A Randomized, Double-blind, Single Ascending Dose Study to Determine the Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of GSK3772847 Administered Subcutaneously in Healthy Participants
Phase: PHASE1
Conditions: Healthy Volunteers, Asthma
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A randomized, double-blind, single ascending dose study to determine 
the safety and tolerability, pharmacokinetics and pharmacodynamics of GSK3772847 
administered subcutaneously in healthy participants
Protocol Number: 209635 / Amendment 2
Compound Number
or Name:
GSK3772847
Study Phase: Phase 1
Short Title: A study to evaluate the safety and tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3772847 administered subcutaneously in healthy participants
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information Can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s):
IND: 134366
Approval Date: 02-JUL-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

1
From:
Sent:
Thursday, July 2, 2020 8:01 PM
To:
Subject:
FW: Prot-209635-sponsign
 
From: Courtney Crim 
  
Sent: 02 July 2020 14:13 
To: 
 
Subject: RE: Prot-209635-sponsign 
 
I approve. 
 
Courtney 
 
Courtney Crim, M.D. 
Group Director 
Respiratory TAU 
 
From: 
  
Sent: Thursday, July 02, 2020 8:52 AM 
To: Courtney Crim 
 
Subject: Prot-209635-sponsign 
Importance: High 
 
Dear Courtney, 
 
To approve the clinical protocol indicated below, reply to this email and state your approval.  
 
PROTOCOL NUMBER: 209635 
 
DOCUMENT IDENTIFIER: 2020N427367_02 
 
AMENDMENT NUMBER: 02 
 
PROTOCOL TITLE: A randomized, double-blind, single ascending dose study to determine the safety and 
tolerability, pharmacokinetics and pharmacodynamics of GSK3772847 administered subcutaneously in healthy 
participants 
 
Name of Sponsor Signatory: Courtney Crim, M.D 
 
Title of Sponsor Signatory: Director, Clinical Development, Clinical Science, Respiratory, GlaxoSmithKline 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 2
02-JUL-2020
2020N427367_02
Amendment 1
12-Jun-2020
2020N427367_01
Original Protocol
17-Mar-2020
2020N427367_00
Amendment [2] 02-JUL-2020
Overall Rationale for the Amendment:
Amendment to reduce age range from 18 – 65 to 18 – 50 to ensure older populations, 
potentially more at risk of COVID-19 are not recruited into the study and to update 
secondary pharmacodynamics endpoint to specify nominal day as maximum timepoint.
Section # and 
Name
Description of Change
Brief Rationale
Section 5.1 
Inclusion 
Criteria
Change in inclusion from “18 to 
65 years of age, inclusive” to “18 
to 50 years of age, inclusive.”
Reduced age range to ensure older 
populations, potentially more at risk of 
COVID-19, are not recruited into the 
study.
Section 1.1 
Synopsis 
Section 3
Objectives and 
Endpoints
Updated secondary endpoint for 
pharmacodynamics (PD) of 
GSK3772847 from “Maximal 
decrease in free and increase in 
total soluble ST2 levels in serum 
up to a maximum of 89 days post 
dose” to “Maximal decrease in 
free and increase in total soluble 
ST2 levels in serum up to Day 85
visit”
To provide clarity by specifying nominal 
day as maximum timepoint.
Section 1.1
Synopsis
Section 4.1
Overall Design
Clarified participant time in study 
from “16 weeks and 5 days” to 
“17 weeks and 4 days” 
Clarified participant time in study 
from “up to 89 days” to “up to 95 
days”
Updated to clarify a participant’s
maximum time in study due to visit 
window extensions.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................7
1.1.
Synopsis.......................................................................................................7
1.2.
Schema ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................11
1.3.1.
Screening Schedule of Activities..................................................11
1.3.2.
Treatment Period Schedule of Activities ......................................12
2.
INTRODUCTION....................................................................................................16
2.1.
Study Rationale ..........................................................................................16
2.2.
Background ................................................................................................16
2.3.
Benefit/Risk Assessment ............................................................................18
2.3.1.
Risk Assessment .........................................................................19
2.3.2.
Benefit Assessment.....................................................................28
2.3.3.
Overall Benefit: Risk Conclusion..................................................28
3.
OBJECTIVES AND ENDPOINTS...........................................................................29
4.
STUDY DESIGN ....................................................................................................30
4.1.
Overall Design ............................................................................................30
4.2.
Scientific Rationale for Study Design ..........................................................31
4.3.
Justification for Dose ..................................................................................31
4.4.
End of Study Definition ...............................................................................32
5.
STUDY POPULATION...........................................................................................32
5.1.
Inclusion Criteria.........................................................................................33
5.2.
Exclusion Criteria........................................................................................34
5.3.
Lifestyle Considerations..............................................................................37
5.3.1.
Meals and Dietary Restrictions ....................................................37
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................37
5.3.3.
Activity .........................................................................................37
5.4.
Screen Failures...........................................................................................38
6.
STUDY INTERVENTION........................................................................................38
6.1.
Study Intervention(s) Administered .............................................................38
6.2.
Preparation/Handling/Storage/Accountability..............................................40
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................40
6.3.1.
Randomization.............................................................................40
6.3.2.
Blinding........................................................................................41
6.4.
Study Intervention Compliance ...................................................................42
6.5.
Concomitant Therapy..................................................................................42
6.6.
Dose Modification .......................................................................................43
6.7.
Intervention after the End of the Study........................................................43
7.
DISCONTINUATION CRITERIA.............................................................................43
7.1.
Liver Chemistry Stopping Criteria ...............................................................43
7.2.
QTc Stopping Criteria .................................................................................44
7.3.
Participant Discontinuation/Withdrawal from the Study ...............................45
7.4.
Lost to Follow Up........................................................................................45

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8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
8.1.
Efficacy Assessments.................................................................................46
8.2.
Safety Assessments ...................................................................................46
8.2.1.
Physical Examinations.................................................................46
8.2.2.
Vital Signs....................................................................................47
8.2.3.
Electrocardiograms......................................................................47
8.2.4.
Targeted Injection Site Reaction Examination..............................47
8.2.5.
Clinical Safety Laboratory Assessments ......................................47
8.3.
Adverse Events and Serious Adverse Events.............................................47
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................48
8.3.2.
Method of Detecting AEs and SAEs.............................................48
8.3.3.
Follow-up of AEs and SAEs.........................................................48
8.3.4.
Regulatory Reporting Requirements for SAEs .............................49
8.3.5.
Pregnancy ...................................................................................49
8.3.6.
Adverse Events of Special Interest ..............................................49
8.4.
Treatment of Overdose...............................................................................50
8.5.
Pharmacokinetics .......................................................................................50
8.6.
Pharmacodynamics ....................................................................................51
8.6.1.
Soluble ST2.................................................................................51
8.6.2.
Blood eosinophils.........................................................................51
8.7.
Genetics .....................................................................................................51
8.8.
Biomarkers .................................................................................................51
8.8.1.
4βOH cholesterol/cholesterol.......................................................51
8.9.
Immunogenicity Assessments.....................................................................52
8.10.
Health Economics or Medical Resource Utilization and Health 
Economics..................................................................................................52
9.
STATISTICAL CONSIDERATIONS........................................................................52
9.1.
Statistical Hypothesis..................................................................................52
9.2.
Sample Size Determination ........................................................................52
9.3.
Populations for Analyses ............................................................................53
9.4.
Statistical Analyses.....................................................................................54
9.4.1.
General Considerations ...............................................................54
9.4.2.
Primary Endpoint(s).....................................................................54
9.4.3.
Secondary Endpoint(s) ................................................................55
9.4.4.
Other Endpoint(s) ........................................................................55
9.5.
Interim Analyses .........................................................................................55
9.6.
Dose Escalation Committee........................................................................56
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................57
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................57
10.1.1.
Regulatory and Ethical Considerations ........................................57
10.1.2.
Financial Disclosure.....................................................................57
10.1.3.
Informed Consent Process ..........................................................58
10.1.4.
Data Protection............................................................................58
10.1.5.
Committees Structure ..................................................................59
10.1.5.1.
Dose Escalation Committee Structure ........................59
10.1.5.2.
Interim Analysis Data Review Committee 
(DRC).........................................................................59
10.1.6.
Dissemination of Clinical Study Data ...........................................59

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10.1.7.
Data Quality Assurance ...............................................................60
10.1.8.
Source Documents ......................................................................61
10.1.9.
Study and Site Start and Closure.................................................61
10.1.10. Publication Policy.........................................................................61
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................63
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
10.3.1.
Definition of AE............................................................................65
10.3.2.
Definition of SAE..........................................................................66
10.3.3.
Recording and Follow-Up of AE and SAE....................................67
10.3.4.
Reporting of SAE to GSK.............................................................69
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................71
10.4.1.
Definitions:...................................................................................71
10.4.2.
Contraception Guidance ..............................................................72
10.4.3.
Collection of Pregnancy Information: ...........................................73
10.5.
Appendix 5: Genetics..................................................................................75
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................76
10.7.
Appendix 7: COVID-19 Measures...............................................................78
10.7.1.
Study Procedures During COVID-19 Pandemic...........................78
10.7.2.
Protocol Defined Procedures/Visits:.............................................78
10.7.3.
Data Management/Monitoring:.....................................................80
10.8.
Appendix 8: Abbreviations and Trademarks................................................81
10.9.
Appendix 9: Protocol Amendment History...................................................84
11. REFERENCES.......................................................................................................85

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A randomized, double-blind, single ascending dose study to determine 
the safety and tolerability, pharmacokinetics and Pharmacodynamics of GSK3772847 
administered subcutaneously in healthy participants
Short Title: A study to evaluate the safety and tolerability, PK and PD of GSK3772847 
administered subcutaneously in healthy participants 
Rationale:
GSK3772847 is a human immunoglobulin G2 sigma isotype (IgG2) antibody that binds 
Domain 1 of the cell-surface interleukin-33 receptor (IL-33R). Inhibition of IL-33 
signalling via blockade of the IL-33 receptor (Suppressor of tumorigenicity 2 [ST2], also 
known as Interleukin-1 receptor like-1 [IL-1RL1]) presents a potential novel treatment 
for severe asthma as an add-on to standard of care. Agents targeting this mechanism 
could be expected to have effects on both type 2 (T2)-driven and non-T2-driven disease.
The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK)
and pharmacodynamics (PD) of single ascending doses of GSK3772847 administered 
subcutaneously (SC) to healthy participants. It will establish the bioavailability of the SC 
formulation and evaluate the safety (in particular injection site tolerability) of the SC 
route. 
GSK3772847 has been administered intravenously at doses up to and including 10mg/kg 
both as single and repeated doses (207597 [GlaxoSmithKline Document number 
2017N316832_02 and 207972 [final report pending]). This is the first study to evaluate 
the PK and PD of GSK3772847 via the subcutaneous (SC) route. Participants will be 
randomized to receive doses of either 70 (Cohort 1) or 140 mg (Cohort 2, 3 and 4) 
GSK3772847 or placebo SC. Placebo is included to allow a valid evaluation of adverse 
events attributable to treatment versus those independent of treatment. The dose selection 
is based on credible doses for future clinical development and are expected to reduce free 
sST2 by greater than 90% at peak effect. Recovery to near baseline levels is expected 
within the study duration. GSK3772847 will be administered in one of 3 injection sites: 
upper arm, thigh or abdomen. This will allow evaluation of PK and PD via the 3 most 
common sites for SC administration.
Cohorts of healthy Japanese (Cohort 3) and Chinese (Cohort 4) participants will also be 
included to enable us to evaluate PK and PD in these populations.  To minimise the 
number of comparisons the impact of injection site will only be evaluated in cohorts 1 
and 2 only.  Cohorts 3 and 4 will utilise only the upper arm injection site based on the 
ease of administration by a health care professional (HCP).
PK will be evaluated by non-compartmental analysis. In addition, data from this study 
will be included in a population-PKPD analysis together with the historic IV data to 
enable development an appropriate model to describe the PK and PD. This will be 
reported separately from the main clinical study report (CSR). 

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Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of a 
single dose of GSK3772847, compared with 
placebo administered subcutaneously in 
healthy participants including cohorts of 
Japanese and Chinese participants.
.

Occurrence of adverse events (AE’s) and 
serious adverse events (SAE’s) (including 
injection site reactions)

To assess the pharmacokinetics (PK) of a 
single dose of GSK3772847 administered
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants (Cohorts 1 and 2 also 
summarised by injection site)

PK parameters, including but not limited to, 
Area under the plasma-concentration time 
curve (AUC), maximum plasma 
concentration (Cmax), time to Cmax 
(Tmax) and terminal half-life (t1/2) of 
GSK3772847 per cohort 
Secondary

To evaluate the pharmacodynamics (PD) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

Maximal decrease in free and increase in 
total soluble ST2 levels in serum up to Day 
85 visit

To assess the immunogenicity of a single 
dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

occurrence of anti-GSK3772847 antibodies

To assess potential changes in Cytochrome 
P450 3A4 (CYP3A4) enzyme activity
following a single dose of GSK3772847 in 
healthy participants including cohorts of 
Japanese and Chinese participants.

Plasma 4β-Hydroxycholesterol (4βOH)
cholesterol/cholesterol ratio as an 
endogenous marker for CYP3A4 activity 
pre-treatment and following a single dose 
of GSK3772847
Other 

To further assess the safety and tolerability of 
a single dose of GSK3772847, compared with 
placebo administered subcutaneously in 
healthy participants including cohorts of 
Japanese and Chinese participants.

12-lead electrocardiogram (ECG)
measurements

Clinical chemistry laboratory tests

Vital signs

To evaluate the pharmacodynamics (PD) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

Free and total soluble ST2 levels in serum

Blood eosinophil levels

To assess the pharmacokinetics (PK) of a 
single dose of GSK3772847 administered
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

GSK3772847 levels in serum

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Overall Design:
This is a single centre, randomized, placebo-controlled, double-blind, ascending dose 
study in healthy participants.  
Following a screening period (of up to 28 days), participants who meet the eligibility 
criteria will be assigned to one of four cohorts and will be randomly allocated within each 
cohort to receive a single dose of either GSK3772847 or placebo.  All treatments will be 
administered subcutaneously by an HCP. The site of injection will be randomized to the 
upper arm, abdomen or thigh for cohorts 1 and 2 with cohorts 3 and 4 receiving injections 
in the upper arm only.
Before dosing in Cohorts 2, 3 and 4 can begin, blinded safety data (including injection 
site data from dosing to a minimum of 48 hours post-dose) will be reviewed in at least 20 
subjects who have received a dose in Cohort 1 (see Section 9.6). 
An interim analysis, to assess safety, tolerability, PK and PD, will be performed after a
predefined number of participants from all four cohorts have reached 4 weeks post dose
(see Section 9.5).
Disclosure Statement: This is a sequential safety, tolerability, PK and PD study with 4 
cohorts that is participant and investigator blinded.
Number of Participants:
A total of 64 participants will be initially randomised for a total of 18 evaluable 
participants on GSK3772847 in cohorts 1 and 2, 6 Japanese participants in cohort 3 and 6 
Chinese participants in cohort 4. Participants will be replaced if they withdraw from the 
study prior to completing all PK and sST2 assessments up to and including Day 29.  
Intervention Groups and Duration:
Healthy participants who meet the eligibility criteria will be assigned to one of four 
cohorts and will be randomly allocated within each cohort to receive a single dose of 
either GSK3772847 or placebo detailed below.  
In the event that all the participants from a given cohort cannot be dosed on the same day, 
the subgroup dosed must include participants randomized to each of the 3 injection sites.
Cohort 1: 18 participants 70mg GSK3772847 SC and 6 participants Placebo SC
Cohort 2: 18 participants 140mg (2 x 70mg) GSK3772847 SC and 6 participants
Placebo SC
Cohort 3 (Japanese): 6 participants 140mg (2 x 70mg) GSK3772847 SC and 2 
participants Placebo SC
Cohort 4 (Chinese): 6 participants 140mg (2 x 70mg) GSK3772847 SC and 2 
participants Placebo SC
Each participant will:

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
Be screened within 28 days prior to their first dose

Stay within the clinic for 5 nights post dose

Have follow up visits at days 9, 15, 29, 43, 57, 71 and at day 85

The total duration a participant remains in the study is up to 17 weeks and 4 days
(includes up to 28 days for screening, and up to 95 days post-dose follow up (includes 
6 days in clinic)).
Data Monitoring or Other Committee: Yes

A dose escalation committee will review blinded summary safety data (including 
injection site data obtained to 48 hours post-dose) of at least 20 participants from 
cohort 1 , as detailed in Section 9.6. The dose escalation committee will consist of 
the Principal Investigator and GSK Personnel.

An interim analysis data review committee consisting of GSK personnel will 
review safety, PK and PD data of all participants from all cohorts, 4 weeks post 
dose as detailed in Section 9.5.
1.2.
Schema
Screening Visit (up to 
28 days prior to dose)
Cohort 1 70mg SC (N=24)
Cohort 2 140mg SC(N=24)
Cohort 3 140mg SC Japanese participants (N=8)
Cohort 4 140mg SC Chinese participants (N=8)
Blinded safety review before dosing cohorts 2, 3 and 4
Interim analysis Day 29 (all cohorts)
Final follow up visit (85 
days post dose)

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1.3.
Schedule of Activities (SoA)
1.3.1.
Screening Schedule of Activities 
Table 1
Screening Schedule of Activities
Procedure
Screening
up to 28 days 
before dose
Notes
Informed consent
X
Inclusion and exclusion criteria review
X
Demography and medical history
X
Full physical examination including height and 
weight
X
Alcohol/drug screen
X
Urinary Cotinine Test
X
Safety labs (haematology, clinical chemistry and 
urinalysis)
X
To be taken in non-fasted 
state
Further details are given in 
Appendix 2
Hepatitis B and C and human immunodeficiency 
virus (HIV) screen
X
12-lead ECG
X
Vital signs
X
Supine blood pressure and 
heart rate
Concomitant medications
X
Serious adverse events
X
Pregnancy test
X
Serum at screening and 
urine dipstick test at all other 
visits

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1.3.2.
Treatment Period Schedule of Activities 
Table 2
Treatment Period Schedule of Activities
Procedure
Day 
0
Day 1 (Hours)
Day
2
Day
3
Day
4
Day
5
Day
6
Day 
9
Day 
15
Day 
29
Day 
43
Day
57
Day
71
Day 
85/Early 
withdrawal 
visit
Notes
Time window for 
Outpatient visits: 
Day 9  2 days, Day 
15 4 days, Days 
29, 43 and 57 7 
days, Days 71 and 
85 10 days
Pre-
dose
0
2
4
8
Clinic Visits
Admission to clinic
X
Participants may 
remain in the clinic 
until day 6 with visits 
at days 6-8 as 
outpatient, at the 
investigator’s 
discretion
Inclusion/Exclusion 
criteria review
X
Discharge from 
clinic
X
Out-patient visit
X
X
X
X
X
X
X
Study Intervention
Randomisation
X
SC dosing
X
Safety 
Assessments
Safety labs 
(haematology, 
clinical chemistry 
and urinalysis)
X
X
X
X
X
X
X
WBC differentials 
MUST be blinded 
(see Appendix 2)
To be taken in non-
fasted state

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Procedure
Day 
0
Day 1 (Hours)
Day
2
Day
3
Day
4
Day
5
Day
6
Day 
9
Day 
15
Day 
29
Day 
43
Day
57
Day
71
Day 
85/Early 
withdrawal 
visit
Notes
Time window for 
Outpatient visits: 
Day 9  2 days, Day 
15 4 days, Days 
29, 43 and 57 7 
days, Days 71 and 
85 10 days
Pre-
dose
0
2
4
8
Alcohol/drug screen
X
Urinary Cotinine 
Test
X
12-lead ECG
X
X
X
X
X
X
X
When scheduled at 
the same timepoint, 
ECG’s should be 
taken as close as 
possible to PK 
samples
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Supine blood 
pressure and heart 
rate
Concomitant 
medications
◄===============================================================================================►
SAE/AE Review
◄===============================================================================================►
Including injection site 
reactions
Local Injection site 
reaction evaluation
X
X
X
Targeted evaluation 
at 4 hours post-dose 
on Day 1 & 24 hours 
post-dose on Day 2 
and 48 hours post-
dose on Day 3. 
Spontaneous 
reporting at all other 
times.

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Procedure
Day 
0
Day 1 (Hours)
Day
2
Day
3
Day
4
Day
5
Day
6
Day 
9
Day 
15
Day 
29
Day 
43
Day
57
Day
71
Day 
85/Early 
withdrawal 
visit
Notes
Time window for 
Outpatient visits: 
Day 9  2 days, Day 
15 4 days, Days 
29, 43 and 57 7 
days, Days 71 and 
85 10 days
Pre-
dose
0
2
4
8
Pregnancy test
X
X
X
X
Serum pregnancy test 
at screening and urine 
dipstick test at all 
other visits
Brief Physical 
Examination
X
See Section 8.2.1
Biomarker 
Collection
PK blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 samples 1 
hours. Days 2-6 2 
hours relative to time 
of dosing
Free sST2 and total 
sST2 blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples should be 
taken within 2 
minutes of PK
Immunogenicity 
blood sample
X
X
X
X
X
Collect pre-dose on 
Day 1
4βOH 
cholesterol/choleste
rol plasma sample
X
X
X
X
X
All samples should be 
in non-fasted state for 
comparison with 
baseline.
Pharmacogenetic 
(PGx) blood sample
X
May be taken at any 
time post-dose

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
The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic/biomarker or other
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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation.

When scheduled at the same timepoints, vital signs should be conducted followed by ECG’s prior to any blood draws.

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2.
INTRODUCTION
2.1.
Study Rationale
GSK3772847 is a human immunoglobulin G2 sigma isotype (IgG2) antibody that binds 
Domain 1 of the cell-surface interleukin-33 receptor (IL-33R). Inhibition of IL-33 
signalling via blockade of the IL-33 receptor (Suppressor of tumorigenicity 2 [ST2], also 
known as Interleukin-1 receptor like-1 [IL-1RL1]) presents a potential novel treatment 
for severe asthma as an add-on to standard of care. Agents targeting this mechanism 
could be expected to have effects on both type 2 (T2)-driven and non-T2-driven disease.
The purpose of this study is to evaluate the safety and tolerability, PK and PD of single 
ascending doses of GSK3772847 administered subcutaneously (SC) to healthy 
participants. It will establish the bioavailability of the SC formulation and evaluate the 
safety (in particular injection site tolerability) of the SC route. 
GSK3772847 has been administered intravenously at doses up to and including 10mg/kg 
both as single and repeated doses (207597 [GlaxoSmithKline Document Number
2017N316832_02 and 207972 [final report pending]). This is the first study to evaluate 
the PK and PD of GSK3772847 via the subcutaneous (SC) route. Subjects will be 
randomised to receive doses of either 70 mg (Cohort 1) or 140 mg (Cohort’s 2, 3 and 4) 
GSK3772847 or placebo SC. Placebo is included to allow a valid evaluation of adverse 
events attributable to treatment versus those independent of treatment. The dose selection 
is based on credible doses for future clinical development and are expected to reduce free 
sST2 by greater than 90% at peak effect. Recovery to near baseline levels is expected 
within the study duration. GSK3772847 will be administered in one of 3 injection sites: 
upper arm, thigh or abdomen. This will allow evaluation of PK and PD via the 3 most 
common sites for SC administration.
Cohorts of healthy Japanese (Cohort 3) and Chinese (Cohort 4) participants will also be 
included to enable us to evaluate PK and PD in these populations.  To minimise the 
number of comparisons the impact of injection site will be evaluated in cohorts 1 and 2 
only.  Cohorts 3 and 4 will utilise only the upper arm injection site. 
PK will be evaluated by non-compartmental analysis. In addition, data from this study 
will be included in a population-PKPD analysis together with the historic IV data to 
enable development of an appropriate model to describe the PK and PD. This will be 
reported separately from the main clinical study report (CSR). 
2.2.
Background
Severe asthma represents approximately 5-10 % of the asthma population and is 
associated with a greater frequency of asthma exacerbations, decreased health-related 
quality of life and greater symptom burden [Aburuz, 2007;Chung, 2014;Moore, 2007]. 
Current biologic agents approved for the management of patients with severe asthma 
have demonstrated efficacy for T2-driven disease (i.e., eosinophilic and/or elevated 

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serum immunoglobulin E [IgE]) however, there is no currently approved therapy that 
targets non-T2-driven asthma. 
GSK3772847 (formerly CNTO 7160 which was in-licensed from Janssen) is a human 
IgG2monoclonal antibody (mAb) that binds to the extracellular domain of interleukin-
33 receptor (IL-33R) and neutralizes IL-33-mediated IL-33R signalling. The IL-33R gene 
codes for both a soluble form (sST2) and a membrane-bound “long” form (ST2L or IL-
33R). Soluble ST2 exists in the serum and is elevated in severe asthmatics during an 
exacerbation [Smithgall, 2008; Oshikawa, 2001].
IL-33R is expressed on immune cells, such as mast cells, basophils, eosinophils, and T 
helper cell type 2 (Th2) cells and has been shown to be upregulated on macrophages, 
neutrophils, and dendritic cells. It is also expressed on non-immune cells such as 
endothelial, epithelial and smooth muscle cells and fibroblasts. IL-33 has been shown to 
be released after endothelial or epithelial cell damage during trauma, physicochemical / 
microbarometric stress or infection [Arshad, 2016]. IL-33R signalling causes downstream 
production of Type 2 cytokines. The engagement of IL-33R with its ligand IL-33 
contributes to Th2-mediated pathologies and allergic responses [Yagami, 2010;Smithgall, 
2008]. , but has also been shown to promote Th1- and Th17-mediated responses [Arshad, 
2016;Smithgall, 2008].. Inhibition of IL-33 signalling via blockade of the IL-33R may 
result in down regulation of immune cell responses and therefore presents a potential 
novel treatment for severe asthma on top of standard of care [Arshad, 2016].
The findings from the completed toxicology package comprising of IV and SC repeat 
dose studies (26 weeks in dosing duration and the enhanced pre and post-natal (ePPND)
study), with the associated target engagement and pharmacokinetic data support the 
administration of GSK3772847 by IV and SC routes of administration for the proposed 
clinical use and is detailed in the Investigators Brochure [GlaxoSmithKline document 
number 2017N316832_02].
To date there have been three clinical studies conducted with GSK3772847 all using the 
IV formulation.  This will be the first study to use the SC formulation.  The SC 
formulation is being developed as this route of administration provides an easy to 
administer, cost effective dosage regimen which is generally preferred by patients.
Janssen  conducted a Phase I randomized, double-blind, placebo-controlled, IV single 
ascending dose study in healthy participants and multiple ascending dose study in 
participants with asthma and participants with atopic dermatitis (Janssen Study 
CNTO7160ASH1001; (GSK study 208736, GlaxoSmithKline Document Number 
2017N344518_00])). A summary of the data from this study is included in the 
investigator brochure [GlaxoSmithKline document number 2017N316832_02].
Study 207597 was a double-blind, parallel group, multicentre, stratified study evaluating 
the efficacy, safety and tolerability, PK and PD profiles of repeat doses of 10 mg/kg 
GSK3772847 given intravenously every 4 weeks (Weeks 0, 4, 8 and 12) compared with 
placebo in participants with moderately severe, uncontrolled asthma.  The study used an 
inhaled steroid (ICS) titration design to evaluate whether GSK3772847 maintains 

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protection of asthma control.  A summary of the data from this study is included in the 
investigator brochure [GlaxoSmithKline document number 2017N316832_02].
Study 207972 is a 28-week Phase IIa (planned n=46), multi-center, randomized, double-
blind, placebo-controlled, parallel group study in moderate to severe asthma patients with 
allergic fungal airway disease (AFAD). This study was terminated early due to
challenges in identifying suitable participants. The clinical phase has completed but the 
study has not yet reported.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK3772847 is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2017N316832_02].
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3772847 may be found in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2017N316832_02].

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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3772847]
Cardiovascular (CV)
There is evidence to suggest that the IL-33/ST2 
pathway may be protective in the cardiovascular 
system. Components of the IL-33/ST2 pathway 
are expressed in a number of cellular 
components of the heart and blood vessels in 
rodents and human patients. 
Increased circulating levels of soluble ST2 are 
markers of a poor prognosis in patients with 
hemodynamic stress (e.g. hemodynamic-
hypertrophy, chamber dilation, fibrosis; 
ischemic- apoptosis and infarct volume). The 
effect was abolished in rodents with genetic 
knockout of ST2. 
Atherosclerotic plaque development was 
significantly reduced in ApoE -/- mice given 
exogenous IL-33 while plaques were larger in 
mice treated with soluble ST2 (which binds and 
blocks IL-33).
Non-clinical:
No GSK3772847-related changes noted in 
(non-GLP) IV and SC 4 week monkey study at 
doses ≤100 mg/kg/week, or in the good 
laboratory practice (GLP) 3 or 6 month IV 
repeat dose toxicity study at doses 
≤100 mg/kg/week)  Also, no CV related 
changes noted in pregnant monkeys or infants 
of dams administered GSK3772847 (up to the 
age of 6 months) noted at doses 100 
mg/kg/week. 
However, it should be noted that the animals in 
toxicity studies are healthy and, therefore, are 
unlikely to detect the potential target related CV 
liability.
Clinical:
In Janssen study CNTO7160ASH1001, several 
episodes of sinus tachycardia on telemetry were 
reported in a 20-year-old male healthy 
volunteer, between 1 and 9 hours post-dose 
(10 mg/kg), accompanied on one occasion by 
mild vertigo and malaise (no chest pain).
Exclude participants with abnormal, clinically 
significant finding(s) from 12-lead ECG at 
Screening/Visit 1 (Section 5.2 includes 
examples of types of abnormal and clinically 
significant ECGs
Participants who meet protocol-defined QTc 
stopping criteria specified in Section 7.2 will be 
withdrawn from the study.
CV events will be monitored in all clinical trials.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Troponin I, N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) were normal 
pre dose and Day 5, also normal ECG and vital 
signs including temperature. The event was 
considered by the investigator to be likely 
related to the investigational product. No 
specific cause was identified. Data on this event 
was reviewed by GSK (Internal Cardiac Safety 
Panel and CMO), and was not considered to 
impact further clinical development.
During 12 hours post-dose telemetry monitoring 
in Part 1 of Janssen study CNTO7160ASH1001, 
6 out of 60 completed subjects were assessed 
to have abnormal findings by the investigator. 
These events of sinus tachycardia (4 subjects 
on GSK3772847 and 1 subject on placebo) and 
idioventricular rhythm (1 subject on 
GSK3772847) were recorded as adverse 
events. 
In Part 2 of the Janssen study 
CNTO7160ASH1001, there were four reports of 
non-sustained ventricular tachycardia. Of these 
reports, one participant received placebo and 
two received GSK3772847 at 3 mg/kg and one 
received GSK3772847 at 10 mg/kg. The events 
were non-symptomatic, and a monomorphic 
pattern (i.e., not Torsades de pointes), which is 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
a pattern thought not to be indicative of 
increased risk for sudden ventricular 
tachycardia and sudden death. Heart rate (HR) 
analysis did not identify any safety concern (no 
pattern of increased HR suggestive of an 
increase in sympathetic tone). All 4 participants 
had normal results from exercise test and 
echocardiogram. Dosing was continued as 
planned, and the dose escalated to 10 mg/kg.
In the phase IIa study 207597, CV findings 
included ventricular tachycardia in 4% of 
placebo and 1% of GSK3772847 participants 
(all cases were asymptomatic NSVT and 
deemed by the investigator as not related to 
study drug). The iSRC reviewed all 
cardiovascular safety data at three separate 
points during the study (following the 12 week 
visit of the 35th, 70th, and 105th subjects). There 
were no significant findings (cardiac or 
otherwise) at any point during the study that 
warranted early study termination.
Increased risk of infections & 
immunosuppression 
Studies in mice indicate a potential role for IL-33 
in infection control. IL-33 was shown to activate 
neutrophils in BALB/c mice subjected to cecal 
Preclinical: 
No GSK3772847-related changes in clinical 
signs, white blood cell count or no microscopic 
changes (inflammatory cell infiltrates) in any 
tissues indicative of infection observed in 
monkey 4 week IV/SC IV 3 or 6 month toxicity at 
Appropriate inclusion/exclusion criteria will be 
implemented in clinical protocols, to include: 
exclusion of participants with a known, pre-
existing parasitic infestation within 6 months 
prior to Screening; exclusion of participants with 
the presence of hepatitis B surface antigen 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
ligation and puncture thus preventing 
polymicrobial sepsis. Similarly, IL-33 is thought 
to stimulate neutrophil recruitment from the 
bone marrow to the periphery in response to 
fungal infection. Mice infected with flu virus and 
administered an IL-33 inhibitor exhibited a lower 
number of clusters of differentiated CD90+ and 
cluster of differentiated CD25+ innate lymphoid 
cells with consequent impaired lung function 
compared to phosphate buffered saline treated 
controls. IL-33 has also been shown to be 
produced in the helminth infected cecum of 
parasite infected mice and is shown to be 
important in expulsion of the parasite.
doses ≤100 mg/kg/week. Also no GSK3772847 
related changes in in clinical signs, white blood 
cell counts in pregnant monkeys or infants of 
dams administered GSK3772847 (up to the age 
of 6 months) noted at doses 100 mg/kg/week 
Clinical: 
Safety data from Janssen study 
CNTO7160ASH1001 Single Ascending Dose 
(SAD) has shown the most frequent adverse 
events reported as infections, including 
nasopharyngitis, rhinitis, gastroenteritis and 
upper respiratory tract infection. The frequency 
of these events was similar in GSK3772847 and 
placebo groups (18/45 [40%] of participants 
administered GSK3772847 versus 6/24 [40%] 
administered placebo).
Safety data from Part 2 of the Janssen study 
CNTO7160ASH1001 have shown the System-
organ class (SOC) with the most frequent 
adverse events reported was ’Infections and 
infestations’. The number of asthma participants 
experiencing infections and infestations was 
similar between the group receiving 
GSK3772847 (9/18 [50%]) and the group 
receiving placebo (4/6 [66.7%]). The frequency
(HBsAg), positive hepatitis C antibody test result 
at screening or within 3 months prior to first 
dose of study treatment; exclusion of 
participants with Immunodeficiency (a known 
immunodeficiency such as human 
immunodeficiency virus infection); 
Participants who develop an infection will be 
requested to seek medical advice, and subject 
to close monitoring. 
Exclude patients with ongoing or recurrent 
infections.
EU Regulatory guidance on development of 
asthma drugs request that agents that interact 
with the immune system should be investigated 
for their effect on the host response to infection 
and tumours. The incidence of infections will be 
monitored in clinical studies. Incidence of 
tumours and development of paradoxical 
immune responses (e.g. idiopathic 
thrombocytopenic purpura, autoimmune 
thyroiditis, multiple sclerosis-like syndrome) will 
be monitored in clinical trials via adverse event 
review.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
of infection events in participants with atopic 
dermatitis was greater in participants in the 
GSK3772847 group compared with the placebo 
group (6/11 [54.5%] versus 1/4 [25%]). The 
most frequently-reported infection was 
nasopharyngitis.
In the phase IIa study 207597, the number of 
participants experiencing infections and 
infestations was similar between the group 
receiving GSK3772847 (15/83 [18%]) and the 
group receiving placebo (16/82 [20%]). Among 
the most frequently reported adverse events 
(≥3%) were nasopharyngitis (5% in both 
groups), influenza (GSK3772847 1% and 
placebo 5%) and upper respiratory tract 
infection (5% and 1%), and cough (4% and 1%). 
One participant (1%) receiving placebo had an 
on-treatment SAE of pneumonia.
Increased risk of hyper-sensitivity, 
anaphylaxis, cytokine release syndrome 
(CRS) 
Therapy with other mAbs has been associated 
with hypersensitivity reactions which may vary 
in severity and time of onset.
Nonclinical:
Two maternal deaths at 20 mg/kg/week that 
occurred following 14 or 17 weekly doses were 
noted in the pre and post-natal cynomolgous 
monkey development study. These were
considered to be due to a delayed-ADA 
mediated infusion reaction. Animals are not 
considered predictive for ADA-mediated 
If a hypersensitivity or anaphylactic reaction 
occurs appropriate therapy should be given 
immediately. Agents to treat reaction should be 
available immediately. Guidance on reactions is 
given in Section 8.3.6. This is a single dose 
study and all participants will be dosed in the 
clinic by an appropriately qualified HCP.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
adverse reactions in humans, including infusion 
reactions, hypersensitivity reactions or 
anaphylaxis.
Clinical:
Not observed in Janssen study 
CNTO7160ASH1001 in healthy volunteers 
following single doses up to 10 mg/kg, and 
multiple doses in asthma and atopic dermatitis 
patients at doses up to 10 mg/kg (3 doses, once 
every two weeks [q2W] over four weeks).
Based on in vitro cytokine release data and 
safety experience in Janssen study 
CNTO7160ASH1001 the risk of CRS is 
considered negligible.
No cases of GSK3772847-related 
hypersensitivity, anaphylaxis or CRS occurred 
in study 207597 where participants received 
either GSK3772847 10 mg/kg or placebo every 
4 weeks for a total of 4 doses over 12 weeks.
Possible interaction with live virus or 
bacterial vaccines
As GSK3772847 is an immunomodulator, there 
is a possibility that the subject will not mount an 
adequate immune response to a vaccine or 
even cause the infection the vaccine should 
protect against.
Non-clinical:
In the monkey 13-week toxicity study no 
GSK3772847-related changes in the T cell 
dependent B cell response (IgM or IgG) was 
observed at doses ≤100 mg/kg/week. No 
changes in lymphocyte sub populations, T-
helper cell sub populations or T cell dependent 
B cell response in infants.  This data is 
In the study, participants should not be 
vaccinated with live or attenuated vaccines 
within 4 weeks prior to receiving IP or up to 6 
months after dose administration of 
GSK3772847. However, vaccines containing 
killed bacteria or inactivated virus will be 
permitted.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Vaccination will also drive a systemic immune 
response to the pathogen antigen that runs the 
risk of causing some immunomodulation of the 
lung immune responses.  This has been best 
studied in murine models where eosinophilic 
lung inflammation has been suppressed by 
systemic toll-like receptor activation.
indicative that healthy adult and infant monkeys 
were able to mount a response against the 
antigen challenge during GSK3772847 
administration at doses where near complete 
inhibition of IL-33 was anticipated.
Based on this data GSK3772847 is considered 
unlikely to blunt/inhibit the generation of a 
response to vaccinations.
Clinical:
Not observed in Janssen study 
CNTO7160ASH1001 in healthy volunteers 
following single doses up to 10 mg/kg, and 
multiple doses in asthma and atopic dermatitis 
patients at doses up to 10 mg/kg (3 doses, once 
every two weeks over four weeks).
Not observed in study 207597, where 
participants with asthma received either 
GSK3772847 10 mg/kg or placebo every 4 
weeks for a total 4 doses over 12 weeks.
Potential of embryofetal development effects
Non-clinical:
In the enhanced pre- and post-natal monkey 
study, there was no evidence of GSK3772847-
related effects on pregnancy or on the survival, 
growth, and development of foetuses and 
infants.  GSK3772847 was detected in maternal 
milk on PPD28 at 1000-fold lower than serum 
concentration values at the same interval.
FRP will be included in clinical studies. 
Women who are pregnant, lactating or are 
planning on becoming pregnant during the study 
are not eligible to participate.
To minimize the probability of pregnancy 
exposure: 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical:
Females of reproductive potential were included 
in Part 2 of Janssen study CNTO7160ASH1001 
and no pregnancies were reported.
Females of reproductive potential were included 
in protocol 207597 and no pregnancies were 
reported.

FRP will be required to have 
established, proper of a highly effective 
method for avoiding pregnancy at 
screening to ensure there a minimum of 
1 month of effective contraception prior 
of first dose, and to utilize one form of 
highly effective contraception 
throughout the study until follow-up.

Pregnancy testing will be performed 
prior to dosing, at regular intervals 
during treatment, until follow-up as 
documented in the clinical protocol.
A positive pregnancy test will require immediate 
cessation of treatment.
Gastrointestinal disorders
Nausea
Vomiting
Clinical:
In Part 2 of Janssen study 
CNTO7160ASH1001, the incidence of 
gastrointestinal disorders was greater in 
participants in the GSK3772847 groups 
compared with the placebo groups: 6/18 
(33.3%) participants in the asthma cohort and 
3/11 (27.3) participants in the atopic dermatitis 
cohort as compared with 0 participants in either 
the asthma cohort or atopic dermatitis cohort 
placebo groups. Gastrointestinal disorders 
events included nausea (1/18 participants in the 
asthma cohort, 2/11 participants in the atopic 
dermatitis cohort), vomiting, diarrhoea.
The incidence and severity of nausea and 
vomiting will be monitored.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
In the phase IIa study 207597, the number of 
participants experiencing nausea was 1% in 
both groups while the number of participants 
experiencing vomiting was 1% in the 
GSK3772847 group and 0 in the placebo group. 
Skin and subcutaneous tissue disorders

Contact dermatitis
Clinical:
In Part 2 of Janssen study 
CNTO7160ASH1001, the incidence of contact 
dermatitis was greater in participants in the 
GSK3772847 groups compared with the 
placebo groups. In the asthma cohort, the 
number of participants with contact dermatitis 
was 4/18 (22.2%) in the combined GSK3772847 
groups versus 1/6 (16.7%) in the placebo group. 
In the atopic dermatitis, the number of 
participants with contact dermatitis was 3/11 
(27.3%) in the combined GSK3772847 versus 
0/4 (0%) in the placebo group.
No cases of contact dermatitis were reported in 
the phase IIa study 207597.
The incidence and severity of contact dermatitis 
will be monitored.
Study Procedures
Risk associated with blood draws
Fainting, mild pain, bruising, irritation or redness 
at phlebotomy site, may be associated with 
blood draws.
Experienced site staff will follow standard 
approaches for managing events related to 
blood draws.

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2.3.2.
Benefit Assessment
There is no clinical benefit for healthy participants taking part in this study. However, 
participants will undergo a medical evaluation during screening (including physical 
examination, electrocardiogram (ECG), vital signs and laboratory assessments), which 
may provide important health information.
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the proposed measures to be taken to minimize risk to participants 
participating in this study, the potential risks identified in association with GSK3772847 
are considered justified and adequately mitigated.

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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of a 
single dose of GSK3772847, compared with 
placebo administered subcutaneously in 
healthy participants including cohorts of 
Japanese and Chinese participants.
.

Occurrence of adverse events (AE’s) and 
serious adverse events (SAE’s) (including 
injection site reactions)

To assess the pharmacokinetics (PK) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants (Cohorts 1 and 2 also summarised 
by injection site)

PK parameters, including but not limited 
to, Area under the plasma-concentration 
time curve (AUC), maximum plasma 
concentration (Cmax), time to Cmax 
(Tmax) and terminal half-life (t1/2) of 
GSK3772847 per cohort 
Secondary

To evaluate the pharmacodynamics (PD) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

Maximal decrease in free and increase in 
total soluble ST2 levels in serum up to Day 
85 visit

To assess the immunogenicity of a single dose 
of GSK3772847 administered subcutaneously
in healthy participants including cohorts of 
Japanese and Chinese participants.

occurrence of anti-GSK3772847 
antibodies 

To assess potential changes in Cytochrome 
P450 3A4 (CYP3A4) enzyme activity following 
a single dose of GSK3772847 in healthy 
participants including cohorts of Japanese and 
Chinese participants.

Plasma 4β-Hydroxycholesterol (4βOH) 
cholesterol/cholesterol ratio as an 
endogenous marker for CYP3A4 activity 
pre-treatment and following a single dose 
of GSK3772847
Other 

To further assess the safety and tolerability of 
a single dose of GSK3772847, compared with 
placebo administered subcutaneously in 
healthy participants including cohorts of 
Japanese and Chinese participants.

12-lead ECG measurements

Clinical chemistry laboratory tests

Vital signs

To evaluate the pharmacodynamics (PD) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

Free and total soluble ST2 levels in serum

Blood eosinophil levels

To assess the pharmacokinetics (PK) of a 
single dose of GSK3772847 administered 
subcutaneously in healthy participants 
including cohorts of Japanese and Chinese 
participants.

GSK3772847 levels in serum

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4.
STUDY DESIGN
4.1.
Overall Design
This is a single centre, randomized, placebo-controlled, double-blind, ascending dose 
study in healthy participants.  
Following a screening period (of up to 28 days), participants who meet the eligibility 
criteria will be assigned to one of four cohorts and will be randomly allocated within each 
cohort to receive a single dose of either GSK3772847 or placebo.  All treatments will be 
administered subcutaneously by a health care professional (HCP). The site of injection 
will be randomized to the upper arm, abdomen or thigh for cohorts 1 and 2 with cohorts 3 
and 4 receiving injections in the upper arm only.

Cohort 1: 18 participants will be randomly allocated to receive GSK3772847 70 mg 
SC and 6 will receive placebo SC. 

Cohort 2: 18 participants will receive GSK3772847 140 mg SC and 6 will receive 
placebo SC.  

Cohort 3: 6 Japanese participants will receive GSK3772847 140 mg SC and 2 will 
receive placebo SC.  

Cohort 4: 6 Chinese participants will receive GSK3772847 140 mg SC and 2 will 
receive placebo SC.
Each participant will:

Be screened (within 28 days of dosing)

Be admitted to the unit the day prior to dosing (Day 0) and be discharged after 
completion of assessments on day 6

Attend follow up visits on days 9, 15, 29, 43, 57, 71 and 85 (for time windows see 
SoA Section 1.3)
Before dosing in Cohorts 2, 3 and 4 can begin, blinded safety data (including injection 
site data from dosing to a minimum of 48 hours post-dose) will be reviewed in at least 20 
subjects who have received a dose in Cohort 1 see Section 9.6. 
An interim analysis, to assess safety, tolerability and PK, will be performed after a
predefined number of participants from all four cohorts have reached Day 29 as detailed 
in Section 9.5
A participant will be considered having completed the study if they complete the final 
visit.

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The total duration a participant remains in the study is up to 17 weeks and 4 days
(includes up to 28 days for screening and up to 95 days post-dose follow up (includes 6 
days in clinic)).
4.2.
Scientific Rationale for Study Design
This is a single centre, randomized, placebo-controlled, double-blind, ascending dose 
study in healthy participants to determine the safety (in particular injection site 
tolerability), PK and PD of GSK3772847 via the SC route. A total of 64 participants will 
be initially randomized for a total of 18 evaluable participants on GSK3772847 and 6 on 
placebo in cohorts 1 and 2, 6 Japanese participants in cohort 3 on GSK3772847 and 2 on 
placebo and 6 Chinese participants on GSK3772847 and 2 on placebo in cohort 4. 
Placebo is included to allow a valid evaluation of adverse events attributable to treatment 
versus those independent of treatment.  SC GSK3772847 will be administered on a single 
occasion and participants will be followed up for over 3 half-lives (85 days) to ensure 
sufficient PK and PD information is gathered and to ensure that GSK3772847 PK has
reached low enough levels to have insignificant pharmacological effects. 
A healthy subject population is considered to be suitable for the evaluation of 
GSK3772847 PK comparability as all treatments will be administered to the same 
population and any differences would therefore be detected appropriately. Healthy 
subjects are considered to be a suitable population for biopharmaceutical PK 
comparability studies and the data can be extrapolated to other populations
[CPMP/EWP/QWP/1401/98].
PK will be evaluated by non-compartmental analysis. In addition, data from this study 
will be included in a population-PKPD analysis together with the historic IV data to 
enable development an appropriate model to describe the PK and PD. This will be 
reported separately from the main clinical study report (CSR). 
4.3.
Justification for Dose
Doses of 70 and 140mg SC have been selected based on a preliminary population PK/PD 
model built using data from the IV FIH study (Janssen Study CNTO7160ASH1001; 
(GSK study 208736, GlaxoSmithKline Document Number 2017N344518_00). This 
model accounts for both the linear elimination pathway and for target mediated 
elimination via interaction with the target (ST2). These doses are expected to deliver 
exposures and ST2 suppression suitable for progression into later phase studies and are 
lower than the 10mg/kg IV dose utilised in studies 207597 [GlaxoSmithKline Document 
Number 2017N316832_02 and 207972 [final report pending]. The fraction of drug 
absorbed into the systemic circulation (F) after SC dosing was set at 0.8 based on 
precedented data for similar monoclonal antibodies. This value represents a credible 
estimate for the upper end of absorption and so the predicted exposures and safety 
margins are considered to be relatively conservative. The rate of absorption was similarly 
set to reflect precedence and predicts a Tmax from approximately 3 to 10 days. Safety 
margins were calculated against both the 26 week IV and 4 week SC toxicity studies. The 
predicted exposures are given in the table below and show that the exposures are 
expected to be significantly below those in these key toxicity studies 

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Table 3
Predicted clinical exposures and safety margins for study 209635 
following single SC dosing of 70mg and 140mg.
DOSE
Median 
AUC (0-
Day85) 
(µg.day/mL) 
Exposure 
margin 
vs 26 
week IV 
tox 
studya
Exposure 
margin vs 4 
week SC tox 
studyb
Median 
Cmax 
(µg/mL)
Exposure 
margin 
vs 26 
week IV 
tox 
studya
Exposure 
margin 
vs 4 
week SC 
tox 
studyb
70 mg
272
141x
52.1x
7.89
936x
287x
140 
mg
570
67x
24.8x
16.0
460x
141x
a.
Margins calculated against mean maximum serum concentration (Cmax) and AUC(0-t) on week 26  in study  
5002200 "GSK3772847A: A 26-Week (Once weekly) Intravenous Infusion Toxicity Study in Cynomolgus 
Monkeys" 
b.
Margins calculated against mean maximum serum concentration (Cmax) and AUC(0-t) on week 4  in study  
P32464G. "The Toxicokinetics of GSK3772847A in Cynomolgus Monkeys Following Once Weekly Subcutaneous 
Injection of GSK3772847A During a 4-Week Toxicity Study"
Sentinel dosing is not required as GSK3772847 has been dosed to over 160 participants 
in two completed studies (first time in human study CNTO7160ASH1001 and phase 2a 
study 207597 [GlaxoSmithKline Document Number 2017N316832_02) predominately at 
a significantly higher dose (10 mg/kg by intravenous injection).
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the final follow up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.

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5.1.
Inclusion Criteria
AGE
1.
Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 
2.
Participants who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and cardiac 
monitoring. A participant with a clinical abnormality or laboratory parameter(s) 
not specifically listed in the exclusion criteria that is outside the reference range 
for the population being studied may be included only if the investigator, in 
consultation with the Medical Monitor (if required), agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with 
the study procedures or results.
GEOGRAPHIC ANCESTRY – JAPANESE PARTICIPANTS ONLY
3.
Japanese Participants are eligible based on meeting all of the following:

Healthy male and female participants born in Japan

are descendants of four ethnic Japanese grandparents and two ethnic Japanese 
parents

holding a Japanese passport or identity papers

being able to speak Japanese

have lived outside Japan for less than 10 years at the time of screening.
GEOGRAPHIC ANCESTRY – CHINESE PARTICIPANTS ONLY
4.
Chinese Participants are eligible based on meeting all of the following:

Healthy male and female participants born in mainland China

are descendants of four Chinese grandparents and two Chinese parents

holding a Chinese passport or identity papers

being able to speak Chinese

have lived outside China for less than 10 years at the time of screening.
WEIGHT
5.
Body weight 35-150 kg and body mass index (BMI) within the range 18-32 kg/m2 
(inclusive).
SEX
6.
Male and Female Participants – see Appendix 4
Female Participants: 

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o
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies:
o
Is not a woman of childbearing potential (WOCBP) 
o
OR
o
Is a WOCBP and using an acceptable contraceptive method as described in 
Appendix 4 during the intervention period (at a minimum until after the last 
dose of study intervention). The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of 
study intervention.
o
A WOCBP must have a negative highly sensitive (Appendix 2) pregnancy 
test ([urine] as required by local regulations) within 24 hours before the first 
dose of study intervention.
o
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), 
a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
o
Additional requirements for pregnancy testing during and after study 
intervention are located in Appendix 2
o
The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy
o
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
INFORMED CONSENT
7.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
5.2.
Exclusion Criteria
MEDICAL CONDITIONS (INCLUDES LIVER)
1. Alanine transaminase (ALT) >2x upper limit of normal (ULN)
2. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%).

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3. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic
gallstones)
4. Ongoing or recurrent infections
5. QT interval corrected for heart rate by Fridericia’s formula (QTcF) >450 msec or 
any of the following abnormal and clinically significant ECG findings:

Sinus bradycardia <45bpm
*Note: Sinus bradycardia <45bpm should be confirmed by two additional readings at least 5 minutes 
apart.

Sinus tachycardia 110bpm
*Note: Sinus tachycardia 110 should be confirmed by two additional readings at least 5 minutes 
apart.

Multifocal atrial tachycardia (wandering atrial pacemaker with rate >100bpm)

Evidence of Mobitz II second degree or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4mV (4mm with 
10mm/mV setting)] or >25% of the height of the corresponding R wave, providing the R 
wave was >0.5mV [5mm with 10mm/mV setting], appearing in at least two contiguous 
leads.
*Note: prior evidence (i.e., ECG obtained at least 12 months prior) of pathological Q waves that are 
unchanged are not exclusionary; and the investigator will determine if the subject is precluded from 
entering the study.

Evidence of ventricular ectopic couplets, bigeminy, trigeminy or multifocal premature 
ventricular complexes.

For subjects without complete right bundle branch block: QT interval corrected for heart rate 
by Fridericia’s formula (QTc[F]) 450 msec or an ECG that is unsuitable for QT 
measurements (e.g., poor defined termination of the T wave).

For subjects with complete right bundle branch block: QTc(F) 480 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave).
*Note: All potentially exclusionary QT measurements should be confirmed by two additional 
readings at least 5 minutes apart.

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)
*Note: prior evidence (i.e., ECG obtained at least 12 months prior) of ST-T waves that are 
unchanged are not exclusionary and the investigator will determine if the subject is precluded from 
entering the study.

Clinically significant conduction abnormalities (e.g., Wolff-Parkinson-White syndrome or 
bifascicular block defined as complete left bundle branch block or complete right bundle branch 
block with concomitant left fascicular block)

Clinically significant arrhythmias (e.g., atrial fibrillation with rapid ventricular response, 
ventricular tachycardia)

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PRIOR/CONCOMITANT THERAPY
6. Use of prescription or non-prescription drugs, including vitamins, herbal and 
dietary supplements (including St John’s Wort) within 7 days (or 14 days if the 
drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the 
first dose of study medication and until study completion, unless in the opinion of 
the investigator and GSK Medical Monitor the medication will not interfere with 
the study procedures or compromise subject safety.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
7. The participant has been 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).
8. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day.
DIAGNOSTIC ASSESSMENTS & OTHER EXCLUSIONS
9. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention.
10. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
first dose of study intervention.
NOTE: Participants with positive Hepatitis C antibody due to prior resolved 
disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is 
obtained.
11. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention.
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
12. A positive test for HIV antibody.
13. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 3 months.
14. A positive pre-study drug/alcohol screen.
15.Any history of substance abuse or a positive test for drugs of abuse at screening or 
admission

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16.Known, pre-existing parasitic infestations within 6 months prior to Screening
17.Vaccinated with live or attenuated vaccines within 4 weeks prior to receiving IP 
and up to 6 months after dose administration of GSK3772847
18. A positive highly sensitive pregnancy test (urine or serum as required by local 
regulations) at screening.
19. Positive urinary cotinine test indicative of smoking history at screening or each in-
house admission to the clinical research unit or regular use of tobacco- or nicotine-
containing products (e.g. nicotine patches or vaporizing devices) within 6 months 
prior to screening.
20. Participants with allergy or intolerance to a monoclonal antibody or biologic or to 
any components of the formulation used in this study.
21. A vulnerable subject. Defined as individuals whose willingness to volunteer in a 
clinical trial may be unduly influenced by the expectation, whether justified or not, 
of benefits associated with participation, or of a retaliatory response from senior 
members of a hierarchy in case of refusal to participate.
22. Subjects who work for the Sponsor, CRO, or one of the study centres
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 
days before the start of study intervention until after the final follow up.

Participants will be required to be in a non-fasted state for ALL clinical 
laboratory tests and 4βOH cholesterol/cholesterol samples
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, and chocolate) for 8 hours before all
ECG assessments.

Participants will abstain from alcohol for 24 hours before dose and for 24 
hours prior to the collection of all safety, pharmacokinetic and 
pharmacodynamic samples.

Use of tobacco products of any kind is not allowed as outlined in the exclusion 
criteria
5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each 
blood collection for clinical laboratory tests. Participants may participate in 

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light recreational activities during studies (e.g., walking, watching television, 
reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized into the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).
Participants who fail eligibility may be rescreened once (restriction for rescreening not 
applicable for reserves).  If rescreening is performed, participants must be assigned a 
different unique subject identification number for the rescreening, and all screening 
procedures must be repeated (unless agreed otherwise by the investigator and GSK 
medical monitor). 
In the event of out-of-range results of safety tests, the tests may be repeated once within 
the screening window.  If a retest result is again outside the reference range and 
considered clinically significant by the investigator and GSK medical monitor, the 
subject will be considered a screen failure.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
ARM Name
GSK3772847 Injection, 70 mg and 
140 mg arms
Placebo to Match
Intervention 
Name
GSK3772847 Injection, 70 mg, SC 
Formulation buffer solution for 
injection
Type
Biologic
N/A
Dose 
Formulation
The GSK3772837 Injection is a 
solution for injection that formulated 
with phosphate buffer, L-arginine 
hydrochloride, sucrose, polysorbate 
80, and water for injection.  
The placebo to match GSK3772847 
is supplied as solution for injection 
with the same GSK3772847 
Injection formulation but without the 
active drug substance.

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Unit Dose 
Strength(s)
70 mg/mL (1 mL nominal volume) in a 
3 mL glass vial.
Dosage levels vary per cohort.
1 mL nominal volume in a 3 mL 
glass vial.
number of injections to match active 
dose.
Dosage 
Level(s)
For 70 mg dose
The dose can be administered using a 
single 1 mL injection
For 140 mg dose
The dose can be administered using 
two x 1 mL injections 
To match active (i.e. the same 
volume and number of injections as 
the participants on GSK3772847 in 
that cohort)
Route of 
Administration
Subcutaneous injection
Subcutaneous injection
Use
Experimental
Placebo
IMP and NIMP
IMP
NIMP
Sourcing
Provided centrally by GSK
Provided centrally by GSK
Packaging 
and Labelling
Study intervention supplied by GSK as 
a sterile, preservative-free liquid in a 3 
mL type 1 untreated borosilicate clear 
glass vial with a 13-mm fluorinated-
polymer coated grey rubber stopper 
and a 13-mm aluminium seal.  Each 
vial will be labelled as required per 
country requirement.
Placebo supplied as a sterile, 
preservative-free liquid in a 3 mL 
type 1 untreated borosilicate clear 
glass vial with a 13-mm fluorinated-
polymer coated grey rubber stopper 
and a 13-mm aluminium seal.  Each 
vial will be labelled as required per 
country requirement.

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6.2.
Preparation/Handling/Storage/Accountability

GSK3772847 must be prepared by an unblinded pharmacist or other appropriately 
licensed and authorized personnel.

Unblinded site staff will be responsible for receipt, storage and labelling, and 
accountability of investigational product.

GSK3772847 should be inspected visually for particulate matter and discoloration 
prior to administration whenever solution and container permit. If visibly opaque 
particles, discoloration, or other foreign particles are observed, the solution should 
not be used. 

Detailed instructions for storage conditions, dose preparation, and administration will 
be provided in the unblinded site staff reference manual. Required storage conditions 
and expiration date are indicated on the label.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Because the likely difference in colour between the GSK3772847 and placebo 
solutions, an unblinded pharmacist or other qualified individual will prepare the 
GSK3772847 or placebo injections and apply a tape to cover the colour. Further 
details will be described in the study reference manual (SRM).

Further guidance and information for the final disposition of unused study 
intervention are provided in the study reference manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Randomization

On Day 1, participants will be assigned a unique number (randomization number) in 
ascending numerical order. The randomization number encodes the participant’s 
assignment to one of the 4 arms of the study, according to the randomization schedule 
generated prior to the study under the guidance of the Statistics Department at GSK.
Participants will also be randomised to one of 3 injection sites for cohorts 1 and 2.

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Each participant will be dispensed blinded study intervention, labelled with [his/her] 
unique randomization number, throughout the study.

A replacement schedule will be generated for any participant who is randomized, 
receives treatment and withdraws prior to Day 29. Replacement participants will be 
allocated to the same randomized treatment, but with a different randomization 
number. 

Participants will be randomized in a 3:1 ratio to receive study intervention. 
Investigators will remain blinded to each participant’s assigned study intervention 
throughout the course of the study. In order to maintain this blind, an otherwise 
uninvolved 3rd party will be responsible for the reconstitution and dispensation of all 
study intervention and will endeavour to ensure that there are no differences in time 
taken to dispense following randomization.

Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will 
be allowed access to un-blinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately.
6.3.2.
Blinding
This will be a double blind (GSK Statistics & Programming and GSK Clinical 
Pharmacology Modelling & Simulation (CPMS) open) study. All study staff involved in 
the clinical assessments (which includes the investigator, sub-investigators other site 
staff), and the participant will be blinded to the treatment allocated to individual 
participants. Statistics & Programming and CPMS will be unblinded after the dose 
escalation committee review to enable reporting of the D29 data. See Section 9.5 .  An 
unblinded qualified site staff member will be required to prepare the study treatment for 
dosing as described in the Study Reference Manual. The unblinded site staff member is 
not permitted to communicate the participants treatment allocation with blinded site staff. 
The dose escalation committee (DEC) will review blinded summary data (including 
injection site data from up to 48 hours post-dose) as detailed in Section 9.6.
The interim analysis data review committee (DRC) will review data detailed in Section 
9.5. Details of the committee are given in Section 10.1.5.2.
The following will also apply:

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. 

Investigators have direct access to the participant’s individual study treatment. 

In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is 
warranted. Participant safety must always be the first consideration in making 

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such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact GSK prior to unblinding a 
participant’s treatment assignment unless this could delay emergency treatment of 
the participant. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, 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 event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
In the event of unblinding the Medical monitor/GSK team should be contacted to 
determine whether subject withdrawal is required. Should a participant’s treatment 
assignment be unblinded and the Medical monitor/GSK team determine that the 
participant must be withdrawn from IP, the participant must be followed-up as per 
protocol until the completion of the Safety Follow-up assessments. 
A participant whose treatment assignment is inadvertently unblinded (either to 
investigative staff or the participant themselves) will be permitted to remain in the study. 
Accidental unblinding will be recorded as a protocol deviation and the participant will be 
subject to review as to their inclusion in analyses as per the procedures set out in Section 
9.3.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.
6.4.
Study Intervention Compliance

Participants will receive study intervention 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 intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention.  

Used vials should NOT be discarded before the unblinded monitor has 
conducted a visit.
6.5.
Concomitant Therapy
Details for concomitant medications are detailed in Section 5.2. Any use of 
prohibited medications (including the use of paracetamol/acetaminophen) will be 
reviewed on a case-by-case basis by the medical monitor.

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6.6.
Dose Modification
The decision to proceed to the next dose level of 140mg will be made by the Dose 
Escalation Committee (DEC) and the investigator based on blinded safety data (including 
injection site data obtained 48 hours post dose) from at least 20 participants from cohort
1. 
Details of the DEC are given in Section  9.6.
6.7.
Intervention after the End of the Study
As this is a healthy participant study, no intervention will be given to participants 
following the end of study.
7.
DISCONTINUATION CRITERIA
Participants who meet any of the below criteria should, where possible, continue to be 
followed up until the completion of all safety, PK and PD follow-up assessments, at day 
85:

Liver Chemistry: protocol-defined liver chemistry stopping criteria

QTc: protocol-defined stopping criteria

Pregnancy: Positive pregnancy test (see Appendix 4)

Hypersensitivity or anaphylactic reactions (see Section 8.3.6)
7.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm 

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant. 

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Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm


Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious 
adverse event; ULN = upper limit of normal.

Refer to Appendix 6 for required Liver Safety Actions and Follow up 
Assessments 
7.2.
QTc Stopping Criteria
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study intervention.  

QTcF>500 msec,

Change from baseline: QTcF >60 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on the average of triplicate ECG readings obtained 
over a brief (e.g., 5-10 minute) recording period.  

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7.3.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of the study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

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
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

Study procedures and their timing are summarized in the SoA (Section 1.3)

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA (Section 1.3), 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. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA
(Section 1.3)
8.1.
Efficacy Assessments
Not applicable
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

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.

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8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse
8.2.3.
Electrocardiograms

12-lead ECG’s will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. 

Refer to Section 7.2 for QTc withdrawal criteria and additional QTc readings 
that may be necessary.
8.2.4.
Targeted Injection Site Reaction Examination
A targeted visual assessment of the injection site is to be conducted at 4, 24- and 48-
hours post-dose. Any injection site reactions will be recorded in the CRF.
8.2.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) 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 should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified, and the 
sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).

Clinical safety laboratory data for white blood cell differentials must be blinded 
post-dose (see Appendix 2). Further details for laboratory requisition orders can 
be found in the study reference manual.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The definitions of device-related safety events, (adverse device effects (ADEs) and 
serious adverse device effects (SADEs)), can be found in Appendix 3.

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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the informed consent form until 
the final follow-up visit at the time points specified in the SoA (Section 1.3). 

All AEs will be collected from Day 0 until the final follow-up visit at the time 
points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 8.3.6), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is given in Appendix 3.

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8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

For all studies except those utilizing medical devices investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female 
partners of male participants will be collected after the start of study 
intervention and until the final follow up at Day 85.

If a pregnancy is reported, the investigator should inform GSK within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAE.
8.3.6.
Adverse Events of Special Interest 
Participants will be monitored for injection site reactions during the study as indicated in 
the SoA (Section 1.3). 
Injection site reaction guidance
Injection-related reactions occurring subsequent to administration of monoclonal 
antibodies can be characterised as either acute or delayed.  

Acute reactions occur within 24 hours, but usually within 10 minutes to 4 hours after 
receiving the drug

Delayed reactions can occur from 24 hour to 14 days, but usually occur after 5-7 
days

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Both acute and delayed reactions can be further characterised as mild, moderate or 
severe, depending on the accompanying signs and symptoms.  
Acute Reactions:
Acute reactions can be IgE-mediated Type I hypersensitivity (anaphylactic) reactions or 
non-allergic (anaphylactoid) reactions.  Symptoms of a true allergic IgE-mediated 
anaphylactic reaction include bronchospasm or wheezing, hypotension, laryngeal or 
pharyngeal swelling, and urticaria.  
Non-allergic reactions make up the overwhelming majority of acute infusion reactions. 
Symptoms generally include headache, nausea, fever, chills, dizziness, flushing, pruritus, 
and chest or back pain.  
Delayed Reactions:
Delayed reactions may also occur in patients who receive monoclonal antibodies.  Both 
Type III (immune complex) and Type IV (cell mediated) hypersensitivity should be 
considered.  Delayed hypersensitivity reactions need to be clearly delineated from 
infusion reactions so collection and evaluation of non-acute clinical symptoms following 
administration of a therapeutic protein should be completed.  Symptoms of a delayed 
reaction may include myalgia, arthralgia, fatigue, fever, headache, skin rash and pruritus.    
8.4.
Treatment of Overdose
For this study, any dose of GSK3772847 greater than 70mg (cohort 1) or 140mg 
(cohorts2-4) within a 24-hour time period will be considered an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3772847 can no longer be detected systemically (at least 12 weeks).
3.
Obtain a plasma sample for PK analysis immediately after dose of study intervention
and where possible continue to sample as per the SoA (Section 1.3).
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.
8.5.
Pharmacokinetics
Whole blood samples of approximately 3 mL will be collected for measurement of serum 
concentrations of GSK3772847as specified in the SoA (Section 1.3 ). The timing of PK 

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samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring. The actual date and time (24-hour clock time) of each 
sample will be recorded.
Detailed instructions for processing, storage and shipment will be provided in the 
appropriate Study Reference Manual.
8.6.
Pharmacodynamics
8.6.1.
Soluble ST2
Whole blood samples of approximately 3mL will be collected during this study for the 
purposes of measuring free and total sST2 levels. Samples will be collected at the time 
points indicated in the SoA (Section 1.3 ). The timing of the collections may be adjusted 
on the basis of emerging PK or PD data from this study or other new information in order 
to ensure optimal evaluation of the biomarker endpoints. The actual date and time of each 
sample collection will be recorded.
Detailed instructions for processing, storage and shipment will be provided in the 
appropriate Study Reference Manual
8.6.2.
Blood eosinophils
Blood eosinophil levels will be collected as part of routine safety laboratory sample 
collection. The timing of collection is detailed in the SoA (Section 1.3). 
Detailed instructions will be provided in the study reference manual.
8.7.
Genetics
Information regarding genetic research is included in Appendix 5.
Genetic sampling is optional. Participants can refuse genetic sampling but will still be 
allowed to participate in the study.
8.8.
Biomarkers
8.8.1.
4βOH cholesterol/cholesterol

Whole blood samples of approximately 3 mL will be collected for measurement 
of 4β hydroxycholesterol/cholesterol ratio as specified in the SoA (Section 1.3 ). 
The actual date and time (24-hour clock time) of each sample will be recorded.

Detailed instructions for processing, storage and shipment will be provided in the 
Study Reference Manual.

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8.9.
Immunogenicity Assessments

Serum samples of approximately 2mL will be collected and tested for the 
presence of antibodies that bind to GSK3772847, as specified in the SoA (Section 
1.3 ). The actual date and time (24-hour clock time) of each sample will be 
recorded.

The presence of anti-GSK3772847 antibodies will be assessed using a tiered 
approach including screening assay, a confirmation assay and calculation of titre.

Detailed instructions for processing, storage and shipment will be provided in the 
Study Reference Manual.
8.10.
Health Economics or Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypothesis
The primary objective of this study is to evaluate the safety, tolerability and the 
pharmacokinetics of GSK3772847 administered subcutaneously. There are no formal 
hypothesis tests associated with this objective and no formal significance tests. 
The information acquired from this study will be used to quantify the effects of 
GSK3772847 on safety and tolerability via the SC route where the main focus will be on 
injection site reactions and to assess the pharmacokinetics across the 3 injection sites and 
doses. In addition, PK will be evaluated in Japanese and Chinese participants.
An interim analysis will be performed after the minimum number of participants 
specified in Section 9.5 have reached 4 weeks post dose in Cohorts 1-4. The purpose of 
this interim analysis is to assess safety, tolerability and PK to inform on the properties of 
GSK3772847 dosed via the SC route.
9.2.
Sample Size Determination
The study comprises:

Cohort 1: 18 subjects on GSK3772847 70mg and 6 subjects on Placebo

Cohort 2: 18 subjects on GSK3772847 140mg and 6 subjects on Placebo

Cohort 3:  6 Japanese subjects on GSK3772847 140mg and 2 Japanese subjects on 
Placebo 

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
Cohort 4:  6 Chinese subjects on GSK3772847 140mg and 2 Chinese subjects on 
Placebo 
This design will ensure that we have an adequate understanding of the tolerability of 
GSK3772847 when dosed subcutaneously and will enable estimation of the key PK 
parameters (AUC and Cmax) with adequate precision (1 SE expected to be ~7% of the 
geometric mean for each dose (n=18) assuming a CV no greater than 30%, based on 
precedence with comparable mAbs). In addition, the sample size for the critical 
evaluations of dose and injection site comparisons are in line with appropriate guidance 
where the minimum number of subjects should not be smaller than 12 (NB in this context 
the injection sites are combined across both doses).
A total of 64 participants will be initially randomised for a total of 18 evaluable 
participants on GSK3772847 in cohorts 1 and 2, 6 Japanese participants in cohort 3 and 6 
Chinese participants in cohort 4. Participants will be replaced if they withdraw from the 
study prior to completing all PK and sST2 assessments up to and including D29.  It is 
anticipated that the number of such participants will be low (<10%), meaning that up to 
72 participants would be randomised to achieve the required number evaluable.
An evaluable participant is one who receives a dose of GSK3772847 and has PK and 
sST2 data up to and including Day 29.
9.3.
Populations for Analyses
The following populations (as defined below), will include participants who are 
randomized and replaced because they withdraw prior to D29.:
Population
Description
Enrolled
All participants who sign the ICF
Randomized
All participants who were randomized. A participant who is 
recorded as a screen or run-in failure and also randomized will be 
considered to be randomized in error provided they have not 
performed any study assessments. If a participant is a screen or 
run in failure but has been randomized and dosed and continues 
in the study, then they will be included in this population. They will 
be footnoted as a protocol deviation.  If they were not dosed (but 
randomized in error), they will be excluded from the population.
PK/PD
All randomized subjects who received at least one dose of study 
treatment, and for whom at least one pharmacokinetic sample was 
obtained, analyzed and was measurable. Displays will be based 
on the treatment to which the participant actually received

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Population
Description
Safety
All randomized participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received.
9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to FPFV and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.4.1.
General Considerations
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modelling and Simulation (CPMS) department within GlaxoSmithKline. Plasma 
GSK3772847 concentration-time data will be analysed by non-compartmental methods 
with WinNonlin. Calculations will be based on the actual sampling times recorded during 
the study. 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-t), 
and AUC(0-∞)] and apparent terminal phase half-life (t½).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarised descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Respiratory Clinical Statistics, GlaxoSmithKline.
Free and total sST2 data will be presented in graphical and/or tabular form and will be 
summarised descriptively.
The PK and sST2 data are planned to be incorporated into a multi study population 
PKPD analysis. This will be reported separately from the main clinical study report 
(CSR).
9.4.2.
Primary Endpoint(s)
The following primary safety endpoints will be summarised descriptively by treatment 
group and cohort: Incidence and frequency of AEs and SAEs, including injection site 
reactions.

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Adverse events (AEs) will be coded using the standard GSK dictionary, Medical 
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. The 
number and percentage of subjects experiencing at least one AE of any type, AEs within 
each body system and AEs within each preferred term will be presented for each 
treatment group. Separate summaries will be provided for all AEs, drug related AEs, fatal 
AEs, non-fatal SAEs, adverse events of special interest (AESIs) and AEs leading to 
withdrawal.
Deaths and SAEs, if applicable, will be documented in case narrative format.
The PK parameters, including but not limited to, Area under the plasma-concentration 
time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax) and 
terminal half-life (t1/2) of GSK3772847 will be summarised and listed per cohort. 
Cohorts 1 and 2 will also be summarised by injection site.
9.4.3.
Secondary Endpoint(s)
Maximal decrease from baseline in free sST2 and maximal increase from baseline in total 
soluble sST2 levels in serum will be analysed. sST2 will be log transformed prior to 
analysis. An Analysis of Variance (ANCOVA) will be fitted to each cohort separately 
with the baseline value included as a covariate along with treatment. Treatment 
differences and 95% CIs will be presented.
Incidence and prevalence of anti-GSK3772847 antibodies and Plasma 4βOH 
cholesterol/cholesterol ratio (pre-treatment and following dosing of GSK3772847) will 
be listed and summarised by cohort (and injection site for cohorts 1 and 2) over time.
9.4.4.
Other Endpoint(s)
12-Lead ECGs, clinical laboratory safety tests, vital signs, blood eosinophil levels, free 
and total soluble sST2 levels in serum and GSK3772847 levels in the serum will be listed 
and summarised by cohort (and injection site for cohorts 1 and 2) over time.
Further details will be included in the RAP.
9.5.
Interim Analyses
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
An interim analysis will be performed after the following minimum number of 
participants have reached Day 29. Assuming a 10% dropout, this corresponds to: 

Cohort 1: at least 22 individuals (out of a total of 24 randomised)

Cohort 2: at least 22 individuals (out of a total of 24 randomised)

Cohort 3: at least 7 individuals (out of a total of 8 randomised)

Cohort 4: at least 7 individuals (out of a total of 8 randomised)

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The purpose of this interim analysis is to assess safety, tolerability and PK to inform on 
the properties of GSK3772847 dosed via the subcutaneous route and allow the project to 
move forward to the next phase of development but will not affect progression of this 
study since all subjects will have finished dosing.
Data reviewed will be PK, sST2 (both free and Total), and AE and SAE data. The PK 
free and total sST2 concentrations will be summarised and plotted up to 4 weeks. Cohorts 
1 and 2 will also be summarised by injection site.  
The interim analyses will be performed by GSK Clinical Statistics and programming and 
only the responsible statistician (and Quality control [QC] statistician), programmer and 
the CPMS representative will have access to individual participant data. The findings of 
the interim analyses will be shared with the DRC as detailed in the Interim Analysis 
Review Charter, (see Appendix 1, Section 10.1.5.2).
Analyses will also be conducted by CPMS as part of a multi-study population PKPD
analyses to inform on the PK and PD properties of GSK3772847. These analyses will not 
have any impact on this study and will be reported separately.  
9.6.
Dose Escalation Committee
The Dose Escalation charter will describe the procedures related to DEC operations in 
greater detail.
For details on the dose escalation committee structure, refer to Section 10.1.5
The dose escalation committee (DEC), comprised of members from the GSK Study Team 
(namely safety and clinical) and the Investigator(s), will review blinded available data 
from at least 20 participants in cohort 1 before initiating dosing in cohorts 2,3 and 4.  
Dose escalation may occur only after review of individual injection site data. 
The decision to proceed to dosing in cohorts 2,3 and 4 will be made by the Dose 
Escalation Committee based on assessment of the injection site data at 70 mg dose level
as detailed in the Dose Escalation Charter.
Data may be reviewed in an unblinded fashion by a subset of the DEC (namely safety and 
clinical) should a significant safety concern arise during the blinded review. 

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.

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10.1.3.
Informed Consent Process

The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised 
designee will inform each participant of the possibility of further research not 
related to the study/disease. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate tick box will be required to document a 
participant's agreement to allow any participant data and/or remaining leftover 
samples to be used for further research not related to the study/disease. 
Participants who decline further research will tick the corresponding “No” box.

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 

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by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
10.1.5.1.
Dose Escalation Committee Structure
During the dose escalation data review blinded study safety data will be reviewed by the 
dose escalation committee for the purposes outlined in the dose escalation charter (DEC). 
The dose escalation committee (DEC), comprised of members from the GSK Study Team 
(namely safety and clinical) and the Investigator(s)
Further details of interim analysis data review the dose escalation committee are found in 
the dose escalation charter.
10.1.5.2.
Interim Analysis Data Review Committee (DRC)
During the Interim Analysis data will be reviewed by the DRC for the purposes outlined 
in the data review charter. The DRC will be composed of a predefined subset of the study 
team, including but not limited to GSK Clinical Statistics and the responsible statistician, 
programmer and the CPMS representative, Lead Physician, Clinical Scientist and Safety.
Further details of interim analysis data review committee are found in the interim data 
review charter.
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 

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data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the (Electronic) case report form (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 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 

Quality tolerance limits (QTLs) will be pre-defined in the Integrated Project 
Management Plan to identify systematic issues that can impact participant safety 
and/or reliability of study results. These pre-defined parameters will be 
monitored during and at the end of the study, and all deviations from the QTLs 
and remedial actions taken will be summarized in the clinical study report.

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10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement.
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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:

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 intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up
10.1.10.
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.

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
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be conducted by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel 
Pregnancy Testing:
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention 

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 30 days 
and correspond with the time frame for female participant contraception in 
Section 5.1, Inclusion Criteria
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC 
Indices:
WBC count with Differential
(see footnote 3):
RBC Count
MCV
WBC
Neutrophils
Haemoglobin
MCHC
Lymphocytes
Haematocrit
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline 
phosphatase
Albumin
Magnesium
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination and UACR (if blood or protein is 
abnormal [evidence of microalbuminuria or haematuria of ≥ 1+])
Other tests

hsCRP

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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

HIV

Hepatitis B 

Hepatitis C (Hep C antibody)

FSH and estradiol (as appropriate)

Alcohol, cotinine and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); BUN = blood urea 
nitrogen; FSH = follicle stimulating hormone; HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis 
B core antibody; hsCRP = highly sensitive C-reactive protein; MCHC = mean corpuscular haemoglobin 
concentration; MCV = mean corpuscular volume; RBC = red blood cell; UACR = urinary albumin-
creatinine ratio; WBC = white blood cell, pH= hydrogen ion concentration.
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 6 All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.
3.
WBC differentials will be reviewed at screening only, in order to confirm participant eligibility. At all other times 
the site must order haematology test with blinded differentials. 

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 
interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the 
participant’s condition.

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
The disease/disorder being studied or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the 
condition that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 

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

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
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with 
normal everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AE and SAE can be 
assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of 
causality.

There may be situations in which an SAE has occurred and the investigator 
has minimal information to include in the initial report to GSK. However, it 
is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data 
to GSK.

The investigator may change his/her opinion of causality in light of follow-
up information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.

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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.
10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE
data collection tool (see next section) in order to report the event within 24 
hours.

The site will enter the SAE data into the electronic system as soon as it 
becomes available.

The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and 
verification of the relationship of each SAE to IP/study participation 
(causality) within 72 hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection 
tool will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data 
collection tool has been taken off-line, then the site can report this 
information on a paper SAE form (see next section) or to the medical 
monitor by telephone.

Contacts for SAE reporting can be found in Study reference manual.

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SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to 
transmit this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent 
by overnight mail or courier service.

Initial notification via telephone does not replace the need for the 
investigator to complete and sign the SAE CRF pages within the designated 
reporting time frames.

Contacts for SAE reporting can be found in study reference manual.

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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.

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10.4.2.
Contraception Guidance

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% 
per year when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) b

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year 
when used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulationc

oral

intravaginal

transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable

Sexual abstinence

Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant.

ACCEPTABLE METHODSd

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action

Male or female condom with or without spermicidee

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with 

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spermicide (double-barrier methods)c
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
d.
Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception. 
e.
Male condom and female condom should not be used together (due to risk of failure with friction).
10.4.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male 
participant’s female partner of a male study participant who becomes pregnant 
while participating in this study. This applies only to male participants who 
receive study intervention.

After obtaining the necessary signed informed consent from the pregnant 
female partner directly, the investigator will record pregnancy information on 
the appropriate form and submit it to GSK within 24 hours of learning of the 
partner’s pregnancy. 

The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded 
to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

The initial information will be recorded on the appropriate form and submitted 
to GSK within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, 
which will be forwarded to GSK Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

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
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE 
and will be reported as such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported 
to GSK as described in Appendix 3. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn 
of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will be withdrawn from the study

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10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for deoxyribonucleic acid (DNA) analysis

DNA samples may be used for research related to GSK3772847. They may 
also be used to develop tests/assays including diagnostic tests) related to 
GSK3772847. 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)

DNA samples will be analysed for genetic effects on response. This may 
include, but not be limited to, an investigation as to whether polymorphisms 
from IL33 and IL1RL1 gene regions associate with IL33 or soluble ST2 
expression levels or associate with efficacy or safety responses. Additional 
analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analysed as part of a multi-study assessment of genetic 
factors involved in the response to GSK3772847 or study interventions of this 
class. The results of genetic analyses may be reported in the clinical study 
report or in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 

The samples will be retained while research on GSK3772847 (or study 
interventions of this class) continues but no longer than 15 years after the last 
subject last visit or other period as per local requirements.

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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology 
Phase 1 liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin <2xULN and 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

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 

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Liver Chemistry Stopping Criteria 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 

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10.7.
Appendix 7: COVID-19 Measures 
COVID-19 pandemic may impact the conduct of the clinical study. Challenges may arise 
from quarantines, site closure, travel limitations or other considerations if site personnel 
or study participants become infected with COVID-19. These challenges may lead to 
difficulties in meeting protocol-specified procedures, including adhering to protocol-
mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for the site if impacted 
by the COVID-19 pandemic. The purpose of the appendix is to provide information on 
the measures to be taken to protect participants’ safety, welfare and rights, and promote 
data integrity.
The site will follow its pre-defined COVID-19 measures for testing participants, 
providing PPE to participants and staff and infection control.
These measures will remain in place until the site is able to resume normal working 
activities. 
10.7.1.
Study Procedures During COVID-19 Pandemic
During the special circumstances caused by the current COVID-19 pandemic, the site 
should consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants.
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up when clinical trial site visits are not possible.
For the duration of these special circumstances, the following measures may be 
implemented for enrolled participants. 

Clinical investigators should document in site files and in participant notes how 
restrictions related to COVID-19 led to the changes in study conduct and duration of 
those changes and indicate which trial participants were impacted and how those trial 
participants were impacted (as per the current local COVID-19 related regulatory 
guidance). 

Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. 
10.7.2.
Protocol Defined Procedures/Visits:

Where applicable country and local regulations and infrastructure for home 
healthcare allow, home healthcare may take place at a location other than the 
clinical trial site to perform study assessments, which (at the discretion of the 
Investigator) may include collection of blood and urine samples and measurement 
of vital signs, ECG’s and weight. It is the responsibility of the investigator to 
inform the CRO and GSK when this occurs and to document in source notes.

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
Remote visits may be performed at the participant’s home by qualified study 
personnel or at a local medical facility, unless the Investigator deems that a site 
visit is necessary.

Additional unscheduled safety assessments such as blood or urine sampling may 
be performed at the discretion of the Investigator including in the participant’s 
home, if deemed necessary. Biological samples should not be collected if they 
cannot be processed in a timely manner or appropriately stored until the intended 
use. 

The assessments conducted at Day 9, 15, 29, 43, 57, 71 and 85 may be completed 
by a home health nurse to alleviate the burden on subjects of frequent visits to the 
study site

If visits to a site/home are not feasible, then the medical evaluation of safety may 
take place by telemedicine which will use secure video conferences, phone calls, 
and a web portal and/or mobile application as a way of communicating with and 
monitoring the participant’s progress. The CRO will be accountable for working 
with the vendor to ensure the site has the required equipment, training and support 
for this model and the CRO and GSK should be notified as soon as possible by 
the investigator that the service is required.

As part of this model, study visits are completed using the vendors platform, 
which should be a software interface that connects participants to their 
investigators and study teams through either a study-issued smartphone or 
participant’s own device (BYOD) model in addition to providing a data collection 
platform. This technology may be used in combination with visits from mobile 
study personnel (e.g. mobile nurses) to participants’ homes for various lab 
collections and designated study procedures. 

The study investigator is responsible for ensuring that the identification, 
management, and reporting of AEs and SAEs are completed in accordance with 
the protocol and applicable regulations. AEs are first reported by participants to 
the investigator/study team or may be identified by the study team during 
interactions with the participants via telemedicine encounters. In addition, mobile 
nurses may identify AEs as well and report them to the investigator for 
evaluation. Additionally, AEs may be identified from lab reports, ECG reports, 
and other records. As determined by the investigator, the appropriate medical 
intervention, therapeutic intervention, and/or support measures are instituted, as 
necessary. Provision of a study-issued smartphone or the vendors platform on a 
participant’s own device allows for study participants to report AEs at any time. 
Participants can also request a timely secure videoconference with the investigator 
and/or site staff.

The participant should be informed of the plan and any potential risks associated 
with the virtual medium and sign a revised Informed Consent Form if required. 
IRB/Ethics committee should be informed and/or approve of this change in 
approach and the process documented in study files.

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10.7.3.
Data Management/Monitoring:

If on-site monitoring is no longer permitted, GSK will consider remote Source Data 
Verification/Source Document Review (SDV/SDR) where permitted by national 
legislation and the clinical site. Remote SDV/SDR will be proposed to study sites to 
meet a participant and/or critical quality need, e.g., to assess participant safety or to 
ensure data integrity. In case of remote SDV/SDR, GSK will work with the site to 
ensure subject privacy. 

eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
PI may sign/re-sign the eCRF from any computer/location by accessing InForm (or 
other eDC platform) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly. 

Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK

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10.8.
Appendix 8: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
AST
Aspartate Transaminase
AUC
Area Under the Curve
BUN
Blood Urea Nitrogen
BYOD
Bring Your Own Device
CI
Confidence Interval
CV
Cardiovascular
Cmax
maximum serum concentration
CONSORT
Consolidated Standards of Reporting Trials
CSR
Clinical Study Report
CYP3A4
Cytochrome P450 3A4
DNA
Deoxyribonucleic acid
DoR
Delegation of Responsibility
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
EW
Early Withdrawal
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GLP
Good laboratory practice
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen
HCP
Health care professional
HIV
Human Immunodeficiency Virus
HR
Heart rate
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG2
human immunoglobulin G2 sigma isotype
IgG
Immunoglobulin G
IL-33R
Interleukin-33 receptor
IL-1RL1
Interleukin-1 receptor like-1
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous

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Kg
Kilogram
mAb
monoclonal antibody
MedDRA
Medicinal Dictionary for Regulatory Activities
mcg (g)
Microgram
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
mg
Milligram
min
Minute
mIU
Milli international units
mL
Milliliter
L
Microlitre
mm
Millimeter
mV
Millivolt
msec
Millisecond
PD
Pharmacodynamic
PGx
Pharmacogenetic
PI
Principal Investigator
PK
Pharmacokinetic
PPE
Personal Protective Equipment
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SDV/SDR
Source Data Verification/Source Document Review
SGPT
Serum Glutamic-Oxaloacetic Transaminase
SoA
Schedule of Activities
SRM
Study Reference Manual
ST2
Suppressor of tumorigenicity 2
sST2
Soluble ST2
ULN
Upper Limit of Normal
VT
Ventricular Tachycardia
WBC
White Blood Cell
WOCBP
Woman of childbearing potential
w/v
Weight/volume
4βOH
4β-Hydroxy

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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
WinNonlin

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10.9.
Appendix 9: 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] 12-JUN-2020
Overall Rationale for the Amendment:
An amendment to include a COVID-19 measures appendix, increase outpatient visit 
windows and define sample collection window for Free sST2 and total sST2 blood 
samples. 
Section # and 
Name
Description of Change
Brief Rationale
Section 1.3 
Schedule of 
Activities (SoA)
Table 2
Increase in visit windows from 
“Day 9 and 15 ± 2 days, 
thereafter ± 4 days” to “Day 9 ± 2 
days, Day 15 ± 4 days, Days 29, 
43 and 57 ± 7 days, Days 71 and 
85 ± 10 days
Define sample collection window 
for Free sST2 and total sST2 
blood sample from “samples must 
be taken at the same time as PK” 
to “samples should be taken 
within ± 2 minutes of PK”
To increase flexibility of participant 
outpatient visits from Day 15 to 85.
To provide clarity on the defined window 
for Free sST2 and total sST2 blood 
sample collection windows.
Section 10. 
Supporting 
documentation 
and operational 
considerations
Inclusion of “Appendix 7: COVID-
19 measures”
To outline measures that may be 
applicable if the site is impacted by the 
COVID-19 pandemic, including allowing 
home health nursing and telemedicine 
for outpatient visits.

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11.
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