted based on 
review of the safety, tolerability, PK and PD data from prior dose levels by the DEC. 
These dose adjustments may involve either an increase or a decrease in the planned dose
but the average exposure in a cohort at any planned dose will not intentionally exceed the 
Cmax of 42 ng/ml or total daily AUC of 255 ng/ml.h.  
Individuals in each cohort will be monitored throughout the study.  If 2 or more
participants in a given cohort at the same dose level exceed these PK stopping criteria, 
dose escalation will be halted. 
Furthermore, throughout all parts of the study, either a population PK model or the results 
of a non-compartmental analysis will be used to help inform the choice of the next dose 
level as part of dose escalation discussions.  For either approach, it is planned that the 
95th percentile for the predicted total daily AUC values will not exceed 1/3 of the mean 
AUC observed at the cynomolgus monkey NOAEL and the 95th percentile of the 
predicted Cmax will not exceed 1/3 of the mean Cmax observed at the cynomolgus monkey 
NOAEL.
Doses investigated in Part B or Part C will not exceed the magnitude of those 
investigated in Part A.
The dosing schedule may also be adjusted to address the following:

Expand a cohort to further evaluate safety, PK or PD findings at a given 
GSK3358699 dose level.

To add cohorts to evaluate additional dose levels. 
PPD


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
To change the dosing regimen to less than or more than once daily.  
Dosing may also be halted before all planned dose levels have been completed if stopping 
criteria have been met or if a review of the data determines that evaluation of further dose 
levels is not necessary to meet study objectives. 
In addition, decisions relating to the challenge agent administrations may be taken during 
the course of the study based on newly available data. This may include:

The decision to alter the timing of the LPS or GM-CSF challenge agent 
administrations.

The decision to evaluate more than one challenge agent administration timing.

The inclusion of challenge agents in earlier cohorts (Cohorts 5 – 7).

Expansion of existing cohorts or addition of new cohorts.

Inclusion of blister induction and blister fluid harvest in cohorts prior to Cohort 8.  

Reduction to fewer than 14 days dosing in the challenge Cohorts.
Alterations may also be made to the randomisation ratio of active to placebo for Cohort 8 
and any subsequent additional cohorts based on all available safety, PK and PD data 
following the conclusion of Cohort 7.  
7.3.
Method of Treatment Assignment
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 randomised to a treatment 
group through RAMOS NG. RAMOS NG will confirm the participants CRF number 
(Participant number) and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation 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.
Therefore, the randomisation is centrally controlled by RAMOS NG.
Part A
Within each cohort, participants will be assigned to one of three dosing sequences in a 
1:1:1 ratio for the dose escalation phase, where participants will be randomised to:
Cohort 1
Cohort 2
Sequence
PCE
APE
ACP
PDF
BPF
BDP


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Where the treatment codes are as follows:
Treatment code
Treatment Description
A
1 mg GSK3358699 
B
3 mg GSK3358699 
C
10 mg GSK3358699 
D
20 mg GSK3358699 
E
35 mg GSK3358699 
F
45 mg GSK3358699 
P
Placebo
Of the nine participants within each Cohort, six will then receive GSK3358699 and three 
will receive placebo in treatment Period 4, as per the randomisation schedule. Dose level 
of GSK3358699 to be determined following the completion of the dose escalation phase.
Part B
Participants will be assigned to one of two dosing sequences in a 1:1 ratio, where 
participants will be randomised to:
Cohort 3
Sequence
GH
HG
Where the treatment codes are as follows:
Treatment code
Treatment Description
G
GSK3358699 Fed
H
GSK3358699 Fasted
The dose level of GSK3358699 will be determined following the completion of Part A.
Part C
Within each cohort participants will be assigned to either GSK3358699 or placebo in a 
5:2 ratio (Cohort 4) or a 1:1 ratio (Cohorts 5-8). The treatments will be determined 
following the completion of Part A, where the treatment codes will be:
Treatment code
Treatment Description
I
Dose 1 GSK3358699 QD
J
Dose 2 GSK3358699 QD
K
Dose 3 GSK3358699 QD
L
Dose 4 GSK3358699 QD
P
Placebo


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7.4.
Blinding
This will be a double blind (sponsor open) study with respect to allocation of 
GSK3358699 or placebo to participants.  All site staff will be blinded with the exception of 
unblinded pharmacists and analytical laboratory staff involved with the intracellular PK 
monocyte isolation process. Investigators will be unblinded with respect to the LPS and 
GM-CSF allocation.  The food effect part of the study (Part B) will be open-label.
The following will apply:

RAMOS NG will be programmed with blind-breaking instructions. The
investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
investigator.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK within 24 hours of breaking the blind, but without revealing the
treatment 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 treatment 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.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment 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 treatment assignment, may be sent
to investigators in accordance with local regulations and/or GSK policy.

Sponsor open refers only to the GSK DEC members involved in the review of
the unblinded safety data on an as required basis and at the dose escalation 
meetings. No-one outside of this committee will be unblinded to the study data.
The investigator (or delegate) will be a member of the DEC, but will review 
only blinded data.  Further details of how this will be managed are included in 
Section 12.3 and is included in the DEP.
7.5.
Preparation/Handling/Storage/Accountability
1.
GSK3358699 solutions will be prepared by dissolving drug substance in water for 
injection at a concentration of 0.2 mg/mL. Solutions will contain doses from 1 mg up 
to 10 mg. A visually matching placebo solution of water for injection will also be 
prepared 


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2.
GSK3358699 capsules for oral administration will be prepared by filling capsules 
with the drug substance only.  Capsules will contain doses between 3 mg and a 
maximum of 70 mg GSK3358699.  A visually matching placebo capsule will also be 
prepared by filling capsules with microcrystalline cellulose.
3.
The capsules and solutions will be extemporaneously prepared at the clinical site 
using a Manufacturing Batch Record which will be reviewed and approved by GSK 
prior to use. The Manufacturing Batch Record will contain full details of the 
procedures to be followed. 
4.
The capsule formulation will be administered within 28 days of preparation.
5.
The solution formulation will be administered within 7 days of preparation.
6.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
7.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
8.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
9.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 
7.5.1.
GSK3358699

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

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.
7.5.2.
Cantharidin
Cantharidin is not expected to pose significant occupational safety risk to site staff under 
proposed conditions of use and administration.  Adequate precautions will be taken to 
avoid direct eye or skin contact and the generation of aerosols or mists. Precaution will be 
taken to avoid direct contact with the challenge agent.  A MSDS describing occupational 
hazards and recommended handling precautions will be provided to the investigator.  In 
the case of unintentional occupational exposure, the monitor, medical monitor and/or 
study manager will be notified.  
One part of Cantharone will be mixed with 2.5 parts of pharmaceutical grade acetone 
according to standard practice.  This reconstituted challenge agent will be used within 4 


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hours and any residual material will be discarded according to standard GSK waste-
streams.
7.5.3.
LPS
LPS is not expected to pose significant occupational safety risk to site staff under the 
proposed conditions of use and administration.  Adequate precautions will be taken to 
avoid direct eye or skin contact and the generation of aerosols or mists. Precaution will be 
taken to avoid direct contact with the challenge agent.  A MSDS describing occupational 
hazards and recommended handling precautions will be provided to the investigator.  In 
the case of unintentional occupational exposure, the monitor, medical monitor and/or 
study manager will be notified.
The dose of LPS will be calculated according to body weight and injected as a bolus over 
less than 2 minutes. Any residual material will be discarded according to standard GSK 
waste-streams.
7.5.4.
GM-CSF
GM-CSF is not expected to pose significant occupational safety risk to site staff under the 
proposed conditions of use and administration.  Adequate precautions will be taken to 
avoid direct eye or skin contact and the generation of aerosols or mists. Precaution will be 
taken to avoid direct contact with the challenge agent.  A MSDS describing occupational 
hazards and recommended handling precautions will be provided to the investigator.  In 
the case of unintentional occupational exposure the monitor, medical monitor and/or 
study manager will be notified.
The dose of GM-CSF will be calculated based on body surface area (BSA) (Mosteller 
formula: BSA = 0.016667 × Weight (kg)0.5 × Height (cm)0.5 [Mosteller et al 1987] and 
intravenously infused over approximately a 2 hour period. Any residual material will be 
discarded according to standard GSK waste-streams.  
7.6.
Treatment 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. 

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment 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 treatment.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.


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7.7.
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 
enrollment or receives during the study must be recorded along with:

reason for use.

dates of administration including start and end dates.

dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Participants receiving blister challenges in the study must abstain from use of emollients 
containing hydrocortisone during their participation in the study and must also abstain 
from applying topical creams as detailed in Section 6.3.3.
Paracetamol, at doses of 2 grams/day, is permitted for use any time during the study
except for 12 hours before or after intravenous LPS for those participants receiving this 
challenge. Other concomitant medication may be considered on a case-by-case basis by 
the investigator in consultation with the Medical Monitor.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for this study.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant may be discontinued from study treatment according to the protocol 
stopping criteria. 
8.1.1.
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 treatment for abnormal liver tests is required when a participant 
meets one of the conditions outlined in the algorithm.


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
In addition discontinuation of study treatment will be required if bilirubin is > 2xULN 
and conjugated (direct) bilirubin >35% and the Liver Stopping Event Algorithm will be 
followed.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 12.7.
8.1.2.
QTc Stopping Criteria
A participant that meets either of the bulleted criteria below will be withdrawn from the 
study.  

QTcF > 500 msec

Change from baseline: QTcF > 60 msec

The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
8.1.3.
Haematological Stopping Criteria
A participant that meets the criteria below, where the finding is persistent, confirmed on 
repeat testing and is regarded as clinically significant by the Investigator, will be
withdrawn from the study. It should be noted that following acute LPS or GM-CSF 
challenge transient changes in haematological criteria are expected.  Since the challenges 
are only administered after the final dose of GSK3358699 in any given part of the study, 
haematological results following challenge administration will be reviewed and any 
action based on evaluation of results will be at Investigator discretion in conjunction with 
the Medical Monitor. 


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
Haemoglobin ≤ 9 g/dL (5.58 mmol/L) or an absolute decrease of ≥3 g/dL from 
baseline (pre-dose Day 1)

Neutrophils ≤ 1.0 x 109/L, or neutrophils >1.0-1.5 x 109/L if the results are 
deemed clinically significant at the discretion of the Investigator.

Lymphocytes ≤ 0.5 × 109/L

Platelets 50,000/mm3
8.1.4.
Lipid Stopping Criteria
A participant that meets the criteria below, where the finding is persistent, confirmed on 
repeat testing and is regarded as clinically significant by the Investigator, will be 
withdrawn from the study.  Lipid stopping criteria do not apply to the food effect part of 
the study (Part B) since lipid elevations are expected after a high fat meal.

Fasted Triglycerides > 5.7 mmol/L

Fasted Total cholesterol > 10.3 mmol/L
8.1.5.
Gastrointestinal Stopping Criteria
If a participant reports any persistent gastrointestinal symptom (i.e., nausea, abdominal 
pain/discomfort, diarrhea, or vomiting) which causes the participant concern or interferes 
with daily activities (including eating and sleeping) during any dosing Period, and is 
considered at least possibly related to the investigational product, then the participant
should be withdrawn from the study. 
If the participant reports a gastrointestinal AE of concern during dosing or at follow up, 
the Investigator will complete a clinical assessment of the gastrointestinal adverse 
event(s) of concern and could consider referral to a Gastroenterologist.
8.1.6.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, is 
possibly, probably or definitely related to investigational product, then the 
participant should be withdrawn from the study.
8.1.7.
Dose Adjustment/Stopping Pharmacokinetic Criteria
The following dose adjustment / PK stopping criteria will apply:

If mean cohort exposure exceeds or is predicted to exceed the Cmax of 42 ng/ml or 
total daily AUC of 255 ng/ml.h, dose escalation will be stopped.

Individuals in each cohort will be monitored throughout the study.  If 2 or more
participants in a given cohort at the same dose level exceed these stopping criteria, 
dose escalation will be halted. 

If the PK stopping criteria is reached with initial doses, the dose escalation will be 
stopped. The GSK team will decide based on safety, PK and any available PD 


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information whether to evaluate any lower doses or repeat doses already evaluated in 
remaining periods to collect additional safety, PK and PD data.
Throughout all parts of the study, either a population PK model or the results of a non-
compartmental analysis will be used to help inform the choice of the next dose level as 
part of dose escalation discussions.  For either approach, it is planned that the 95th
percentile for the predicted total daily AUC values will not exceed 1/3 of the mean AUC 
observed at the cynomolgus monkey NOAEL and the 95th percentile of the predicted 
Cmax will not exceed 1/3 of the mean Cmax observed at the cynomolgus monkey NOAEL.
8.1.8.
Dose Adjustment/Stopping Pharmacodynamic Criteria
The PD of GSK3358699 will be evaluated throughout the study.  The DEC will apply the 
following PD stopping criteria which are relevant to any cohort evaluated in any part of 
the study.  If these criteria are met before the highest planned dose level or other stopping 
criteria are reached, the PD data obtained up to the point the PD stopping criteria is met 
will provide sufficient information to model effective doses in future studies and 
therefore, the decision will be taken not to proceed with higher dose levels.

MCP-1 and TNF inhibition in participant blood stimulated ex vivo with LPS, 
where maintenance of ≥ 90% MCP-1 and TNF inhibition for a minimum of 12 
hours post dose relative to baseline is achieved.

Additionally, if the PD effect of GSK3358699 appears to have become saturated 
over the course of 2 consecutive dose levels, dose escalation will be halted.
8.1.9.
Dose Escalation / Study Progression Stopping Safety Criteria
Progression to the next higher dose level will be halted if:

Two or more participants in the same cohort experience severe non-serious 
adverse reactions (i.e. severe non-serious adverse events considered as, at least 
possibly related to the administration of GSK3358699), independent of within or 
not within the same system-organ-class.

Any participant experiences a serious adverse reaction (i.e. a serious adverse 
event considered at least possibly related to the administration of GSK3358699).

Three or more participants in a cohort experience the same adverse event of 
moderate severity that can be reasonably attributed to dosing with GSK3358699.
The dose escalation will be temporarily halted and no further participants will be dosed 
until a full safety review of the study has taken place. Relevant reporting and discussion 
with the GSK medical monitor, relevant GSK personnel, and with the IRB / IEC will then 
take place prior to any resumption of dosing, which may include the evaluation of lower 
doses.
If dosing is halted, and if deemed acceptable by GSK internal safety review to proceed 
with or modify dose escalation to further characterize the safety profile of GSK3358699, 


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a formal request with appropriate data and a substantial amendment will be submitted to 
the MHRA for approval before further dosing takes place.
An exception will be if taste/smell AEs are reported when a solution formulation of 
GSK3358699 is being utilised, in which case escalation can continue as planned based on 
the judgement of the investigator and the GSK medical monitor.
All other stopping criteria will apply even if no PK or PD stopping criteria have been 
met.
8.1.10.
Rechallenge
8.1.10.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after any stopping criteria are met by any 
participant in this study is not allowed for that individual.
8.2.
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.

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.

Refer to the SoA for data to be collected at the time of follow-up and for any 
further evaluations that need to be completed.
8.3.
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 and 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.


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
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Acceptable time 
windows around the nominal time points for specific assessments will be included in 
the SRM and assessments performed within these time windows will not constitute a 
protocol deviation.

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 treatment.

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 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, is not planned to
exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any 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 treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study treatment until the follow-up 
visit at the time points specified in the SoA (Section 2).  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 


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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 treatment until the follow-up 
visit at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded as Medical History in the 
participant’s source notes not the AE section of the CRF.

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 4. 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 in former study 
participants. 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 treatment or study 
participation, the investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
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. 
9.2.3.
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 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
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 treatment 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 treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/ IEC, and investigators.


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
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 (eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the final follow-up visit.

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 Section 12.5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
For this study, any dose of GSK3358699, LPS challenge agent, GM-CSF challenge agent 
or cantharidin, greater than the protocol planned doses or doses defined as part of dose 
escalation decisions, will be considered an overdose.
9.3.1.
GSK3358699
In the event of an overdose of GSK3358699, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 48 hours).
3.
Obtain a plasma sample for PK analysis within 8 hours of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis).
4.
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.
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose.
9.3.2.
Cantharidin
Participants will not have access to cantharidin and overdose is therefore extremely 
unlikely. In the event of overdose, the clinical management will be based on symptomatic 


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treatment and supportive measures as indicated and required according to current UK 
guidelines.
In case of any overexposure to Cantharone refer to the MSDS. 
Inhalation: Remove victim to fresh air. Give oxygen or artificial respiration if necessary.
Skin Contact: Immediately flood affected skin with water while removing and isolating 
all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and 
water. Seek medical attention if warranted.
Eye Contact: First check the victim for contact lenses and remove if present. Flush 
victim's eyes with water or normal saline solution for 20 to 30 minutes while 
simultaneously calling a hospital or poison control centre. Do not put any ointments, oils, 
or medication in the victim's eyes without specific instructions from a physician. 
Immediately transport the victim after flushing eyes to a hospital even if no symptoms 
(such as redness or irritation) develop.
Ingestion: Do not induce vomiting. If the victim is conscious and not convulsing, give 1 
or 2 glasses of water to dilute the chemical and immediately call a hospital or poison 
control centre. Immediately transport the victim to a hospital. If the victim is convulsing 
or unconscious, do not give anything by mouth, ensure that the victim's airway is open, 
and lay the victim on his/her side with the head lower than the body. Transport the victim 
immediately to a hospital.
9.3.3.
LPS
LPS dose selection has been made on the basis of a lower dose and potency than is 
usually reported in the literature, and thus overdose is not anticipated.
Intravenous LPS has the potential to be extremely harmful in overdose and induce 
symptoms and organ dysfunction in keeping with septic shock.  Participants who receive 
an overdose of intravenous LPS will be hydrated with rapid intravenous fluid boluses.  
Clinical staff may need to expedite immediate transfer to hospital in the event that 
volunteers exhibit clinical signs of septic shock.  Mild pyrexia and malaise may be 
observed.
9.3.4.
GM-CSF
GM-CSF dose selection has been made on the basis of a lower dose than is usually 
reported in the literature/given to patients, and thus overdose is not anticipated.
In case of overdose, participant will be carefully monitored for white blood cell (WBC)
increase and respiratory symptoms. Symptomatic management will be carried out 
according to existing guidelines.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.


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9.4.1.
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.
9.4.2.
Body Weight
Body weight will be measured at the time points in the SoA. In Part A, body weight 
measured in treatment Period 4 Day -1 will be used to calculate the dose of LPS and GM-
CSF to be used.  In Part C (Cohort 4 and 8 only) body weight measured on the day prior 
to challenge administration will be used to calculate the dose of LPS and GM-CSF to be 
used. 
9.4.3.
Assessment of blister sites

Visual assessment of blister site will be carried out at selected visits as detailed 
in the SoA.
9.4.4.
Vital Signs

Tympanic temperature, heart rate, respiratory rate, and blood pressure will be 
assessed.

Vital signs measurements are to be taken before blood collection for laboratory 
tests.  

Tympanic temperature and respiratory rate will be taken as single measurements 
at the timepoints detailed in the SoA.

Blood pressure and pulse measurements will be assessed in a semi-supine 
position 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, in a semi-supine position,
without distractions (eg, television, cell phones).

In Part A and Part B, blood pressure and pulse measurements will be performed 
as follows.  

Day -1, Day 1 pre-dose, 24 h and 48 h post-dose: triplicate measurements

Day 1 post-dose: single measurements throughout except for:

GSK3358699 Cmax timepoint; triplicate measurement

For 12 hours post-LPS challenge: triplicate measurement 


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
In Part C (Cohorts 4 and 8), blood pressure and pulse measurements will be 
performed as follows:

Day – 1 to Day 13: triplicate measurements

Day 14 pre-dose, Day 15 and Day 16: triplicate measurements

Day 14 post-dose: single measurements throughout except for:

GSK3358699 approximate Cmax timepoint; triplicate measurement

For 12 hours post-LPS challenge: triplicate measurement 

In Part C (Cohorts 5 - 7), blood pressure and pulse measurements will be 
performed as follows:

Day – 1 to Day 13: triplicate measurements

Day 14 pre-dose, Day 15 and Day 16: triplicate measurements

Day 14 post-dose: single measurements throughout except for:

GSK3358699 approximate Cmax timepoint; triplicate measurement

At timepoints where triplicate measurements of pulse and blood pressure are 
required, 3 consecutive readings will be recorded at intervals of at least 
1 minute.
9.4.5.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained in the study at the time points detailed 
in the SoA and at other times in the study if clinically indicated (Section 2.3; 
single ECGs at all other time points) using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. Refer 
to Section 8.1.2 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 4 minutes apart. The full set of triplicates should be completed in less than 
8 minutes.

Holter monitoring will be performed at screening only. This 24-hour Holter will 
be performed to eliminate participants with non-clinically overt cardiac 
arrhythmias or other exclusionary criteria.  
9.4.6.
Cardiac Telemetry
Continuous cardiac telemetry will be performed in the study at the time points detailed in 
the SoA and at other times in the study if clinically indicated as detailed in the SoA 
(Section 2.3).


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9.4.7.
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 or within 7-14 days after the last dose of study 
treatment 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 etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If a cardiac arrhythmia occurs, a PK sample and drugs of abuse test should be 
taken as close to the time of the event as possible.

Laboratory results at Day -1 are for the purposes of providing baseline values 
prior to dosing.  The review of laboratory abnormalities at Day -1 for eligibility 
will be based on Investigator discretion and clinical judgement.
9.4.8.
Participant Diary Card
Participants will be given a diary card for them to record the healing time of the blisters 
as well as to record any adverse events or medications taken whilst outside of the unit.
9.5.
Pharmacokinetics
9.5.1.
Blood sample collection and analysis

Blood will be collected into appropriate tubes (type to be confirmed pending on-
going stability investigations) for measurement of GSK3358699 and 
GSK3206944 concentrations in plasma (approximately 1 mL per time-point up to 
and including 6 hours post dose and approximately 2 mL per time-point after 6
hours post-dose). [S1] and [S2]

Blood (6 mL per time point) will be collected into sodium heparin tubes for the 
isolation of monocytes and for measurement of GSK3206944 concentrations in 
monocytes, as specified in the SoA. [S3]   


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
Instructions for the processing, storage and shipping of biological samples will be 
provided by the sponsor in the SRM. The actual date and time (24-hour clock 
time) of each sample will be recorded.

Samples will be used to evaluate the PK of GSK3358699 and GSK3206944 in 
plasma and GSK3206944 in monocytes. Samples collected for analyses of 
GSK3358699 and GSK3206944 plasma concentration may also be used to 
evaluate safety or PD aspects related to concerns arising during or after the study.

Once the plasma has been analyzed for GSK3358699 and GSK3206944 any 
remaining plasma will be analyzed qualitatively for other compound-related 
metabolites and the results reported under a separate protocol. [E4]  

Genetic analyses will not be performed on these plasma samples unless consent 
for this was included in the informed consent. Participant confidentiality will be 
maintained. 
Drug concentration information that may unblind the study will not be reported to the 
investigator site or blinded personnel until the study has been unblinded.
9.5.2.
Urine Sample Collection and Analysis

Urine will be collected for qualitative analysis of compound-related metabolites 
according to the SoA time points. Immediately prior to dosing, each participant 
will be instructed to void their bladder into a collection container and no more 
than 20 mL of this urine sample will be retained as a pre-dose control sample.  A 
0-24 hour urine collection will begin immediately following dose administration. 
Participants will be instructed to collect all urine voided on each occasion into a 
collection container and the urine will be transferred / pooled in a 0-24 h storage 
container for further processing after the end of the collection period, with the 
exception of the samples required for urinalysis testing during this period which 
will be collected separately. Further instructions on urine sample processing, 
storage and shipment will be provided in the SRM. The results of this analysis 
will be reported under a separate protocol. [E4].
9.6.
Pharmacodynamics
There will be several measures of PD taken in the study using whole blood or blood-
derived samples, as outlined in the SoA.  
9.6.1.
Ex vivo PD sample
1 mL whole blood samples will be collected according to the timings specified in the
SoA.  At each timepoint, one 1mL sample will be drawn into a TruCulture tube 
containing LPS and a second 1mL sample will be drawn into a 1 “GSK3358699 LPS”
TruCulture tube, and incubated for 24 hours. For all samples, cellular and soluble 
contents will be separated and inflammatory mediators (MCP-1, IL-6 and TNF) analysed 
in the soluble fraction. [S4]


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9.6.2.
Circulating inflammatory biomarkers / proteins
Approximately 2 mL of blood will be collected into heparin tubes according to the 
timings on the SoA. This will allow for analysis of plasma to measure inflammatory 
mediators, such as MCP-1, IL-12p40 and MMP-9. Measurement of soluble inflammatory 
mediators will be carried out in batch analysis. [E1a]
9.6.3.
Gene array panel
Approximately 2.5 mL of blood will be collected into PAXgene tubes for gene array 
analysis according to the timings on the SoA.  Samples will be used to extract ribonucleic 
acid (RNA) and prepare complementary deoxyribonucleic acid (cDNA) which will 
subsequently be used for analysis by gene array panels.  [E1b]
Other measures of pharmacodynamics will be measured as part of the in vivo challenges 
(LPS, GM-CSF or cantharidin) and the measurements are described in Biomarkers in 
Section 9.8.
9.7.
Genetics
All randomized subjects will be required to provide a 2 mL blood sample for potential 
companion diagnostic development, if test development is required by regulatory 
authorities to identify subjects who are appropriate for GSK3358699 treatment. This 2 
mL blood sample will be stored frozen at the central lab. 
All randomized subjects will be required to provide a 6 mL blood sample for 
investigation of genetic variation of genes that encode carboxyesterase (CES) according 
to the timings on the SoA [E5]. Additionally, this sample will be used for additional 
genetics research for those participants who have consented in the optional exploratory 
genetics analysis component of the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Section 12.6 Appendix 6 for information regarding genetic research. Details on 
processes for collection and shipment and destruction of these samples can be found in 
the SRM.
9.8.
Biomarkers
There will be several different types of biomarker samples collected during the study as 
outlined in the SoA, including biomarkers from blood and blister fluid.  The biomarkers 
will be induced using the inflammatory stimuli (LPS, GM-CSF, cantharidin) as described 
in Section 5.1.  The biomarkers will include cellular and soluble proteins and gene 
expression, and the effect of GSK3358699 on these measures of inflammation will be 
determined.  


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9.8.1.
Biomarkers in blood
Biomarkers in blood will be collected pre- and post- challenge (in vivo challenge with 
LPS or GM-CSF).  Cellular and soluble activation markers will be determined at several 
time points as specified in the SoA.  Leukocyte counts for each sample will be recorded 
in the eCRF.  [E2]
9.8.1.1.
Cellular activation markers blood sample (all cohorts in Part C)
Approximately 2 mL of blood will be collected into heparin tubes for measurement of 
leukocyte number and activation markers by flow cytometry (see indicative list in 
endpoints) [E2b].
9.8.1.2.
Circulating inflammatory biomarkers blood sample (challenge cohorts
only)
Approximately 2 mL of blood will be collected into heparin tubes according to the 
timings on the SoA. This will allow for analysis of plasma to measure inflammatory 
mediators.  Methods of analysis which may be used on these samples are detailed in the 
SRM. Measurement of soluble inflammatory mediators will be carried out in batch 
analysis. [E2a]
9.8.1.3.
Gene array panels (challenge cohorts only)
Approximately 2.5 mL of blood will be collected into PAXgene tubes for gene array 
analysis according to the timings on the SoA.  Samples will be used to extract RNA and 
prepare cDNA which will subsequently be used for analysis by gene array panels to 
determine the effects of compound on challenge with LPS or GM-CSF.  [E2d]
9.8.2.
Biomarkers in blisters
Biomarkers in blisters will be collected by piercing the blister with a needle and 
aspirating the blister contents with a pipette into a polypropylene micro-centrifuge tube. 
Cellular and soluble contents will be separated. The volume of the blister sample will be 
calculated and recorded in the eCRF. [E3]. The baseline blister samples collected will be 
repeated if > 4 months elapses between the baseline blister and the challenge treatment
Period (eg if a reserve in the study is not dosed and is subsequently rescreened for a later 
cohort). 
9.8.2.1.
Cellular blister sample
Blister sample will be used to measure leukocyte number and activation markers by flow 
cytometry (see indicative list in Section 4), at times specified in the SoA [E3].
9.8.2.2.
Soluble blister sample
The soluble fraction from the blister sample will be used to measure inflammatory 
mediators. Methods of analysis which may be used on these samples are detailed in the 
SRM [E3].


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9.8.3.
RNA Expression Research of a Subset of RNA Species
As detailed in Section 9.6.3 and Section 9.8.1.3, samples will be used to extract RNA and 
prepare cDNA which will subsequently be used for analysis by gene array panels.  [E1b, 
E2d]
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
This is not applicable to this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
As the primary objective of the study is to assess the safety of GSK3358699 in
healthy volunteers, there are no formal hypotheses. There are also no formal hypotheses 
to be tested for the single or repeat dose PK data.
An estimation approach will be used to quantify the single dose PK for each dose level 
studied, the food effect and also to assess PK parameters following 14 days repeat dosing 
relative to single dosing.
10.2.
Sample Size Determination
10.2.1.
Sample size assumptions
At each dose level studied in Part A there will be approximately nine participants; six
randomised to each of the GSK3358699 treatment groups and three receiving placebo in 
any one period. In Part A, each participant will be randomised to one of three sequences
for the dose escalation phase.
In Part B of the study there will be approximately six participants, all receiving 
GSK3358699 (randomised to either fed or fasted administration), each participant will be 
randomised to one of two sequences. In Part C approximately fourteen participants in 
Cohort 4 were planned (ten randomised to the GSK3358699 treatment group and four 
receiving placebo, in a 5:2 ratio).  In Cohorts 5 - 7 approximately eighteen participants 
are planned (nine randomised to each of the GSK3358699 treatment groups and nine 
receiving placebo, in a 1:1 ratio) and in Cohort 8 approximately twenty subjects are 
planned (ten randomised to the GSK3358699 treatment group and ten receiving placebo, 
in a 1:1 ratio).
Refer to Section 7.2 for further information on sample size and randomisation changes in 
the event of any dose modifications.
The sample size is based on feasibility.
The primary objective of the study is safety, where the number of safety events would be 
of interest, for example the number of participants experiencing a particular adverse 
event. At each dose level in Part A six participants will receive GSK3358699. If 0/6 of a 


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particular safety event in the GSK3358699 group is observed, using a Bayesian approach 
to determine the credible interval around an observed safety event, we would assume a 
flat Beta (1,1) prior, and if we were to observe 1 safety event in 6 then the posterior 
distribution would be Beta (2, 6), where we can be 95% certain that the true probability 
of the safety event lies between 0.04 and 0.58.
Sample size sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates.  If the number of subjects who completed each 
active dose reduces, then the true incidence rates of safety events that could not be ruled 
out would change.  These changes are outlined below:
N on 
GSK3358699 
Completing 
Cohort
Number of a particular 
safety event observed with 
GSK3358699
Upper limit of exact 95%CI indicating 
that a true incidence rate of x% could 
not be ruled out
6
2
71%
3
82%
5
0
46%
1
64%
2
78%
4
0
52%
1
72%
2
85%
Sample size re-estimation
There is no sample size re-estimation planned. 
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF.
Randomized
All participants who are randomised into the study and receive a 
randomisation number.
Evaluable
A participant is considered evaluable if they complete both 
screening and all their planned treatment Periods in Part A; both 
Periods in Part B, or the 14 day treatment Period and subsequent 
assessment Period in Part C.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
Pharmacokinetic
All participants in the Safety Population who receive an active dose 
and for whom a PK sample was obtained and analysed. 


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Population
Description
PK/PD
The Safety Population will be used so that participants receiving 
placebo can be included.
10.4.
Statistical Analyses
Parts A, B and C will be reported separately in the outputs.
10.4.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
Will be presented in tabular and/or graphical format and summarised descriptively 
according to GSK's Integrated Data Standards Library standards.
10.4.2.
Pharmacokinetic Analyses
All PK analyses will be performed on the Pharmacokinetic Population. 
Endpoint
Statistical Analysis Methods
Secondary
Plasma GSK3358699 and the metabolite GSK3206944 concentration-
time data will be analysed by non-compartmental methods. Calculations 
will be based on the actual sampling times recorded during the study. 
Concentration-time data will be listed for each participant and treatment 
and summarized by planned time point and treatment.
From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit: maximum observed 
plasma concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve [AUC(0-24), AUC(0-t) and AUC(0-∞)], and 
apparent terminal phase half-life (t1/2). 
PK parameters will be listed for each participant and treatment and 
summarized descriptively by treatment using the PK population. For each 
of these parameters, except tmax, the following summary statistics will be 
calculated for the active treatment group at each cohort: median, 
maximum, minimum, arithmetic mean, 95% confidence interval (CI) for 
the arithmetic mean, standard deviation, coefficient of variation, 
geometric mean, 95% confidence interval for the geometric mean and 
standard deviation of logarithmically transformed data. For tmax, median, 
maximum, minimum, arithmetic mean and standard deviation will be 
calculated. The first point, last point and number of points used in the 
determination of lz will be included on the listing of the derived 
parameters.


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Endpoint
Statistical Analysis Methods
Part A: Dose proportionality will be assessed by analysis of loge-
transformed parameters AUC(0-∞) [or if not available AUC(0-t)] and Cmax
using the power model. Further details will be included in the RAP.
Part B: A mixed effects model will be fitted on the loge-transformed 
parameters AUC(0-∞) [or if not available AUC(0-t)] and Cmax with fed status 
as a fixed effect and participant as a random effect. Point estimates and 
corresponding 90% CIs will be constructed for GSK3358699 fed -
GSK3358699 fasted using the residual variance. These will then be back 
transformed to provide point estimates and corresponding 90% CIs for 
the geometric mean ratio GSK3358699 fed to GSK3358699 fasted.
Part C: The extent of accumulation after repeat dosing, the observed 
accumulation ratio (Ro) will be determined. The plasma steady state ratio 
(Rs) and an assessment of plasma steady state across the trough 
concentrations will also be made. Dose proportionality will be assessed 
using similar methods to the single dose Part A. 
10.4.3.
Other Analyses
The intra-cellular acid parameters and PD parameters collected during the study and after 
each challenge will be listed for each participant and treatment and summarized 
descriptively by treatment. If deemed appropriate the dose response relationship at each 
time point for the change from baseline in key PD parameters will be determined.
PD and biomarker exploratory analyses will be described in the RAP.
It is intended that a population PK model will be built to predict the exposures at the next 
ascending dose from the currently available PK data.
The population PK and PK/PD analyses and exploratory biomarker analyses may be 
presented separately from the main clinical study report (CSR). 
10.4.4.
Interim Analyses
If a decision is made to perform challenges on a previously tested dose (i.e. not evaluate a 
new dose regimen) in the challenge cohort (Cohort 8), a formal interim statistical analysis 
will be performed on the completed cohorts in Part A, Part B and Part C of the study once 
all participants complete Cohort 7 of Part C to aid internal decision making. There will be 
no changes to the study design or planned number of participants in Cohort 8 as a direct 
result of the interim analysis.
Dose escalation meetings will also occur after each Period in Part A and after the 
completion of up to 14 days dosing of each cohort in Part C.
The decision to proceed to the next cohort, and next dose strength to be studied, or to the 
next study Part, will be made by the DEC based on assessment of safety, plasma 


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GSK3358699 pharmacokinetic concentrations and target engagement data obtained in all 
participants at the prior dose level. Individual safety data (AEs, laboratory safety tests, 
ECGs and vital signs) will be reviewed, according to the DEP.
This study is double blind (sponsor open), where the participant, investigator and site 
staff will remain blinded to the treatment allocation. Sponsor open refers only to those 
members of the DEC. Note that Part B will be open label. 
The RAP will describe the planned interim analyses in greater detail.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE 
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AMD
Age-related Macular Degeneration
API
Active Pharmaceutical Ingredient
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC 
Area Under the Curve
BET
Bromodomain and Extra Terminal domain
BMI
Body Mass Index
BP
Blood Pressure
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CD
Cluster of Differentiation
CDER
Center for Drug Evaluation and Research
cDNA
Complementary DNA
CES
Carboxyesterase
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum Concentration
CK
Creatine Kinase
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine Phosphokinase
(e)CRF
(electronic) Case Report Form
CRP
C-reactive protein
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Cardiovascular
CYP3A4
Cytochrome P450 3A4
DDI
Drug Interaction
DEC
Dose Escalation Committee
DEP
Dose Escalation Plan
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
EDTA
Ethylenediaminepentaacetic acid
Emax
Maximum Effect Possible
ESM
Esterase Sensitive Motif
EU
European Union


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FDA
Food and Drug Administration
FTIH
First Time In Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GM-CSF
Granulocyte-Macrophage Colony-Stimulating Factor
GSK
GlaxoSmithKline
HED
Human Estimated Dose
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HLA-DR
Human Leukocyte Antigen - antigen D Related
HPLC
High Performance Liquid Chromatography
HR
Heart Rate
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IG
Immunoglobulin
IL 
Interleukin
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
INR
International Normalized Ratio
IP
Interferon gamma-induced Protein
IUD
Intra-Uterine Device
IUS
Intra-Uterine hormone releasing System
IV
Intravenous 
IRB/IEC
Institutional Review Boards /Independent Ethics Committees
LDH
Lactose Dehydrogenase
LPS
Lipopolysaccharide
MABEL
Minimum Anticipated Biological Effect Level
MCH
Mean Corpuscular Hemoglobin
MCP
Monocyte chemoattractant protein
MCV
Mean Corpuscular volume
MDC
Macrophage-Derived Chemokine
MHRA
Medicines and Healthcare Products Regulatory Agency
MMP
Matrix Metallopeptidase
MSDS
Material Safety Data Sheet
NOAEL
No Observed Adverse Effect Level
NOEL
No Observed Effect Level
PBO
Placebo
PBPK
Physiologically Based Pharmacokinetic
PD
Pharmacodynamics
PK
Pharmacokinetics


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PT
Prothrombin Time
QD
Once Daily
QTc
Electrocardiogram QT interval corrected for heart rate
QTcF
Electrocardiogram QT interval corrected for heart rate using Fridericia’s 
formula
RA
Rheumatoid Arthritis
RAP
Reporting Analysis Plan
RBC
Red Blood Cell
RDW
Red cell Distribution Width
RNA
Ribo Nucleic Acid
Ro
Accumulation Ration
Rs
Plasma steady state ratio
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SD
Standard Deviation
SoA 
Schedule of Activities
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SNP
Single Nucleotide Polymorphism
SPF
Sun Protection Factor
SRM
Study Reference Manual
SST
Serum-Separating Tube
SUSAR
Suspected Unexpected Serious Adverse Reactions
TARC
Thymus and Activation Regulated Chemokine
TBC
To Be Confirmed
TE
Target Engagement
TGF
Transforming Growth Factor
Tmax
Time to Cmax
TNF
Tumour Necrosis Factor
ULN
Upper limit of normal
UVA/B
Ultra Violet A/B
WBC
White Blood Cell
WCC
White Cell Count
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Cantharone
Leukine


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 6 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 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 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Clotting 
parameters:
APTT
PT times
Fibrinogen
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical Chemistry1
CRP
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and 
direct 
bilirubin
Albumin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (fasting
during Part C2)
Calcium
Alkaline 
phosphatase
Cholesterol2,3
Low Density 
Lipoprotein2,3
High Density 
Lipoprotein2,3
Triglycerides2,3
Gamma-glutamyl 
transferase (GGT)4
Creatine kinase
(CK)4
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)


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Laboratory 
Assessments
Parameters
Other Clinical Laboratory Tests
alcohol breath test and urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody) 
Urine cotinine
The results of each test will be loaded electronically into the eCRF.
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 8.1 and Appendix 7 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. In Part C at certain time points as per the SoA lipids and glucose samples are required to be taken fasted.
3. Screening samples are required to be taken fasted.
4. To be analysed at screening, Day-1 and follow up only
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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12.3.
Appendix 3: Study Governance Considerations
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 (eg, 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 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations.
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.
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. 


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
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.
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. 

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.
Committees Structure
Dose Escalation Committee
The DEC will make the decision to proceed to the next dose level of GSK3358699 at the 
end of each single dose (Cohorts 1-2) and repeat dose cohort (Cohorts 4-8); along with 
making the decision on the dose for Part B of the study and the decision to move into 
Part C of the study. For details of the information to be considered as part of this 
decision making process see Section 5.1.
Safety, PK and PD stopping criteria will be strictly applied.  Details of these criteria can 
be found in Section 8.  There will be an open and closed part to the dose escalation 
meeting as required. At the beginning of the meeting blinded data will be discussed in an 
open forum with the investigator in attendance. If required, the data will then be 
reviewed in an unblinded fashion by the unblinded members of the DEC. These 
unblinded members include the Medical Monitor, GSK GCSP representative, GSK 


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statistician and GSK pharmacokineticist. In instances where the TE data is reviewed the 
GSK biology representative will also be present at the dose escalation meeting. A DEP 
will be written outlining in detail how the study team will ensure data integrity used in 
dose selection decisions by performing clinical data review and appropriate quality 
control of data prior to making dose selection decisions, as well as outlining the 
responsibilities of the investigators and site staff for reporting safety data, participation 
during dose escalation meetings, and confirmation that the data used for dose escalation 
are accurate and complete.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
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 results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
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 (eg, 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. 


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
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

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 25 years from the issue of the final 
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. 
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 the Source Document 
Agreement.
Study and Site Closure
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 
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:


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
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.

Discontinuation of further study treatment development.


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.
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 treatment.
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, 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 treatment 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 
treatment 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.
Medical or surgical procedure (eg, 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).


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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.
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 (eg, 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:
a. Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been 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 fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent 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, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f. 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 


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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, 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 sufficiently discomfort and interferes with normal 
everyday activities.
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.


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Assessment of Causality
The investigator is obligated to assess the relationship between study treatment 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 treatment 
administration will be considered and investigated.
The investigator will also consult the 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.
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.


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Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the SAE coordinator.
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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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 7 when having 
penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm for duration of 
study and for 91 days from last dose
Table 7
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb
injectable 
Highly Effective Methods That Are User Independent 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
bilateral tubal occlusion


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NOTES:
a. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment Period and for at least 91 days after the last dose of study treatment 
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 who becomes pregnant while participating in this study. This applies 
only to participants who receive study treatment.

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. 

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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12.6.
Appendix 6: Genetics
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin et al 2012] with certain 
variants reported to influence treatment response [Chen et al 2012]. Thus, knowledge of 
the genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
CES Genotyping
There is known genetic variation [Merali et al 2014] with the potential to impact CES-1
activity and potentially impact its ability to hydrolyse GSK3358699 to form the active 
compound GSK3206944. A sample will be collected from all participants to allow 
mandatory assessment of CES variation [E5]. Additionally, that same sample may be 
used for exploratory genetic analysis in participants who have consented to participate in 
the genetics analysis component of the study.  Participation in the exploratory genetics 
analysis is optional.  Participants who do not wish to participate in the exploratory 
genetic research may still participate in the study.
Additionally, a blood sample will be collected from all participants will be stored frozen
for use in the development of a companion diagnostic in the event of a Regulatory 
Authority requirement.
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples may be used for research related to GSK3358699 and related diseases. 
They may also be used to develop tests/assays including diagnostic tests related to
GSK3358699 and rheumatoid arthritis plus other potential inflammatory indications 
such as psoriasis and fibrotic liver disease. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate)


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
DNA samples will be analysed for CES variation and may be analyzed for genetic 
variation in additional genes if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3358699 or study treatments of these drug classes. 
The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3358699 or rheumatoid arthritis
plus other potential inflammatory indications such as psoriasis and fibrotic liver 
disease continues but no longer than 15 years after the last participant last visit or 
other Period as per local requirements.


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
Bilirubin > 2xULN and conjugated (direct) bilirubin >35%
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 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 treatment
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, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24
hrs
Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline
A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs
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, obtained within 8 hours of 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
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 


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Liver Chemistry Stopping Criteria 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
globulins.
Serum acetaminophen adduct high 
performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week [James et al 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 treatment for that participant 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, 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); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment 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.


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12.8.
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 1 (25th January 2018)
Overall Rationale for the Amendment: Medicines and Healthcare Products Regulatory 
Agency (MHRA) feedback on the protocol requires wording to be added to the Dose 
Escalation / Study Progression Stopping Safety Criteria section. Some minor 
administrative / typographical revisions have also been made within the SoA tables.
Section # and Name
Description of Change
Brief Rationale
Section 2.2 Part B 
Food Effect 
Schedule of Activities
Reference to ‘agent’ and ‘placebo’ deleted 
on page 25
Part B of the study does not 
involve challenge agents or 
placebo
Section 2.3 Part C 
General Schedule of 
Activities 
‘X’ added to ‘Visual Forearm Check’ on 
Days 15 and 16.
Updated for consistency 
with Section 2.3.2 and 
Section 2.3.3 where this 
assessment is already 
included on Days 15 and 
16.  
Section 8.1.8
Dose Escalation / 
Study Progression 
Stopping Safety 
Criteria
Wording added to indicate that, if any of the 
dose escalation stopping criteria are met, an 
application for a substantial amendment with 
the MHRA must be submitted and approved 
before further dosing takes place. 
Change required by MHRA.
Amendment 2 (21st March 2018)
Overall Rationale for the Amendment:  This is a non-substantial amendment primarily 
to correct a discrepancy in the API storage temperature; the protocol stated temperature is 
incorrect however the API labelling and other documentation is correct. Some minor 
administrative / typographical revisions have also been made.


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Section # and Name
Description of Change
Brief Rationale
Synopsis and Section 
5.5.1.1 Part A Study
Schematic;
Section 7.3 Method of 
Treatment 
Assignment
QD (once daily) removed.
It is clearly described in the text that 
Parts A and B of the study are 
single-dose.  However to avoid 
confusion regarding the use of the 
term QD these sections have been 
updated.
Section 2.1 Part A 
Schedule of Activities
Added note to SoA to clarify that 24 
and 48 hour safety sampling will be 
done prior to participants receiving 
breakfast. 
To increase clarity.
Section 2.3 Part C 
Schedule of Activities 
Tables
Some minor revisions to the Days 
referenced in the comments 
column, (eg Day 4-12 changed to 
Days 4, 8 and 12)
To increase clarity
Section 2.3 Part C 
General Schedule of 
Activities 
‘X’ added to ‘Blood sampling for 
intracellular PK’ on Day 16.
Updated for consistency with
Section 2.3.1 where this 
assessment is already included on 
Day 16.  
Section 5.3 
Participant and Study 
Completion
Added ‘…for which he was eligible’ 
to the end of the first sentence
To increase clarity.
Section 7.5
Preparation/Handling/
Storage/Accountability
Bullet 4 deleted
Bullet 4 described a specific 
storage temperature for the bulk 
API which is incorrect and not in 
line with the storage conditions on 
other documentation. Since bullet 8 
(now bullet 7) contains an 
acceptable, more general statement 
on storage conditions, bullet 4 is not 
required.
Section 2, SoA;
Section 3.3.1 Risk 
Assessment;
Section 5.5.1 Part A 
Dose Justification
Section 7.1 (Table 5)
Section 8.1.3 
Haematological 
Stopping Criteria
Section 10.4.2 
Pharmacokinetic 
Analysis
Minor typographical corrections to 
include superscripts or subscripts, 
eg Cmax changed to Cmax, 106 
changed to 106
Section 5.5.4
Updated cross-reference 5.1.1 to 
5.5.1.
Correction of cross-reference


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Amendment 3 (29 May 2018)
This is a substantial amendment being made primarily for two reasons.  
Firstly, capsule formulation development has been ongoing in order to allow doses lower 
than 10 mg to be administered as a capsule; currently doses from 1 mg up to 10 mg 
require solution administration.  The amendment will allow dose levels from 3 mg to be 
administered as a capsule formulation, which will be of particular benefit in the repeat 
dose part of the study (Part C) should administration of lower dose levels be required.
In addition, the flexibility of participation in Part A has been increased to facilitate 
subject recruitment.  The protocol has therefore undergone a thorough review and 
appropriate changes made in order to increase flexibility for, and to aid recruitment and 
retention of, participants, while ensuring participant safety is maintained.
Other minor revisions have also been made in response to logistical / operational 
considerations now that the study is underway, and to provide additional clarification on 
some points.
The specific revisions are summarised below:


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Section # and Name
Description of Change
Brief Rationale
SoA tables (all)
Stipulated fasted screening safety 
clinical chemistry samples
To ensure exclusion criteria #19 and 
#20 (now #18 and #19), and on-
treatment fasted lipid levels, are 
compared with fasted lipid levels at 
screening 
2.1, 2.2 and 2.3 SoA 
General Activities 
Tables for Parts A, B 
and C
Clarification of Day -1 
Inclusion/Exclusion criteria
To ensure that it is known that this is to 
recheck eligibility against medical 
conditions, prior therapy etc and not 
against Day -1 lab tests such as clinical 
chemistry and haematology etc. 
2.1 SoA Part A 
Visual forearm screening clarification 
Clarification that a visual forearm check 
is required in Treatment Period 3 only if 
the participant is eligible for Treatment 
Period 4.
2.1.1 SoA. Part A 
Period 4 
Note added to state that participants 
taking part in treatment Period 4 only 
will undergo screening prior as 
detailed in Section 2.1.
Day -10 column corrected to ‘3 days’ 
For clarification
Correction – previously said ‘+/ 3 days’
2.1.1.1., 2.1.1.2 (SoA 
Part A Period 4 [LPS 
and GM-CSF]), 2.3.2 
and 2.3.3 (SoA Part C 
[LPS and GM-CSF])
Removed the 10hr column
There are no assessments at the 10 
hour timepoint other than vitals where 
timepoints are already covered in the 
notes column.
2.3, 2.3.2 and SoA 
tables Part C
Added coagulation tests on Day 13 
(Section 2.3) and Day 13 and 14  
(Section 2.3.2)
Added Day 16 cellular activation 
sample (E2b)
To allow post-LPS challenge 
coagulation to be assessed as already 
included in Part A
Missed in error
2.3 SoA table Part C 
and 2.3.1 Part C Day 
14 SoA
Added S4 sample time points.
Missed in error
2.3.1 Part C Day 14 
SoA
Added a note to state that S3 samples 
only collected until start of challenge 
administration
Missed in error
2.3.3 Part C Day 14 
GM-CSF
Moved 10 h haematology sample to 
8 h
Correction
Synopsis and 5.1.1.1 
Part A Single 
Ascending Doses
Paragraph added to increase flexibility 
of participation in Part A
Text regarding: timing of dosing of 
remainder of cohort after sentinels 
updated
To increase recruitment / retention 
potential in Part A.
To clarify that the 48 hours is not a 
specific timepoint.
Synopsis and 5.1.1.3 
Part A Total Duration
Study durations added for participants 
not taking part in all four treatment 
Periods
Required with text included in Section 
5.1.1.1 to add flexibility in Part A 
participation
Synopsis and 5.2 
Number of 
Added text to explain that participants 
randomised to one part of the study 
To aid recruitment/retention.


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Section # and Name
Description of Change
Brief Rationale
Participants
can enrol on another part, excluding 
those who have received an LPS 
challenge.
Added text to ‘Additional participants / 
cohorts’ paragraph’ to state this 
means as part of a new cohort
Clarification. 
5.2 Number of 
Participants
Text added to clarify that any new 
participants taking part in Treatment 
Period 4 only will be classed as 
replacement subjects for participants 
who took part in treatment Periods 1-
3.
To allow flexibility within the current 
cohorts and thus ensuring minimal 
impact to the randomisation set-up. 
5.4 Scientific 
Rationale
Added text to Part A paragraph to 
explain why flexibility of participation 
has been included
To aid recruitment / retention
6.1 Inclusion Criteria 
#1
Upper age limit has been increased to 
55 years for participants having 
challenge agents. 
Upper age limit increased to 65 years 
for participants not having challenge 
agents. 
To aid recruitment/retention. Team 
agreed this could be increased slightly 
without impact.
No requirement to restrict age range 
6.2 Exclusion #3
Added text to clarify this criterion only 
applies to participants having blister 
induction
To aid recruitment into parts of the 
study where no blister induction is 
required, as this assessment is not 
necessary.
6.2 Exclusion #7
Changed time period from previous 
trial from 90 days to 30 days 
To aid recruitment / retention.  Was 90 
days in line with enabling study 
protocol (Study ID 207654) but 30 days 
is standard for heathy volunteer 
studies.
6.2 Exclusion #10
Exclusion 10 has been deleted.
To aid recruitment. Study team have 
agreed that only prior LPS exposure 
requires exclusion and not prior blister 
induction or GM-CSF exposure, 
therefore no need to exclude all 
enabling study participants.
6.2 Diagnostic 
assessments Header
Added ‘at screening’
To clarify that the Day -1 tests are not 
for eligibility.
6.2 Exclusion #16 
(now #15) 
Added text to clarify CRP 
abnormalities must be clinically 
significant 
Match exclusion #17 (now #16)
6.2 Exclusion #19 
(now #18)
Stipulated fasted levels and increased 
limit
Fasted triglycerides are appropriate for 
screening thresholds. Also ensures on-
treatment fasted triglyceride levels are 
compared with fasted triglyceride levels 
at screening.  Criterion changed to 
reflect CTCAE guidelines
6.2 Exclusion #20 
(now #19)
Stipulated fasted levels and increased 
limit
Fasted total cholesterol is appropriate 
for screening thresholds. Also ensures 


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Section # and Name
Description of Change
Brief Rationale
on-treatment fasted cholesterol levels 
are compared with fasted cholesterol 
levels at screening.  Criterion changed 
to reflect CTCAE guidelines
7.1 Treatments 
Administered; Table 3
Amended capsule unit dose strength 
to ‘from 3 mg to 70 mg’ and added 
note to bottom of table
3 mg capsule formulation being 
developed to avoid need for a repeat 
dose solution administration at lower 
doses.
Maximum dose strength updated to be 
in line with Investigational Medicinal 
Product Dossier (IMPD) and note 
added to bottom of table to clarify this 
is not the maximum planned dose in 
the study.
7.5 Preparation 
/Handling /Storage 
/Accountability
Amended item 2 to include 3 mg 
capsule strength and maximum 70 mg 
capsule strength.
Amended items 4 and 5
3 mg capsule formulation being 
developed to avoid need for a repeat 
dose solution administration at lower 
doses. Maximum dose strength 
updated to be in line with IMPD
Stability work is now complete 
therefore the shelf-life information can 
be confirmed.
7.7 Concomitant 
Therapy
Wording amended to make it clearer 
that abstention from emollients 
containing hydrocortisone and topical 
creams only applies in parts of the 
study with blister challenges. 
Clarification as blister challenges may 
not be performed in Part C or for some 
subjects in Part A.
8.1.3 Haematological 
stopping criteria
Added that safety stopping criteria are 
for persistent abnormalities that are 
confirmed on repeat testing where 
applicable.
Amended to ‘neutrophils ≤ 1.0 x 109/L 
or neutrophils >1.0-1.5 x 109/L which 
is clinically significant’
Risk of lab errors or spurious results 
meeting stopping criteria 
Neutrophils > 1.0-1.5 have been 
observed in asymptomatic healthy 
volunteers
8.1.4. Lipid stopping 
criteria
Added that safety stopping criteria are 
for persistent abnormalities that are 
confirmed on repeat testing where 
applicable.  
Stipulated fasted levels.
Added text that lipid stopping criteria 
do not apply to Part B.
Increased stopping limits
Risk of lab errors or spurious results 
meeting stopping criteria.
Rationale as described for Section 6.2 
To avoid unnecessary withdrawals as 
lipid elevations are expected after food.
In line with CTCAE criteria.
8.1.9.1 Study 
Treatment Restart or 
Rechallenge
Clarified this is for that individual’s 
restart or rechallenge
Could be misinterpreted as applying to 
the whole study


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Section # and Name
Description of Change
Brief Rationale
9 Study Assessments
2nd bullet from bottom – changed such 
that total blood volume is not planned 
to exceed 500 mL (rather than will not)
Required repeat sampling e.g. for 
safety monitoring may increase blood 
volume draw. Language then 
consistent with ICF
9.2.1 Time Period & 
Frequency for 
AE/SAE Info
Updated bullet 3 on medical 
occurrences to state that these are 
recorded in source notes
Noted that PIMS does not have a Med 
History / Current Med conditions page
9.4.4 Vital Signs
Text revised to change some triplicate 
timepoints to single measurements
To aid with assessment logistics – not 
deemed essential to have all 
timepoints as triplicate.
9.4.7 Clinical Safety 
Laboratory 
Assessments
Added bullet that Day -1 clinical lab 
safety samples are for baseline 
assessment
Clarification that the purpose of the 
Day -1 samples is not for specific 
review against eligibility criteria.
9.5.2. Urine Sample 
Collection and 
Analysis
Wording added regarding handling of 
urinalysis samples during the 0-24h 
urine collection period
To clarify that samples collected for 
urinalysis will not be part of the overall 
0-24h collection.
10.2.1 Sample size 
assumptions 
The word ‘approximately’ added to 
Part A, B and C paragraphs.
To align with the minimum evaluable 
number of subjects required for data 
analysis
12.2 Appendix 2 
Clinical Lab tests
Added clarification on fasting sample 
requirements
To ensure exclusion criteria #19 and 
#20 (now #18 and #19), and on-
treatment fasted lipid levels, are 
compared with fasted lipid levels at 
screening

SAP_001.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
207546 
 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for GSK3358699 First time in 
human study 207546: A randomised, double-blind (sponsor 
open), placebo-controlled, three part study to evaluate the 
safety, tolerability, pharmacokinetics and 
pharmacodynamics of single (in both fed and fasted states) 
or repeat doses of GSK3358699 in healthy male 
participants. 
Compound Number  : GSK3358699 
Study Number 
:  207546 
Effective Date  
: Refer to Document Date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol GlaxoSmithKline Document 
Number 2017N332348_05.  
• 
This RAP is intended to describe the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of GSK3358699 (and GSK3206944 where applicable), in 
single (in both fed and fasted states) and repeat oral doses in healthy participants.  
• This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverables. 
 
 
RAP Author: 
Approver 
Date 
Approval 
Method 
NA 
NA 
Statistician  
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
207546 | Statistical Analysis Plan  RAP 22 Jun 2020 | TMF-1817519 | 1.0
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CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
207546 
 
 
2 
 
RAP Team Review Confirmation: 
Reviewer 
Date 
Confirmation 
Method 
12-JUN-2020 
email 
Director (CPMS) 
12-JUN-2020 
email 
Global Clinical Development Director (GCSD) 
12-JUN-2020 
email 
Scientific Director (Adaptive Immunity RU)  
12-JUN-2020 
email 
Data Manager (GCDO) 
12-JUN-2020 
email 
Programmer (II TA Clinical Programming) 
Scientific Director (Adaptive Immunity RU) 
12-JUN-2020 
email 
12-JUN-2020 
email 
Director (Discovery Medicine) 
12-JUN-2020 
email 
Director (GCSP) 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Approval Method 
Pharma TMF 
eSignature 
Statistics Director 
Pharma TMF 
eSignature 
 
Clinical Programming Manager 
 
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CONFIDENTIAL 
 
207546 
 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objectives and Endpoints ................................................................... 7 
2.3. 
Study Design ................................................................................................ 7 
2.4. 
Statistical Analyses ..................................................................................... 12 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 14 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 15 
5.1. 
General ....................................................................................................... 15 
5.2. 
Study Treatment Display Descriptors .......................................................... 15 
5.3. 
Baseline Definitions .................................................................................... 16 
5.3.1. 
Part A single dose (cross-over) .................................................... 16 
5.3.2. 
Part C repeat dose (parallel) ........................................................ 16 
5.4. 
Re-enrolled Participants .............................................................................. 16 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 17 
6. 
STUDY POPULATION ANALYSES ....................................................................... 17 
7. 
EFFICACY ANALYSES .......................................................................................... 17 
8. 
SAFETY ANALYSES ............................................................................................. 17 
8.1. 
Adverse Events Analyses ........................................................................... 17 
8.2. 
Clinical Laboratory Analyses ....................................................................... 18 
8.3. 
Other Safety Analyses ................................................................................ 19 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 19 
9.1. 
Endpoint / Variables .................................................................................... 19 
9.1.1. 
Drug Concentration Measures ..................................................... 19 
9.1.2. 
Derived Pharmacokinetic Parameters .......................................... 20 
9.1.3. 
Summary Measure ...................................................................... 21 
9.1.4. 
Population of Interest ................................................................... 21 
9.1.5. 
Statistical Analyses / Methods ..................................................... 21 
9.1.5.1. 
Dose proportionality (Part A) ...................................... 21 
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 22 
10.1. 
Primary Pharmacodynamic and Biomarker Analyses .................................. 22 
10.1.1. 
Endpoint / Variables ..................................................................... 22 
10.1.2. 
Summary Measure ...................................................................... 22 
10.1.3. 
Population of Interest ................................................................... 22 
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10.1.4. 
Statistical Analyses / Methods ..................................................... 23 
11. EXPLORATORY ANALYSES ................................................................................. 23 
12. REFERENCES ....................................................................................................... 24 
13. APPENDICES ........................................................................................................ 25 
13.1. 
Appendix 1: Schedule of Activities .............................................................. 25 
13.1.1. 
Part A General Schedule of Activities .......................................... 25 
13.1.1.1. Part A Period 4 Schedule of Activities......................... 31 
13.1.1.2. Part A Period 4 Detailed SoA for LPS 
Challenge and Biomarker Sampling ........................... 34 
13.1.1.3. Part A Period 4 Detailed SoA for GM-CSF 
challenge and Biomarker Sampling ............................ 35 
13.1.2. 
Part C General Schedule of Activities Cohorts 5-7 (no 
challenges) .................................................................................. 37 
13.1.2.1. Part C Day 14 Detailed SoA for PK and PD / 
Biomarker Sampling Cohorts 5-7 (no 
challenges) ................................................................. 41 
13.1.3. 
Part C General Schedule of Activities Cohorts 4 and 8 
(with challenges) .......................................................................... 42 
13.1.3.1. Part C Day 14 Detailed SoA for Challenge 
Administration and PK Sampling Cohorts 4 and 
8 (with challenges)...................................................... 47 
13.1.3.2. Part C Day 14 Detailed SoA for LPS Challenge 
and Biomarker Sampling Cohorts 4 and 8 (with 
challenges) ................................................................. 48 
13.1.3.3. Part C Day 14 Detailed SoA for GM-CSF 
Challenge and Biomarker Sampling Cohorts 4 
and 8 (with challenges) ............................................... 49 
13.2. 
Appendix 2: Assessment Windows ............................................................. 51 
13.2.1. 
Definitions of Assessment Windows for Analyses ........................ 51 
13.3. 
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 52 
13.3.1. 
Study Phases for Parts A and C .................................................. 52 
13.3.1.1. Study Phases for Concomitant Medication ................. 52 
13.3.2. 
Treatment Emergent Flag for Adverse Events ............................. 53 
13.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 54 
13.4.1. 
Reporting Process ....................................................................... 54 
13.4.2. 
Reporting Standards ....................................................................... 54 
13.4.3. 
Reporting Standards for Pharmacokinetic .................................... 56 
13.5. 
Appendix 5: Derived and Transformed Data ............................................... 57 
13.5.1. 
General (Parts A and C) .............................................................. 57 
13.5.2. 
Study Population .......................................................................... 57 
13.5.3. 
Pharmacokinetics ........................................................................ 58 
13.5.4. 
Pharmacodynamic ....................................................................... 58 
13.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 60 
13.6.1. 
Premature Withdrawals ................................................................ 60 
13.6.2. 
Handling of Missing Data ............................................................. 60 
13.6.2.1. Handling of Missing and Partial Dates ........................ 61 
13.7. 
Appendix 7: Values of Potential Clinical Importance and Normal 
Ranges ....................................................................................................... 62 
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13.7.1. 
Vital Signs .................................................................................... 62 
13.7.2. 
Laboratory Values ........................................................................ 62 
13.7.3. 
ECG ............................................................................................. 64 
13.8. 
Appendix 8: Abbreviations & Trade Marks .................................................. 65 
13.8.1. 
Abbreviations ............................................................................... 65 
13.8.2. 
Trademarks ................................................................................. 66 
13.9. 
Appendix 9: List of Data Displays ............................................................... 67 
13.9.1. 
Data Display Numbering .............................................................. 67 
13.9.2. 
Mock Example Shell Referencing ................................................ 67 
13.9.3. 
Deliverables ................................................................................. 67 
13.9.4. 
Study Population Tables .............................................................. 68 
13.9.5. 
Safety Tables ............................................................................... 72 
13.9.6. 
Safety Figures ............................................................................. 79 
13.9.7. 
Pharmacokinetic Tables ............................................................... 80 
13.9.8. 
Pharmacokinetic Figures ............................................................. 82 
13.9.9. 
Pharmacodynamic Tables ........................................................... 84 
13.9.10. Pharmacodynamic Figures .......................................................... 85 
13.9.11. ICH Listings ................................................................................. 86 
13.9.12. Non-ICH Listings .......................................................................... 93 
 
 
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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 Clinical Study Report for Protocol: 
Revision Chronology: 
2017N332348_01 
30-NOV-2017 
Original 
2017N332348_02 
25-JAN-2018 
Amendment 1 
2017N332348_03 
21-MAR-2018 
Amendment 2 
2017N332348_04 
29-MAY-2018 
Amendment 3 
2017N332348_05 
11-DEC-2018 
Amendment 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The following changes were made from the originally planned statistical analysis specified 
in protocol GlaxoSmithKline Document Number 2017N332348_05 [(Dated: 11-DEC-
2018)]: 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
Section 10.3: the populations 
described are Enrolled, 
Randomised, Evaluable, Safety, 
PK, PK/PD. 
• 
Section 4: the populations 
described are Enrolled, 
Screened, Safety, PK. 
• 
Randomised and Evaluable 
population not needed in 
any table, figure or listing. 
• 
PK/PD population and 
Safety population coincide. 
• 
Enrolled population needed 
for Tables of Age Ranges. 
Due to the early termination of the study, the planned exploratory analysis detailed in the 
protocol will not be included in the main SAC delivery. Exploratory analysis will be 
performed separately in cases where it is deemed clinically or scientifically relevant. The 
study was terminated prior to any subjects being dosed with study treatment in Part B and 
therefore only minimal listings of screening data will be produced for this part. 
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2.2. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• [P1] To evaluate the safety and 
tolerability of single and repeat oral 
doses of GSK3358699 in healthy male 
participants. 
• AE reporting. 
• Laboratory safety data (clinical chemistry, 
haematology, urinalysis). 
• Vital signs (blood pressure, heart rate, body 
temperature). 
• 12 lead ECGs. 
Secondary 
• [S1] To evaluate the systemic 
pharmacokinetic (PK) profile following 
single and repeat oral doses of 
GSK3358699 in healthy male 
participants. 
• Plasma concentrations of GSK3358699 plus 
derived PK parameters. 
 
• [S2] To evaluate the systemic PK 
profile of the acid metabolite, 
GSK3206944 following single and 
repeat oral doses of GSK3358699 in 
healthy male participants. 
• Plasma concentrations of GSK3206944 plus 
derived PK parameters. 
• [S3] To evaluate the intracellular PK 
profile of GSK3206944 in target cells 
following single and repeat oral doses 
of GSK3358699 in healthy male 
participants. 
• Monocyte intracellular quantification of 
GSK3206944. 
• [S4] To understand the extent of target 
engagement (TE) after ex vivo LPS 
challenge following single and repeat 
oral doses of GSK3358699 in healthy 
male participants. 
• Plasma concentrations of monocyte 
chemoattractant protein (MCP)-1, interleukin 
(IL)-6 and tumour necrosis factor (TNF) in 
blood stimulated ex vivo with LPS over time. 
 
P1: Primary Objective 1 – Safety 
S1: Secondary Objective 1 – GSK3358699 systemic PK 
S2: Secondary Objective 2 - GSK3206944 systemic PK 
S3: Secondary Objective 3 - GSK3206944 intracellular PK 
S4: Secondary Objective 4 - TE 
2.3. 
Study Design 
This study will be a randomised, double-blind (sponsor open), placebo-controlled, three 
part study of oral administration of GSK3358699 in healthy male participants.  Part A will 
be a single ascending dose crossover design in two interlocking cohorts of participants 
(Cohorts 1 and 2). Part B will be a single dose, open-label two-way crossover study with 
GSK3358699 administered under fed and fasted conditions in a further cohort of 
participants (Cohort 3).  Part C is planned to be a repeat dose design in 5 sequential cohorts 
of participants (Cohorts 4-8). 
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207546 
 
 
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All participants in Part A, Part B and Part C of the study will attend a screening visit within 
35 days prior to their first dose (with the exception of Cohort 8 where the screening visit 
will be within 45 days prior to their first dose) and a follow up visit within 7-14 days of 
their last dose.  A second follow up visit will also be conducted approximately 5 weeks 
after the last dose for those participants in cohorts where challenges and blisters are being 
administered.  If warranted, additional follow-up visits may be scheduled. 
Note: Due to early termination of the study Parts B and C were not completed as planned. 
No subjects were randomised or dosed in Part B and subjects were only dosed in Cohorts 
4 and 5 of Part C. 
The table below provides an overview of the study design and the key features. 
Part A: Single Ascending Doses and LPS / GM-CSF challenges 
Part A 
Design 
features 
• Participants who are randomised into Part A can be enrolled in 
another part of the study if they still fulfil all eligibility criteria 
(which means that participants having received LPS challenge in 
Part A will not be eligible to participate in another part of the study). 
• In the Part A dose escalation phase (treatment periods 1-3), there 
will be two interlocking cohorts (Cohorts 1 and 2) each with up to 
9 healthy participants. Each participant will receive a maximum of 
2 single ascending oral doses of GSK3358699 and 1 placebo dose.  
• At each dose level, GSK3358699 and placebo will be administered 
in a 2:1 ratio, within each period, according to the randomisation 
schedule, in a blinded manner.  Up to a maximum of 6 dose levels 
will be studied in total in Part A. Participants who are enrolled in 
the dose escalation treatment Periods of Part A may choose to only 
take part in the dose escalation treatment Periods 1-3, or may choose 
to also take part in the challenge treatment period (Period 4). If a 
participant chooses to participate in the dose escalation treatment 
Periods 1-3 only, or does not (at screening) meet the eligibility 
criteria specific to challenges (treatment Period 4), a new participant 
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Part A: Single Ascending Doses and LPS / GM-CSF challenges 
will be recruited for treatment Period 4 only and will be regarded as 
a replacement participant. If a subject prematurely discontinues the 
study during Part A, additional replacement participants will be 
recruited and assigned to the same treatment sequence, starting from 
the next planned dosing Period following the premature 
discontinuation. 
• Staggering of the first two participants (sentinel dosing) will be 
implemented in each cohort in each treatment period for this single 
dose phase.  No participant will be a sentinel participant more than 
once. On Day 1, one of the two participants will receive the active 
dose and the other will receive placebo.  Assuming adequate safety 
from these two participants over the first 48 hrs post-dose, the 
remaining participants in the cohort can then be dosed. 
• Data, and hence dose level, will be reviewed between each period. 
There will be a minimum 14 days between the start of dosing (i.e. 
dosing of sentinel participants) in Cohort 1 and Cohort 2 in each 
treatment period.  
• The decision to proceed to the next dose level of GSK3358699 will 
be made at a Dose Escalation Committee (DEC) meeting 
• Upon conclusion of the dose escalation phase of Part A, an 
additional dosing period (treatment period 4) will be included.  
Participants in both cohorts will attend the clinic for outpatient 
visits, on Day -10 ( 3 days) to have control blisters induced on the 
forearm (0.2% cantharidin), and will have a blister sample taken at 
a timepoint between approximately 48hrs post-blister induction.  
• Participants in Cohort 1 will be administered an IV in vivo LPS 
challenge at a dose of 0.75 ng/kg following treatment with 
GSK3358699 or placebo and will then have blisters induced on the 
forearm (0.2% cantharidin) approximately 20 minutes after the 
challenge.  The final selection of LPS dose will take into account all 
available pre-clinical and clinical safety and PD data at the time of 
study initiation.   
• Participants in Cohort 2 will be administered 60 g/m2 in vivo GM-
CSF challenge as an IV infusion following treatment with 
GSK3358699 or placebo and will then have blisters induced on the 
forearm (using 0.2% cantharidin) approximately 20 minutes after 
the end of the GM-CSF infusion.  
• Of the nine participants within each cohort, six will receive 
GSK3358699 and three will receive placebo in treatment period 4, 
as per the randomisation schedule. 
Part A 
Time & 
Events 
• Refer to Appendix 1: Schedule of Activities 
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Part A: Single Ascending Doses and LPS / GM-CSF challenges 
Part A 
Treatmen
t 
sequences 
• Illustration of actual treatments after dose escalation in Part A.  
 
 
Period 1 
Period 2 
Period 3 
Cohort 
1 
N=3 
P 
 
10mg 
 
40mg 
 
N=3 
1mg 
 
P 
 
40mg 
 
N=3 
1mg 
 
10mg 
 
P 
 
Cohort 
2 
N=3 
 
P 
 
20mg 
 
30mg 
N=3 
 
3mg 
 
P 
 
30mg 
N=3 
 
3mg 
 
20mg 
 
P 
P= Placebo;  1-40mg = GSK3358699 
 
• The GSK3358699 dose for the challenge agent treatment Period 4 will 
be confirmed following completion of the dose escalation treatment 
periods 1-3.   
• The GSK3358699 dose for Part B, and the first cohort in Part C will be 
confirmed by the DEC following completion of the dose escalation and 
challenge treatment periods in Part A.  Doses for subsequent cohorts in 
Part C will be confirmed following completion of the previous Part C 
cohort at the prior dose level. 
• Within each cohort, participants will be assigned to one of six dosing 
sequences for the dose escalation phase, where participants will be 
randomised to: 
 
 
Cohort 1 
Cohort 2 
Sequence 
PCER 
APER 
ACPR 
PCEP 
APEP 
ACPP 
PDFR 
BPFR 
BDPR 
PDFP 
BPFP 
BDPP 
 
Where the treatment codes are as follows: 
Treatment code 
Treatment Description 
A 
1 mg GSK3358699 SD 
B 
3 mg GSK3358699 SD 
C 
10 mg GSK3358699 SD 
D 
20 mg GSK3358699 SD 
E 
40 mg GSK3358699 SD 
F 
30 mg GSK3358699 SD 
P 
Placebo SD 
R 
25 mg GSK3358699 SD 
 
• Treatments E, F and R in the table above contain the description of the 
actual doses following DEC decisions, not the dose descriptions as 
given by RandAll (see Section 5.2). 
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Part A: Single Ascending Doses and LPS / GM-CSF challenges 
• Of the nine participants within each Cohort, six will then receive 
GSK3358699 and three will receive placebo in treatment Period 4, as 
per the randomisation schedule.  
 
 
Part C: Multiple Ascending Doses and LPS or GM-CSF challenge with cantharidin-induced 
blisters 
 
Part C 
Design 
features 
• Participants who are randomised into Part C can be enrolled in Part B 
of the study, as well as be enrolled in a later cohort of Part C, if they 
still fulfil all eligibility criteria (which means that participants having 
received LPS challenge in Part A or Part C cohort 4 will not be eligible 
to participate in another cohort of the study). 
• Will consist of five cohorts of healthy participants: 14 participants in 
Cohort 4, 18 in each of Cohorts 5-7, 20 in Cohort 8. Note: Due to the 
early termination of the study subjects were only dosed in Cohorts 4 
and 5. 
• Cohorts 5-7 will be dosed sequentially (i.e., Cohort 6 starts after dosing 
in Cohort 5 is completed). The decision to proceed to the next cohort 
and the associated dose level of GSK3358699 will be made at a DEC 
meeting. 
• Each cohort will take part in one repeat dose treatment period with 14 
days of once-daily dosing. 
• In Cohort 4, participants will be randomised in a 5:2 ratio to receive 
either GSK3358699 or placebo, according to the randomisation 
schedule, once daily from Day 1 to Day 14 inclusive. 
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Part C: Multiple Ascending Doses and LPS or GM-CSF challenge with cantharidin-induced 
blisters 
• In Cohort 5-8, participants will be randomised in a 1:1 ratio to receive 
either GSK3358699 or placebo, according to the randomisation 
schedule, once daily from Day 1 to Day 14 inclusive. 
• On Day 14 of Cohorts 4 and 8, an IV in vivo LPS challenge at a dose 
of 0.75 ng/kg or a 60 g/m2 GM-CSF challenge as an IV infusion will 
be administered, followed by blister induction. 
• LPS / GM-CSF administration may be performed at low systemic 
concentrations of GSK3358699 when intracellular concentrations of 
the acid GSK3206944 are high; The decision on the timepoint for 
administration will be based on emerging data and will be no more 
than 24 h after dosing with GSK3358699 or placebo on Day 14.  
• In Cohort 4, of the 14 randomised participants, 7 will receive LPS 
challenge and 7 GM-CSF challenge. Of the 7 participants receiving 
each challenge, 5 will be randomised to receive GSK3358699 and 2 to 
receive placebo at the start of the cohort. 
• 
In Cohort 8, of the 20 randomised participants, 10 will receive LPS 
challenge and 10 GM-CSF challenge. Of the 10 participants receiving 
each challenge, it is planned that 5 will be randomised to receive 
GSK3358699 and 5 to receive placebo. 
Part C 
Time & 
Events 
• Refer to Appendix 1: Schedule of Activities 
Part C 
Treatment 
Sequences 
• Within each cohort participants will be assigned to either 
GSK3358699 or placebo in a 5:2 ratio (Cohort 4) or a 1:1 ratio 
(Cohorts 5-8). The treatments will be determined following the 
completion of Part A. The treatment codes will be: 
Treatment code 
Treatment Description 
I 
10 mg GSK3358699 RD 
J 
10 mg GSK3358699 RD 
P 
Placebo 
  
2.4. 
Statistical Analyses 
The primary objective is to determine the safety and tolerability of single and repeat oral 
doses of up to 14 days with GSK3358699 in healthy participants. 
There are no formal hypotheses being tested in the study. 
An estimation approach will be used to quantify the single dose PK for each dose level 
studied and also to assess PK parameters following 14 days repeat dosing relative to single 
dosing. 
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3. 
PLANNED ANALYSES 
3.1. 
Final Analyses 
The final planned analyses (Parts A, B and C) will be performed after the completion of 
the following sequential steps: 
1. All participants have completed the study as defined in the protocol (Section 5.3 of the 
protocol): The end of the study is defined as the date of the last visit (including follow-
up) of the last participant in the study (Parts A, B and Part C). 
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 randomisation codes have been met.  
4. Randomisation codes have been distributed according to RandAll NG procedures. 
Due to the early termination of the study, the planned exploratory analysis will not be 
included in the main SAC delivery. Exploratory analysis will be performed separately in 
cases where it is deemed clinically or scientifically relevant. The study was terminated 
prior to any subjects being dosed with study treatment in Part B and therefore only minimal 
listings of screening data will be produced for this part. 
 
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4. 
ANALYSIS POPULATIONS 
Population 
Description 
 
Outputs 
Enrolled 
• All participants who sign the ICF 
• Study Population 
(specific only) 
Screened  
• All participants who were screened for eligibility • Study Population 
(specific only) 
Safety 
• All screened participants who received at least 
one dose of study treatment. 
• This population will be based on the actual 
treatment the participant received. 
• Study Population 
(all others) 
• Safety 
• PD 
 
PK 
• All participants in the Safety population who 
receive an active dose and for whom a PK 
sample was obtained and analysed. 
• This population will be based on the actual 
treatment the participant received. 
 
Note: Non-quantifiable [NQ] values will be 
considered as non-missing values for the purposes 
of deriving the PK population. 
• PK 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient 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. 
• 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.  
• This dataset will be the basis for the listings of protocol deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
output 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. 
General 
Separate outputs will be generated for each of Parts A, B and C. The presence of 
participants taking part in multiple parts/cohorts of the study will be appropriately notified 
in the relevant Safety outputs. 
5.2. 
Study Treatment Display Descriptors 
In the Tables, Listings and Figures (TLF), treatment should be presented with placebo first, 
then in order of increasing dose within each part. 
Part A: Treatment group descriptions 
RandAll NG 
Data displays for reporting 
Code RandAll description 
Table/Figure 
Label 
Listing Label 
Order in TLF 
A 
1 mg GSK3358699 SD 
1 mg SD 
1 mg SD – A 
2 
B 
3 mg GSK3358699 SD 
3 mg SD 
3 mg SD – B 
3 
C 
10 mg GSK3358699 SD 
10 mg SD 
10 mg SD – C 
4 
D 
20 mg GSK3358699 SD 
20 mg SD 
20 mg SD – D 
5 
E 
35 mg GSK3358699 SD 
40 mg SD 
40 mg SD – E 
8 
F 
45 mg GSK3358699 SD 
30 mg SD 
30 mg SD – F 
7 
R 
Dose X GSK3358699 SD 25 mg SD 
25 mg SD – R 
6 
P 
Placebo SD 
Placebo SD 
Placebo SD – P 
1 
Note: doses in RandAll descriptions and display descriptions differ for treatments E, F, R 
due to DEC decisions. 
 
 
Part C: Treatment group descriptions 
RandAll NG 
Data displays for reporting 
Code Description 
Table/Figure Label Listing Label 
Order in 
TLF 
I 
Dose 1 GSK3358699 RD 
10 mg RD 
10 mg RD - I 
2 
J 
Dose 2 GSK3358699 RD 
10 mg RD 
10 mg RD - I 
2 
Q 
Placebo RD 
Placebo RD 
Placebo RD - Q 
1 
Note: the same dose level was administered in both Cohorts 4 and 5 due to the early 
termination of Cohort 4. Subjects in the active treatment group from both cohorts will be 
summarised and listed under the same treatment label. 
 
 
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5.3. 
Baseline Definitions 
5.3.1. 
Part A single dose (cross-over) 
• Baseline definitions are applied to each period. 
• The baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits unless otherwise 
stated below: For ECGs and Vitals, baseline is defined as the mean of 
triplicate measurement at the latest pre-dose assessment. 
 
• For PD S4 assay, MCP-1, IL-6 and TNF, baseline is defined as an average 
of the day -1 1pm and day 1 pre-dose samples.  
• If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
• Replicate assessments at a timepoint will be averaged, and the mean value will be 
used. 
• Unless otherwise stated, if baseline data is missing no derivation will be 
performed and baseline will be set to missing. 
5.3.2. 
Part C repeat dose (parallel) 
• The baseline value will be the latest assessment prior to any dosing with a non-missing 
value, including those from unscheduled visits unless otherwise stated below:  
• For ECGs and Vitals, baseline is defined as the mean of triplicate measurement at 
the latest pre-dose assessment. 
• For PD S4 assay, MCP-1, IL-6 and TNF, baseline is defined as an average of the Day 
-1 1pm and Day 1 pre-dose samples. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline. 
• Replicate assessments at a timepoint will be averaged, and the mean value will be 
used. 
• Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.4. 
Re-enrolled Participants 
The protocol allows participants to take part in more than one cohort in this study. Instances 
where this occurred were as follows:  
Subject Number  
Cohort 1 
Cohort 2 
Cohort 4 
Cohort 5 
 
 
  
  
  
  
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Participants who take part in more than one cohort are to be considered distinct participants 
for the purposes of the reporting of all the data in this study. However relevant displays 
will be footnoted.  
5.5. 
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 
13.2 
Appendix 2: Assessment Windows 
13.3 
Appendix 3: Study Phases and Treatment Emergent Adverse Events 
13.4 
Appendix 4: Data Display Standards & Handling Conventions 
13.5 
Appendix 5: Derived and Transformed Data 
13.6 
Appendix 6: Reporting Standards for Missing Data 
13.7 
Appendix 7: Values of Potential Clinical Importance and Normal Ranges 
 
6. 
STUDY POPULATION ANALYSES 
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic characteristics, prior and concomitant medications, and exposure 
will be based on GSK Core Data Standards. 
Details of the planned displays are presented in Appendix 9: List of Data Displays. 
7. 
EFFICACY ANALYSES 
There are no efficacy analyses to be included in this FTIH study. 
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 4 of the protocol. 
Analyses of AEs will include all events, classified as in Section 13.3. 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. 
Details of the planned displays are presented in Appendix 9: List of Data Displays. 
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8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations will be based on GSK Core Data Standards and will include: 
• Hematology laboratory tests  
• Chemistry laboratory tests 
• Urinalysis 
• Liver function tests 
• Other screening tests 
Clinical laboratory analyses will include all assessments post-baseline. Unscheduled visits 
will not be included in summary tables and figures, but will be included in listings – see 
Section 13.4.2. 
Details of the planned displays are presented in Appendix 9: List of Data Displays. 
The laboratory assessments for each category are displayed below (Table 6 of the protocol): 
Laboratory 
Assessments 
Parameters 
Haematology 
Clotting 
parameters: 
APTT 
PT times 
Fibrinogen 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical Chemistry1 
CRP 
Blood Urea 
Nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and 
direct 
bilirubin 
Albumin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
Glucose 
(fasting during 
Part C2) 
Calcium 
Alkaline 
phosphatase 
Cholesterol2,3 
Low Density 
Lipoprotein2,3 
High Density 
Lipoprotein2,3 
Triglycerides2,3 Gamma-
glutamyl 
Creatine kinase 
(CK)4 
 
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Laboratory 
Assessments 
Parameters 
transferase 
(GGT)4 
Routine Urinalysis 
• Microscopic examination (if blood or protein is abnormal) 
1. 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 8.1 and Appendix 7 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. In Part C at certain time points as per the SoA lipids and glucose samples are required to be taken fasted. 
3. Screening samples are required to be taken fasted. 
4. To be analysed at screening, Day-1 and follow up only 
1.  
8.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results will be based on GSK Core Data 
Standards, unless otherwise specified.  
The non-laboratory safety test results include: 
• ECGs 
• Vital signs 
• Telemetry and Holter monitoring  
Details of the planned displays are presented in Appendix 9: List of Data Displays. 
9. 
PHARMACOKINETIC ANALYSES 
The PK analyses described below will be carried out for GSK3358699 and GSK3206944 
(acid metabolite) if the latter is quantifiable. 
9.1. 
Endpoint / Variables 
9.1.1. 
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3 
Reporting Standards for Pharmacokinetic) to generate the plasma GSK3358699 and 
GSK3206944 concentration-time data, and the intracellular GSK3206944 concentration-
time data, after single and repeat doses (Parts A and C), under fasted conditions. 
In addition to the intracellular GSK3206944 raw concentration which is measured as ng 
per mL in reagent, the molar concentration within the monocytes will also be derived (see 
Appendix 5, Section 13.5.3). 
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9.1.2. 
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 of non-compartmental parameters will be based on actual 
sampling times.  
Pharmacokinetic parameters listed below will be determined from the plasma 
GSK3358699 and GSK3206944 concentration-time data for Parts A and C, 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-∞) 
• Area under the concentration-time curve extrapolated to infinity 
• Calculated as: AUC(0-∞) = AUC(0-t) + C(t) / lambda_z 
• This parameter is calculated for Part A only 
AUC(0-24) 
• Area under the concentration-time curve from time zero to 24 hours 
post-dose 
• Using the same method as for AUC(0-t) 
AUC(0-tau) 
• Area under the concentration-time curve from time zero to the end of 
the dosing period (dosing interval of duration tau) 
Cmax 
• Maximum observed concentration 
• Determined directly from the concentration-time data. 
tmax 
• Time to reach Cmax 
• Determined directly from the concentration-time data. 
t1/2(terminal) • Terminal half-life [The time it takes for the concentration levels to fall 
to 50% of their value in the terminal phase]. 
• Calculated as: t1/2 = ln(2) / lambda_z 
• Lambda_z is the terminal phase rate constant estimated by linear 
regression analysis of the log transformed concentration-time data 
 
t1/2(initial) 
• Actual initial half-life [The time it takes for the concentration levels to 
fall to 50% of their value in the initial phase]. 
• Calculated as: t1/2 = ln(2) / lambda_ini 
• Lambda_ini is the initial phase rate constant estimated by linear 
regression analysis of the log transformed concentration-time data 
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9.1.3. 
Summary Measure 
In addition to the parameters mentioned above, the following will also be calculated: 
Part C (repeat dose) 
R0 
• Accumulation between 1 single dose (Day 1) and repeat dose (Day 14) 
• Calculated as R0 =AUC(0-tau) Day 14/AUC(0-tau) Day 1 
Rs 
• Steady state ratio (time invariance kinetics) 
• Calculated as Rs=AUC(0-tau) Day 14/AUC(0-inf) Day 1 
9.1.4. 
Population of Interest  
The pharmacokinetic analyses will be based on the Pharmacokinetic population, unless 
otherwise specified. 
9.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are presented in Appendix 9: List of Data Displays and will 
be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.1 will be summarised 
using descriptive statistics, graphically presented (where appropriate) and listed. 
9.1.5.1. 
Dose proportionality (Part A) 
Dose proportionality will be assessed for GSK3358699 by visual inspection of: 
- 
Part A (single dose - fasted state): dose normalised AUC(0-∞) [or if not available 
AUC(0-t)] and Cmax values versus dose. 
If data permits, dose proportionality may also be assessed for GSK3358699 using the 
power model described below. 
Dose proportionality (Parts A and C) 
Endpoints 
• Part A (single dose - fasted state): AUC(0-t), AUC(0-∞) and Cmax 
 
Model specification 
• Power model (log-log linear model):  
𝑦=  𝛼 × 𝑑𝑜𝑠𝑒𝛽 ⟺ log𝑒(𝑦) = log𝑒(𝛼) +  𝛽 × log𝑒(𝑑𝑜𝑠𝑒) 
Where  
o y        = endpoint of interest 
o dose   = actual dose received under fasted condition 
o β        = parameter associated to dose (slope) 
o α       = participant-specific random effect (intercept) 
• Terms fitted in the power model: 
o Response: log transformation of the endpoint of interest log𝑒(𝑦)  
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o Fixed continuous covariates: log𝑒(𝑑𝑜𝑠𝑒) 
o Random: participant 
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure on the random effects terms (SAS: G matrix, 
random statement) will be used. 
Model checking & diagnostics 
• Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus 
the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model, respectively) to gain confidence that the model assumptions 
are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will 
be explored using appropriate transformed data. 
Model results presentation 
Table of the estimated slopes and 90% CI (slope close to 1 implies dose proportionality). 
The following will be derived: 
• Fold-increase for doubling dose: 2𝛽, where 𝛽 is the slope 
• 90% CI for fold-increase: (2𝑏𝑙, 2𝑏𝑢), where (𝑏𝑙, 𝑏𝑢) is the 90% CI for the slope 
 
10. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
10.1. 
Primary Pharmacodynamic and Biomarker Analyses 
The PD parameters collected during the study will be listed for each participant and 
treatment and summarised descriptively by treatment.  
10.1.1. 
Endpoint / Variables 
See Appendix 5: Derived and Transformed Data for the full list of biomarkers and the 
related displays planned for final SAC. 
10.1.2. 
Summary Measure 
Continuous summaries of absolute values, percentage inhibition and predicted percentage 
inhibition will be presented for each biomarker detailed in Appendix 5, Section 13.5.4. 
10.1.3. 
Population of Interest 
These analyses will be based on the Safety population, unless otherwise specified. 
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10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are presented in Appendix 9: List of Data Displays and will 
be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 
11. 
EXPLORATORY ANALYSES 
Exploratory analysis detailed in the protocol will be covered outside of this RAP and 
reported separately from the main study reporting. 
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24 
 
12. 
REFERENCES 
GlaxoSmithKline Document Number 2017N332348_05. Study ID 207546: A randomised, 
double-blind (sponsor open), placebo-controlled, three part study to evaluate the safety, 
tolerability, pharmacokinetics and pharmacodynamics of single (in both fed and fasted 
states) or repeat doses of GSK3358699 in healthy male participants. 11-DEC-2018. 
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13. 
APPENDICES 
13.1. 
Appendix 1: Schedule of Activities 
13.1.1. 
Part A General Schedule of Activities 
Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
General 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
See separate Period 4 Schedule of Activities
  
  
  
Inclusion and exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Day -1 assessment is to recheck 
eligibility against medical conditions, 
prior therapy etc, but not against Day -
1 clinical chemistry and haematology 
results (see Section 9.4.7 of Protocol 
GlaxoSmithKline Document Number 
2017N332348_05).   
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical/medication/drug/ 
alcohol history  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Includes substance usage and family 
history of premature cardiovascular 
(CV) disease and current medical 
conditions. 
Admission to unit for in-patient 
stay 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
Discharge from Unit following in-
patient stay 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
Outpatient visit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
Safety Assessments including laboratory tests 
Full Physical Exam 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
See separate Period 4 Schedule of Activities
  
  
  
Brief Physical Exam 
  
X 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
  
Vital Signs 
X 
X 
X 
  
  
  
 
X 
X 
  
X  
X 
X 
X 
X 
X 
Blood pressure (BP), heart rate (HR), 
temperature, respiratory rate.  See 
Section 9.4.4 of Protocol 
GlaxoSmithKline Document Number 
2017N332348_05 for details on 
triplicate and single measurement 
timepoints. 
12-Lead ECGs 
X 
X 
X 
  
  
  
  
X 
X 
  
X  
X 
X 
X 
X 
  
12 Lead ECGs will be performed in 
triplicate at screening, Day-1, Day 1 
pre-dose, Day 2 and Day 3. Single 
ECGs will be performed at other time 
points and if any cardiac symptoms 
are experienced. ECGs to be 
performed prior to blood draws and 
dosing where these fall at the same 
nominal time.  
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Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
Telemetry 
  
  
<============================================
=====> 
  
  
  
from 1 h pre-dose to 24 h post-dose 
Holter monitoring (24 hours) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a participant is rescreened the 
Holter will not need to be repeated. 
HIV, Hep B, Hep C 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Haematology 
X 
X 
  
  
  
  
  
  
 
  
X  
  
X 
X 
X 
  
Fasted screening samples. 24 and 48 
hour samples will be taken prior to 
participants receiving breakfast 
Coagulation 
X 
  
  
  
  
  
  
  
  
  
 X 
  
X 
X 
X 
  
Fasted screening samples. 24 and 48 
hour samples will be taken prior to 
participants receiving breakfast 
Clinical Chemistry 
X 
X 
  
  
  
  
  
  
 
  
X 
  
X 
X 
X 
  
Fasted screening samples. 24 and 48 
hour samples will be taken prior to 
participants  
Urinalysis 
X 
X 
  
  
  
  
  
  
 
  
 X 
  
X 
X 
X 
  
Fasted screening samples. 24 and 48 
hour samples will be taken prior to 
participants receiving breakfast 
Drug / Alcohol Test 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine Cotinine 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Visual forearm check (cosmetic 
assessment or blister healing 
where appropriate) 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Visual forearm checks are only 
required if participant is scheduled to 
take part in treatment period 4. Details 
of checks:  
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Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
• 
Screening check prior to first 
treatment period (cosmetic 
assessment) 
• 
Day -1 check in treatment 
Period 3 only. Between Day 
-1 and Day 2 (ie 48 hour 
window) (cosmetic 
assessment)  
• 
Period 4 (cosmetic 
assessment and blister 
healing).  For further detail 
on time points in Period 4 
see Section 13.1.1.1. 
• 
Follow-up visits 1 and 2 
(blister healing) 
 
 
 
 
AE / SAE review 
SAEs collected from signing of informed consent form until the final follow up visit; AEs collected 
continuously from time of first dose until the final follow up visit 
 
Concomitant Medication Review 
  
  
Monitored from first dose until the end of the final treatment Period 
  
  
  
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Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
Treatment Administration 
Study Drug / Placebo 
Administration 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
See Period 4 SoA
  
  
  
Pharmacokinetics, Pharmacodynamics and Genetics Samples 
Blood sampling for systemic PK 
[S1] and [S2] 
  
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See separate Period 4 Schedule of Activities
  
  
  
Blood sampling for intracellular 
PK [S3] 
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
X 
  
  
  
Blood sample for ex vivo PD 
assay [S4] 
  
X 
X 
  
  
  
X 
  
X 
  
X 
X 
X 
X 
  
  
Six samples (3 LPS and 3 null) are 
required on Day -1:  to be taken (LPS 
and null) at approximately 13:00, 
17:00 and 20:00. Day 1: Two pre-dose 
samples (LPS and null) to be taken at 
approximately 08:00. 
Blood sample for circulating 
proteins [E1a] 
  
  
X 
  
  
  
  
X 
X 
  
X 
 
X 
  
  
  
  
Blood sample for gene panel 
[E1b] 
  
  
X 
  
  
  
  
X 
X 
  
X 
  
X 
  
  
  
  
Blood sample for companion 
diagnostic development 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample to be taken on Day -1 in 
treatment Period 1 only. 
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Procedure 
Screening (up to 35 Days prior to 
Day 1) 
Treatment Period 1-3 
Treatment Period 4
Follow-up 1 (7-14 days post-last 
dose) 
Follow-up 2  (5 weeks after last 
dose   3 days) 
Notes 
Day -1 
Day 1 
Day 2 
Day 3 
  
Pre-dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
4 h 
6 h 
8 h 
12 h 
24 h 
48 h 
The 2nd follow up visit is only required 
for those participants where 
challenges are being administered 
and blisters induced i.e. treatment 
period 4 
Genetics sample for CES 
genotyping and optional genetic 
research [E5] 
 
 X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Sample to be taken on Day -1 in 
treatment Period 1 only. 
Urine sample for metabolite 
analysis [E4] 
  
  
X 
<========================================
====> 
  
  
  
Pre-dose sample, immediately prior to 
dosing participants will be instructed 
to void their bladder into a collection 
container.  Following dosing 
participants will be instructed to collect 
all urine voided for a 0-24 hour 
collection. 
 
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13.1.1.1. 
Part A Period 4 Schedule of Activities 
Procedure 
 
 
Treatment Period 4 
Notes 
Day -10 (3 
24-48h following  
Day -10 visit 
Day -1 
Day 1 
Day 2 
Day 3 
If participants only take part in treatment Period 4 they 
will undergo screening assessments prior to this 
treatment Period as detailed in Section 13.1.1. 
  
Pre-
dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
3 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
General 
Admission to unit for 
in-patient stay 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge from Unit 
following in-patient 
stay 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Outpatient visit 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For baseline blister induction and sampling; see 
Section 13.1.1.2 and Section 13.1.1.3. The baseline 
blister samples collected will be repeated if > 4 months 
elapses between the baseline blister and the challenge 
treatment Period (eg if a reserve in the study is not 
dosed and is subsequently rescreened for a later 
cohort). 
Safety Assessments including laboratory tests 
Brief Physical Exam 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
   
Vital signs 
 
 
X 
X 
See Section 13.1.1.2 and Section 13.1.1.3 for vital signs 
measurements in relation to challenges 
BP, HR, temperature, respiratory rate. 
Body weight 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Body weight will be measured on Day -1 to calculate 
doses for challenges. 
12-Lead ECGs 
 
 
X 
X 
  
  
  
  
X 
  
X 
  
 X 
X 
X 
X 
12 lead ECGs will be performed in triplicate at Day -1, 
pre-dose Day 1, Day 2 and Day 3.  Single ECGs will 
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Procedure 
 
 
Treatment Period 4 
Notes 
Day -10 (3 
24-48h following  
Day -10 visit 
Day -1 
Day 1 
Day 2 
Day 3 
If participants only take part in treatment Period 4 they 
will undergo screening assessments prior to this 
treatment Period as detailed in Section 13.1.1. 
  
Pre-
dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
3 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
be performed at other time points and if any cardiac 
symptoms are experienced.  ECGs to be performed 
prior to any blood draws or dosing scheduled for the 
same nominal time point. 
Telemetry 
 
 
  
<===================================================
===> 
  
From 1 h pre-dose to 24 h post-dose. For participants 
receiving the LPS-challenge, telemetry must be 
performed for a minimum of 12 hours post-LPS or until 
their telemetry shows no clinically significant findings 
for 4 hours (whichever is longer). 
Haematology 
 
 
X 
  
  
  
  
  
  
  
 
 X 
 
  
X 
X 
24 and 48 hour samples will be taken prior to 
participants receiving breakfast 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
24 and 48 hour samples will be taken prior to 
participants receiving breakfast 
Clinical Chemistry 
 
 
X 
  
  
  
  
  
  
  
 
X 
 
  
X 
X 
24 and 48 hour samples will be taken prior to 
participants receiving breakfast 
Urinalysis 
 
 
X 
  
  
  
  
  
  
  
 
 X 
 
  
X 
X 
 24 and 48 hour samples will be taken prior to 
participants receiving breakfast 
Drug / Alcohol Test 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine Cotinine 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Visual forearm 
check (including 
cosmetic 
assessment) 
X 
 
X 
See Section 13.1.1.2 and Section 13.1.1.3 for visual forearm 
checks in relation to challenges 
  
  
  
AE / SAE review 
 
 
SAEs collected from signing of informed consent form; AEs collected continuously 
from time of first dose 
  
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Procedure 
 
 
Treatment Period 4 
Notes 
Day -10 (3 
24-48h following  
Day -10 visit 
Day -1 
Day 1 
Day 2 
Day 3 
If participants only take part in treatment Period 4 they 
will undergo screening assessments prior to this 
treatment Period as detailed in Section 13.1.1. 
  
Pre-
dose 
0 h 
15 mins 
30 mins 
1 h 
2 h 
3 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
Concomitant 
Medication Review 
 
 
  
Monitored from first dose until the end of the final treatment Period 
  
Treatment  / agent administration and PK sampling 
Study Drug / 
Placebo 
Administration 
 
 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
In vivo LPS 
Challenge 
 
 
  
  
  
  
<=========
=> 
  
  
  
  
  
  
  
LPS administration to be performed at GSK3358699 
systemic Cmax; anticipated to be between 0.5-2hrs post 
GSK3358699 dose. 
OR in vivo GM-CSF 
Challenge 
 
 
  
  
  
  
<==================
=> 
  
  
 
  
  
GM-CSF administration to be performed at 
GSK3358699 systemic Cmax; GM-CSF will be 
administered as an infusion over 2 hours and the start 
of the infusion is anticipated to be between 0.5-2hrs 
post GSK3358699 dose.  
Blood sampling for 
systemic PK [S1] 
and [S2] 
 
 
  
X 
 
X 
X 
X 
X 
  
X 
 X 
X 
X 
X 
X 
  
Blood sampling for 
intracellular PK [S3] 
 
 
  
  
  
  
  
  
  
  
X  
  
 
  
X 
 
 
Cantharidin 
application and PD 
sampling 
 
See Section 13.1.1.2 and Section 13.1.1.3 
  
 
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13.1.1.2. 
Part A Period 4 Detailed SoA for LPS Challenge and Biomarker Sampling 
 Procedure 
Day -10 ( 3 days) 
24-48 hours following 
Day -10 visit 
Day -1 
Day 1 - pre-dose and all post-dose times below are in 
relation to the administration time of LPS not GSK3358699 
administration 
Day 2 
Day 3 
Notes 
Pre-
dose
0 h 
20 mins 
1 h 
2 h 
3h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
 
LPS challenge administration 
 
 
  
 
X 
 
 
 
 
 
 
 
 
  
  
See Section 13.1.1.1 for timing of LPS 
administration in relation to GSK3358699 / 
placebo dose. 
Visual forearm check (including 
blister healing and cosmetic 
assessment) 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pre-cantharidin check to be within three hours 
prior to cantharidin application. 
Cantharidin application 
X 
 
  
  
  
X 
  
  
  
  
  
  
  
  
  
Day – 10: to be applied in the morning. Day 1: 
to be applied 20 minutes post LPS challenge. 
Intravenous hydration with 
normal Saline at a rate of 250 
mL / hr 
 
 
  
<=======================================
==> 
 
  
  
From 4 hours prior to LPS challenge 
administration until 8 hours after LPS challenge 
administration. 
Vital Signs 
 
 
X 
X 
<=======================================
===> 
X 
X 
BP, HR, temp, respiratory rate. Pre-dose vital 
signs to be taken pre-LPS challenge 
administration then post-LPS challenge as 
follows: every half hour for the first 4 hours, 
hourly until 12 hours, then 6- 8 hourly until 
discharge. Frequency can be increased if 
symptomatic. 
Blood sample for circulating 
inflammatory biomarkers [E2a] 
 
 
  
X 
  
  
X 
X 
  
X 
X 
 
  
X 
X 
  
Blood sample for cellular 
activation markers [E2b] 
 
 
  
X 
  
  
X 
 
 
 
 X 
  
  
X 
  
  
Blood sample for gene panel 
[E2d] 
 
 
  
X 
  
  
X 
  
X 
  
X 
  
  
X 
  
  
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 Procedure 
Day -10 ( 3 days) 
24-48 hours following 
Day -10 visit 
Day -1 
Day 1 - pre-dose and all post-dose times below are in 
relation to the administration time of LPS not GSK3358699 
administration 
Day 2 
Day 3 
Notes 
Pre-
dose
0 h 
20 mins 
1 h 
2 h 
3h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
 
Blister sample for biomarkers, 
blister volume and cell counts 
[E3] 
 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
  
Sample to be taken approx 24-48 hours post 
blister induction (time point being defined as 
part of ongoing enabling study). 
13.1.1.3. 
Part A Period 4 Detailed SoA for GM-CSF challenge and Biomarker Sampling 
Procedure  
Day -10 ( 3 days) 
24-48 hours 
following Day -10 
Day -1 
Day 1 - pre-dose and all post-dose times below are in relation to the 
start time of the GM-CSF infusion not GSK3358699 administration 
Day 
2
Day 
3
Notes 
Pre-
dose
0 h 
1 h 
2 h 
2.3 h 
3 h 
4 h 
5h 
6 h 
8 h 
12 h 
24 h 
48 h 
 
GM-CSF challenge 
administration 
 
 
  
  
<===========
> 
  
  
  
  
  
  
  
  
  
See Section 13.1.1.1 for timing of the 
start of the GM-CSF infusion in 
relation to GSK3358699 / placebo 
dose. GM-CSF will be administered 
as an infusion over 2 hours. 
Visual forearm check (including 
blister healing and cosmetic 
assessment) 
X 
 
X 
  
 
X 
 
 
 
 
 
 
 
 
X 
X 
Pre-cantharidin check to be within 
three hours prior to cantharidin 
application. 
Cantharidin application 
X 
 
  
  
  
 
 
X 
 
  
  
  
 
  
  
  
Day – 10: to be applied in the 
morning. Day 1: 2 hours and 20 
minutes after the start of the GM-
CSF challenge. 
Vital Signs 
 
 
X 
X 
<==============================================
=====> 
X 
X 
BP, HR, temp, respiratory rate.   Pre-
dose vital signs to be taken pre-GM-
CSF challenge administration then 
post-GM-CSF challenge as follows: 
every half hour for the first 4 hours, 
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Procedure  
Day -10 ( 3 days) 
24-48 hours 
following Day -10 
Day -1 
Day 1 - pre-dose and all post-dose times below are in relation to the 
start time of the GM-CSF infusion not GSK3358699 administration 
Day 
2
Day 
3
Notes 
Pre-
dose
0 h 
1 h 
2 h 
2.3 h 
3 h 
4 h 
5h 
6 h 
8 h 
12 h 
24 h 
48 h 
 
hourly until 8 hours, then 6- 8 hourly 
until discharge. Frequency can be 
increased if symptomatic. 
Blood sample for circulating 
inflammatory biomarkers [E2a] 
 
 
  
X 
  
  
X 
  
X 
X 
X 
X 
X 
 
X 
X 
  
Blood sample for cellular 
activation markers [E2b] 
 
 
  
X 
  
  
X 
  
X 
 
 X 
 
X 
  
X 
  
  
Blood sample for gene panel 
[E2d] 
 
 
  
X 
  
 
  
  
X 
  
X 
  
X 
  
X 
  
  
Blister sample for biomarkers, 
blister volume and cell counts 
[E3] 
 
X 
  
  
  
 
  
  
  
  
  
  
  
  
X 
  
Sample to be taken approx 24-48 
hours post blister induction (time 
point being defined as part of 
ongoing enabling study). 
 
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13.1.2. 
Part C General Schedule of Activities Cohorts 5-7 (no challenges) 
Procedure 
Screening (up to 35 
Days prior to Day 1) 
Treatment Period 
Follow-up 1 (7-14 days 
post-last dose) 
Notes 
  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
  
General 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion and exclusion 
criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Day -1 assessment is to recheck eligibility against 
medical conditions, prior therapy etc, but not against Day 
-1 clinical chemistry and haematology results (see 
Section 9.4.7 of Protocol GlaxoSmithKline Document 
Number 2017N332348_05).    
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical/medication/ 
drug/alcohol history  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Includes substance usage and family history of premature 
CV disease and current medical conditions. 
Admission to unit for in-
patient stay 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge from Unit 
following in-patient stay 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
Outpatient visit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Safety Assessments including laboratory tests 
Full Physical Exam 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief Physical Exam 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
Vital Signs 
X 
X X X 
 
X 
 
 
 
X 
 
 
 
X X X X 
X 
X 
BP, HR, temperature, respiratory rate. See Section 
13.1.2.1 for time points on Day 13, 14, 15 and 16. 
Measurements will be performed pre-dose on other 
dosing days. 
12-Lead ECGs 
X 
X X X X X X X X X X X X X X X X 
X 
X 
12 Lead ECGs will be performed in triplicate at screening, 
Day-1, pre-dose Day 1, Day 4, Day 8, Day 14 and Day 
16.  Single ECGs will be performed at other time points 
and if any cardiac symptoms are experienced.  ECGs to 
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38 
 
Procedure 
Screening (up to 35 
Days prior to Day 1) 
Treatment Period 
Follow-up 1 (7-14 days 
post-last dose) 
Notes 
  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
  
be performed prior to any blood draws or dosing 
scheduled for the same nominal time point.   
Telemetry 
 
  
X   
 
X  
  
  
X   
  
  
  
  
X 
  
  
  
Continuous cardiac telemetry on each designated day 
from 1hr pre-dose until 24 h post-dose, and on other days 
if QTcF >450msec.  
Holter monitoring (24 hours) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a participant is rescreened the Holter will not need to be 
repeated. 
HIV, Hep B, Hep C 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Haematology 
X 
X X X 
  
X 
  
  
  
X 
  
  
  
X X X X 
X 
X 
Fasted screening samples. Sample to be taken pre-dose 
on Day 1, 2, 4, 8, 12 and 13. See Section 13.1.2.1 for 
haematology time points on Day 14, 15 and 16. Follow-up 
visit samples do not require fasting. 
Coagulation 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
 
X 
  
  
 X 
Fasted screening samples. Sample to be taken pre-dose 
on Day -1, 4 and 8. See Section 13.1.2.1 for further 
details of Day 14 sample timings.   Follow-up visit 
samples do not require fasting 
Fasting lipids and glucose 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
Fasted screening samples. Sample to be taken pre-dose 
on each day.  Both fasting lipids and glucose will be 
tested from same sample. Follow-up visit samples do not 
require fasting 
Clinical Chemistry 
X 
X X X 
  
X 
  
  
  
X 
  
  
  
X X 
  
X 
X 
X 
 Fasted screening samples. Sample to be taken pre-dose 
on each day. Follow-up visit samples do not require 
fasting. GGT and CK to be included at screening, Day-1 
and follow up only 
Urinalysis 
X 
X X X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
 Fasted screening samples. Sample to be taken pre-dose 
on each day. Follow-up visit samples do not require 
fasting 
Drug / Alcohol Test 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Ad-hoc testing to be performed in the event of any 
cardiac arrhythmias, as close as possible to the time of 
occurrence 
Urine Cotinine 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AE / SAE review 
SAEs collected from signing of informed consent form until the final follow up visit; 
AEs collected continuously from time of first dose until the final follow up visit. 
  
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Procedure 
Screening (up to 35 
Days prior to Day 1) 
Treatment Period 
Follow-up 1 (7-14 days 
post-last dose) 
Notes 
  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
  
Concomitant Medication 
Review 
  
  
Monitored continuously from first dose until the end of the 
treatment period 
  
  
Treatment  / agent administration 
Study Drug Administration 
  
  
X X X X X X X X X X X X X X   
  
  
Once-daily in the morning on Days 1-14 inclusive. 
Pharmacokinetics, Pharmacodynamics and Genetics Sample 
Blood sampling for systemic 
PK [S1] and [S2] 
 
 
X X 
 
X 
 
 
 
X 
 
 
 
X 
 
X X 
X 
 
On Day 1 samples will be taken at pre-dose, 15mins, 
30mins, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose, Pre-
dose samples Days 4, 8 and 12. See Section 13.1.2.1 
for Day 14, 15 and 16 sample timings.  Ad-hoc sample to 
be taken in the event of any cardiac arrhythmias, as 
close as possible to the time of occurrence 
Blood sampling for 
intracellular PK [S3] 
  
  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X X 
X 
  
On Day 1 samples will be taken at 1h, 4h and 8h post-
dose. Pre-dose samples Days 4, 8 and 12. See Section 
13.1.2.1 for Day 14, 15 and 16 sample timings. 
Blood sample for ex vivo PD 
assay [S4] 
  
X X X 
  
X 
  
  
  
X 
  
  
  
X 
  
X X 
X 
  
Day -1 samples to be taken at approximately 13:00. Day 
1 and Day 14 pre-dose samples to be taken at 
approximately 08:00. Day 1 post-dose samples to be 
taken at 1h, 4h and 8h post-dose. Samples to be taken 
pre-dose Days 2, 4, 8 and 12. See Section 2.3.1 of 
protocol for Cohorts 5-7 and Section 2.4.1 of protocol for 
Cohort 8, for Day 14, 15 and 16 sample timings . All 
sample timepoints pre- and post-dose require 1 LPS and 
1 LPS + GSK3358699 sample. 
Blood sample for circulating 
proteins [E1a] 
 
 
X X 
 
X 
 
 
 
X 
 
 
 
X 
 
X X 
 
 
On Day 1 samples will be taken at pre-dose, 2h, 4h and 
8h post-dose. Samples to be taken pre-dose Day 2, 4, 8 
and 12. See Section 13.1.2.1 for Day 14 and 15 sample 
timings. 
Blood sample for gene 
panel [E1b] 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
X X 
  
  
On Day 1 samples will be taken at pre-dose, 2h and 4h 
post-dose. Samples to be taken pre-dose Days  4, 8 and 
12. See Section 13.1.2.1 for Day 14 and 15 sample 
timings. 
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40 
 
Procedure 
Screening (up to 35 
Days prior to Day 1) 
Treatment Period 
Follow-up 1 (7-14 days 
post-last dose) 
Notes 
  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
  
Blood sample for cellular 
activation markers [E2b] 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
X 
 
 
  
Pre-dose samples Days 1, 4, 8 and 12. See Section 
13.1.2.1 for Day 14 sample timings. 
Blood sample for potential 
companion diagnostic 
development 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for CES 
genotyping and optional 
genetic research [E5] 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Urine sample for metabolite 
analysis [E4] 
  
  
X X 
  
  
  
  
  
  
  
  
  
  
  
X X 
  
  
A 0-24 urine collection will be made on Day 1 and Day 
14.  In each case, for the pre-dose sample, immediately 
prior to dosing participants will be instructed to void their 
bladder into a collection container.  Following dosing 
participants will be instructed to collect all urine voided 
for a 0-24 hour collection. 
 
 
 
 
 
 
 
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13.1.2.1. 
Part C Day 14 Detailed SoA for PK and PD / Biomarker Sampling Cohorts 5-7 (no challenges) 
 Procedure 
Day 13 
Day 14. 
Day 15 
Day 16 
Notes 
Pre-dose 
0 h 
15 mins  
30 mins  
1 h 
2 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
Treatment  / agent administration and PK sampling 
Study Drug / Placebo 
Administration 
  
 
X 
 
 
 
 
 
 
 
 
  
  
  
Vital Signs 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Haematology 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Coagulation 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood sampling for 
systemic PK [S1] and [S2] 
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Ad-hoc sample to be taken in the event of any cardiac 
arrhythmias, as close as possible to the time of occurrence 
Blood sampling for 
intracellular PK [S3] 
  
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood sample for ex vivo 
PD assay [S4] 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood sample for 
circulating proteins [E1a] 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
Blood sample for gene 
panel [E1b] 
 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
Blood sample for cellular 
activation markers [E2b] 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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13.1.3. 
Part C General Schedule of Activities Cohorts 4 and 8 (with challenges) 
Procedure 
Screening (up to 45 
Days prior to Day 1) 
Day -10 ( 3 days) 
24-48 hours following  
Day -10 visit 
Treatment Period 
Follow-up 1 (7-14 
days post-last dose) 
Follow-up 2 (5 weeks 
after last dose   3 
days)
Notes 
  
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16 
 The 2nd follow up visit is only required for those 
participants where challenges are being administered 
and blisters induced 
General 
Informed consent 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion and 
exclusion criteria 
X 
 
 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Day -1 assessment is to recheck eligibility against 
medical conditions, prior therapy etc, but not against 
Day -1 clinical chemistry and haematology results (see 
Section 9.4.7 of Protocol GlaxoSmithKline Document 
Number 2017N332348_05).    
Demography 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical/medicatio
n/ 
drug/alcohol 
history  
X 
 
 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Includes substance usage and family history of 
premature CV disease and current medical conditions. 
Admission to unit 
for in-patient stay 
 
 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge from 
Unit following in-
patient stay 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
Outpatient visit 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
Safety Assessments including laboratory tests 
Full Physical 
Exam 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief Physical 
Exam 
 
 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
  
Body Weight 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
  
  
  
  
Body weight will be measured on Day 13 to calculate 
doses for challenges. 
Vital Signs 
X 
 
 
X X X 
 
X 
 
 
 
X 
 
 
 
X X X X 
X 
X 
X 
BP, HR, temperature, respiratory rate. See Section 
13.1.3.2 and Section 13.1.3.3 for time points on Day 13, 
14, 15 and 16. Measurements will be performed pre-
dose on other dosing days. 
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Procedure 
Screening (up to 45 
Days prior to Day 1) 
Day -10 ( 3 days) 
24-48 hours following  
Day -10 visit 
Treatment Period 
Follow-up 1 (7-14 
days post-last dose) 
Follow-up 2 (5 weeks 
after last dose   3 
days)
Notes 
  
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16 
 The 2nd follow up visit is only required for those 
participants where challenges are being administered 
and blisters induced 
12-Lead ECGs 
X 
 
 
X X X X X X X X X X X X X X X X 
X 
X 
  
12 Lead ECGs will be performed in triplicate at 
screening, Day-1, pre-dose Day 1, Day 4, Day 8, Day 
14 and Day 16.  Single ECGs will be performed at other 
time points and if any cardiac symptoms are 
experienced.  ECGs to be performed prior to any blood 
draws or dosing scheduled for the same nominal time 
point.   
Telemetry 
 
 
 
  
X   
 
X  
  
  
X   
  
  
  
  
X   
  
  
  
Continuous cardiac telemetry on each designated day 
from 1hr pre-dose until 24 h post-dose, and on other 
days if QTcF >450msec. For participants receiving the 
LPS-challenge, the Day 14 telemetry must be performed 
for a minimum of 12hrs post-LPS or until their telemetry 
shows no clinically significant findings for 4 hours 
(whichever is longer). 
Holter monitoring 
(24 hours) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a participant is rescreened the Holter will not need to 
be repeated. 
HIV, Hep B, Hep 
C 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Haematology 
X 
 
 
X X X   
X   
  
  
X   
  
  
X X X X 
X 
X 
  
Fasted screening samples. Sample to be taken pre-
dose on Day 1, 2, 4, 8, 12 and 13. See Section 13.1.3.2 
and Section 13.1.3.3 for haematology time points on 
Day 14, 15 and 16. Follow-up visit samples do not 
require fasting. 
Coagulation 
X 
 
 
X   
  
  
X   
  
  
X   
  
  
  
X X   
  
 X 
  
Fasted screening samples. Sample to be taken pre-
dose on Day -1, 4, 8 and 13. See Section 13.1.3.2 for 
further details of Day 14 sample timings. Day 13 and 
Day 14 samples are only performed for subjects 
receiving LPS.  Follow-up visit samples do not require 
fasting 
Fasting lipids and 
glucose 
X 
 
 
X   
  
  
X   
  
  
X   
  
  
  
  
X   
  
  
  
Fasted screening samples. Sample to be taken pre-
dose on each day.  Both fasting lipids and glucose will 
be tested from same sample. Follow-up visit samples do 
not require fasting 
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CONFIDENTIAL 
 
 
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44 
 
Procedure 
Screening (up to 45 
Days prior to Day 1) 
Day -10 ( 3 days) 
24-48 hours following  
Day -10 visit 
Treatment Period 
Follow-up 1 (7-14 
days post-last dose) 
Follow-up 2 (5 weeks 
after last dose   3 
days)
Notes 
  
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16 
 The 2nd follow up visit is only required for those 
participants where challenges are being administered 
and blisters induced 
Clinical Chemistry 
X 
 
 
X X X   
X   
  
  
X   
  
  
X X   
X 
X 
X 
  
 Fasted screening samples. Sample to be taken pre-
dose on each day. Follow-up visit samples do not 
require fasting GGT and CK to be included at screening, 
Day-1 and follow up only. 
Urinalysis 
X 
 
 
X X X   
X   
  
  
X   
  
  
X   
  
  
X 
X 
  
 Fasted screening samples. Sample to be taken pre-
dose on each day. Follow-up visit samples do not 
require fasting 
Drug / Alcohol 
Test 
X 
 
 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Ad-hoc testing to be performed in the event of any 
cardiac arrhythmias, as close as possible to the time of 
occurrence 
Urine Cotinine 
X 
 
 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Visual forearm 
check (including 
blister healing 
and cosmetic 
assessment) 
X 
X 
 
X   
  
  
  
  
  
  
  
  
  
  
  
X X X 
 X 
X 
X 
Pre-cantharidin check to be within three hours prior to 
cantharidin application. See Section 13.1.3.2 and 
Section 13.1.3.3 for further details of timing of forearm 
checks on Day 13, 14, 15 and 16 in relation to 
challenges. 
AE / SAE review 
SAEs collected from signing of informed consent form until the final follow up visit; AEs collected 
continuously from time of first dose until the final follow up visit. 
  
Concomitant 
Medication 
Review 
 
 
  
  
Monitored continuously from first dose until the end of the 
treatment period 
  
  
  
Treatment  / agent administration 
Study Drug 
Administration 
 
 
  
  
X X X X X X X X X X X X X X   
  
  
  
Once-daily in the morning on Days 1-14 inclusive. 
Cantharidin 
application 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
  
  
  
Day – 10: to be applied in the morning. See Section 
13.1.3.2 and Section 13.1.3.3 for further details on Day 
14 blister timings. 
In vivo LPS or 
GM-CSF 
Challenge 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
  
  
  
See Section 13.1.3.1 for further details. 
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45 
 
Procedure 
Screening (up to 45 
Days prior to Day 1) 
Day -10 ( 3 days) 
24-48 hours following  
Day -10 visit 
Treatment Period 
Follow-up 1 (7-14 
days post-last dose) 
Follow-up 2 (5 weeks 
after last dose   3 
days)
Notes 
  
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16 
 The 2nd follow up visit is only required for those 
participants where challenges are being administered 
and blisters induced 
Pharmacokinetics, Pharmacodynamics and Genetics Sample 
Blood sampling 
for systemic PK 
[S1] and [S2] 
 
 
 
 
X X 
 
X 
 
 
 
X 
 
 
 
X 
 
X X 
X 
 
 
On Day 1 samples will be taken at pre-dose, 15mins, 
30mins, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose, Pre-
dose samples Days 4, 8 and 12. See Section 13.1.3.1 
for Day 14, 15 and 16 sample timings.  Ad-hoc sample 
to be taken in the event of any cardiac arrhythmias, as 
close as possible to the time of occurrence 
Blood sampling 
for intracellular 
PK [S3] 
 
 
  
  
X 
 
 
X 
 
 
 
X 
 
 
 
X X X X 
X 
  
  
On Day 1 and Day 13 samples will be taken at 1h, 4h 
and 8h post-dose. Pre-dose samples Days 4, 8 and 12.  
See Section 13.1.3.1 for Day 14, 15 and 16 sample 
timings. 
Blood sample for 
ex vivo PD assay 
[S4] 
 
 
  
X X X   
X   
  
  
X   
  
  
X X X X 
  
  
  
Day -1 samples to be taken at approximately 13:00. Day 
1 and Day 14 pre-dose samples to be taken at 
approximately 08:00. Day 1 post-dose samples to be 
taken at 1h, 4h and 8h post-dose. Samples to be taken 
pre-dose Days 2, 4, 8 and 12. See Section 2.3.1 of 
protocol for Cohorts 5-7 and Section 2.4.1 of protocol for 
Cohort 8, for Day 14, 15 and 16 sample timings . All 
sample timepoints pre- and post-dose require 1 LPS 
and 1 LPS + GSK3358699 sample. 
Blood sample for 
circulating 
proteins [E1a] 
 
 
 
 
X X 
 
X 
 
 
 
X 
 
 
 
X 
 
X X 
 
 
 
On Day 1 samples will be taken at pre-dose, 2h, 4h and 
8h post-dose. Samples to be taken pre-dose Day 2, 4, 8 
and 12. See Section 13.1.3.1 for Day 14 and 15 sample 
timings. 
Blood sample for 
gene panel 
[E1b/E2d] 
 
 
  
  
X   
  
X   
  
  
X   
  
  
X   
X X 
  
  
  
On Day 1 samples will be taken at pre-dose, 2h and 4h 
post-dose. Samples to be taken pre-dose Days  4, 8 
and 12. See Section 13.1.3.1, Section 13.1.3.2 and 
Section 13.1.3.3 for Day 14 and 15 sample timings for 
E2d. 
Blood sample for 
circulating 
inflammatory 
biomarkers [E2a] 
 
 
  
  
 
  
  
 
  
  
  
 
  
  
  
 
  
X X 
X 
  
  
See Section 13.1.3.2 and Section 13.1.3.3 for sample 
timings. 
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Procedure 
Screening (up to 45 
Days prior to Day 1) 
Day -10 ( 3 days) 
24-48 hours following  
Day -10 visit 
Treatment Period 
Follow-up 1 (7-14 
days post-last dose) 
Follow-up 2 (5 weeks 
after last dose   3 
days)
Notes 
  
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16 
 The 2nd follow up visit is only required for those 
participants where challenges are being administered 
and blisters induced 
Blood sample for 
cellular activation 
markers [E2b] 
 
 
  
  
X   
  
X   
  
  
X   
  
  
X   
X X 
X 
  
  
Pre-dose samples Days 1, 4, 8 and 12. See Section 
13.1.3.2 and Section 13.1.3.3 for Day 14, 15 and 16 
sample timings. 
Blister sample for 
biomarkers, 
blister volume 
and cell counts 
[E3] 
 
 
 X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 X 
  
  
Blisters harvested approx 48 h post cantharidin 
application  See Section 13.1.3.2 and Section 13.1.3.3 
for further detail on Day 16 sample timings. 
Blood sample for 
potential 
companion 
diagnostic 
development 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
CES genotyping 
and optional 
genetic research 
[E5] 
 
 
 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Urine sample for 
metabolite 
analysis [E4] 
 
 
  
  
X X 
  
  
  
  
  
  
  
  
  
  
  
X X 
  
  
  
A 0-24 urine collection will be made on Day 1 and Day 
14.  In each case, for the pre-dose sample, immediately 
prior to dosing participants will be instructed to void their 
bladder into a collection container.  Following dosing 
participants will be instructed to collect all urine voided 
for a 0-24 hour collection. 
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47 
 
13.1.3.1. 
Part C Day 14 Detailed SoA for Challenge Administration and PK Sampling Cohorts 4 and 8 (with challenges) 
 Procedure 
Day 13 
Day 14 - pre-dose and all post-dose times below are 
in relation to the administration time of GSK3358699. 
Day 15 
Day 16 
Notes 
Pre-dose 
0 h 
15 mins  
30 mins  
1 h 
2 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
Treatment  / agent administration and PK sampling 
Study Drug / Placebo 
Administration 
  
 
X 
 
 
 
 
 
 
 
 
  
  
  
In vivo LPS Challenge 
  
 
 
 
< 
======================= 
> 
 
  
  
LPS administration may  be performed at low systemic 
GSK3358699 concs when intracellular levels of GSK3206944 
are high; the decision on the timepoint will be based on emerging 
data and will be no more than 24hrs after dosing on Day 14. 
OR in vivo GM-CSF 
Challenge 
  
 
 
 
< 
=========================== 
> 
 
 
GM-CSF administration may be performed at low systemic 
GSK3358699 concs when intracellular levels of GSK3206944 
are high; the decision on the timepoint will be based on emerging 
data. GM-CSF will be administered as an infusion over 2 hours 
and the start of the infusion will be no more than 24hrs after 
dosing on Day 14.  
Blood sampling for systemic 
PK [S1] and [S2] 
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Ad-hoc sample to be taken in the event of any cardiac 
arrhythmias, as close as possible to the time of occurrence 
Blood sampling for 
intracellular PK [S3] 
 X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 Pre-challenge samples. To be collected only until the start of 
challenge administration 
Blood sample for ex vivo 
PD assay [S4] 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Pre-challenge samples. To be collected only until the start of 
challenge administration.  
Blood sample for circulating 
proteins [E1a] 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
Pre-challenge samples. To be collected only until the start of 
challenge administration. 
Blood sample for gene 
panel [E1b] 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
Pre-challenge samples. To be collected only until the start of 
challenge administration. 
Cantharidin application and 
PD sampling 
See Section 13.1.3.2 and Section 13.1.3.3 
  
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13.1.3.2. 
Part C Day 14 Detailed SoA for LPS Challenge and Biomarker Sampling Cohorts 4 and 8 (with challenges) 
 Procedure 
Day 13 
Day 14 - pre-dose and all post-dose times below are in 
relation to the administration time of LPS not 
GSK3358699 administration 
Day 15 
Day 16 
Notes 
Pre-
dose
0 h 
20 mins 
1 h 
2 h 
3 h 
4 h 
6h 
8 h 
12 h 
24 h 
48 h 
LPS challenge 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
See Section 13.1.3.1 for timing of LPS administration in 
relation to GSK3358699 / placebo dose. 
Visual forearm check 
(including blister healing 
and cosmetic assessment) 
X 
X 
 
 
 
 
 
 
 
 
  
X 
X 
Pre-cantharidin check to be within three hours prior to 
cantharidin application. 
Cantharidin application 
  
  
  
X 
  
  
  
  
  
  
  
  
  
To be applied 20 minutes post LPS challenge. 
Intravenous hydration with 
normal Saline at a rate of 
250 mL / hr 
  
<======================================
===> 
  
  
  
From 4 hours prior to LPS challenge administration until 8 
hours after LPS challenge administration. 
Vital Signs 
X 
X 
<======================================
===> 
X 
X 
BP, HR, temperature, respiratory rate.   Pre-dose vital signs 
to be taken pre-LPS challenge administration then post-LPS 
challenge as follows: every half hour for the first 4 hours, 
hourly until 12 hours, then 6- 8 hourly until discharge. 
Frequency can be increased if symptomatic. 
Haematology 
X 
  
  
  
  
  
  
 
X  
  
X 
 X 
X 
  
Coagulation 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Blood sample for circulating 
inflammatory biomarkers 
[E2a] 
  
X 
  
  
X 
X 
X 
 
X 
 
  
X 
X 
  
Blood sample for cellular 
activation markers [E2b] 
  
X 
  
  
X 
 
 
 
 X 
  
  
X 
X 
  
Blood sample for gene 
panel [E2d] 
  
X 
  
 
X 
  
X 
  
X 
  
  
X 
  
  
Blister sample for 
biomarkers, blister volume 
and cell counts [E3] 
  
  
  
  
  
  
  
  
  
  
  
 
X  
Blisters harvested approx 48 h post cantharidin application. 
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13.1.3.3. 
Part C Day 14 Detailed SoA for GM-CSF Challenge and Biomarker Sampling Cohorts 4 and 8 (with challenges) 
 Procedure 
Day 13 
Day 14 - pre-dose and all post-dose times below are in relation to 
the start time of the GM-CSF infusion not GSK3358699 
administration 
Day 15 
Day 16 
Notes 
Pre-dose 
0 h 
1 h 
2 h 
2h 
20mins
3 h 
4 h 
5h 
6 h 
8 h 
12 h 
24 h 
48 h 
 
GM-CSF challenge 
administration 
 
 
<==========> 
 
 
 
 
 
 
 
 
 
See Section 13.1.3.1 for timing of the start of the GM-CSF 
infusion in relation to GSK3358699 / placebo dose. GM-CSF 
will be administered as an infusion over 2 hours. 
Visual forearm check 
(including blister healing 
and cosmetic assessment) 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Pre-cantharidin check to be within three hours prior to 
cantharidin application. 
Cantharidin application 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
2 hours and 20 minutes after the start of the GM-CSF 
challenge. 
Vital Signs 
X 
X 
<==============================================
==> 
X 
X 
BP, HR, temperature, respiratory rate.   Pre-dose vital signs 
to be taken pre-GM-CSF challenge administration then post-
GM-CSF challenge as follows: every half hour for the first 4 
hours, hourly until 8 hours, then 6- 8 hourly until discharge. 
Frequency can be increased if symptomatic. 
Haematology 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
  
Blood sample for circulating 
inflammatory biomarkers 
[E2a] 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
  
Blood sample for cellular 
activation markers [E2b] 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
  
Blood sample for gene 
panel [E2d] 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
  
Blister sample for 
biomarkers, blister volume 
and cell counts [E3] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blisters harvested approx 48 h post cantharidin application. 
 
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• 
The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic/biomarker assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study assessments 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 Institutional Review Board / Independent 
Ethics Committee (IRB/IEC) will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the Informed 
Consent (ICF). 
• 
Acceptable time windows around the nominal time points for specific 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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13.2. 
Appendix 2: Assessment Windows 
13.2.1. 
Definitions of Assessment Windows for Analyses 
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits. 
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13.3. 
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events 
13.3.1. 
Study Phases for Parts A and C 
Assessments and events will be assigned to the relevant treatment Period dependent on 
whether they are spontaneous events (i.e. data collected in a log such as Adverse Events 
and Concomitant Medications, and Disposition) or planned events (i.e. data with 
timeslicing assigned such as ECG, Laboratory, and Vital Signs).  
Spontaneous events are assigned to period according to the time of occurrence relative to 
the start date/time of the study treatment within the period up to, but not including, the 
start date/time of the study treatment in the next period. Planned assessments, including 
unscheduled visits are assigned to period according to the date of first visit of that period 
(including Day -1 and Day -10 assessments as applicable) up to the day prior to the first 
visit of the next period or day prior to Follow-Up visit (including Day -1 and Day -10 
assessments as applicable). 
For planned events, assessments prior to the date of first visit in Period 1 for Part A (or 
Period 7 for Part C) are assigned as Screening. For spontaneous events, events prior to 
the datetime of first dose in Period 1 for Part A are assigned as Pre-Treatment (or Period 
7 for Part C). 
For planned events, assessments on or later than date of first Follow-Up visit are assigned 
as Follow-Up. For spontaneous events, events later than date of last dose + 7 days are 
assigned as Follow-Up. 
13.3.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to 
screening visit 
Concomitant 
Any medication that is not a prior 
1. NOTE:  
• Refer to Appendix 6: Reporting Standards for Missing Data for handling of missing 
and partial dates for concomitant medication. Use the rules in the table above if 
concomitant medication date is completely missing. 
• Pre-trial medications are assumed concomitant if the stop date is within 28 days of the 
screening visit. 
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13.3.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date & on or before treatment stop 
date +1. 
• 
For crossover parts (Part A), if AE onset is during one period and worsens 
during a later period it would be counted in both periods. For the initial period 
the logic would be as above. For the later period the logic would use the 
treatment dates associated with the later period: 
       
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date + 1 days. 
NOTES:  
• If the AE start/worsening date is on or after treatment start date, and treatment stop 
date is missing, then the AE will be considered to be Treatment Emergent. 
• Time of study treatment dosing and start/stop time of AEs should be considered, if 
collected. 
 
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13.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
13.4.1. 
Reporting Process 
Software 
•
The currently supported versions of SAS software will be used.
Reporting Area 
HARP Server 
: UK1SALX00175 
HARP 
Compound 
: \arprod\gsk3358699\mid207546\data_look_01 
: \arprod\gsk3358699\mid207546\final_01 
Analysis Datasets 
•
Analysis datasets will be created according to Integrated Data Standards Library
(IDSL) Legacy GSK A&R dataset standards.
Generation of RTF Files 
•
RTF files will be generated for all tables within the final_01 reporting effort for SAC.
13.4.2. 
Reporting Standards 
General 
•
The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated
(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
•
Do not include participant level listings in the main body of the GSK Clinical Study 
Report. All participant level listings should be located in the modular appendices as 
ICH or non-ICH listings
•
All data displays (Tables, Figures and Listings) will use the term “Subject” which 
reflects CDISC and GSK data display standards terminology.
Formats 
•
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) 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.
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• 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 participant’s 
listings.  
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables and figures. 
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 – do not report 95% CI 
unless otherwise specified. 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
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13.4.3. 
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 PKOne standards. 
Note: Concentration values will be imputed as per GUI_51487 
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 GUI_51487 for 
descriptive summary statistics/analysis and summarised graphical 
displays only.  
Pharmacokinetic Parameter Derivation 
PK Parameter to 
be Derived by 
Programmer 
N, n, geometric mean, 95% CI of geometric mean, standard deviation 
(SD) of logged data and between subject geometric coefficient of 
variation (CVb (%)) will be reported. 
CVb (%) = √ (exp(SD²) - 1) * 100 
(SD = SD of log transformed data) 
Pharmacokinetic Parameter Data 
Is NQ impacted 
PK Parameters 
Rule Being 
Followed 
No 
Descriptive 
Summary 
Statistics, 
Graphical 
Displays and 
Listings 
Refer to IDSL PK Display Standards. 
Refer to Standards for the Transfer and Reporting of PK Data using 
HARP. 
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13.5. 
Appendix 5: Derived and Transformed Data 
13.5.1. 
General (Parts A and C) 
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, except for blood pressure 
measurements as only the average of the 3 blood pressure readings will be recorded 
on the CRF.  
• Subjects who have 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 day 
• Calculated as the number of days from first dose date: 
• ref date = missing           → study day = missing  
• ref date < first dose date → study day = ref date – first dose date 
• ref date ≥ first dose date → study day = (ref date – first dose date) + 1     
Age 
• Birth date will be presented in listings as ‘YYYY’. Only the year of birth will be 
captured, and therefore the date of birth is then derived as follows: 
      Year of birth = YYYY → Date of birth = 30th June YYYY 
• Age calculated based on the data of screening date: 
Age = integer part (date of screening – 30th June YYYY) / 365.25. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)²] 
13.5.2. 
Study Population 
Extent of exposure  
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = (Treatment Stop Date – Treatment Start Date) 
+ 1 
• Participants who were randomised but did not report a treatment start date will be 
categorised as having zero days of exposure.  
• The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
• If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly. 
• Average dose is the cumulative dose divided by the duration of exposure. 
 
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13.5.3. 
Pharmacokinetics 
Monocyte concentration 
• In addition to the intracellular GSK3206944 raw concentration, x, which is measured 
as ng per mL in reagent, it will be also derived the molar concentration within the 
monocytes, y, which is: 
y(nM) = x(ng/mL)/MMV/MW/20*10^9 
where the mean monocyte volume (MMV) is equal to 261 fL which is derived from 
the average of 150a, 250a, 480a, 167b fL reported in literature, 
the molecular weight (MW) is equal to 468.6 (see Technical Evidence Document) 
and assuming that 20 is the number of millions of cells per mL of reagent. In practical 
terms this is equivalent to y(nM) = x(ng/mL)*408.8154. 
 
a https://www.ncbi.nlm.nih.gov/pubmed/7354131 
b https://www.sciencedirect.com/science/article/pii/S0009898118301311#f0005 
13.5.4. 
Pharmacodynamic 
Percent inhibition 
• The percentage inhibition (Truculture assay), to be calculated for select biomarkers, 
is defined as the reduction from baseline in %, e.g. a 15% reduction from baseline 
would be a 15% inhibition. 
• The predicted percentage inhibition (y) in undiluted samples, to be calculated for 
selected biomarkers, from the above percentage inhibition (z(%)) in the 3-fold 
diluted samples of Truculture assay as: 
𝑦(%) =
100
1 + ( 1
𝐷𝐹)
ℎ𝑖𝑙𝑙
∗100 −𝑧(%)
𝑧(%)
 
where the dilution factor (DF) is equal to 3 
Hill coefficient (hill) is equal to 1.4 
The above formula assumes that the in vivo-inhibition versus PK concentration 
follows the in vitro Emax model relationship with the same concentration generating 
50% effect, ec50, and the same hill coefficient and same Emax=1.  
In fact from 
𝑧(%) =
𝑥ℎ𝑖𝑙𝑙
𝑥ℎ𝑖𝑙𝑙+ 𝑒𝑐50ℎ𝑖𝑙𝑙∙100 
it is possible to derive 
𝑒𝑐50ℎ𝑖𝑙𝑙= 𝑥ℎ𝑖𝑙𝑙∙100 −𝑧(%) ∙𝑥ℎ𝑖𝑙𝑙
𝑧(%)
 
and substituting 𝑒𝑐50ℎ𝑖𝑙𝑙in the equation of undiluted samples, where the ec50 is DF 
fold lower we obtain:  
𝑦(%) =
𝑥ℎ𝑖𝑙𝑙
𝑥ℎ𝑖𝑙𝑙+ (𝑒𝑐50
𝐷𝐹)
ℎ𝑖𝑙𝑙∙100 =
𝑥ℎ𝑖𝑙𝑙
𝑥ℎ𝑖𝑙𝑙+ 𝑥ℎ𝑖𝑙𝑙∙100 −𝑧(%) ∙𝑥ℎ𝑖𝑙𝑙
𝐷𝐹ℎ𝑖𝑙𝑙∙𝑧(%)
∙100 
which, after simplification by 𝑥ℎ𝑖𝑙𝑙 , results in the above equation 
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Biomarkers 
Biomarker Code (BICATCD), Biomarker Test Code (BITESTCD), Biomarker Testing 
Method Code (BIMETHCD) and Units of Measurement (BIORRESU) are summarised 
below.  
Name 
(Analyte) 
Biomarker 
Description  
BICATCD 
BITESTCD/ 
BIMETHCD/ 
BIORRESU 
SAC 
ENDPOINTS 
Soluble 
Inflammatory 
Mediators 
(Blood) 
TruCulture 
Interleukin 6 
IL6 
CONC/ 
ECLIA/ 
PG/ML 
S4 
Monocyte 
chemotactic protein-1 
MCP1 
CONC/ 
ECLIA/ 
PG/ML 
S4 
Tumour necrosis 
factor alpha 
(TNF-α) 
TNFA 
CONC/ 
ECLIA/ 
PG/ML 
S4 
 
 
 
 
 
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13.6. 
Appendix 6: Reporting Standards for Missing Data 
13.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• A participant is considered to have completed:  
o Part A (Cohorts 1 and 2) of the study if he has completed all the 
periods of Part A, including both follow-up visits. 
o Part C of the study if he has completed all visits including both 
follow-up visits. 
• Withdrawn participants may be replaced in the study. Additional 
replacement participants may be randomised to guarantee that sufficient 
participants are treated with GSK3358699 at any given dose before 
escalating to the following dose. Replacement participants will be 
assigned to the same treatment sequence (Parts A) or treatment (Part C) 
but have different subject numbers and randomisation numbers 
assigned. 
• 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.  
• Data from withdrawal visits will be listed. 
• In Part C, Cohorts 4 and 5 were terminated prematurely while some 
subjects were part way through the treatment phase. Safety and PK data 
collected after the date of termination in each cohort should not be 
included in summary tables/figures, but should be listed under a visit label 
of ‘Early Termination’. The dates of termination were: 
o Cohort 4: 14NOV2018 
o Cohort 5: 18MAR2019 
13.6.2. 
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 participant 
listing displays. Unless all data for a specific visit are missing in 
which case the data is excluded from the listing.  
o Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such. 
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13.6.2.1. 
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 Section 13.3. 
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. 
Concomitant 
Medications 
• 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' (last day of the 
relevant month) will be used for the day and 'Dec' will be used 
for the month. 
• The recorded partial date will be displayed in listings. 
 
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13.7. 
Appendix 7: Values of Potential Clinical Importance and 
Normal Ranges 
13.7.1. 
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 
Respiratory Rate 
breaths/min 
< 11 
> 20 
Temperature 
°C 
< 35.5 
> 38.0 
 
13.7.2. 
Laboratory Values 
Hematology – PCI Criteria 
Laboratory Parameter 
 
Units 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 
1 
 
0.54 
Hemoglobin  
g/L 
 
 
180 
Lymphocyte Count  
x109/ L 
0.8 
 
Neutrophil Count  
x109/ L 
1.5 
 
Platelet Count  
x109/ L 
100 
550 
White Blood Cell Count 
(WBC) 
x109/ L 
3 
20 
 
Hematology – Normal Ranges 
Laboratory Parameter 
 
Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Activated Partial 
Thromboplastin Time (APTT) 
secs 
25 
37 
Basophil Count 
x109/ L 
0.0 
0.1 
Eosinophil Count 
x109/ L 
0.0 
0.4 
Fibrinogen 
g/L 
1.5 
4.0 
Mean Corpuscle Hemoglobin 
(MCH) 
pg 
26.0 
33.5 
Mean Corpuscle Volume 
(MCV) 
fL 
80 
99 
Monocyte Count 
x109/ L 
0.2 
1.0 
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Hematology – Normal Ranges 
Laboratory Parameter 
 
Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Prothrombin Time (PT) 
secs 
10 
12 
Red Blood Cell Count (RBC) 
x1012/ L 
4.4 
5.8 
Reticulocyte Count 
% 
0.38 
2.64 
 
Clinical Chemistry – PCI Criteria 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
G/L 
30 
 
Calcium 
mmol/L 
2 
2.75 
Creatinine 
mmol/L 
 
1.3 X ULN 
Glucose 
mmol/L 
3 
9 
Potassium 
mmol/L 
3 
5.5 
Sodium 
mmol/L 
130 
150 
 
Clinical Chemistry – Normal Ranges 
Laboratory Parameter 
Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Alanine Aminotransferase 
(ALT) 
IU/L 
10 
50 
Alkaline Phosphatase (ALP) 
IU/L 
40 
129 
Aspartate Aminotransferase 
(AST) 
IU/L 
0 
37 
Blood Urea Nitrogen (BUN) 
mg/dL 
4.76 
23.24 
C-reactive Protein 
mg/L 
0.0 
5.0 
Cholesterol 
mmol/L 
2.3 
4.9 
Direct Bilirubin 
umol/L 
0 
5 
High Density Lipoprotein 
mmol/L 
0.9 
1.5 
Low Density Lipoprotein 
mmol/L 
0 
3.0 
Total Bilirubin 
umol/L 
0 
20 
Total Protein 
g/L 
63 
83 
Triglycerides 
mmol/L 
0 
2.3 
 
 
 
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13.7.3. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
<110 
>220 
Absolute QRS Interval 
msec 
<75 
>110 
Change from Baseline 
Increase from Baseline 
QTcF 
msec 
 
>60 
 
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13.8. 
Appendix 8: Abbreviations & Trade Marks 
13.8.1. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
A&R 
Analysis and Reporting  
BMI 
Body Mass Index 
CI 
Confidence Interval 
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 
DEC 
Dose Escalation Committee 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results 
Disclosure 
Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
RD 
Repeat Dose 
SAC 
Statistical Analysis Complete 
SD 
Single Dose 
SDSP 
Study Data Standardization Plan 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
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Abbreviation 
Description 
TLF 
Tables, Listings and Figures  
13.8.2. 
Trademarks 
 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline 
Group 
of 
Companies 
HARP 
 
NONMEM  
 
 
SAS 
 
 
WinNonlin 
 
 
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13.9. 
Appendix 9: List of Data Displays 
13.9.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.21 
- 
Safety 
2.1 to 2.44 
2.1 to 2.2 
Pharmacokinetic 
3.1 to 3.9 
3.1 to 3.18 
Pharmacodynamic 
5.1 to 5.4 
5.1 to 5.4 
Section 
Listings 
ICH Listings 
1 to 64 
Other Listings 
65 to 76 
13.9.2. 
Mock Example Shell Referencing 
Table, listing and figure shells will be produced in documents separate to the RAP. These 
shells will follow the IDSL standards as appropraite and include study specific 
programming notes to facilitate programming. 
13.9.3. 
Deliverables 
Delivery 
Description 
SAC 
Final Statistical Analysis Complete 
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13.9.4. 
Study Population Tables 
Part A 
Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Disposition 
1.1. 
Safety 
ES1a 
Part A: Summary of Subject Disposition for the 
Subject Conclusion Record 
Add footnote: Note: 
“Subjects” is used to refer to 
“Participants” in all data 
displays to reflect GSK 
display standards.  
 
Note: Three Subjects were 
enrolled in more than one 
cohort of Study 207546. They 
are considered distinct 
subjects for the purposes of 
reporting. Subject
(Part A 
Cohort 1) is the same subject 
as subject 
 (Part C Cohort 
4).  Subject 
(Part A 
Cohort 2) is the same subject 
as subject 
 (Part C Cohort 
5). Subject 
 (Part C 
Cohort 4) is the same subject 
SAC 
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PPD
PPD
PPD
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
as subject
(Part C Cohort 
5). 
1.2. 
Safety 
 
Part A: Summary of Subject Disposition for the 
Subject Conclusion Record at Each Study 
Period/Phase by Arm 
 
SAC 
1.3. 
Screened 
ES6 
Part A: Summary of Screening Status and Reasons 
for Screen Failure 
 
SAC 
1.4. 
Safety 
ES4 
Part A: Summary of Subject Disposition at Each 
Study Epoch 
Crossover part: the “treatment 
group” column will indicate 
the treatment that the subject 
was exposed to most recently 
at the time of withdrawal. 
SAC 
1.5. 
Enrolled 
NS1 
Part A: Summary of Number of Subjects Enrolled by 
Country and Centre ID 
 
 
SAC 
Protocol Deviations 
1.6. 
Safety 
DV1 
Part A: Summary of Important Protocol Deviations 
Crossover part: only totals are 
presented 
SAC 
Demography 
1.7. 
Safety 
DM3 
Part A: Summary of Demographic Characteristics 
Crossover part: only totals are 
presented 
SAC 
1.8. 
Safety 
 
Part A: Summary of Demographic Characteristics by 
Arm 
 
SAC 
1.9. 
Enrolled 
DM11 
Part A: Summary of Age Ranges 
Crossover part: only totals are 
presented. 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Add footnote: For calculating 
Age, birth date is imputed as 
30th June in the year of birth.  
1.10. 
Safety 
DM5 
Part A: Summary of Race and Racial Combinations 
Report only categories if n>0 
count; crossover part: only 
totals are presented 
SAC 
Concomitant Medications 
1.11. 
Safety 
CM1 
Part A: Summary of Concomitant Medications 
 
SAC 
 
Part C 
Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Disposition 
1.12. 
Safety 
ES1 
Part C: Summary of Subject Disposition for the 
Subject Conclusion Record 
Note: Three Subjects were 
enrolled in more than one 
cohort of Study 207546. They 
are considered distinct 
subjects for the purposes of 
reporting. Subject 
(Part A 
Cohort 1) is the same subject 
as subject 
(Part C Cohort 
4). Subject 
(Part A 
Cohort 2) is the same subject 
as subject 
(Part C Cohort 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5). Subject 
(Part C 
Cohort 4) is the same subject 
as subject 
(Part C Cohort 
5). 
1.13. 
Screened 
ES6 
Part C: Summary of Screening Status and Reasons 
for Screen Failure 
 
SAC 
1.14. 
Safety 
ES4 
Part C: Summary of Subject Disposition at Each 
Study Epoch 
 
SAC 
1.15. 
Enrolled 
NS1 
Part C: Summary of Number of Subjects Enrolled by 
Country and Centre ID 
 
 
SAC 
Protocol Deviations 
1.16. 
Safety 
DV1 
Part C: Summary of Important Protocol Deviations 
 
SAC 
Demography 
1.17. 
Safety 
DM1 
Part C: Summary of Demographic Characteristics 
 
SAC 
1.18. 
Enrolled 
DM11 
Part C: Summary of Age Ranges 
Add footnote: For calculating 
Age, birth date is imputed as 
30th June in the year of birth.  
SAC 
1.19. 
Safety 
DM5 
Part C: Summary of Race and Racial Combinations 
Report only categories if n>0 
count 
SAC 
Concomitant Medications 
1.20. 
Safety 
CM1 
Part C: Summary of Concomitant Medications 
 
SAC 
Exposure 
1.21. 
Safety 
EX1 
Part C: Summary of Exposure to Study Treatment 
 
SAC 
 
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13.9.5. 
Safety Tables 
Part A 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.1. 
Safety 
AE5a 
Part A: Summary of All Adverse Events by 
Maximum Intensity by System Organ Class and 
Preferred Term 
Add footnote listing the 
subjects who re-enrolled in 
other Parts (only add this 
footnote if they had AEs both 
here and in another Part) 
Include total column. 
SAC 
2.2. 
Safety 
AE5a 
Part A: Summary of All Drug Related Adverse 
Events by Maximum Intensity by System Organ 
Class and Preferred Term 
Include total column. 
SAC 
2.3. 
Safety 
AE16 
Part A: Summary of Serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative. 
SAC 
2.4. 
Safety 
AE15 
Part A: Summary of Common (>=5%) Non-serious 
Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and 
Occurrences) 
 
SAC 
2.5. 
Safety  
AE3 
Part A: Summary of Common (>=5%) Adverse 
Events by Overall Frequency 
 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.6. 
Safety  
AE3 
Part A:  Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study 
 
SAC 
2.7. 
Safety 
AE3 
Part A: Summary of Non-Serious Drug-Related 
Adverse Events by Overall Frequency 
 
SAC 
2.8. 
Safety 
AE3 
Part A: Summary of Serious Drug-Related Adverse 
Events by Overall Frequency  
 
SAC 
Laboratory 
2.9. 
Safety 
LB1 
Part A: Summary of Chemistry Changes from 
Baseline  
Order parameters 
alphabetically. 
 
SAC 
2.10. 
Safety 
LB17 
Part A: Summary of Worst Case Chemistry Results 
by PCI Criteria Post-Baseline Relative to Baseline 
Order parameters 
alphabetically, include 
parameters with PCI criteria 
listed in Appendix 7. 
 
SAC 
2.11. 
Safety 
LB15 
Part A: Summary of Worst Case Chemistry Results 
Relative to Normal Range Post-Baseline Relative to 
Baseline 
Order parameters 
alphabetically, include 
parameters with Normal 
Ranges listed in Appendix 7. 
 
SAC 
2.12. 
Safety 
LB1 
Part A: Summary of Hematology Changes from 
Baseline 
Order parameters 
alphabetically. 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.13. 
Safety 
LB17 
Part A: Summary of Worst Case Hematology Results 
by PCI Criteria Post-Baseline Relative to Baseline 
Order parameters 
alphabetically, include 
parameters with PCI criteria 
listed in Appendix 7.  
SAC 
2.14. 
Safety 
LB15 
Part A: Summary of Worst Case Hematology Results 
Relative to Normal Range Post-Baseline Relative to 
Baseline 
Order parameters 
alphabetically, include 
parameters with Normal 
Ranges listed in Appendix 7. 
SAC 
ECG 
2.15. 
Safety 
EG1 
Part A: Summary of ECG Findings 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
SAC 
2.16. 
Safety 
EG10 
Part A: Summary of Maximum QTcF Values Post-
Baseline Relative to Baseline by Category 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
SAC 
2.17. 
Safety 
EG11 
Part A: Summary of Maximum Increase in QTcF 
Values Post-Baseline Relative to Baseline by 
Category 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.18. 
Safety 
EG2 
Part A: Summary of Change from Baseline in ECG 
Values by Visit 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
SAC 
Holter 
2.19. 
Safety 
HM1 
Part A: Summary of Holter Interpretations 
 
SAC 
2.20. 
Safety 
HM2 
Part A: Summary of Holter Abnormalities 
 
SAC 
Vital Signs 
2.21. 
Safety 
VS1 
Part A: Summary of Change from Baseline in Vital 
Signs 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
SAC 
2.22. 
Safety 
VS7 
Part A: Summary of Worst Case Vital Sign Results 
by PCI Criteria Post-Baseline Relative to Baseline 
 
 
Crossover part: counts and 
percentages are based on the 
number of subjects in each 
treatment, so participants will 
appear in multiple treatments. 
SAC 
 
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Part C 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.23. 
Safety 
AE5a 
Part C: Summary of All Adverse Events by 
Maximum Intensity by System Organ Class and 
Preferred Term 
Include total column. 
SAC 
2.24. 
Safety 
AE5a 
Part C: Summary of All Drug Related Adverse 
Events by Maximum Intensity by System Organ 
Class and Preferred Term 
Include total column. 
SAC 
2.25. 
Safety 
AE16 
Part C: Summary of Serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurances) 
 
SAC 
2.26. 
Safety 
AE3 
Part C: Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by Overall Frequency 
 
SAC 
2.27. 
Safety 
AE15 
Part C: Summary of Common (>=5%) Non-serious 
Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and 
Occurrences) 
 
SAC 
2.28. 
Safety  
AE3 
Part C: Summary of Common (>=5%) Adverse 
Events by Overall Frequency 
 
SAC 
2.29. 
Safety 
AE3 
Part C: Summary of Non-Serious Drug-Related 
Adverse Events by Overall Frequency 
 
SAC 
2.30. 
Safety 
AE3 
Part C: Summary of Serious Drug-Related Adverse 
Events by Overall Frequency  
 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
2.31. 
Safety 
LB1 
Part C: Summary of Chemistry Changes from 
Baseline  
Order parameters 
alphabetically. 
SAC 
2.32. 
Safety 
LB17 
Part C: Summary of Worst Case Chemistry Results 
by PCI Criteria Post-Baseline Relative to Baseline 
Order parameters 
alphabetically, include 
parameters with PCI criteria 
listed in Appendix 7.  
SAC 
2.33. 
Safety 
LB15 
Part C: Summary of Worst Case Chemistry Results 
Relative to Normal Range Post-Baseline Relative to 
Baseline 
Order parameters 
alphabetically, include 
parameters with Normal 
Ranges listed in Appendix 7. 
 
SAC 
2.34. 
Safety 
LB1 
Part C: Summary of Hematology Changes from 
Baseline 
Order parameters 
alphabetically. 
SAC 
2.35. 
Safety 
LB17 
Part C: Summary of Worst Case Hematology Results 
by PCI Criteria Post-Baseline Relative to Baseline 
Order parameters 
alphabetically, include 
parameters with PCI criteria 
listed in Appendix 7. 
SAC 
2.36. 
Safety 
LB15 
Part C: Summary of Worst Case Hematology Results 
Relative to Normal Range Post-Baseline Relative to 
Baseline 
Order parameters 
alphabetically, include 
parameters with Normal 
Ranges listed in Appendix 7. 
 
SAC 
ECG 
2.37. 
Safety 
EG1 
Part C: Summary of ECG Findings  
 
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No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.38. 
Safety 
EG10 
Part C: Summary of Maximum QTcF Values Post-
Baseline Relative to Baseline by Category 
 
SAC 
2.39. 
Safety 
EG11 
Part C: Summary of Maximum Increase in QTcF 
Values Post-Baseline Relative to Baseline by 
Category 
 
SAC 
2.40. 
Safety 
EG2 
Part C: Summary of Change from Baseline in ECG 
Values by Visit 
 
SAC 
Holter 
2.41. 
Safety 
HM1 
Part C: Summary of Holter Interpretations 
 
SAC 
2.42. 
Safety 
HM2 
Part C: Summary of Holter Abnormalities 
 
SAC 
Vital Signs 
2.43. 
Safety 
VS1 
Part C: Summary of Change from Baseline in Vital 
Signs 
 
SAC 
2.44. 
Safety 
VS7 
Part C: Summary of Worst Case Vital Sign Results 
by PCI Criteria Post-Baseline Relative to Baseline 
 
 
SAC 
 
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13.9.6. 
Safety Figures 
Part A 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
2.1. 
Safety 
AE10 
Part A: Plot of Common (>=5%) Adverse Events 
and Relative Risk 
 
SAC 
 
Part C 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
2.2. 
Safety 
AE10 
Part C: Plot of Common (>=5%) Adverse Events 
and Relative Risk 
 
SAC 
 
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13.9.7. 
Pharmacokinetic Tables 
Part A 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
3.1. 
PK 
PK01 
Part A: Summary of Plasma Pharmacokinetic 
Concentration-time Data by Compound 
(GSK3358699 or GSK3206944) 
By treatment group and 
compound (GSK3358699 or 
GSK3206944). 
SAC 
3.2. 
PK 
PK01 
Part A: Summary of Intracellular Pharmacokinetic 
Concentration-time Data 
By treatment group. 
SAC 
3.3. 
PK 
PK01 
Part A: Summary of Intracellular Molar 
Concentration Pharmacokinetic Concentration-time 
Data 
By treatment group. 
SAC 
PK Derived Parameters 
3.4. 
PK 
PK06 
Part A: Summary of Derived Plasma 
Pharmacokinetic Parameters (Non-transformed and 
Log-transformed) by Compound (GSK3358699 or 
GSK3206944) 
By treatment group and 
compound (GSK3358699 or 
GSK3206944). 
SAC 
Dose Proportionality 
3.5. 
PK 
[Non 
standard] 
PK_T1 
Part A: Summary of Estimated Slope and 90% CI of 
Dose Proportionality Model 
By endpoint (AUC(0-t), 
AUC(0-∞), Cmax). 
SAC 
 
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Part C 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
3.6. 
PK 
PK01 
Part C: Summary of Plasma Pharmacokinetic 
Concentration-time Data by Compound 
(GSK3358699 or GSK3206944) 
By treatment group and 
compound (GSK3358699 or 
GSK3206944). 
SAC 
3.7. 
PK 
PK01 
Part C: Summary of Intracellular Pharmacokinetic 
Concentration-time Data 
By treatment group. 
SAC 
3.8. 
PK 
PK01 
Part C: Summary of Intracellular Molar 
Concentration Pharmacokinetic Concentration-time 
Data 
By treatment group. 
SAC 
PK Derived Parameters 
3.9. 
PK 
PK06 
Part C: Summary of Derived Plasma 
Pharmacokinetic Parameters (Non-transformed and 
Log-transformed) by Compound (GSK3358699 or 
GSK3206944) 
By treatment group and 
compound (GSK3358699 or 
GSK3206944). 
SAC 
 
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13.9.8. 
Pharmacokinetic Figures 
Part A 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.1. 
PK 
PK16b 
Part A: Individual Subject Plot: Plasma 
Concentration by Subject (Linear and Semi-log) by 
Compound (GSK3358699 or GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944). 
SAC 
3.2. 
PK 
PK16b 
Part A: Individual Subject Plot: Intracellular 
Concentration by Subject (Linear and Semi-log) 
 
SAC 
3.3. 
PK 
PK16b 
Part A: Individual Subject Plot: Intracellular Molar 
Concentration by Subject (Linear and Semi-log) 
 
SAC 
Mean/Median Concentration Plots 
3.4. 
PK 
PK17 
Part A: Mean Plot: Plasma Concentrations (Linear 
and Semi-log) by Compound (GSK3358699 or 
GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944). 
SAC 
3.5. 
PK 
PK17 
Part A: Mean Plot: Intracellular Concentrations 
(Linear and Semi-log) 
 
SAC 
3.6. 
PK 
PK17 
Part A: Mean Plot: Intracellular Molar 
Concentrations (Linear and Semi-log) 
 
SAC 
3.7. 
PK 
PK18 
Part A: Median Plot: Plasma Concentrations (Linear 
and Semi-log) by Compound (GSK3358699 or 
GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944). 
SAC 
3.8. 
PK 
PK18 
Part A: Median Plot: Intracellular Concentrations 
(Linear and Semi-log) 
 
SAC 
3.9. 
PK 
PK18 
Part A: Median Plot: Intracellular Molar 
Concentrations (Linear and Semi-log) 
 
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Part C 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.10. PK 
PK16a 
Part C: Individual Subject Plot: Plasma 
Concentration by Subject (Linear and Semi-log) by 
Compound (GSK3358699 or GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944) 
SAC 
3.11. PK 
PK16a 
Part C: Individual Subject Plot: Intracellular 
Concentration by Subject (Linear and Semi-log) 
 
SAC 
3.12. PK 
PK16a 
Part C: Individual Subject Plot: Intracellular Molar 
Concentration by Subject (Linear and Semi-log) 
 
SAC 
Mean/Median Concentration Plots 
3.13. PK 
PK17 
Part C: Mean Plot: Plasma Concentrations (Linear 
and Semi-log) by Compound (GSK3358699 or 
GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944) 
SAC 
3.14. PK 
PK17 
Part C: Mean Plot: Intracellular Concentrations 
(Linear and Semi-log) 
 
SAC 
3.15. PK 
PK17 
Part C: Mean Plot: Intracellular Molar 
Concentrations (Linear and Semi-log) 
 
SAC 
3.16. PK 
PK18 
Part C: Median Plot: Plasma Concentrations (Linear 
and Semi-log) by Compound (GSK3358699 or 
GSK3206944) 
Page by compound 
(GSK3358699 or 
GSK3206944) 
SAC 
3.17. PK 
PK18 
Part C: Median Plot: Intracellular Concentrations 
(Linear and Semi-log) 
 
SAC 
3.18. PK 
PK18 
Part C: Median Plot: Intracellular Molar 
Concentrations (Linear and Semi-log) 
 
SAC 
 
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13.9.9. 
Pharmacodynamic Tables 
Part A 
 
Pharmacodynamic (and or Biomarker): Tables 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Soluble Inflammatory Mediators 
5.1. Safety 
 
Part A: Summary of Absolute Values and 
Percentage Inhibition of Soluble Inflammatory 
Mediators in Blood After Ex-Vivo LPS Activation 
Page by Biomarker [S4] 
(note: this “[S4]” refers to 
the endpoint corresponding 
to this display; use the table 
in Section 13.5.4 for a list 
of biomarkers for each 
endpoint; applies to all PD 
displays). 
SAC 
5.2. Safety 
 
Part A: Summary of Predicted Percentage 
Inhibition of Soluble Inflammatory Mediators in 
Blood After Ex-Vivo LPS Activation 
Page by Biomarker [S4]. 
SAC 
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Part C 
 
13.9.10. 
Pharmacodynamic Figures 
Part A 
 
Pharmacodynamic (and or Biomarker): Tables 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Soluble Inflammatory Mediators 
5.3. Safety 
 
Part C: Summary of Absolute Values and 
Percentage Inhibition of Soluble Inflammatory 
Mediators in Blood After Ex-Vivo LPS Activation 
Page by Biomarker [S4].  
 
SAC 
5.4. Safety 
 
Part C: Summary of Predicted Percentage 
Inhibition of Soluble Inflammatory Mediators in 
Blood After Ex-Vivo LPS Activation 
Page by Biomarker [S4]. 
SAC 
Pharmacodynamic (and or Biomarker): Figures 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Soluble Inflammatory Mediators 
5.1. Safety 
 
Part A: Individual Plot of Soluble Inflammatory 
Mediators in Blood Over Time After Ex-Vivo LPS 
Activation 
[S4] Page by dose, then 
individual. 
SAC 
5.2. Safety 
 
Part A: Mean (+/- SE) Plot of Soluble 
Inflammatory Mediators in Blood Over Time After 
Ex-Vivo LPS Activation 
[S4]. 
 
SAC 
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Part C 
 
 
 
 
13.9.11. 
ICH Listings 
Part A 
ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  Screened 
ES7 
Part A: Listing of Reasons for Screen Failure 
 
SAC 
2.  Safety 
ES3 
Part A: Listing of Reasons for Study Withdrawal 
 
SAC 
3.  Safety 
BL2 
Part A: Listing of Subjects for Whom the 
Treatment Blind was Broken 
 
SAC 
4.  Safety 
TA1 
Part A: Listing of Planned and Actual Treatment 
 
SAC 
Protocol Deviations 
5.  Safety 
DV2a 
Part A: Listing of Important Protocol Deviations  
 
SAC 
Pharmacodynamic (and or Biomarker): Figures 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Soluble Inflammatory Mediators 
5.3. Safety 
 
Part C: Individual Plot of Soluble Inflammatory 
Mediators in Blood Over Time After Ex-Vivo LPS 
Activation 
[S4]. 
SAC 
5.4. Safety 
 
Part C: Mean (+/- SE) Plot of Soluble 
Inflammatory Mediators in Blood Over Time After 
Ex-Vivo LPS Activation 
[S4]. 
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.  Safety 
IE4 
Part A: Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations 
 
SAC 
Demography 
7.  Safety 
DM4 
Part A: Listing of Demographic Characteristics 
 
SAC 
8.  Safety 
DM10 
Part A: Listing of Race 
 
SAC 
Populations Analysed 
9.  Screened 
SP3a 
Part A: Listing of Subjects Excluded from Any 
Population 
 
SAC 
Concomitant Medications 
10.  Safety 
CM5 
Part A: Listing of Concomitant Medications 
  
SAC 
Exposure 
11.  Safety 
EX4 
Part A: Listing of Exposure Data 
 
SAC 
Adverse Events 
12.  Safety 
AE9CP 
Part A: Listing of All Adverse Events 
 
SAC 
13.  Safety 
AE7 
Part A: Listing of Subject Numbers for Individual 
Adverse Events 
 
SAC 
14.  Safety 
AE2 
Part A: Listing of Relationship Between Adverse 
Event System Organ Classes, Preferred Terms, 
and Verbatim Text 
 
SAC 
15.  Safety 
AE14 
Part A: Listing of Reasons for Considering as a 
Serious Adverse Event 
 
SAC 
16.  Safety 
AE9CPa 
Part A: Listing of Serious Adverse Events 
 
SAC 
17.  Safety 
AE9CP 
Part A: Listing of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study  
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
18.  Safety 
LB6 
Part A: Listing of All Laboratory Data for 
Subjects with Any Value Outside of Normal 
Range or of Potential Clinical Importance 
 
SAC 
19.  Safety 
LB6 
Part A: Listing of All Laboratory Values Outside 
of Normal Range or of Potential Clinical 
Importance 
 
SAC 
20.  Safety 
LB14 
Part A: Listing of Laboratory Data with Character 
Results 
 
SAC 
21.  Safety 
UR2B 
Part A: Listing of Urinalysis Data for Subjects 
with Any Value of Potential Clinical Importance 
 
SAC 
22.  Safety 
MH2 
Part A: Listing of Medical Conditions for 
Subjects with Liver Stopping Events 
 
SAC 
23.  Safety 
SU2 
Part A: Listing of Subtance Use for Subjects with 
Liver Stopping Events 
 
SAC 
24.  Safety 
LIVER6 
Part A: Listing of Liver Stopping Event 
Information for RUCAM Score  
 
SAC 
25.  Safety 
LIVER5 
Part A: Listing of Liver Monitoring/Stopping 
Event Reporting 
 
SAC 
ECG 
26.  Saftey 
EG4 
Part A: Listing of All ECG Values for Subjects 
with Any Value of Potential Clinical Importance 
 
SAC 
27.  Safety 
EG4 
Part A: Listing of ECG Values of Potential 
Clinical Importance 
 
SAC 
28.  Safety 
EG6 
Part A: Listing of All ECG Findings for Subjects 
with an Abnormal ECG Finding 
 
SAC 
29.  Safety 
EG6 
Part A: Listing of Abnormal ECG Findings 
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
30.  Safety 
VS5 
Part A: Listing of All Vital Signs for Subjects 
with Any Value of Potential Clinical Importance 
 
SAC 
31.  Safety 
VS5 
Part A: Listing of Vital Signs of Potential 
Clinical Importance 
 
SAC 
 
Part B 
ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
32.  Screened 
ES7 
Part B: Listing of Reasons for Screen Failure 
 
SAC 
Demography 
33.  Safety 
DM4 
Part B: Listing of Demographic Characteristics 
 
SAC 
 
Part C 
ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
34.  Screened 
ES7 
Part C: Listing of Reasons for Screen Failure 
 
SAC 
35.  Safety 
ES2 
Part C: Listing of Reasons for Study Withdrawal 
 
SAC 
36.  Safety 
BL1 
Part C: Listing of Subjects for Whom the 
Treatment Blind was Broken 
 
SAC 
37.  Safety 
TA1 
Part C: Listing of Planned and Actual Treatment 
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviations 
38.  Safety 
DV2 
Part C: Listing of Important Protocol Deviations  
 
SAC 
39.  Safety 
IE3 
Part C: Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations 
 
SAC 
Demography 
40.  Safety 
DM2 
Part C: Listing of Demographic Characteristics 
 
SAC 
41.  Safety 
DM9 
Part C: Listing of Race 
 
SAC 
Populations Analysed 
42.  Screened 
SP3 
Part C: Listing of Subjects Excluded from Any 
Population 
 
SAC 
Concomitant Medications 
43.  Safety 
CM3 
Part C: Listing of Concomitant Medications 
  
SAC 
Exposure 
44.  Safety 
EX3 
Part C: Listing of Exposure Data 
 
SAC 
Adverse Events 
45.  Safety 
AE8CP 
Part C: Listing of All Adverse Events 
 
SAC 
46.  Safety 
AE7 
Part C: Listing of Subjects Numbers for 
Individual Adverse Events 
 
SAC 
47.  Safety 
AE2 
Part C: Listing of Relationship Between Adverse 
Event System Organ Classes, Preferred Terms, 
and Verbatim Text 
 
SAC 
48.  Safety 
AE14 
Part C: Listing of Reasons for Considering as a 
Serious Adverse Event 
 
SAC 
49.  Safety 
AE8CPa 
Part C: Listing of Serious Adverse Events 
  
SAC 
50.  Safety 
AE8CP 
Part C: Listing of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study  
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
51.  Safety 
LB5 
Part C: Listing of All Laboratory Data for 
Subjects with Any Value Outside of Normal 
Range or of Potential Clinical Importance 
 
SAC 
52.  Safety 
LB5 
Part C: Listing of All Laboratory Values Outside 
of Normal Range or of Potential Clinical 
Importance 
 
SAC 
53.  Safety 
LB14 
Part C: Listing of Laboratory Data with Character 
Results 
 
SAC 
54.  Safety 
UR2A 
Part C: Listing of Urinalysis Data for Subjects 
with Any Value of Potential Clinical Importance 
PCI is defined as per 
IDSL - an increase in 
Protein or Occult Blood 
post-baseline relative to 
baseline, or if microscopy 
is performed. 
SAC 
55.  Safety 
MH2 
Part C: Listing of Medical Conditions for 
Subjects with Liver Stopping Events 
 
SAC 
56.  Safety 
SU2 
Part C: Listing of Subtance Use for Subjects with 
Liver Stopping Events 
 
SAC 
57.  Safety 
LIVER6 
Part C: Listing of Liver Stopping Event 
Information for RUCAM Score  
 
SAC 
58.  Safety 
LIVER5 
Part C: Listing of Liver Monitoring/Stopping 
Event Reporting 
 
SAC 
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ICH: Listings 
No. Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
59.  Saftey 
EG3 
Part C: Listing of All ECG Values for Subjects 
with Any Value of Potential Clinical Importance 
 
SAC 
60.  Safety 
EG3 
Part C: Listing of ECG Values of Potential 
Clinical Importance 
 
SAC 
61.  Safety 
EG5 
Part C: Listing of All ECG Findings for Subjects 
with an Abnormal ECG Finding 
 
SAC 
62.  Safety 
EG5 
Part C: Listing of Abnormal ECG Findings 
 
SAC 
Vital Signs 
63.  Safety 
VS4 
Part C: Listing of All Vital Signs for Subjects 
with Any Value of Potential Clinical Importance 
 
SAC 
64.  Safety 
VS4 
Part C: Listing of Vital Signs of Potential Clinical 
Importance 
 
SAC 
 
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13.9.12. 
Non-ICH Listings 
Part A 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
65.  
PK 
PK08 
Part A: Listing of GSK3358699 Plasma 
Pharmacokinetic Concentration-time Data 
 
SAC 
66.  
PK 
PK08 
Part A: Listing of GSK3206944 Plasma 
Pharmacokinetic Concentration-time Data 
 
SAC 
67.  
PK 
PK08 
Part A: Listing of GSK3206944  Intracellular 
Pharmacokinetic Concentration-time Data 
 
SAC 
68.  
PK 
PK14 
Part A: Listing of Derived GSK3358699 Plasma 
Pharmacokinetic Parameters 
 
SAC 
69.  
PK 
PK14 
Part A: Listing of Derived GSK3206944 Plasma 
Pharmacokinetic Parameters 
 
SAC 
Biomarkers: Soluble Inflammatory Mediators 
70.  
Safety 
[Non standard] 
BIO_L1 
Part A: Listing of Absolute Values Percentage 
Inhibition and Predicted Percentage Inhibition of 
Soluble Inflammatory Mediators in Blood After 
Ex-Vivo LPS Activation 
S4 
SAC 
 
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Part C 
 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
71.  
PK 
PK07 
Part C: Listing of GSK3358699 Plasma 
Pharmacokinetic Concentration-time Data 
 
SAC 
72.  
PK 
PK07 
Part C: Listing of GSK3206944 Plasma 
Pharmacokinetic Concentration-time Data 
 
SAC 
73.  
PK 
PK07 
Part C: Listing of GSK3206944 Intracellular 
Pharmacokinetic Concentration-time Data 
 
SAC 
74.  
PK 
PK13 
Part C: Listing of Derived GSK3358699 Plasma 
Pharmacokinetic Parameters 
 
SAC 
75.  
PK 
PK13 
Part C: Listing of Derived GSK3206944 Plasma 
Pharmacokinetic Parameters 
 
SAC 
Biomarkers: Soluble Inflammatory Mediators 
76.  
Safety 
[Non 
standard] 
BIO_L1 
Part C: Listing of Absolute Values, Percentage 
Inhibition and Predicted Percentage Inhibition 
of Soluble Inflammatory Mediators in Blood 
After Ex-Vivo LPS Activation 
S4 
SAC 
207546 | Statistical Analysis Plan  RAP 22 Jun 2020 | TMF-1817519 | 1.0


Signature Page for  207546 TMF-1817519 v1.0
Signature Page for TMF-1817519 v1.0
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Role: Approver
Date of signature: 22-Jun-2020 11:39:29 GMT+0000
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 22-Jun-2020 16:34:51 GMT+0000
207546 | Statistical Analysis Plan  RAP 22 Jun 2020 | TMF-1817519 | 1.0
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