A Multi-center, Randomized, Double-blind (Sponsor Open), Placebo-controlled, Repeat-dose, Proof of Mechanism Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Explore Efficacy of GSK2330811 in Participants With Diffuse Cutaneous Systemic Sclerosis
Phase: PHASE2
Conditions: Scleroderma, Systemic
Sponsor: GlaxoSmithKline

2016N269831_05
CONFIDENTIAL
GlaxoSmithKline group of companies
201247
1
TITLE PAGE
Protocol Title: A multi-centre, randomized, double-blind (sponsor open), placebo-
controlled, repeat-dose, proof of mechanism study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics and explore efficacy of GSK2330811 in 
participants with diffuse cutaneous systemic sclerosis.
Protocol Number: 201247/05
Short Title: Proof of mechanism study of GSK2330811 in diffuse cutaneous systemic 
sclerosis.
Compound Number:
GSK2330811
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): P-IND 131823 and EudraCT number
2016-003417-95
Approval Date: 01-APR-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
201247 | Protocol Amendment Protocol amendment 5 01 Apr 2020 | TMF-1737684 | 1.0

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2 0 1 2 4 7 | Pr ot oc ol A me n d me nt Pr ot oc ol a me n d me nt 5 0 1 A pr 2 0 2 0 | T M F- 1 7 3 7 6 8 4 | 1. 0

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 5
01-Apr-2020
Amendment 4
12-Nov-2018
Amendment 3
20-Jul-2017
Amendment 2
12-Dec-2016
Amendment 1
01-Nov-2016
Original Protocol
13-Sep-2016
Amendment 5 01-Apr-2020
Overall Rationale for the Amendment: This amendment was executed to provide 
clarification on the points detailed below:
Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities
9 Study Assessments and 
Procedures
Updated to allow a virtual or 
telephone visit at Day 113, Day 
155, Day 197 and Early 
Withdrawal (if required) to 
perform any study assessments 
that can be conducted remotely in 
circumstances in which an on-
site visit is not possible due to 
the COVID-19 pandemic.
At the time of this amendment, 
all study participants have 
completed the treatment 
period.
In response to the COVID-19 
pandemic, the option of 
virtual/telephone visits added 
to ensure safety monitoring 
during the off-treatment follow-
up period.
2 Schedule of Activities
Updated to extend the visit 
window on Day 113 to 5 
days, and on Day 155 and Day 
197 to 10 days.
At the time of this amendment, 
all study participants have 
completed the treatment 
period.
In response to the COVID-19 
pandemic, the visit window has 
been extended to provide 
flexibility to ensure safety 
monitoring during the off-
treatment follow-up period.
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Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities
12.2 Appendix 2: Clinical 
Laboratory Tests
Updated to allow safety 
(hematology and chemistry) 
labs and pregnancy tests to be 
run locally at the clinical site or 
within the community at the 
discretion of the Investigator 
for the Day 113, Day 155, Day 
197 and Early Withdrawal (if 
required) visits.
Updated to allow urine 
pregnancy test to be performed 
for the Day 197 and Early 
Withdrawal (if required) visits if 
a serum pregnancy test can 
not be performed.
At the time of this amendment, 
all study participants have 
completed the treatment 
period.
In response to the COVID-19 
pandemic, local safety labs 
and pregnancy tests can be 
run to ensure safety monitoring 
during the off-treatment follow-
up period.
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................15
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................15
3.3.
Benefit/Risk Assessment ............................................................................17
3.3.1.
Risk Assessment .........................................................................17
3.3.2.
Benefit Assessment.....................................................................24
3.3.3.
Overall Benefit:Risk Conclusion...................................................24
4.
OBJECTIVES AND ENDPOINTS...........................................................................24
5.
STUDY DESIGN ....................................................................................................26
5.1.
Overall Design ............................................................................................26
5.2.
Number of Participants, Treatment Arms and Duration...............................27
5.3.
Participant and Study Completion...............................................................28
5.4.
Scientific Rationale for Study Design ..........................................................28
5.5.
Dose Justification........................................................................................29
6.
STUDY POPULATION...........................................................................................30
6.1.
Inclusion Criteria.........................................................................................30
6.2.
Exclusion Criteria........................................................................................32
6.3.
Lifestyle Restrictions...................................................................................35
6.3.1.
Meals and Dietary Restrictions ....................................................35
6.4.
Screen Failures...........................................................................................35
7.
TREATMENTS.......................................................................................................36
7.1.
Treatments Administered............................................................................36
7.2.
Dose Modification .......................................................................................37
7.3.
Method of Treatment Assignment ...............................................................39
7.4.
Blinding.......................................................................................................39
7.5.
Preparation/Handling/Storage/Accountability..............................................40
7.6.
Treatment Compliance................................................................................41
7.7.
Concomitant Therapy..................................................................................41
7.7.1.
Permitted medications and Non-Drug Therapies..........................41
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.8.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................44
8.1.
Discontinuation of Study Treatment ............................................................44
8.1.1.
Individual Safety Stopping Rules .................................................44
8.1.2.
Liver Chemistry Stopping Criteria ................................................45
8.1.3.
QTc Stopping Criteria ..................................................................46
8.1.4.
Haematological Stopping Criteria.................................................47
8.1.5.
Temporary Discontinuation ..........................................................47
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8.1.6.
Interrupted Dosing .......................................................................48
8.1.6.1.
Study Treatment Restart or Rechallenge....................48
8.1.6.2.
Missed Doses.............................................................48
8.2.
Withdrawal from the Study..........................................................................48
8.3.
Lost to Follow-Up........................................................................................48
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
9.1.
Efficacy Assessments.................................................................................51
9.1.1.
FVC .............................................................................................51
9.1.2.
Scleroderma Health Assessment Questionnaire (SHAQ).............51
9.1.3.
Physician Global Assessment of Disease Activity (PhGA) ...........51
9.1.4.
Patient Global Assessment of Disease Activity (PtGA) ................52
9.1.5.
Modified Rodnan Skin Score (mRSS)..........................................52
9.1.6.
Composite Response Index in diffuse cutaneous Systemic 
Sclerosis (CRISS)........................................................................52
9.2.
Adverse Events...........................................................................................53
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................53
9.2.2.
Method of Detecting AEs and SAEs.............................................53
9.2.3.
Follow-up of AEs and SAEs.........................................................54
9.2.4.
Regulatory Reporting Requirements for SAEs .............................54
9.2.5.
Cardiovascular and Death Events................................................54
9.2.6.
Pregnancy ...................................................................................54
9.3.
Treatment of Overdose...............................................................................55
9.4.
Safety Assessments ...................................................................................55
9.4.1.
Physical Examinations.................................................................55
9.4.2.
Vital Signs....................................................................................55
9.4.3.
Electrocardiograms......................................................................56
9.4.4.
Clinical Safety Laboratory Assessments ......................................56
9.4.5.
Immunogenicity Assessments......................................................56
9.5.
Pharmacokinetics .......................................................................................57
9.6.
Pharmacodynamics ....................................................................................57
9.6.1.
OSM Target Engagement in Blood ..............................................57
9.7.
Genetics .....................................................................................................57
9.8.
Biomarkers .................................................................................................57
9.8.1.
Exploratory Biomarkers in Blood..................................................58
9.8.2.
Exploratory Biomarkers in Skin Biopsy ........................................58
9.8.3.
PK and PD in Suction Blister Fluid...............................................59
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................60
10. STATISTICAL CONSIDERATIONS........................................................................60
10.1.
Sample Size Determination ........................................................................60
10.2.
Populations for Analyses ............................................................................61
10.3.
Statistical Analyses.....................................................................................62
10.3.1.
Safety Analyses...........................................................................62
10.3.2.
Other Analyses ............................................................................62
10.3.3.
Interim Analyses ..........................................................................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................68
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12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................71
12.3.
Appendix 3: Study Governance Considerations..........................................74
12.3.1.
Safety Review Team (SRT) .........................................................75
12.3.2.
Data Review Committee (DRC) ...................................................76
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................85
12.6.
Appendix 6: Genetics..................................................................................89
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................90
12.8.
Appendix 8: Haematological Grades for Stopping Criteria (CTCAE 
criteria, V4.03: June 14, 2010)....................................................................93
12.9.
Appendix 9: Country-specific requirements.................................................94
12.10. Appendix 10: Protocol Amendment History.................................................95
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1.
SYNOPSIS
Protocol Title: A multi-centre, randomized, double-blind (sponsor open), placebo-
controlled, repeat-dose, proof of mechanism study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics and explore efficacy of GSK2330811 in 
participants with diffuse cutaneous systemic sclerosis.
Short Title: Proof of mechanism study of GSK2330811 in diffuse cutaneous systemic 
sclerosis.
Rationale: Systemic sclerosis (SSc) is a rare autoimmune disease with high morbidity 
and mortality. There are no approved disease-modifying therapies and it is an area of 
high unmet medical need. GSK2330811 is a monoclonal antibody that binds and 
neutralises Oncostatin M (OSM). The biological roles of OSM indicate that blocking 
OSM signalling would be expected to inhibit the key pathologic processes of SSc. This is 
a proof of mechanism study to evaluate the safety, tolerability, pharmacokinetics (PK) 
and pharmacodynamics (PD) of repeat subcutaneous doses of GSK2330811 in 
participants with diffuse cutaneous SSc (dcSSc). 
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the safety and tolerability of 
repeat subcutaneous doses of 
GSK2330811 in participants with dcSSc

Adverse event reporting 

Laboratory safety data (clinical 
chemistry, haematology, urinalysis) 

Vital signs (blood pressure, heart rate, 
body temperature) 

12 lead ECGs
Secondary

To evaluate the pharmacokinetic profile 
of repeat subcutaneous doses of 
GSK2330811 in participants with dcSSc

Plasma concentrations of GSK2330811 
and derived pharmacokinetic parameters 
(e.g Ctrough, apparent clearance (CL/F) 
and apparent volume of distribution 
(Vss/F))

To assess the target engagement of 
repeat subcutaneous doses of 
GSK2330811 in the blood of participants
with dcSSc

Serum levels of total OSM

Serum levels of free OSM
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Objective
Endpoint

To assess the potential for anti-drug 
antibody formation following repeat 
subcutaneous doses of GSK2330811 in  
participants with dcSSc

Incidence and titres of anti-GSK2330811 
antibodies
Additional exploratory endpoints are included to explore the pharmacology of repeat 
subcutaneous doses of GSK2330811 and its effect on selected clinical endpoints and 
biomarkers of fibrosis, inflammation and vasculopathy in the blood and skin.
Overall Design: This is a multi-centre, randomised, double-blind (sponsor open) placebo 
controlled, repeat-dose, proof of mechanism study of subcutaneous administration of 
GSK2330811 in males and females with dcSSc.
Participants with active disease and a disease duration of ≤60 months will be enrolled. 
Mycophenolate and low dose corticosteroids are permitted as background therapies. 
The study includes two sequential cohorts. Cohort 1 will evaluate the safety and 
tolerability of a repeat-dose predicted to provide sub-maximal inhibition of OSM, leading 
to a dose escalation decision. Cohort 2 will then evaluate a repeat-dose predicted to 
provide maximal inhibition of OSM to test proof of mechanism. A Data Review 
Committee will be responsible for determining progression from cohort 1 to cohort 2.
Participants will be randomised in a 3:1 ratio within each cohort to GSK2330811 and 
placebo respectively.
Assessments performed during the study will include skin biopsies, home spirometry 
(forced vital capacity) and an optional skin suction blister procedure for participants in 
cohort 2.
Number of Participants: A minimum of approximately 24 participants and a maximum 
of 40 participants will be randomised across the two cohorts.
Treatment Groups and Duration: Participants in both cohorts will be dosed 
subcutaneously for 10 weeks (total of 6 doses) with either GSK2330811 or placebo. 
Cohort 1 will receive 100 mg GSK2330811 or placebo every other week and cohort 2 
will receive 300 mg GSK2330811 or placebo every other week.
The duration of the study for the participants will be up to 34 weeks including a screening 
period of up to 6 weeks, a treatment period of 12 weeks and a follow-up period of 16 
weeks.
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2.
SCHEDULE OF ACTIVITIES (SOA)
The timing and number of planned pharmacokinetic, target engagement and biomarker 
assessments may be altered during the course of the study based on newly available data 
(e.g. to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
Any changes in the timing or addition of time points for these assessments must be 
documented and approved by the relevant study team member and then archived in the 
sponsor and site study files.
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
Screening 
Procedure
Screening (between -42 and -1 
days)
Notes
Informed Consent
X
The screening period for women of child bearing potential 
(WOCBP) must be at least 28 days to allow for a 28 day 
interval between the screening and Day 1 pregnancy tests.
See Appendix 1 for abbreviations.
1.
Respiratory laboratory FVC will be used for study eligibility 
and will be entered into the eCRF.
2.
The participant will be trained in FVC measurement using 
a hand held device. The first set of triplicate readings will be 
recorded by the participant at the clinical site. Thereafter 
approximately weekly measurements will be collected by the 
participant and entered into a paper diary.
3.
QuantiFERON-TB Gold PLUS test is also acceptable.
Inclusion and Exclusion Criteria
X
Demographics
X
Complete Physical Exam 
X
Medical History
X
mRSS
X
Respiratory Laboratory FVC1
X
Home spirometry FVC2
X
DLCO - corrected for haemoglobin
X
Concomitant Medications
X
12 lead ECG - single measurement
X
Vital Signs (blood pressure, heart rate, body temperature)
X
QuantiFERON-TB Gold test3
X
Serum Pregnancy Test (WOCBP only)
X
Oestradiol + FSH (as needed see Appendix 2)
X
HIV, Hepatitis B and Hepatitis C
X
Standard Haematology / Clinical Chemistry / Urinalysis(listed in Appendix 2)
X
Additional Haematology (listed in Appendix 2)
X
CRP
X
SAE - commencing from time of informed consent
X
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
Treatment Days and Follow-Up
Procedure
Treatment Period (Days)
Day  113
± 5 days
Day  155
± 10 days
Day 197 ± 10
days (Final Follow 
–Up)
Early Withdrawal13
(refer Section 8.2)
Day  1 
Day  15 
± 2 days
Day  29 
± 2 days
Day  43 
± 2 days
Day  57 
± 2 days
Day  71
± 3 days
Day  85 
± 3 days
Study Week
W2
W4
W6
W8
W10
W12
W1613
W2213
W2813
Study Treatment
Randomisation 
X1
Study Treatment Administration
X
X
X
X
X
X
Baseline Assessments
Autoantibodies
X1
Medical History2
X1
Safety Assessments and Cardiac Monitoring
Complete Physical Exam
X1
X
X
Brief Physical Exam
X
X
X
X
X
X
X
X
Vital Signs (blood pressure, heart rate, temperature)
X1
X1
X1
X1
X1
X1
X
X
X
X
X
12 –lead ECG (triplicate at day 1 or if QTc abnormal)
X1
X1
X1
AE/SAE Review3, 13
Continuous throughout study
Concomitant Medication Review13
Continuous throughout study
Serum Pregnancy Test (WOCBP)13
X14
X14
Urine Pregnancy Test (WOCBP)13
X1
X1
X1
X1
X1
X1
X
X
X
Standard Haematology/Clinical Chemistry (see Appendix 2)13
X1, 4
X
X
X
X
X
X4
X
X
X
X
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Procedure
Treatment Period (Days)
Day  113
± 5 days
Day  155
± 10 days
Day 197 ± 10
days (Final Follow 
–Up)
Early Withdrawal13
(refer Section 8.2)
Day  1 
Day  15 
± 2 days
Day  29 
± 2 days
Day  43 
± 2 days
Day  57 
± 2 days
Day  71
± 3 days
Day  85 
± 3 days
Study Week
W2
W4
W6
W8
W10
W12
W1613
W2213
W2813
Additional Haematology (see Appendix 2 for list)
X1
X
X
X
Urinalysis
X1
X
X
X
Pharmacokinetics, Pharmacodynamics, Immunogenicity and Genetics
Optional Suction Blister5
--------X--------
Immunogenicity Sampling
X1
X
X
X
X
X
Pharmacokinetic Blood Sampling
X1
X
X
X
X
X
X
X
X
Target Engagement (OSM) Blood Sampling
X1
X
X
X
X
X
X
X
X
Genetic Sampling6
X
Disease markers (efficacy) Assessment
Skin Biopsy
X1
X7
X8
Blood Biomarkers (see Section 9.8.1)
X1,9
X
X
X9
X
C-reactive protein (CRP)
X1
X
X
X
X
X
X
X
mRSS
X1
X
X
X
X10
Respiratory Laboratory FVC
X1
X
X
X10
Home Spirometry FVC11
<------------------------------------------weekly--------------------------------------->
SHAQ /PhGA//PtGA/CRISS data12
X1
X
X
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1. To be performed pre-dose. 
2. Medical history will include smoking history and information regarding the participant’s most recent HRCT scan if available. Medical occurrences that begin before the start of study 
treatment (Day 1) but after obtaining informed consent will be recorded as medical history. 
3. SAEs will be recorded from signing of informed consent; AEs will be recorded from administration of first study treatment.
4. Day 1 predose sample and Day 85 (Week 12) will be fasted and include lipid assessments.
5. Suction blister is an optional procedure for cohort 2 and additional consent will be required. Suction blister will only be performed once per participant (at anytime from the Day 57 
(Week 8) visit to the Day 85 (Week 12) visit inclusive) at selected sites
6. Genetics sampling is an optional assessment and additional consent will be required. Genetic sample can be taken any time after randomisation.
7. Skin biopsy scheduled for Day 85 (Week 12) may be taken on an alternative day to the rest of the assessments, but must remain within the Day 85 (Week 12 3 days) time window.
8. Skin biopsy only performed if the early withdrawal visit occurs on or after the Day 57 (Week 8) visit but before when the Day 85 (Week 12) visit would have been scheduled and the 
participant is willing. 
9. At the Day 1 and Day 85 (Week 12) visits, additional blood volume is required for possible proteomic and transcriptomic analyses.
10. Respiratory Laboratory FVC and mRSS will only be performed if the early withdrawal visit occurs on or after the Day 57 (Week 8) visit.   
11. Home spirometry FVC measured weekly by the participant via a hand held device, until the Day 197 (Week 28) visit.
12. Data to support CRISS calculation will be collected at Day 1, Day 85 (Week 12) and Day 197 (Week 28).
13. If an on-site visit is not possible due to the COVID-19 pandemic, a virtual or telephone visit can be performed for any study assessments that can be conducted remotely (e.g., 
AE/SAE review & concomitant medication review). In these circumstances, scheduled safety (standard hematology and clinical chemistry) labs and pregnancy tests should be 
performed if feasible and may be performed locally at the clinical site or within the community (all at the discretion of the Investigator).
14. If it is not possible for a serum pregnancy test to be performed due to the COVID-19 pandemic, a urine pregnancy test should be performed if possible. 
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3.
INTRODUCTION
3.1.
Study Rationale
Systemic sclerosis (SSc) is a rare autoimmume disease with high morbidity and 
mortality. There are no approved disease modifying therapies and it is an area of high 
unmet medical need. This is a proof of mechanism (POM) study to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of repeat subcutaneous 
(SC) doses of GSK2330811 in participants with diffuse cutaneous systemic sclerosis 
(dcSSc).
This is the first study with GSK2330811 in participants with SSc and as such the primary 
objective is to assess the safety and tolerability of repeat-doses of GSK2330811. 
Secondary and exploratory objectives include an assessment of the PK profile and 
immunogenicity of GSK2330811 with repeat-doses and proof of target engagement and 
pharmacology in blood and skin.
Mechanistic biomarkers of fibrosis, inflammation and vasculopathy will be measured in 
blood and skin in order to provide evidence of the modulation of key biological pathways 
involved in the pathogenesis of SSc by GSK2330811. Clinical data on the extent of skin 
and lung involvement by disease will be collected in order to provide further 
understanding of the mechanism of action and potential for clinical efficacy of 
GSK2330811 in SSc. However due to the small size and short duration of the study, no 
formal hypothesis will be tested. 
3.2.
Background
GSK2330811 is a humanised immunoglobulin G1(IgG1) monoclonal antibody that 
binds and neutralises Oncostatin M (OSM) with high affinity and specificity. This 
inhibits the downstream actions of OSM, which include effects on fibroblasts, endothelial 
cells and leukocytes that have been associated with fibrosis, vasculopathy and 
inflammation in a number of diseases.  
OSM is a member of a family of secreted cytokines that also includes interleukin 6, 
leukemia inhibitory factor (LIF) and interleukin 31. It is produced by leukocytes,
including macrophages, activated T cells and neutrophils and acts primarily via OSM 
receptors (OSMR) on a broad range of cell types, including chondrocytes, fibroblasts, 
keratinocytes and endothelial cells [Gearing, 1992; Mosley, 1996] to elicit diverse 
biological functions [Hermanns, 2015]. Depending on context, OSM is capable of 
endothelial activation; inducing an acute phase response; inducing cellular proliferation, 
migration or differentiation (e.g. of fibroblasts, epithelial cells and keratinocytes); 
inducing the release of inflammatory mediators and promoting wound healing [Richards, 
2013; Modur, 1997]. OSM also has a secondary role in regulating erythropoesis and 
megakaryopoesis [Tanaka, 2003; Minehata, 2006]. In a mouse model, intranasal OSM 
was able to induce lung fibrosis accompanied by significant increases in alveolar 
macrophages, lymphocytes and neutrophils [Mozaffarian, 2008]. 
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SSc is a multisystem autoimmune disease, in which the interrelated processes of
inflammation, fibrosis and microvascular damage result in a complex pattern of organ-
based complications with high mortality and morbidity [Allanore, 2015]. There are no 
approved drugs for the treatment of SSc and as such it remains an area of great unmet 
medical need [Denton, 2013]. Given the concordance between the known biological roles 
of OSM and the key pathologic processes in SSc (i.e. inflammation, microvascular 
damage and fibrosis), inhibiting OSM signalling in patients with SSc has potential to 
slow or stop the disease process thereby providing a disease-modifying therapeutic 
benefit. This is further supported by elevated serum levels of OSM in SSc patients 
compared to healthy controls, by elevated OSM levels in bronchoalveolar fluid of SSc 
patients with alveolitis and by increased tissue expression of OSM and OSMR in 
involved skin of SSc patients by immunohistochemistry [Feeney, 2015; Mozaffarian, 
2008].
The safety profile of GSK2330811 was evaluated in a repeat-dose subcutaneous toxicity 
study in the cynomolgus monkey. The only observed findings were reduction in red cell 
parameters in peripheral blood and bone marrow with evidence of a regenerative 
reticulocyte response. The no observed adverse effect level (NOAEL) was considered to 
be 300 mg/kg (highest dose tested). Detailed information can be found in the 
Investigator’s Brochure (IB) for GSK2330811 [GlaxoSmithKline Document Number 
2016N284919_00].
There has been one study of GSK2330811 in humans to date. In a Phase I, single dose 
escalation study in healthy males and females of non-childbearing potential, 30 
participants were exposed to GSK2330811 at doses ranging from 0.1 mg/kg to 6.0 mg/kg. 
GSK2330811 was well-tolerated, with no deaths or other serious adverse events (SAEs) 
reported. The pharmacokinetic profile of GSK2330811 was consistent with that of an 
IgG1 monoclonal antibody against a soluble cytokine and high levels of target 
engagement were observed. A dose-dependent, reversible reduction in platelet count was 
observed at dose levels of 1 mg/kg and above, and a low-grade, reduction in haemoglobin 
and red cell count was observed at the highest 6 mg/kg dose level. These effects are both 
felt to relate to inhibition of the known actions of OSM by GSK2330811. Detailed 
information can be found in the IB for GSK2330811 [GlaxoSmithKline Document 
Number 2016N284919_00]. 
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3.3.
Benefit/Risk Assessment
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2330811]
Haematological
Thrombocytopaenia
Anaemia

OSM has been shown to modulate haematopoiesis 
through an effect on bone marrow stromal cells and 
haematopoietic progenitors [Wallace, 1995; 
Miyajima, 2000].

OSM also positively influences the maturation of 
megakaryocytes and affects the expression of 
other cytokines in the bone marrow stroma, which 
regulate the bone marrow microenvironment 
[Tanaka, 2003].

A FTIH study of single doses of GSK2330811 in 
healthy participants demonstrated a reversible 
reduction in platelet count at doses between 1 
mg/kg and 6 mg/kg and on red cell parameters 
including haemoglobin and red cell count at the 
highest dose level of 6 mg/kg. A rebound 
reticulocytosis was evident from Day 21 in 
participants receiving 3 mg/kg and 6 mg/kg. Refer 
to IB for details [GlaxoSmithKline Document 
Number 2016N284919_00].

A 3 month repeat-dose cynomolgus monkey 
toxicology study with GSK2330811 showed a 
reduction in red cell parameters and bone marrow 
myeloid to erythroid ratios with a compensatory 
increase in reticulocyte count, without clinical 

Only participants with Haemoglobin  110g/L 
and platelet count 150x109/L   at screening, 
will be included in the study. 

Participants with known bleeding or coagulation 
disorders will be excluded.

Participants receiving treatment with anti-
coagulant medications will be excluded.

Participants receiving treatment with anti-
platelet medications, other than aspirin or non-
steroidal anti-inflammatory drugs, will be 
excluded.

Red cell and platelet parameters will be tested 
every two weeks during the treatment period 
(from the Day 1 to the Day 85 (Week 12) visit 
and then at each scheduled visit until the end of 
the follow-up period to ensure careful 
monitoring. 

Dosing of an individual participant will cease if 
haemoglobin <80g/L or platelet count <50x109/L 
with additional testing prior to dosing, if 
necessary (see Section 8.1.4).

Dosing of an individual participant will be held if 
platelet count between 50x109/L  and 75x109/L 
(see Section 8.1.4).
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
correlates. There was partial to complete recovery 
of red cell parameters and reticulocytes at the end 
of the off drug phase (18 weeks). Refer to IB for 
details [GlaxoSmithKline Document Number 
2016N284919_00].

A marginal decrease in platelet count (platelet 
counts remained within the reference range) was 
also observed in the same 3 month toxicology 
study. These showed partial to complete recovery 
whilst administration of GSK2330811 was ongoing 
and full recovery at the end of the off drug period 
(18 weeks). Refer to IB for details [GlaxoSmithKline 
Document Number 2016N284919_00].

The effect of a submaximal dose of 
GSK2330811 on haematologic parameters will 
be evaluated in an initial safety cohort (cohort 1) 
before a decision is made to enrol participants 
into the higher dose cohort (cohort 2).

Study safety monitoring will include in-stream 
monitoring of haemoglobin and platelet counts 
and planned safety reviews will be conducted 
after 4, 8, 12 participants in cohort 2 (see 
Appendix 3).
Risk of infection (including of reactivation 
of Mycobacterium tuberculosis)

OSM contributes to immunity in synergy with other 
cytokines such as TNF and IL-1 [Barksby, 2006], 
which may protect against infection. Therefore, the 
possibility of an increase in the frequency and/or 
severity of infection following dosing of GSK2330811 
cannot be excluded.

No dose-related fall in white cell count or leukocyte 
subsets was observed in the FTIH single ascending 
dose study of GSK2330811. No excess of infection 
adverse events was observed in participants 
receiving GSK2330811.

In cynomolgus monkey toxicology studies of 
GSK315234, another IgG anti-OSM monoclonal 
antibody with similar affinity for cynomolgus OSM, no 
changes in the adaptive immune response (T cell 
dependent B cell response), white cell count, or 

Participants to be screened for Human 
Immunodeficiency virus (HIV), Hepatitis B 
Hepatitis C and latent Tuberculosis prior to 
enrolment and excluded if positive.

Participants with a history of opportunistic 
infections within 6 months of the Day 1 visit or 
recurrent  infection, as determined by the 
investigator, will be excluded. 

Participants with a history of serious infection 
requiring intravenous (IV) antibiotics and/or 
hospitalisation within 3 months prior to the Day 1 
visit will be excluded.

Participants that have taken oral antibiotics, for 
the treatment of an acute or chronic infection, 
within 4 weeks prior to the Day 1 visit.

Participants with active or unresolved infection, 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
leukocyte subpopulations including T lymphocyte 
subsets were noted.

No specific studies have been conducted in 
nonclinical species to investigate the effect of 
GSK2330811 on the response to viral or bacterial 
infection.
including osteomyelitis, at the Day 1 visit will be 
excluded.

Investigators are expected to assess 
participants’ vaccination status and to follow local 
and/or national guidelines with respect to 
vaccinations.

Participants will not be allowed to receive live 
vaccines within the 4 weeks prior to Day 1, until 
the end of follow-up.

Close monitoring of participants for infections: 
Investigators will be made aware of the 
importance of reporting infections. Participants  
will be asked specifically regarding signs and 
symptoms of infection. White cell count and 
differential and vital signs will be obtained at 
each study visit. In the event of a serious 
infection, study treatment will be discontinued.
Immunogenicity

Biopharmaceutical products may elicit anti-drug 
antibodies (ADA), which have the potential to 
modulate PK, PD and/ or produce adverse 
reactions. 

There were no treatment-related anti-GSK2330811 
antibodies detected in the FTIH study with 
GSK2330811. Treatment unrelated pre-existing 
antibodies were detected in 3 participants at 
baseline including in one participant receiving 
placebo. These were low titre and not associated 
with any specific AEs.

The risk of developing ADA and their clinical 
consequences are mitigated as GSK2330811 is 
a fully humanized monoclonal antibody. Fully 
human antibodies are less immunogenic than 
their murine or chimeric monoclonal 
counterparts [Schroff, 1985; Shawler, 1985].

Serum samples will be collected for detection of 
ADA at timepoints aligned with regulatory 
guidelines [EMA, 2010; FDA, 2009].
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity

A potential risk of hepatotoxicity is inferred from 
studies in OSMRβ knockout mice showing impaired 
hepatocyte proliferation and tissue remodelling with 
impaired liver regeneration after liver injury. 
Administration of OSM ameliorated liver injury in 
wild-type mice [Nakamura, 2004].

However, in a 3 month toxicity study in healthy 
cynomolgus monkeys, treatment with GSK2330811 
was not associated with any observed liver effects 
(no changes in liver weights, macroscopic or 
microscopic changes, or elevations in liver 
transaminases at doses up to and including 300 
mg/kg/week). Refer to IB for details 
[GlaxoSmithKline Document Number 
2016N284919_00].

Mild, isolated, transient elevations in ALT, AST and 
serum bilirubin were observed in a small number of 
participants across treatment groups including 
placebo in the FTIH study of single doses of 
GSK2330811 in healthy participants. Refer to IB for 
details [GlaxoSmithKline Document Number 
2016N284919_00].

Participants will be screened for Hepatitis C and 
Hepatitis B prior to enrolment and excluded if 
positive.

Participants with a current or chronic history of
liver disease or a history of alcohol misuse will 
be excluded.

Only participants with an acceptable ALT and 
serum bilirubin at screening will be included, as 
detailed in the exclusion criteria.

Standard GSK guidance for phase 2 studies on 
liver monitoring and on liver stopping rules as 
detailed in Appendix 7 and Section 8.1.2 , will 
be followed for all participants.
Reproductive Toxicity

Animal reproductive toxicity studies have not yet 
been carried out with GSK2330811. They will be 
conducted in accordance with current ICH 
guidelines for timings.

Animal reproductive toxicity studies have been 
carried out for GSK315234, another IgG anti-OSM 
monoclonal antibody. GSK2330811 and 
GSK315234 antibodies bind different epitopes but 

Pregnant and lactating females will be excluded.

Women of child bearing potential (WOCBP) are 
required to use highly effective methods of 
contraception, as detailed in Appendix 5, from 
28 days prior to the first dosing day (Day 1) until 
the final follow-up visit.

WOCBP will undergo pregnancy testing at 
screening, prior to each study treatment 
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have similar affinity for OSM in the animal model 
used. No GSK315234 related effects on pregnancy, 
embryofetal development, parturition and lactation 
and on survival, growth and postnatal development 
of the offspring were noted at doses up to 150 
mg/kg/month, the highest dose tested.
administration and at all other study visits. A 
minimum of 28 days between the screening 
pregnancy test and the Day 1 pregnancy test is 
required for WOCBP.

In the event of a pregnancy in a female 
participant, study treatment will be discontinued 
and information on the pregnancy will be 
collected as detailed in Appendix 5. 
Carcinogenicity

There is conflicting evidence for the role of OSM in 
cell proliferation in metastatic cancer. Data is 
primarily from isolated cell-line systems and, 
depending on the cell type, OSM has been shown 
to act both as an anti-proliferative and a proliferative 
factor.

Participants with a history of carcinoma in situ 
and malignant disease will be excluded, with the 
exception of basal cell carcinoma that has been 
completely excised prior to the study.

Adverse event monitoring.
Hypersensitivity

Monoclonal antibodies can be associated with 
systemic hypersensitivity reactions, including 
angioedema, hypotension and anaphylaxis. 

There were no hypersensitivity reactions noted in 
the FTIH study with GSK2330811.

Participants with a history of sensitivity to any of 
the study treatments, or a history of any drug or 
other allergy that in the opinion of the 
investigator precludes their participation, will be 
excluded. 

Administration of GSK2330811 will be 
conducted in a hospital setting, with appropriate 
medical intervention available.

Participants will be informed of the symptoms of 
systemic hypersensitivity reactions and be 
instructed to seek immediate clinical care 
should they occur. This information will also be 
contained within the informed consent form.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Skin Biopsy

Skin biopsy is a well-established procedure 
implemented in a number of clinical studies in SSc 
patients [Guo, 2015; Khanna, 2016; Rice, 2015].

Possible risks of this procedure may include 
discomfort during and after the biopsy skin punch, 
infection and bleeding.

OSM and OSMR are expressed in the epidermis 
and may play a role in wound healing (Duncan, 
1995; Ihn, 2000; Scaffidi, 2002; Canady, 2013). 
However, there were no adverse events related to 
blister healing reported in the FTIH study with 
GSK2330811.

Participants must have no contraindications 
that, in the opinion of the investigator, would 
preclude skin biopsy.

Participants receiving treatment with anti-
coagulant medications will be excluded.

The biopsy procedure will be performed 
according to local practice, by trained personnel 
using aseptic technique to reduce the risk of 
bleeding and scarring.

Participants will be instructed on the signs and 
symptoms of infection and to contact site 
personnel should these develop.

The number of biopsies obtained will be limited 
to four, the minimum number necessary to 
answer the study questions.
Skin Suction Blister

The skin suction blister technique has been 
performed previously on patients with SSc [Clark, 
2015]. 

Possible risks of this procedure may include 
discomfort during the application of the negative 
pressure, skin infection after drawing the blister and 
hyperpigmentation of the skin at the blister 
induction site. 

OSM and OSMR are expressed in the epidermis, 
and may play a role in wound healing Duncan, 
1995; Ihn, 2000; Scaffidi, 2002; Canady, 2013].

Participants must have no contraindications 
that, in the opinion of the investigator, would 
preclude a skin suction blister.

Participants receiving treatment with anti-
coagulant medications will be excluded.

The risk of infection, although minimal given the 
low invasiveness of the procedure, will be 
reduced by dressing the blister after drawing the 
fluid. Participants will be advised to keep the 
site covered and dry for 24 hours before leaving 
open to the air.  
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Skin suction blisters were well tolerated in the FTIH 
study with GSK2330811 and no adverse events 
related to blister healing were reported.

Skin blister healing will be monitored during the 
study as part of adverse event (AE) review.

Participants will be instructed on the signs and 
symptoms of infection, and to contact site 
personnel should these develop.
More detailed information about the known and expected benefits and risks and reasonably expected adverse events of GSK2330811 may 
be found in the IB for GSK2330811 [GlaxoSmithKline Document Number 2016N284919_00]. 
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3.3.2.
Benefit Assessment
Systemic sclerosis is an autoimmune disease with substantial excess morbidity and 
mortality, and for which no licensed disease modifying treatments are available. There is 
pre-clinical evidence to suggest that GSK2330811 may be effective in treating the 
underlying disease process and therefore in ameliorating the signs and symptoms of SSc 
in an individual participant receiving GSK2330811. However, should there be any direct 
benefit to a participant in the study, this may be limited by the short duration of treatment 
in an otherwise chronic disease.
3.3.3.
Overall Benefit:Risk Conclusion
Balanced against the measures taken to minimise them, the potential haematologic and 
other risks to participants in this POM study of GSK2330811 are justified by need to 
develop more effective treatments for SSc.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
repeat subcutaneous doses of 
GSK2330811 in participants with dcSSc

Adverse event reporting 

Laboratory safety data (clinical 
chemistry, haematology, urinalysis) 

Vital signs (blood pressure, heart rate, 
body temperature) 

12 lead ECGs
Secondary

To evaluate the pharmacokinetic profile of 
repeat subcutaneous doses of 
GSK2330811 in participants with dcSSc

Plasma concentrations of GSK2330811 
and derived pharmacokinetic 
parameters (e.g Ctrough, apparent 
clearance (CL/F) and apparent volume 
of distribution (Vss/F))

To assess the target engagement of 
repeat subcutaneous doses of 
GSK2330811 in the blood of participants
with dcSSc

Serum levels of total OSM

Serum levels of free OSM

To assess the potential for anti-drug 
antibody formation following repeat 
subcutaneous doses of GSK2330811 in  
participants with dcSSc

Incidence and titres of anti-GSK2330811 
antibodies
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Objectives
Endpoints
Exploratory

To explore the pharmacology of repeat 
subcutaneous doses of GSK2330811 and 
its effects on biomarkers of fibrosis, 
inflammation and vasculopathy in the 
blood and skin of participants with dcSSc

Endpoints may include (but are not
limited to):
o Skin Biopsies: Change from baseline 
in mRNA expression and protein 
levels of selected markers chosen to 
reflect fibrosis, vasculopathy and 
tissue inflammation (e.g. αSMA, 
CD31 and CD3 respectively) at Day 
85 (Week 12)
o Blood: Change from baseline over 
time in CRP, other soluble protein 
markers (e.g. collagen turnover, 
VEGF and IL-6) and mRNA 
expression

To explore the PK and target engagement 
of repeat subcutaneous doses of 
GSK2330811 in the skin of participants
with dcSSc using suction induced blisters

Endpoints may include (but are not 
limited to):
o Levels of GSK2330811 in blister fluid 
measured anytime between Day 57 
and Day 85 (Week 8 and Week 12)
o Levels of OSM in blister fluid 
measured anytime between Day 57 
and Day 85 (Week 8 and Week 12)

To explore the effect of repeat 
subcutaneous doses of GSK2330811 on 
the extent of skin involvement in 
participants with dcSSc

Change from baseline in modified 
Rodnan skin score (mRSS) over time

To explore the effect of repeat 
subcutaneous doses of GSK2330811 on 
lung function in participants with dcSSc

Rate of change in forced vital capacity 
(FVC) 

Change from baseline in FVC 

To explore the effect of repeat 
subcutaneous doses of GSK2330811 on 
SSc related symptoms, physical function 
and disease activity in participants with 
dcSSc

Change from baseline in Scleroderma 
Health Assessment Questionnaire 
(SHAQ)

Change from baseline in Physician 
Global Assessment of Disease Activity 
(PhGA)

Change from baseline in Patient Global 
Assessment of Disease Activity (PtGA)

Composite Response Index for 
Systemic Sclerosis (CRISS)
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Objectives
Endpoints

To characterise the mechanisms of any 
observed haematological effects of 
GSK2330811.

Change from baseline in selected blood 
markers related to mechanisms of 
anaemia and thrombocytopenia.
5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, randomised, double blind (sponsor open), placebo-controlled, 
repeat-dose, proof of mechanism study of subcutaneous administrations of GSK2330811 
in males and females with dcSSc. 
The study includes two sequential cohorts. Cohort 1 is planned to consist of at least 4 
participants and will evaluate a repeat-dose predicted to provide sub-maximal inhibition 
of OSM, leading to a dose escalation decision once at least 4 participants have reached 
the end of the treatment period (see Section 7.2). Cohort 2 will then evaluate a repeat-
dose, predicted to provide maximal inhibition of OSM, to test POM. The study design, 
for both cohorts, is depicted in Figure 1. 
Figure 1
Study Schematic
Dose 6
Dose 5
Dose 4
Dose 3
D57
(W8)
Screening
Treatment period
GSK2330811 300mg
Follow-up
Screening
Treatment period
Placebo
Follow-up
D -42
(W -6)
Dose 2
Dose 1
D1
D15
(W2)
D29
(W4)
D43
(W6)
D71
(W10)
D85
(W12)
D113
(W16)
D155
(W22)
D197
(W28)
Screening
Treatment period
GSK2330811 100mg
DOSE ESCALATION DECISION
(after 4 participants in cohort 1 have reached
Week 12 unless cohort 1 is expanded)
Cohort 2
n = ~20-36
Cohort 1
n = 4
Follow-up
Screening
Treatment period
Placebo
Follow-up
≤ 6 weeks
12 weeks
16 weeks
Skin biopsy
Optional blister (Cohort 2)
Skin biopsy
Dosing Period
Day 1 to Day 71
Treatment Period
Day 1 to Day 85
Randomisation
3 Active : 1 Placebo
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
Participants who consent will attend the clinical facility for screening and if 
eligible will enter the treatment period of the study within 42 days. 

The screening period will be at least 28 days for WOCBP to allow for a minimum 
28 day interval between the screening and Day 1 pregnancy tests. 

Participants will be randomised in a 3:1 ratio within each cohort to GSK2330811 
and placebo respectively. In cohort 2 treatment allocation will be stratified 
according to mycophenolate concomitant medication status (treated or non-
treated).

Participants will attend the clinical facility to receive a subcutaneous dose of 
GSK2330811 or placebo on Day 1 and then every other week until the sixth and 
final dose at the Day 71 (Week 10) visit.

A Data Review Committee (DRC) will be responsible for determining 
progression from cohort 1 to cohort 2 as described in Section 7.2. 

Interim analyses will be conducted during cohort 2. The rationale, conduct and 
potential outcomes of these are described in Section 10.3.3.

Study safety monitoring will be undertaken in a blinded manner by the Sponsor 
Safety Review Team (SRT) as described in Appendix 3. The Study Medical 
Monitor will also continuously review adverse events and laboratory tests for 
individual participants during the conduct of the study to ensure individual 
participant monitoring.

Skin biopsies will be collected to assess GSK2330811 pharmacology and 
biomarkers at the site of action. Two punch biopsies will be collected from 
involved skin, on the forearm of participants, on both Day 1 and during the Day 
85 (Week 12) visit window.   

A skin suction blister procedure will be performed on involved skin on the 
forearm of participants at selected sites at anytime between the Day 57 (Week 8) 
visit and the Day 85 (Week 12) visit inclusive. This will be optional for 
participants and only performed in participants enrolled in cohort 2. 

After the treatment period, participants will enter a follow-up period of 
approximately 16 weeks.

In addition to study visits, weekly home FVC monitoring will be undertaken 
during the study (from screening until Day 197 (Week 28)).  
5.2.
Number of Participants, Treatment Arms and Duration
Participants with dcSSc, with active disease and a disease duration of ≤ 60 months, will 
be enrolled. A minimum of approximately 24 participants and a maximum of 40 
participants will be randomised across two cohorts. The duration of the study, including 
screening, will be up to 34 weeks for participants.
Participants will be dosed subcutaneously at one of two dose levels every other week for 
10 weeks with either GSK2330811 or placebo. 
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For cohort 1, an initial 4 participants will be randomised to either GSK2330811 or 
placebo. If a decision is made to expand cohort 1 a further 4 participants will be entered 
into cohort 1. For cohort 2, a minimum of approximately 20  participants will be 
randomised. Participants from Cohort 1 will not be eligible to participate in Cohort 2.
A participant in cohort 1 is evaluable for dose escalation if they have received at least 4 
doses of GSK2330811 or placebo, have reached the end of the treatment period and there 
is a standard haematology result from at least one of the Day 71 (Week 10), Day 85 
(Week 12) or Day113 (Week 16) visits. If any participant in cohort 1 cannot be evaluated 
for dose escalation, additional participants may be recruited and assigned to the same 
treatment sequence at the discretion of the sponsor up to a maximum of 8 evaluable 
participants. 
A participant in cohort 1 or cohort 2 is considered evaluable for study endpoints if they 
have received at least 4 doses of GSK2330811 or placebo and have biopsies at both the 
Day 1 and the Day 85 (Week 12) assessment. Additional participants may be entered into 
the study at the discretion of the sponsor up to a maximum of 40 randomised participants 
in the study overall.
5.3.
Participant and Study Completion
Participants will complete the study once they have completed all assessments on Day 
197 (Week 28). This includes participants who discontinue study treatment early but 
continue in the study.
Participants who withdraw from the study early will complete the study once they have 
completed all assessments at the early withdrawal visit (Section 8.2). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4.
Scientific Rationale for Study Design
As this is the first study of GSK2330811 in participants with SSc, and the first repeat 
dose study, the primary endpoint is the safety and tolerability of GSK2330811. In 
addition, this study will include assessments of the pharmacokinetics, target engagement 
and downstream pharmacology of GSK2330811. This will be achieved by assessing 
GSK2330811 and OSM levels in blood and skin blister fluid and mRNA markers of 
GSK2330811 pharmacology in skin biopsies. Skin involvement is emphasised because it 
is readily studied, contributes substantially to the morbidity experienced by patients with 
dcSSc and exemplifies the three major pathological processes involved in the condition.  
The assessment of biomarkers of fibrosis, inflammation and vasculopathy in blood and 
skin biopsies will also be performed, and for this reason the population is enriched for 
early active disease. Changes in these parameters and their association with each other 
and with preliminary measures of clinical efficacy will be assessed. These data are 
intended to provide evidence that GSK2330811 is having an impact on key pathways 
involved in the pathogenesis of SSc. 
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The purpose of cohort 1 is to evaluate the safety and tolerability of repeat doses of a 
pharmacologically active but submaximal dose of GSK2330811, before escalating to a 
higher dose. 
The 12 week duration of the Treatment Phase is based on the expectation that an effective 
therapy should cause changes in the mechanistic parameters at this timepoint [Guo, 2015; 
Khanna, 2016; Rice, 2015].
The GSK2330811 half life is between 19 to 25 days, consistent with a typical monoclonal 
antibody half life for a soluble cytokine (see IB for GSK2330811) [GlaxoSmithKline 
Document Number 2016N284919_00]. Participants will be followed for approximately 
18 weeks after the last administration of GSK2330811.   
The placebo group is required for a valid evaluation of adverse events attributable to 
GSK2330811 treatment versus those independent of GSK2330811 treatment. The 
placebo participants will also serve as negative controls for the biomarker and efficacy 
assessments. 
Participants will be randomised in a 3:1 ratio to GSK2330811 and placebo respectively. 
This unbalanced allocation ratio means that more participants are available for the 
assessment of within-participant changes in biomarkers after dosing with GSK2330811 
and allows more participants to receive GSK2330811.
Participants will be allowed to continue with some background therapies (Section 7.7 ), 
including mycophenolate and low dose oral corticosteroids to avoid excluding potential 
participants in this rare disease. Other immunosuppressive treatments will be excluded, in 
order to minimise inter-participant variability in this small trial.  
5.5.
Dose Justification
Dose levels for this study have been selected on the basis of PK/PD predictions, data 
from the first time in human study with GSK2330811 and preclinical data. Two dose 
levels (a 100 mg sub-maximal dose to test initial safety and tolerability and a 300 mg 
maximal dose to test POM) have been selected based on predicted target engagement 
after repeat dosing. 
An in-vivo affinity of approximately 0.6 nM was estimated from first time in human  
data. The typical GSK2330811 apparent distribution volume was 11.5 L (95% 
Confidence Interval (CI): 10.2-13.1) and the typical apparent systemic clearance was 14.1 
mL/hr (95% CI: 12.7-15.6). The mean terminal half-life ranged between 19 and 25 days. 
The ratio of GSK2330811 mean concentration between skin blister fluid and plasma  
ranged from 19 to 45%.
A target-mediated drug disposition (TMDD) model (Mager, 2005) using a one-
compartment PK model together with binding kinetics of drug and target was developed 
to predict target engagement after repeat dosing. 
First cohort: 100 mg every other week is considered a sub-maximal pharmacologically 
active dose with a predicted target engagement of approximately 80% in serum at trough. 
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Second cohort: 300 mg is predicted to achieve engagement of greater than 90% of OSM 
in serum at trough. 
In addition a PKPD model was developed to assess the relationship between drug 
concentration and platelet count reduction [Wang, 2010] including a feedback 
mechanism. According to the model predictions after repeat dosing at 100 mg every other 
week, no participant is anticipated to achieve a CTCAE grade 2 or greater reduction in  
platelet count.
The NOAEL in the 13 weeks cynomolgus monkey study was 300 mg/kg/week. The PK 
exposure achieved in cynomologous monkey was more than 100 times greater than the 
predicted PK exposure in human (steady state AUC 21300ug.h/mL and Cmax 
68.2ug/mL) at a dose of 300 mg every other week [GlaxoSmithKline Document Number 
2016N284919_00]. 
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
18 years or over, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
Documented diagnosis of systemic sclerosis as defined by the American College of 
Rheumatology / European League Against Rheumatism 2013 criteria (Van den 
Hoogen, 2013), with diffuse cutaneous involvement.
3.
Modified Rodnan Skin Score (mRSS) ≥10 and ≤35 at screening. 
4.
In all cases, a disease duration of ≤60 months at screening, defined as time from 
onset of the first non-Raynaud’s phenomenon manifestation.
5.
Active disease defined by at least one of the following criteria at screening:

CRP ≥6 mg/l (0.6 mg/dL), that in the opinion of the investigator is due to SSc. 

Disease duration ≤18 months at screening, defined as time from the first non-
Raynaud’s phenomenon manifestation.

Increase of  ≥3 mRSS units, compared with an assessment performed within 
the previous 6 months.

Involvement of one new body area (according to mRSS definitions) and an 
increase of  2 mRSS units compared with an assessment performed within 
the previous 6 months. 
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
Involvement of two new body areas (according to mRSS definitions) within 
the previous 6 months.
6.
An area of uninvolved or mildly thickened skin that in the opinion of the investigator 
would allow subcutaneous injection at one of the following locations:

Abdomen

Front, middle region of the thigh

Outer area of the upper arm
7.
An area of involved skin (mRSS ≥1) on the forearm suitable for repeated skin 
biopsies to be collected as described in Section 9.8.2.
8.
Participants who are taking mycophenolate mofetil (≤3,000 mg/day) or equivalent 
mycophenolate sodium (≤2160 mg/day) are permitted in the study if the participant 
has been on a stable dose for ≥3 months at the first dosing day (Day 1) and 
participant and investigator are willing to continue this dose until at least completion 
of the Day 85 (Week 12) visit. If mycophenolate was recently ceased, there must be 
≥3 months between the date mycophenolate was ceased and the first dosing day 
(Day 1).
9.
Participants who are taking oral corticosteroids (≤10 mg/day of prednisone or 
equivalent) are permitted in the study if the participant has been receiving a dose no 
greater than 10 mg/day for at least 4 weeks at the first dosing day (Day 1) and the 
investigator does not anticipate increasing the dose above 10 mg/day during the 
study.
10. Participants who are taking phosphodiesterase 5 (PDE5) inhibitors and endothelin 
receptor antagonists (including bosentan) are permitted in the study if the participant
has been on a stable dose for at least 4 weeks for PDE5 inhibitors and for at least 3 
months for endothelin antagonists at the first dosing day (Day 1) and participant and 
investigator are willing to continue this dose until at least completion of the Day 85 
(Week 12) visit.
11. Participants who are taking non-immunosuppressive medications not specifically 
excluded in Section 6.2 are permitted in the study (e.g. hydroxychloroquine, 
angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor (AR) 
blockers, calcium-channel blockers and proton-pump inhibitors). However no new 
long-term medications and no dose-changes to existing long term medications are 
permitted during the two weeks prior to the first dosing day (Day 1). See Section 
7.7.1.
Sex
12. Male and female participants
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the dosing period and for at least 126 days (18 weeks) after the last 
dose of study treatment and refrain from donating sperm during this period.
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b. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
from 28 days prior to first dosing day (Day 1), during the dosing period and 
for at least 126 days (18 weeks) after the last dose of study treatment. 
Informed Consent
13. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Patients classified to the limited cutaneous SSc subset, as determined by the 
investigator.
2.
Rheumatic autoimmune disease other than dcSSc including but not limited to 
rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue 
disorder, polymyositis, dermatomyositis, systemic vasculitis and primary Sjogren’s 
syndrome, as determined by the investigator.
3.
FVC ≤50% of predicted, or a diffusing capacity of the lung for carbon dioxide 
(DLCO) (corrected for haemoglobin) ≤40% of predicted at screening.
4.
Pulmonary arterial hypertension, as determined by the investigator.
5.
Clinically significant inflammatory myositis (related to SSc), as determined by the 
investigator.
6.
SSc renal crisis within 6 months of the first day of dosing (Day 1).
7.
History of clinically significant or uncontrolled cardiac, endocrinologic, 
hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, 
dermatologic, psychiatric, renal, and/or other major disease at screening not related 
to SSc and that in the opinion of the investigator would prevent participation in the 
study. 
8.
Known bleeding or coagulation disorder.
9.
Major surgery (including joint surgery) within 3 months prior to screening, or 
planned during the duration of the study.
10. Clinically significant multiple or severe drug allergies (including to humanized 
monoclonal antibodies), intolerance to topical corticosteroids, or severe post-
treatment hypersensitivity reactions (including, but not limited to, erythema 
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multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal 
necrolysis, and exfoliative dermatitis).
11. An active infection, or a history of infections as follows:

History of opportunistic infections that have not resolved by 6 months prior to 
the first day of dosing (Day1) or recurrent infection as determined by the 
investigator. This does not include infections that may occur in 
immunocompetent individuals, such as fungal nail infections or vaginal 
candidiasis, unless it is of an unusual severity or frequency. 

A serious infection requiring treatment with IV antibiotics and/or 
hospitalisation, if the last dose of antibiotics or the hospital discharge date was 
within 3 months of the first day of dosing (Day1).

An acute or chronic infection requiring treatment with oral antibiotics or 
antiviral medications, if the last dose was received within 4 weeks of the first 
day of dosing (Day1). 

Any active or unresolved bacterial, viral or fungal infection present on the 
first day of dosing (Day1), whether requiring treatment or not. This does not 
include fungal nail infections.

Active or past osteomyelitis, unless fully resolved in the opinion of the 
investigator.

Symptomatic herpes zoster that has not resolved by 3 months prior to the first 
day of dosing (Day1).

History of Tuberculosis (TB) or a positive QuantiFERON-TB Gold test or 
QuantiFERON-TB Gold PLUS test at screening.
o
If the QuantiFERON-TB Gold test or QuantiFERON-TB Gold PLUS test 
is indeterminate, it can be repeated once. A participant will not be eligible 
unless the second test is negative or they have a negative tuberculin skin 
test (defined as skin induration <5 mm at 48 to 72 hours, regardless of 
Bacillus Calmette-Guerin or other vaccination history). 
o
There must be no other clinical evidence of TB on physical examination of 
the participant (screening examination). 
12. Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
13. Bilirubin >1.5xULN at screening (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%).
14. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
NOTE: Participants with evidence of liver fat on imaging but who are otherwise 
eligible for the study criteria may be enrolled.
15. QTc >480 msec or QTc >500 msec in participants with Bundle Branch Block at 
screening.
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16. A history of carcinoma in situ and malignant disease, with the exception of basal cell 
carcinoma that has been completely excised prior to the study. 
Prior/Concomitant Therapy
17. Treatment with methotrexate within 3 months prior to the first dosing day (Day 1).
18. Previous or planned bone marrow transplant (e.g. autologous stem cell transplant). 
19. Treatment with a biologic within the following timeframes:

Tocilizumab, abatacept or anti-TNF (including etanercept, infliximab, 
certolizumab, golimumab or adalimumab) within 3 months prior to the first 
dosing day (Day 1).

Rituximab within 12 months prior to the first dosing day (Day 1).

For any other biologic consult the medical monitor.
20. Treatment with oral or intravenous cyclophosphamide within 6 months prior to the 
first dosing day (Day 1).
21. Treatment with any other non-biologic systemic immunosuppressive medication 
(e.g. azathioprine, tacrolimus, ciclosporin) not mentioned above within 4 weeks prior 
to the first dosing day (Day 1), with the exception of mycophenolate and oral 
corticosteroid (which are permitted).
22. Treatment with topical immunosuppressive medications (e.g. topical corticosteroids, 
tacrolimus) within 1 week prior to the first dosing day (Day 1).
23. Treatment with intravenous prostanoids (e.g. iloprost) within 2 weeks prior to the 
first dosing day (Day 1) or planned treatment before the Day 85 (Week 12) visit.
24. Treatment with anti-fibrotic medications including tyrosine kinase inhibitors (e.g. 
nintedinib and imatinib) and pirfenidone within 3 months prior to the first dosing day 
(Day 1).
25. Live vaccine(s) within 4 weeks prior to the first dosing day (Day 1), or plans to 
receive such vaccines during the study.
26. Treatment with anti-coagulant medications, including warfarin, heparin, thrombin
inhibitors, and Factor Xa inhibitors within 2 weeks prior to the first dosing day (Day 
1).
27. Treatment with anti-platelet medications (e.g. clopidogrel, prasugrel, ticagrelor and 
dipyridamole) within 2 weeks prior to first dosing day (Day 1). This does not include 
aspirin at doses of 150 mg or less, or non-steroidal anti-inflammatory drugs, which 
are permitted.
Prior/Concurrent Clinical Study Experience
28. Current enrollment or past participation within the last 30 days before signing of 
consent in any other clinical study involving an investigational study treatment.
29. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day (Day 1).
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Diagnostic assessments
30. Any of the following at screening:

Haemoglobin <110 g/L

Platelet count <150x109/L 

Estimated glomerular filtration rate (GFR) (MDRD calculation) of <45 
mL/min/1.73m2
31. A positive human immunodeficiency virus (HIV) antibody test at screening.
32. Presence of Hepatitis B surface antigen (HBsAg) at screening. 
33. Positive Hepatitis B core antibody (HBcAb) test at screening.
34. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
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.
35. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
Contraindications
36. Sensitivity to any of the study treatments or components thereof, or other allergy that 
in the opinion of the investigator, contraindicates participation in the study.
37. Where participation in the study would result in donation of blood or blood products 
in excess of a volume of 500mL during the study.
38. A history of drug and alcohol misuse that could interfere with participation in the 
trial according to the protocol, or in the opinion of the investigator impacts on the 
physical or mental wellbeing of the participant.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants will be required to fast for 12 hours (no food or drink, except water) prior to 
collection of the Day 1 and Day 85 (Week 12) clinical chemistry blood sample. There 
will be no other caffeine, xanthine or dietary restrictions for the rest of the study.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
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Repeat assessments during the 42 day screening period: Assessments, including 
laboratory assessments, may be repeated once if determined necessary by the 
investigator, for example: (a) in cases of technical malfunction (e.g. loss of laboratory 
specimen), (b) in the event of a value close enough to the exclusionary threshold that it 
may reasonably lie within the degree of variability of the assay or an indeterminate result; 
(c) if there is reason to believe the result may be false (i.e. contradicts recent result for the 
same parameter). These are repeat assessments and not rescreening events. If the original 
result was exclusionary and is confirmed by repeat testing, the participant will be 
excluded. 
Rescreening: Individuals who do not meet the criteria for participation in this study 
(screen failure) may be rescreened once at the discretion of the investigator.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Syringes containing GSK2330811 or placebo will be prepared at the study site by an 
unblinded pharmacist or designee. Placebo will be sourced locally by the site while 
GSK2330811 will be provided by GSK. GSK2330811 or placebo will be administered by 
subcutaneous injection in to the abdomen, thigh or upper arm by the investigator or 
designee. Participants will remain at the clinic for observation for at least 30 minutes 
after each dose has been administered. See the Study Reference Manual (SRM) for 
further details.
Study Treatment Name:
GSK2330811
Placebo
Dosage formulation:
Solution for injection; 50 
mM Sodium Acetate, 0.05 
mM EDTA, 1.0% Arginine, 
51 mM Sodium Chloride, 
pH 5.5 with 0.02% 
polysorbate 80
Normal Saline (0.9% w/v 
Sodium Chloride)
Unit dose 
strength(s)/Dosage 
level(s):
1.2mL fill with 1mL 
extractable volume at 100 
mg/mL
Not applicable
Storage:
Store between 2-8C, 
protect from light 
As recommended by supplier 
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Study Treatment Name:
GSK2330811
Placebo
Route of Administration: 
SC injection only
SC injection only
Dosing instructions:
Administered by 
investigator or designee. 
Cohort 1 100 mg dose
1 x 1ml injected via needle 
and syringe 
Cohort 2 300 mg dose
3 x 1ml injected via needle 
and syringe
If a dose lower than 300 
mg is required then the 
volume injected will be 
reduced accordingly. 
Administered by investigator or 
designee.  Injection volume and 
number of injections will match 
active doses administered.
Packaging and Labeling:
Study Treatment will be 
provided in vials and 
packed in 1 vial per carton. 
Each vial and carton will be 
labelled as required per 
country requirement. 
Manufacturer:
GSK
To be sourced locally
7.2.
Dose Modification

Initially, 4 participants will be randomised into cohort 1 and receive a dose of 100 
mg GSK2330811 or placebo (Section 5.5). Cohort 1 may be expanded to 8 
participants in the circumstances described below.

Decisions regarding progression to cohort 2 will be made by the DRC, constituted 
as outlined in Appendix 3.

After 4 evaluable participants (Section 5.2) have reached the end of the treatment 
period (Day 85,Week 12), the DRC will review all available safety and 
tolerability data  for all randomised participants. Any available PK data will also 
be reviewed. Based on this review, the DRC will recommend one of:
1. Progress to cohort 2 at a dose level of 300 mg GSK2330811 as planned.
2. Progress to cohort 2 at a dose level 100 mg and <300 mg GSK2330811. 
3. Expand cohort 1 to recruit an additional 4 participants (3:1 ratio of 
GSK2330811 to placebo).
4. Initiate a full safety review.
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
If any of the following events occur during cohort 1, with a reasonable possibility 
of being related to GSK2330811, then cohort 1 will be immediately expanded to 8 
participants at the same dose level:
1. A participant receiving GSK2330811 experiences a Haemoglobin <80g/L
(CTCAE Grade 3 or greater event) or
2. A participant receiving GSK2330811 experiences a Platelet count 
<50x109/L (CTCAE Grade 3 or greater event) or
3. A participant receiving GSK2330811 experiences an SAE, provided 
continued recruitment is approved by the DRC.

If cohort 1 is expanded, the DRC will review all available safety and tolerability 
data for all randomised participants after 8 evaluable participants have reached the 
end of the treatment period (Day 85, Week 12). All available PK data will also be 
reviewed. Based on this review, the DRC will recommend one of:
1. Progress to cohort 2 at a dose level of 300 mg GSK2330811.
2. Progress to cohort 2 at a dose level 100 mg and <300 mg GSK2330811. 
3. Initiate a full safety review.

If any of the following occur during cohort 1, with a reasonable possibility of 
being related to GSK2330811, then treatment and recruitment will be halted
and a full safety review undertaken:
1. 2 or more participants on GSK2330811 experience a Haemoglobin <80g/L
(CTCAE Grade 3 or greater event) or
2. 2 or more participants on GSK2330811 experience a Platelet count 
<50x109/L (CTCAE Grade 3 or greater event) or
3. A participant on GSK2330811 experiences a Platelet count <50x109/L 
(CTCAE Grade 3 or greater event) and a different participant on 
GSK2330811 experiences a Haemoglobin <80g/L (CTCAE Grade 3 or 
greater event) or
4. 2 or more participants on GSK2330811 experience an SAE.
A full safety review of cohort 1, if undertaken, will involve the analysis of unblinded data 
by the DRC and relevant GSK personnel (Appendix 3). If the study is halted and 
following the safety review a decision is made to recommence study treatment, 
progression to cohort 2 will only occur after notification of the appropriate Regulatory 
Authorities and Ethics Committees, according to local regulatory requirements.
CTCAE grades are defined using the CTCAE criteria V4.03: June 14, 2010 (refer to 
Appendix 8 for both SI and conventional units). If there is any concern that an abnormal 
laboratory result is spurious, a repeat test will be undertaken before implementing any of 
the actions described in this section.
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7.3.
Method of Treatment Assignment
At the time of signing the Informed Consent a unique participant number (eCRF Subject 
Number) will be assigned. The unique participant number will be used to identify 
individual participants during the course of the study.
All participants will be centrally randomized on Day 1 using an Interactive Web 
Response System (IWRS). Before the study is initiated, log in information & directions 
for the IWRS will be provided to each site. Participants will be assigned a unique number 
(randomisation number). Once a randomisation number has been assigned it must not be 
reassigned. The randomisation number encodes the participant’s assignment to one of the 
2 arms of the study, according to the randomisation schedule generated prior to the study 
by the Statistics Department at GSK.
Participants will be randomised to receive GSK2330811 or placebo in a 3:1 ratio.
7.4.
Blinding
This will be a double blind (sponsor open) study where all study staff involved in the 
clinical assessments (which includes the investigator, sub-investigators and other site 
staff) and the participant will be blinded to treatment allocation.
An unblinded pharmacist or designee will be required at site to prepare and dispense the 
study treatment. The unblinded pharmacist will endeavour to ensure that there are no 
differences in temperature or in time taken to dispense following randomisation. The 
unblinded pharmacist is not permitted to communicate the participant’s treatment 
allocation to blinded site staff.  
Unblinded monitors will be assigned to review all pharmacy records, storage and 
procedures.  In addition unblinded monitors and in the event of a Quality Assurance 
audit, the auditor(s) will be allowed access to un-blinded study treatment records at the 
site(s) to verify that randomisation/dispensing has been done accurately.
Sponsor open refers only to specific members of the DRC at defined meetings.  
Committee membership is defined in Appendix 3.  Further details of blinding and how 
the integrity of the study will be maintained will be described in the DRC charter. 
Unblinding of individual participants may occur to ensure appropriate management of a 
participant, e.g. if an SAE is considered by the investigator as being causally related to 
study treament, taking account of the points below:

The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of a medical 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.
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
It is preferred (but not required) that the investigator first contacts the medical 
monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding and within 24 hrs.

The date and reason for the unblinding must be fully documented in the eCRF. 
A participant may continue in the study if that participant’s treatment assignment is 
unblinded, if it remains appropriate for them to do so.
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the treatment 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
The IWRS will be programmed with blind-breaking instructions.  
7.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for the preparation of GSK2330811 
will be detailed in SRM.
1.
The unblinded pharmacist or designee must confirm appropriate temperature 
conditions have been maintained during transit for all study treatment received and 
any discrepancies are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet /equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, 
where this is required by local laws, or is available upon request from GSK.
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7.6.
Treatment Compliance
Participants will be dosed at the site and will receive study treatment directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
7.7.
Concomitant Therapy
7.7.1.
Permitted medications and Non-Drug Therapies
Medications for the treatment of SSc and concomitant diseases may be taken as long as 
they are not prohibited (Section 7.7.2) and as long as specific requirements listed in
Table 1 are adhered to. All concomitant medications taken during the study will be 
recorded in the eCRF according to the guidelines listed in Table 1.
Any deviations from these specific requirements (for example increase in corticosteroid 
dose >10 mg/day) during screening, that cannot be addressed by extending the screening 
period up to a maximum of 42 days, will result in the participant being a screen failure. In 
this case they may be re-screened as described in Section 6.4.
Any deviations from these requirements during the study (for example, for an urgent 
clinical need) must be documented and may affect the evaluability of the participant. If 
safety concerns are raised by deviations from these requirements they must be discussed 
with the Medical Monitor, who will determine if discontinuation of study treatment is 
warranted.
Table 1
Specific requirements for permitted medications during the study
Medication
Requirement
Mycophenolate mofetil (up to 3,000 mg/day) OR 
equivalent mycophenolate sodium (up to 2160
mg/day)
Must have been on a stable dose for at least 3 
months at the first dosing day (Day 1). 
Participants should remain on a stable dose at 
least until completion of the Day 85 (Week 12) 
visit (unless dose must be reduced because of 
a safety concern).
If mycophenolate was recently ceased, there 
must be ≥3 months between the date 
mycophenolate was ceased and the first 
dosing day (Day 1).
Record medication name and dose at first 
dosing day, and record dates and nature of 
any dose changes during study.
All local standard of care practices and product 
labelling for mycophenolate including 
prophylactic therapies, contraception 
requirements, laboratory testing, follow up care 
and other precautions and contraindications 
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Medication
Requirement
should continue to be followed throughout the 
study.
Oral corticosteroids (up to 10 mg/day 
prednisolone or equivalent, dose averaged over 
a 7 day period)
Must have been on a dose ≤10 mg/day for at 
least 4 weeks at the first dosing day (Day 1). 
Participants are encouraged to continue on a 
stable dose at least until completion of the Day 
85 (Week 12) visit (unless dose must be 
reduced because of a safety concern). Doses 
above 10 mg/day are not permitted.
Record medication name and dose at first 
dosing day, and record dates and nature of 
any dose changes during study.
All local standard of care practices and product 
labelling requirements for oral corticosteroids 
including prophylactic therapies (including but 
not limited to calcium supplementation and 
gastric protection), laboratory testing, follow up 
care and other precautions and 
contraindications should continue to be 
followed throughout the study.
PDE5 inhibitors (including but not limited to 
sildenafil)
Must have been on a stable dose for at least 4 
weeks at the first dosing day (Day 1). 
Participants should remain on a stable dose at 
least until completion of the Day 85 (Week 12) 
visit (unless dose must be reduced because of 
a safety concern).
Record medication name and dose at first 
dosing day, and record dates and nature of 
any dose changes during study.
Endothelin receptor antagonists (including but 
not limited to bosentan)
Must have been on a stable dose for at least 3 
months at the first dosing day (Day 1). 
Participants should remain on a stable dose at 
least until completion of the Day 85 (Week 12) 
visit (unless dose must be reduced because of 
a safety concern).
Record medication name and dose at first 
dosing day, and record dates and nature of 
any dose changes during study.
Other permitted long-term (i.e. planned to 
continue for the duration of the study) 
concomitant medications not specifically 
mentioned above (for example, low dose 
aspirin, hydroxychloroquine, ACE-inhibitors, 
calcium-channel blockers, proton pump 
inhibitors)
May not be commenced and dose should not 
be altered during the 2 weeks prior to the first 
dosing day (Day 1). Participants are 
encouraged to continue these therapies on a 
stable dose at least until completion of the Day 
85 (Week 12) visit (unless dose must be 
reduced because of a safety concern).
Record medication name, indication if 
available and dose at first dosing day, and 
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Medication
Requirement
record dates and nature of any dose changes 
during study.
Short-term therapies for symptoms (for 
example, paracetamol, non-steroidal anti-
inflammatory drugs, antacids) or for intercurrent 
illnesses (for example, antimicrobials).
Permitted if not specifically prohibited (Section 
7.7.2), but an AE report may be necessary 
depending on the indication for their use 
(Appendix 4)
Record medication name, indication, dose and 
duration.
Topical therapies, vitamins and other dietary 
supplements (for example, iron supplements, 
folate).
Permitted except for topical 
immunosuppressive medications (Section 
7.7.2). 
Therapies/supplements in this class of specific 
interest will be listed in the SRM and recorded 
in the eCRF.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists prohibited medications for defined periods of time before AND DURING 
the study until after the Day 197 (Week 28) visit. The two exceptions are iloprost and 
topical immunosuppressive therapies, which are only prohibited up to and including the 
Day 85 (Week 12) visit.
Participants who start prohibited medications or therapies (for example, for an urgent 
clinical need) during the treatment period (i.e. Day 1 to the Day 85 (Week 12) visit) will 
be required to permanently discontinue study treatment. Participants who start prohibited 
medications at any time during the study may also be withdrawn from the study at the 
discretion of the medical monitor. If in any doubt, investigators are advised to discuss 
medications with the medical monitor.
Table 2
Prohibited Medications
Medication
Time period prior to first dosing day
Topical immunosuppressive medications (e.g.
topical corticosteroids, tacrolimus)
1 week (and until the Day 85 (Week 12) study 
visit inclusive)
Intravenous prostanoids (e.g. iloprost)
2 weeks (and until the Day 85 (Week 12) study 
visit inclusive)
Anticoagulant medications (including but not 
limited to warfarin, heparin, thrombin inhibitors 
and factor Xa inhibitors)
2 weeks
Antiplatelet medications other than aspirin 150 
mg/day or non-steroidal anti-inflammatory drugs, 
including but not limited to clopidogrel, 
prasugrel, ticagrelor and dipyridamole
2 weeks
Live vaccines
4 weeks
Treatment with any form of non-biologic 
systemic immunosuppressive medication not 
mentioned elsewhere in this table (with the 
4 weeks
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Medication
Time period prior to first dosing day
exception of mycophenolate and oral 
corticosteroids up to 10 mg/d prednisolone or 
equivalent, which are permitted).
Methotrexate
3 months
Tocilizumab, abatacept or any anti-TNF agent 
(including etanercept, infliximab, certolizumab, 
golimumab or adalimumab)
3 months
Antifibrotic medications including tyrosine kinase 
inhibitors (e.g. nintedinib and imatinib) and 
pirfenidone.
3 months
Cyclophosphamide (oral or intravenous)
6 months
Rituximab
12 months
Chlorambucil
Any prior exposure is not permitted
Any other licensed biologic agent not specifically 
mentioned above.
Consult medical monitor
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants will discontinue study treatment if an individual stopping rule is reached. In 
this event participants should continue the study (i.e. continue with study visits and 
assessments).
8.1.1.
Individual Safety Stopping Rules
Study treatment will be permanently discontinued in the event of any of the following:

If a participant experiences a serious or clinically significant severe AE that in the 
opinion of the investigator, after consultation with the medical monitor, has a 
reasonable possibility of relation to GSK2330811 (Appendix 4).

The participant becomes pregnant.

The participant initiates a prohibited medication (Section 7.7.2).

The participant develops a serious infection.

The participant experiences a severe or serious hypersensitivity reaction, 
including anaphylaxis (defined according to Sampson, 2006).

The liver chemistry stopping criteria (Section 8.1.2), QTc stopping criteria 
(Section 8.1.3) or haematological stopping criteria (Section 8.1.4) are met.
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If the study treatment is discontinued, but the participant has received one or more doses 
of study treatment, the remaining study visits should still be performed including skin 
biopsy and home and laboratory FVC monitoring if this is deemed reasonable in the 
opinion of the Investigator and the participant is willing. In particular, the safety 
assessments should still continue as per protocol. The suction blister procedure will not 
be performed if study treatment is discontinued. If the participant declines any further 
follow-up and chooses to withdraw themselves from the study the investigator should 
make every effort to conduct the Early Withdrawal assessments as described in Section 
8.2 and Section 2.
8.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant. 
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7.
8.1.3.
QTc Stopping Criteria
A participant who meets either of the bulleted criteria below, based on the average of 
triplicate ECG readings, will permanently discontinue dosing:
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Discontinuation Criteria: 
1. QTc >530 msec
2. Change from baseline: QTc >60msec

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 single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g. 5-10 minute) recording period (see 
Section 9.4.3).  
8.1.4.
Haematological Stopping Criteria
Study treatment will be permanently discontinued for a participant if any of the following 
haematological stopping criteria are met:

Haemoglobin <80g/L (i.e. CTCAE Grade 3 or greater event), confirmed by a 
repeat sample obtained before the next scheduled dose of GSK2330811.
o
If haemoglobin is <90g/L at any point during the dosing period (Day 1 to 
the Day 71 visit), a repeat haemoglobin will be required within 72 hrs of 
the next scheduled dose, with a result ≥80g/L obtained prior to dosing.

Platelet count <50x109/L  (i.e. CTCAE Grade 3 or greater event), confirmed by a 
repeat sample obtained before the next scheduled dose of GSK2330811).
o
If platelet count is <100x109/L  during the dosing period (Day 1 to the Day 
71 visit), a repeat platelet count will be required within 72 hrs of the next 
scheduled dose. Dosing may proceed if platelet count is ≥75x109/L  (see 
also Section 8.1.5).
See Appendix 8 for CTCAE criteria in both SI and conventional units.
8.1.5.
Temporary Discontinuation
Study treatment for a participant will be temporarily withheld if the most recent platelet 
count taken within 72 hours of the scheduled dose is 50x109/L  and <75x109/L . In this 
event, scheduled study visit assessments should be performed but the dose must NOT be 
administered.
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Once platelet count is  75x109/L study treatment may resume with the next scheduled 
dose. 
8.1.6.
Interrupted Dosing
8.1.6.1.
Study Treatment Restart or Rechallenge
If study treatment is stopped for any reason other than a temporary discontinuation as 
outlined in Section 8.1.5 it will not be restarted.
8.1.6.2.
Missed Doses
A missed dose is defined as a participant not receiving a dose during the visit window. If 
a study treatment dose is missed and a temporary or permanent discontinuation of 
treatment criterion has not been reached (see Section 8.1) then this will be reported as a 
protocol deviation. Study treatment will continue at the next scheduled dosing visit. 
‘Catch-up’ doses must not be administered between study visits. 
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance or administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
The Early Withdrawal Visit will only be performed if the participant withdraws from the 
study and therefore will not undertake any further scheduled visits. The early withdrawal 
visit will only be performed if the participant is willing (see Section 2 for assessments to 
be performed at this visit). 
8.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
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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 with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in Section 2 (Schedule of 
Activities). 

If an on-site visit is not possible due to the COVID-19 pandemic, a virtual or
telephone visit can be performed for any study assessments that can be conducted 
remotely (e.g. AE/SAE review & concomitant medication review) at the Day 113, 
Day 155, Day 197 and Early Withdrawal (if required) visits. The AE/SAE review 
and concomitant medication review should be conducted in a manner as similar as 
possible (in terms of language and approach) as would have taken place with an in-
person clinic visit.

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

All samples (blood, urine, blister fluid or skin biopsy) will be retained for a 
maximum of 15 years after the last participant completes the trial.
Order of Assessments throughout the study
Scleroderma Health Assessment Questionnaire (SHAQ), Physician Global Assessment of 
Disease Activity, 12-lead ECG and vital signs should occur before the blood draw. On 
the study visits where the assessments include a skin biopsy or suction blister these 
should be performed after the mRSS assessment and blood draw. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM. The SRM will provide the site personnel with administrative and 
detailed technical information that does not impact participant safety.
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Screening Assessments
Information collected during the screening assessments described below represents key 
data that identifies and defines the participant’s status.
Informed Consent: Informed consent will be obtained from the participant prior to 
initiation of any study procedures or study-specific data collection. 
During the screening period screening assessments will be performed as outlined in the 
Section 2 and include:
Demographic parameters: Will be captured: year of birth, sex, race and ethnicity.
Medical history: Will be assessed as related to the inclusion/exclusion criteria listed in 
Section 6 (as detailed in the eCRF). 
Respiratory Tests: 
1. Respiratory Laboratory Tests (FVC and DLCO) for Eligibility.
Hospital based lung function equipment will be used to measure lung function tests and 
be overseen by a respiratory physiologist. Lung function tests will be recorded whilst the 
participant is in a sitting position (if taken whilst the participant is on the bed, their legs 
should be over the edge) and may be repeated, until technically acceptable measurements 
have been made. The respiratory laboratory measured FVC and DLCO will be recorded 
in the eCRF. 
2. Home Spirometry (FVC).
The rate of decline in daily FVC, measured at home via a hand held spirometer, in 
patients with IPF has been shown to be highly predictive of outcome and subsequent 
mortality (Russell, 2016). Training on use of the hand held spirometer will be given 
during the screening visit and a refresher course offered at Day 1. After initial training, 
three FVC readings will be obtained and recorded by the participant at the first screening 
visit. The participant will then continue to measure weekly FVC on a day convenient to 
them throughout the screening period and until the end of the study. The participant will 
enter the readings into their paper diary. The paper diary entries will be transcribed into 
the eCRF.  
Baseline Assessments taken at Day 1 only
Autoantibodies: To aid patient characterisation and potential future stratification a blood 
sample will be taken on Day 1 for assessment of autoantibody status, including but not 
limited to Anti-Scl-70, Anti-centromere and Anti-RNAPIII. 
Medical History: Medical history will include SSc-related factors, smoking and 
cardiovascular medical history / risk factors and information from the participant’s most 
recent lung HRCT scan, if available, as detailed in the eCRF.
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9.1.
Efficacy Assessments
9.1.1.
FVC
Respiratory Laboratory Test
FVC will be measured using hospital based lung function equipment at the timepoints 
specified in Section 2 and will be overseen by a respiratory physiologist, as described for 
screening tests in Section 9. 
Home Spirometry
Weekly FVC (triplicate readings), at a day convenient to the participant, will be
performed by the participant using a hand held spirometer and entered into the 
participant’s paper diary, as described for screening tests in Section 9. 
9.1.2.
Scleroderma Health Assessment Questionnaire (SHAQ)
The participant will complete a Scleroderma Health Assessment Questionnaire (SHAQ) 
(Steen, 1997; Pope, 2011) at the time points specified in Section 2. The SHAQ is 
comprised of:

The Health Assessment Questionnaire Disability Index (HAQ-DI) (21 items 
across 8 domains) that assesses physical function

6 individual Visual Analogue Scales assessing the impact of each of the following 
symptoms on activities of daily living: 
o
Pain
o
Gastrointestinal involvement 
o
Lung involvement
o
Vascular (Raynaud’s Phenomenon) 
o
Digital Ulcers
o
Patient Global Assessment of Disease Activity
The SHAQ will be completed by the participant during scheduled clinic visits and before 
any other assessments. 
9.1.3.
Physician Global Assessment of Disease Activity (PhGA)
The investigator or physician designee only will complete a global assessment of disease 
activity using the physician global assessment (PhGA), at the time points specified in 
Section 2. This is a single item numeric rating scale (See SRM for full details).
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2 0 1 6 N 2 6 9 8 3 1 _ 0 5
C O N FI D E N TI A L
2 0 1 2 4 7
5 2
N ote:
T he sa me i n vesti gat or or p h y sicia n desi g nee s h o ul d perf or m all P h G A assess me nts f or a 
partici pa nt f or t he d urati o n of t he st u dy.
9. 1. 4.
P ati e nt Gl o b al A s s e s s m e nt of Di s e a s e A cti v it y (Pt G A)
T he partici pa nt will c o m plete a gl o bal assess me nt of disease acti vit y  usi n g t he patie nt 
gl o bal assess me nt ( Pt G A), at t he ti me p oi nts s pecifie d i n Secti o n 2 . T his is a si n gle ite m 
n u meric rati n g scale ( See S R M f or f ull details).
T he Pt G A will be c o m plete d b y t he partici pa nt d uri n g sc he d ule d cli nic visits a n d bef ore 
a n y ot her assess me nts. 
9. 1. 5.
M o difi e d R o d n a n S ki n S c or e ( m R S S)
T he m R S S pr o vi des a n e val uati o n of s ki n t hic k ness rate d b y cli nical pal pati o n usi n g a 0–
3 scale 
 
) f or eac h of 1 7 s urface a nat o mic areas of t he b o d y 
(Cle me nt s, 1 9 9 5; Czira k , 2 0 0 8). T hese i n di vi d ual val ues are a d de d a n d t he s u m is defi ne d 
as t he t otal s ki n sc ore a n d will ra n ge fr o m 0 t o 5 1. T he m R S S w ill be perf or me d at t he 
ti me p oi nts s pecifie d i n Secti o n 2 .
N ote:
T he sa me i n vesti gat or or p h y sicia n desi g nee s h o ul d perf or m all m R S S assess me nts f or 
eac h partici pa nt f or t he d urati o n of t he st u d y.
9. 1. 6.
C o m p o sit e R e s p o n s e I n d e x i n diff u s e c ut a n e o u s S y st e mi c 
S cl er o si s ( C R I S S)
Data f or t h e C o m p osite Re sp o nse I n de x i n dc S Sc (C RI S S) will be c ollecte d at t he 
ti me p oi nts descri be d i n Secti o n 2 . T he CRI S S i m ple me nts a t w o-ste p al g orit h m t o 
calc ulate a pr o ba bilit y t hat a partici pa nt ’s disease stat us ha s i m pr o ve d fr o m its baseli ne
val ue (K ha n na , 2 0 1 6).
Ste p 1: Partici pa nts w h o de vel o p ne w or w orse ni n g car di o, p ul m o nar y  a n d/ or re nal 
i n v ol ve me nt d ue t o S Sc are c o nsi dere d t o ha ve n ot i m pr o ve d (irres pecti ve of 
i m pr o ve me nt i n ot her c ore ite ms) a n d are assi g ne d a C RI S S sc ore ( pr o ba bilit y ) of 0.    
Ste p 2: F or t he re mai ni n g partici pa nts, t he C RI S S sc ore ( pr o ba bilit y ) is calc ulate d fr o m 
c ha n ge fr o m baseli ne i n t he fi ve c ore ite ms:

m R S S
C CI
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
% predicted FVC

HAQ-DI

PhGA

PtGA
See SRM for further details in conducting this assessment. 
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information
All SAEs will be collected from the signing of the ICF until Day 197 (Week 28, final 
follow-up visit) at the time points specified in Section 2.
All AEs will be collected from the start of treatment (Day 1) until Day 197 (Week 28, 
final  follow-up visit) at the time points specified in Section 2.
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (eCRF) not the AE section.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the 
site becoming aware, as indicated in Appendix 4. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study treatment under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions 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 SAE 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.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until Day 197 
(Week 28, final follow-up) visit.
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
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 5.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK2330811 greater than 100 mg SC every other week for 
cohort 1 and 300 mg (or other dose as determined by DRC) SC every other week for 
cohort 2 after taking into account visit windows, will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the Medical Monitor within 48hrs of the site becoming aware.
2. Monitor the participant at least weekly for AE/SAE and laboratory abnormalities 
(including but not limited to full blood count / complete blood count and liver 
function tests) for 2 weeks, and thereafter as advised by the Medical Monitor.
3. Obtain a plasma sample for PK analysis within 7 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).
4. Document the quantity of the excess dose in the CRF.
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in Section 2.
9.4.1.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded.
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Vital Signs
Single vital signs will be measured in a seated or semi-supine position after 5 minutes of 
rest and will include temperature, systolic and diastolic blood pressure and pulse rate. 
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Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
9.4.3.
Electrocardiograms
12-lead ECGs will be obtained as outlined in Section 2 using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Refer to Section 8.1.3 for QTc withdrawal criteria.
Where single ECG measurements are obtained, if the QTc measurement fulfils a QTc 
withdrawal criterion an additional two QTc readings will be obtained and the average of 
these three measurements will be used.
When triplicate ECG are required, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to Section 
2 for the timing and frequency. The tests include routine clinical safety laboratory 
assessments and additional haematology assessments related to mechanisms of anaemia 
and thrombocytopenia.
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. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
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 etiology should be identified and the sponsor notified.
All laboratory assessments, as defined in Appendix 2, must be conducted in accordance 
with the SRM and the Section 2.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification), this must be documented in the eCRF.
9.4.5.
Immunogenicity Assessments
Serum samples from whole blood will be collected as specified in Section 2. Washout 
samples will be collected at the follow-up visit to minimise interference of circulating 
study treatment in the antibody assessments. Testing will be performed using a tiered 
approach involving screening, confirmation and titration [EMA, 2010; FDA, 2009] 
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performed by Clinical Immunology, GlaxoSmithKline. If sera contain potential anti-
GSK2330811 antibodies in the screening assessment, they will be confirmed by 
immunocompetition using excess drug, followed by a titration assay. Results will include 
the incidence of immunogenicity and titres. Samples testing positive for anti-
GSK2330811 antibodies may be further characterised for the presence of GSK2330811 
neutralizing activity (NAb).
9.5.
Pharmacokinetics
Blood samples will be collected for measurement of plasma concentrations of 
GSK2330811 at the time points specified in Section 2. The actual date and time (24-hour 
clock time) of each sample will be recorded. Plasma analysis will be performed by PTS-
Bioanalysis, GlaxoSmithKline. Concentrations of GSK2330811 will be measured in 
plasma samples using the currently approved bioanalytical methodology. Raw data will 
be archived at the bioanalytical site. Instructions for the collection, processing, storage 
and shipping procedures are provided in the SRM.
9.6.
Pharmacodynamics
9.6.1.
OSM Target Engagement in Blood
Blood samples will be collected for measurement of serum levels of free and total OSM 
protein at the time points specified in Section 2. Analysis will be performed by Clinical 
Immunology, GlaxoSmithKline using the currently approved bioanalytical methodology. 
Raw data will be archived at the bioanalytical site. Instructions for the collection, 
processing, storage and shipment of the samples will be described in the SRM.
9.7.
Genetics
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. 
See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.
9.8.
Biomarkers
The following samples for biomarker research are required and will be collected from all 
participants in this study at the timepoints specified in Section 2: 

Blood

Plasma

Serum
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
Skin Biopsy
In addition, an optional skin suction blister procedure will be performed at selected sites 
for consenting participants enrolled in cohort 2. Suction blister fluid will be collected 
between the Day 57 (Week 8) visit and the Day 85 (Week 12) visit inclusive. 
The results of some of the exploratory biomarker investigations (for example proteomic 
and transcriptomic analysis in blood samples) may be reported separately from the main 
clinical study report.
9.8.1.
Exploratory Biomarkers in Blood
Serum and plasma samples for blood biomarkers including CRP will be collected at the 
timepoints specified in Section 2, to explore changes in levels in response to 
GSK2330811.  Note a CRP measurement is taken at more clinical visits than the 
remaining exploratory biomarkers. Instructions for the collection and handling of 
biological samples will be described in the SRM. Markers may include (but are not 
restricted to):

Fibrosis markers, such as enhanced liver fibrosis (ELF) test and markers of 
collagen turnover.

Inflammation markers, such as IL-6 and CRP.

Vasculopathy markers, such as vWF and VEGF.
Completion of biomarker analysis or emerging evidence in the scientific literature may 
trigger further transcriptomic and proteomic analysis for determining the impact of 
GSK2330811 on pathways of interest and for research related to SSc. Transcriptomic 
analysis may be conducted on blood samples using microarray technology, and/or 
alternative equivalent technologies, which facilitates the simultaneous measurement of 
the relative abundances of thousands of RNA species resulting in a transcriptome profile 
for a skin biopsy sample. The same samples may also be used to confirm findings by 
application of alternative technologies. 
In addition serum samples may undergo proteomic analysis using SomaLogic SOMAscan 
and / or alternative equivalent technologies which facilitate the simultaneous 
measurement of multiple protein species resulting in a proteomic profile. Instructions for 
the collection and handling of biological samples will be described in the SRM.
9.8.2.
Exploratory Biomarkers in Skin Biopsy
Two skin punch biopsies, 3 mm in size, will be collected from clinically involved skin 
(mRSS ≥ 1), preferably hairless, on the forearm of participants, on Day 1 (pre-dose) and 
also on Day 85.  All biopsies for a participant should be collected from the same forearm 
following SRM recommendations. At both timepoints, one biopsy sample will be 
evaluated histologically while the second biopsy sample will be evaluated by 
transcriptomic analysis. Biopsy quality assessments may be performed during the study 
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as described in the SRM. Details of the biomarker skin biopsy sample processing, 
storage, quality assessments and shipping procedures are provided in the SRM. 
Histopathological assessments of the biopsy will explore changes in levels of disease 
biomarkers (protein and / or mRNA and / or pathological evaluation) in response to 
GSK2330811. Markers may include (but are not restricted to):

Fibrosis markers, such as αSMA to assess changes in myofibroblast numbers.

Inflammation markers, such as changes in numbers of CD3+ T cells.

Vasculopathy markers, such as changes in CD31+ endothelial cells.
Transcriptomic analysis will determine the effect of GSK2330811 on OSM and disease 
related gene expression. Gene expression will be measured using microarray technology, 
and/or alternative equivalent technologies, which facilitates the simultaneous 
measurement of the relative abundances of thousands of RNA species resulting in a 
transcriptome profile for a skin biopsy sample. The same samples may also be used to 
confirm findings by application of alternative technologies. Genes may include but are 
not restricted to: 

OSM related genes such as SOCS3 and JAK2.

Fibrosis markers, such as THBS1 and COMP. 
9.8.3.
PK and PD in Suction Blister Fluid
Skin suction blisters provide a minimally invasive opportunity to study skin PK and PD 
[Kuhns, 1992]. The dermal suction blister fluid is representative of skin interstitial fluid 
without affecting normal dermal vascular endothelium [Worm, 1981].
Participants at selected sites have the option to undergo a dermal suction blister 
assessment between the Day 57 (Week 8) visit and Day 85 (Week 12) visit inclusive. 
Suction blister fluid is required from a minimum of 6 participants on GSK2330811 in 
order to explore the PK and target engagement of GSK2330811 in skin. Participants who 
do not wish to participate in the blister assessment may still participate in the study. 
Suction blisters will be induced over a period of approximately 2 hours on involved skin 
(mRSS ≥ 1), preferably hairless, of either forearm. Blister fluid will then be aspirated. 
Details of the induction, aspiration, processing, storage and shipping of samples will be 
described in the SRM.
Markers may include (but are not restricted to):

Total OSM

PK

Free OSM
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9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
No formal sample size calculations have been conducted as the sample size is based on 
feasibility.
The primary objective is safety and tolerability, where for cohort 1 an initial cohort of 
four participants will be randomised to either GSK2330811 or placebo in a 3:1 ratio. In 
cohort 2 a minimum of approximately 20 and a maximum of 36 participants will be 
randomised to GSK2330811 or placebo in a 3:1 ratio. 
Table 3 illustrates the credible interval for observed safety events in the GSK2330811 
group in cohorts 1 and 2. This uses a Bayesian approach assuming a non-informative 
conjugate prior distribution Beta(1,1). This illustrates that if one event in three 
participants is observed, for example, then a true rate of 0.806 for that safety event cannot 
be ruled out.
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Table 3
Inferences on the true event rate
Study Cohort
Observed event rate
(events / treated participants)
Upper limit of 95% credible interval 
for the true event rate
Cohort 1 (N=3)
0/3
0.602
1/3
0.806
2/3
0.932
3/3
0.994
Cohort 2 (N=15)
0/15
0.206
1/15
0.302
2/15
0.383
3/15
0.456
For information, for the exploratory endpoint of fibrosis log (PIIINP) assuming an 
SD=0.521 (Lee, 2001) and a sample size of 15 participants receiving GSK2330811 and 5 
receiving placebo, it is estimated that the lower and upper bounds of the 95% confidence 
interval for the comparison of GSK2330811 to Placebo will be within 0.565 of the point 
estimate. This calculation is based on a two tailed Type I error rate of 5%. The difference 
in log (PIIINP) between healthy volunteers and Systemic Sclerosis patients was 0.42 in 
an observational study (Lee, 2001).
Within the defined range, the final number of participants recruited may depend on an 
interim sample size re-estimation. 
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF.
Safety
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Pharmacokinetic
The ‘PK Population' is defined as participants in the ‘Safety’ 
population who received an active dose and for whom a 
pharmacokinetic sample was obtained and analysed. This 
population is used for the summary of PK data only. In the case of 
PKPD, the Safety Population is used so that participants receiving 
placebo can be included.
All participants that receive at least 4 doses of GSK2330811 or placebo and have biopsies 
at both Day 1 and the Day 85 (Week 12) assessment will be considered evaluable.  
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10.3.
Statistical Analyses
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary and 
Secondary
No formal statistical testing will be performed on safety data. 
If deemed appropriate posterior probabilities of the true rate of an adverse event 
of interest may be calculated using a non-informative prior distribution.
Clinical interpretation will be based upon review and displays of adverse events, 
disease related events, laboratory values and vital signs. The principal 
consideration in this evaluation will be the investigator-reported relationships of 
either adverse events or laboratory abnormalities to investigational product.
Safety data including immunogenicity data will be presented in tabular and/or 
graphical format and summarized descriptively according to GSK’s Integrated 
Data Standards Library (IDSL) standard.
Target Engagement will be presented in tabular and graphical format and 
summarized descriptively according to GSK’s IDSL standard for 
Pharmacodynamic endpoints.
Sparse blood sampling is being implemented in this study to allow the full 
pharmacokinetic profile for each participant to be reconstructed using Bayesian 
prediction from a population pharmacokinetic model using Non Linear Mixed 
Effect Model (NONMEM) version VII or higher and determine the exposure over 
the dosing interval (AUC (0- τ)), apparent systemic clearance (CL/F), and 
apparent volume of distribution (Vss/F).
Plasma GSK2330811 concentration data will be presented in tabular and 
graphical format and summarized descriptively according to GSK’s IDSL 
standards.
Exploratory
Will be described in the reporting and analysis plan (RAP). 
10.3.2.
Other Analyses
PK, pharmacodynamic and biomarker exploratory analyses will be described in the RAP.  
The analysis approach for exploratory biomarkers will be:

Relationships between endpoints, explored graphically and using statistical 
measures of consistency if data allow.

Profiles / Trends over time of individual endpoints
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
Inference using posterior probabilities of the true within participant change from 
baseline and true between group treatment difference using non-informative prior 
distributions.
In addition to the univariate analysis of the change from baseline in each biomarker, a 
multivariate analysis of endpoints of several biomarkers of fibrosis may also be 
performed.
The primary between-group analysis will be between the placebo and GSK2330811 
groups.  However if a difference in baseline levels of key biomarkers of fibrosis is 
observed by mycophenolate use then an alternative primary comparison will be 
considered.
The following PK/PD analyses will be conducted if data permit:

To examine the relationship between plasma concentrations of GSK2330811, and 
target OSM concentration (total). 

To examine the relationship between plasma concentrations of GSK2330811, and 
platelet count.  
10.3.3.
Interim Analyses
In line with routine pharmacovigilance, an internal GSK SRT will review blinded safety 
data at appropriate intervals during the study conduct. See Appendix 3 for further details.
For the purposes of dose escalation a dose escalation review will occur once the 
appropriate data from cohort 1 has been collected. This dose escalation review along with 
the interim analyses outlined below will be conducted by the DRC. The activities of these 
and how the study integrity will be maintained are included in the DRC charter.
For the purpose of assessing target engagement, an unblinded interim analysis of PD and 
PK data will occur once an appropriate number of cohort 2 participants have completed 
the day 57 (Week 8) visit.  The baseline total OSM and mean target engagement relative 
to the modelled predictions will be considered.  
An interim analysis may be conducted to assess the baseline variability of key biomarkers 
once at least 16 participants have been randomised into cohort 2 of the study. This may 
lead to the adjustment of the biomarker assessment strategy. 
An unblinded sample size re-estimation may be conducted once approximately 16 
participants from cohort 2 complete the day 85 (Week 12) visit, where the key systemic 
biomarkers will be reviewed. This may lead to an increase in the sample size up to a 
maximum of 40 participants.
In addition to the formal planned interim analyses, further data reviews may be carried 
out by the DRC and/or senior managers not involved in the study conduct to aid in 
internal decision making. These reviews will have no impact on the conduct of the study.
The RAP will describe the planned interim analyses in greater detail.
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11.
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GlaxoSmithKline Document Number 2016N284919_00. GSK2330811 Investigator’s 
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and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a 
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Exhibiting Target-Mediated Drug Disposition. Pharm Res. 2005; 22(10):1589-1596.
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Oncostatin M in hematopoiesis and liver development. Cytokine & Growth Factor Rev. 
2000;11:177-83.
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACE
Angiotensin Converting Enzyme
ADA
Anti-drug Antibody
AE
Adverse Event
ALT
Alanine Aminotransferase 
APTT
Activated Partial Thromboplastin Time
AR
Angiotensin II Receptor
AST
Aspartate Aminotransferase
AUC
Area Under Concentration-Time Curve
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus Disease 2019
CPK
Creatine Phosphokinase
CRF
Case Report Form
CRISS
Composite Response Index in diffuse cutaneous Systemic Sclerosis
CRP
C-Reactive Protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
Cardiovascular
dcSSc
Diffuse Cutaneous Systemic Sclerosis
DLCO
Diffusion Capacity of the Lungs for Carbon Monoxide
DRC
Data Review Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic Acid
ELF
Enhanced Liver Fibrosis
EMA
European Medicines Agency
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
FTIH
First Time in Human
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
HAQ-DI
Health Assessment Questionnaire Disability Index HAQ-DI
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HDL
High density lipoproteins
HIV
Human Immunodeficiency Virus
hr
Hour(s)
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
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ICF
Informed Consent Form
ICH
International Conference on Harmonization 
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IL-6
Interleukin 6
IP
Investigational Product
INR
International Normalised Ratio
IRB
Institutional Review Board
IV
Intravenous
IWRS
Interactive Web Response System
kg
Kilogram
L
Litre
LDL
Low Density Lipoproteins
LIF
Leukemia Inhibitory Factor
LLN
Lower Limit of Normal
mAb
Monoclonal Antibody
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration
MCP-1
Monocyte Chemotactic Protein 1
MCV
Mean Corpuscular Volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
mRNA
Messenger Ribonucleic Acid
mRSS
Modified Rodnan Skin Score
msec
Milliseconds
NOAEL
No Observed Adverse Effect Level
OSM
Oncostatin M
OSMR
Oncostatin M Receptor
PD
Pharmacodynamic
PDE5
Phosphodiesterase 5
PhGA
Physician Global Assessment 
PK
Pharmacokinetic
POM
Proof of Mechanism
PtGA
Patient Global Assessment
QTc
QT Duration Corrected for Heart Rate
QTcB
QT Duration Corrected for Heart Rate by Bazett’s Formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
SAE
Serious Adverse Event(s)
SC
Subcutaneous
SD
Standard Deviation
SHAQ
Scleroderma Health Assessment Questionnaire
SOP
Standard Operating Procedure
SRM
Study Reference Manual
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SRT
Safety Review Team
SSc
Systemic Sclerosis 
t
Time of last observed quantifiable concentration
TB
Tuberculosis 
TE
Target Engagement
TMDD
Target-Mediated Drug Disposition
TNF
Tumor Necrosis Factor
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
Vss/F
Steady State Volume of Distribution / Bioavailability
vWF
Von Willebrand Factor
WBC
White Blood Cells
WOCBP
Women of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
NONMEM
QuantiFERON-TB Gold
QuantiFERON-TB Gold PLUS
SOMAscan
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12.2.
Appendix 2: Clinical Laboratory Tests
The tests and calculations detailed in Table 4 and Table 5 will be performed by the 
central laboratory or (for calculated values) by GSK. Local laboratory results are required 
in the event that a participant has a haemoglobin of <90g/L or a platelet count of 
<100x109/L during the dosing period (Day 1 to Day 71). A local laboratory result may 
also be acceptable with pre-approval by GSK.
In circumstances where it is not possible to obtain bloods at site or ship bloods to the 
central lab due to the COVID-19 pandemic, scheduled safety (standard hematology and 
clinical chemistry) labs and pregnancy tests for the Day 113, Day 155, Day 197 and Early 
Withdrawal (if required) visits should be performed if feasible and may be performed 
locally at the clinical site or within the community (all at the discretion of the 
Investigator).
If a local sample is required for haemoglobin or platelet count, the results must be entered 
into the eCRF. A simultaneous unscheduled sample should also be sent for central 
analysis.
The tests detailed in Table 4 and Table 5 represent a minimum set of assessments and this 
list may be expanded if determined necessary by the sponsor.
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 4
Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Standard 
Hematology
RBC Count
Haemoglobin
Haematocrit 
MCV
MCH
MCHC
RDW
Platelet Count
Mean Platelet Volume
Reticulocyte Percentage
Absolute Reticulocyte Count
Reticulocyte Production Index1
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry2
Potassium
Sodium
Corrected Calcium
At screening 
only3
TSH
FT4
Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
Alkaline Phosphatase (ALP)
Lactate Dehydrogenase (LD)
Lipids (fasted)4
Total Cholesterol
HDL
Urea
Creatinine
eGFR5
Glucose6
Total bilirubin 
Direct bilirubin
Albumin
Total Protein
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Laboratory 
Assessments
Parameters
FT3
INR
APTT
LDL
Triglycerides
Routine 
Urinalysis

Specific gravity, pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum or urine human chorionic gonadotropin pregnancy test (as needed for 
women of childbearing potential) 7

Serology (HIV antibody, HBsAg, HBcAb and hepatitis C virus antibody)  

QuantiFERON-TB Gold / QuantiFERON-TB Gold PLUS
NOTES :
1.
Calculated value based on reticulocyte percentage/count and haematocrit.
2.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.2 and Appendix 7. All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
3.
Blood for TSH, FT4, FT3, INR and APTT will be taken at screening only.
4.
Blood for lipid tests (fasted) will be taken at predose on Day 1 and Day 85 (Week 12) only. 
5.
Calculated value. Estimated GFR will be calculated using the MDRD formula.
6.
Glucose on Day 1 and Day 85 will be fasted glucose, all other timepoints will be random glucose.
7.
Serum pregnancy testing will be performed at screening, Day 197 (Week 28) and early withdrawal visit and urine 
pregnancy testing will be performed at all other visits unless serum testing is required by local regulation or 
IRB/IEC. Pregnancy testing on dosing days must be performed prior to administration of study treatment. If it is 
not possible for a serum pregnancy test to be performed due to the COVID-19 pandemic, a urine pregnancy test 
should be performed if possible. 
Table 5
Additional HaematologyAssessments
Time Point
Parameters
Screening, Day 1, Day 85 (Week 12) and Day 
197 (Week 28) 
AND if any haematology stopping rule (at the 
next visit) OR early withdrawal is fullfilled
Serum Ferritin
% Transferrin saturation
Serum B12
Serum folate
Day 1, Day 85 (Week 12) and Day 197 (Week 
28) 
Serum Haptoglobin
TPO
EPO 
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Time Point
Parameters
AND if any haematology stopping rule (at the 
next visit) OR early withdrawal is fullfilled
Day 1 and Day 85 (Week 12)
Blood Film
To maintain blinding only results of safety laboratory assessments will be reported to the 
investigative sites or other blinded personnel. No other laboratory data (e.g. PK, target 
engagement and biomarkers) will be provided until study completion.
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:
o
Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:
o
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
o
Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures
o
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
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
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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 center. 

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.
The ICF will contain a section that addresses the use of remaining samples for 
exploratory research. Participants will be told that they may withdraw their consent at any 
time and for any reason during the storage period. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Committees Structure
12.3.1.
Safety Review Team (SRT)
Oversight of study safety will be provided by a sponsor Safety Review Team (SRT). The 
SRT will conduct in-stream review of blinded safety data including AE, SAEs, vital signs 
and laboratory data at appropriate intervals during the study (at a minimum after 4, 8 and 
12 participants have reached Day 85 (Week 12)). The membership of the SRT will 
include the GSK Medical Monitor, GSK Statistician and a GSK Global Clinical Safety 
and Pharmacovigilance representative or appropriate designees.
The SRT may decide to alter the study conduct at any time to ensure participant safety 
and any such changes to study conduct for safety reasons will be promptly communicated 
to the appropriate Regulatory Authorities and IRB/IEC. Additional detail regarding the 
composition and actions of the SRT will be included in the SRT charter. 
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12.3.2.
Data Review Committee (DRC)
The DRC will conduct the dose escalation and interim analysis reviews of the data. No 
members of the study team involved in the direct day to day conduct of the study or in the 
acquisition of data will take part in the DRC. Full details of membership, timing, blinding 
and decision-making framework for DRC reviews will be described in the DRC charter. 
The DRC membership will vary according to the meeting as follows:
Dose escalation: All available safety, tolerability and PK data from cohort 1 will be 
reviewed by the GSK Study Physician(s), GSK Pharmacokineticist and GSK Statistician 
or appropriate designees.
Interim Analyses: For the assessment of the baseline variability of key systemic 
biomarkers and GSK2330811 target engagement, membership will mirror those involved 
in the dose escalation decisions. The unblinded assessment of the disease biomarkers may 
also be reviewed, as part of the DRC, by the GSK Biology Lead, GSK Early 
Development Leader and GSK Senior Stakeholders.
The DRC may also conduct unblinded reviews on an ad hoc basis if required in 
accordance with the DRC charter.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 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.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate.
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
GSK will provide the investigator with the randomisation codes for their site only 
after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
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. GSK has defined the retention 
period as 25 years from the issue of the final Clinical Study Report (CSR)/ 
equivalent summary.
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.
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
Definition of what constitutes source data can be found in the Source Document 
Agreement.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
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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 (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
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related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the 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.
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
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information.
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 for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken 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 contacts for SAE reporting by telephone.

Contacts for SAE reporting can be found in the SRM.
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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 contacts for SAE reporting. 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of 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, a single FSH measurement 
is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-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.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the dosing period and for at least 
126 days (18 weeks) after the last dose of study treatment: 

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 6 when having penile-vaginal 
intercourse with a woman of childbearing potential. 
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
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame.

Refrain from donating sperm for the duration of study.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
ONE of the following from 28 days prior to first dosing day (Day 1), during the dosing 
period and for at least 126 days (18 weeks) after the last dose of study treatment:

A barrier method (male condom or female diaphragm) and one highly effective 
method of contraception used consistently and correctly as described in Table 6.

Two complementary highly effective methods of contraception used consistently and 
correctly as described in Table 6.

Abstinence from heterosexual intercourse as described in Table 6 if this is their 
preferred and usual lifestyle on a long-term and persistent basis.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
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Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
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.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Pregnancy Testing

WOCBP will only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test. 

Additional pregnancy testing must be performed on the day of and prior to each 
dosing during the treatment period and at each visit during the follow-up period and 
as required locally. 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 

Urine pregnancy testing will be performed using the test kit provided by the central 
laboratory in accordance with instructions provided in its package insert.

Serum Pregnancy testing will be performed and assayed in the central laboratory. 
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 participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
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
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 will be reported as an AE or 
SAE. 

A spontaneous abortion 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 treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating will discontinue 
study treatment.  
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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2330811 and / or SSc and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2330811 (or study treatments of this drug class), and SSc. 
Genetic research may consist of the analysis of one or more candidate genes or 
analysis of the entire genome

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2330811 or study treatments 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 GSK2330811 (or study treatments of 
this class) or SSc continues but no longer than 15 years after the last participant 
completes the study or other period as per local requirements.
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted 
(see below)

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and continue participant in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, as soon 
as possible following the occurrence of 
an event.5

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
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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline

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 (CRF) 
page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week (James, 2009). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; HbsAg and HBcAb (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody;  
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);  
Hepatitis E IgM antibody 
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
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treatment prior to PK blood sample draw on the CRF. Instructions for sample handling and shipping are in the 
SRM.  
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
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12.8.
Appendix 8: Haematological Grades for Stopping Criteria (CTCAE criteria, V4.03: June 14, 2010)
Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count 
decreased 
<LLN – 75,000/mm3 ; 
<LLN -75.0 x 109/L
<75,000 – 50,000/mm3;
<75.0- 50.0 x 109/L
<50,000 – 25,000mm3;
<50.0- 25.0 x 109/L
<25,000mm3;
<25.0 x 109/L
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Anemia
Haemoglobin (Hgb) <LLN -10.0 g/dL; 
<LLN - 6.2 mmol/L;                   
<LLN - 100 g/L
Hgb <10.0 - 8.0 g/dL;
<6.2 -4.9 mmol/L;
<100 - 80g/L
Hgb <8.0 g/dL;          
<4.9 mmol/L;
<80 g/L; transfusion 
indicated
Life-threatening 
consequences;
urgent intervention 
indicated
Death
Definition: A disorder characterized by an reduction in the amount of haemoglobin in 100 ml of blood. Signs and symptoms of anemia may include 
pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
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12.9.
Appendix 9: Country-specific requirements
No country-specific requirements exist at this time.
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12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 4 12-Nov-2018
Overall Rationale for the Amendment: This amendment was executed to provide 
clarification on the points detailed below:
Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities
6.2 Exclusion Criteria
12.2 Appendix 2: Clinical 
Laboratory Tests
Updated to reflect use of
QuantiFERON-TB Gold PLUS 
test at central laboratory.
Clarification to support update 
to central laboratory process
6.1 Inclusion Criteria
7.7.1 Permitted medications 
and Non-Drug Therapies
Wording clarified to reflect 
intent that mycophenolate 
sodium dose allowed should 
be equivalent to 
mycophenolate mofetil dose. 
Clarification
10.1 Sample Size 
Determination
10.3.3 Interim Analyses 
Updated text from ‘will’ to ‘may’ 
to indicate that it may not be 
feasible to conduct all interim 
analyses.
Updated to add flexibility 
12.2 Appendix 2: Clinical 
Laboratory Tests
Wording updated to clarify 
circumstances when local 
laboratory results are 
acceptable 
Clarification
Amendment 3 (20-Jul-2017)
Overall Rationale for the Amendment: This amendment was primarily executed to add 
the additional exploratory endpoints of change in the Composite Response Index in 
diffuse cutaneous Systemic Sclerosis (CRISS) and change in Patient Global Assessment. 
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Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities
Updated to include Patient
Global Assessment of 
Disease Activity (PtGA) 
and CRISS data collection 
at Day 1, Day 85 and Day 
197.
Required for calculation of the 
Composite Response Index in diffuse 
cutaneous Systemic Sclerosis 
(CRISS).
4 Objectives and Endpoints
Updated to include the 
exploratory endpoints of 
‘Composite Response 
Index in diffuse cutaneous 
Systemic Sclerosis 
(CRISS)’ and ‘Change 
from baseline in Patient 
Global Assessment of 
Disease Activity (PtGA)’.
To enable calculation of the CRISS as 
an exploratory endpoint.
5.2 Number of Participants, 
Treatment Arms and 
Duration
Statement added to clarify  
that participants in Cohort 
1 are not eligible to 
participate in Cohort 2.
Clarification
6.1 Inclusion Criteria
7.7.1 Permitted 
Medications and Non-Drug 
Therapies
Statement added to 
inclusion criterion 8 and 
Table 1 to clarify that ‘If 
mycophenolate was 
recently ceased, there 
must be ≥3 months 
between the date 
mycophenolate was 
ceased and the first dosing 
day (Day 1)’.
Clarification
6.1 Inclusion Criteria
Inclusion criterion 11 
updated to remove the 
word “other” for clarity.
Clarification
6.2 Exclusion Criteria
Note added to exclusion 
criterion 14 to clarify that 
‘Participants with evidence 
of liver fat on imaging but 
who are otherwise eligible 
for the study criteria may 
be enrolled’.
Clarification
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Section # and Name
Description of Change
Brief Rationale
9.1 Efficacy Assessments
Updated to include 9.1.4 
Patient Global Assessment 
of Disease Activity (PtGA) 
and 9.1.6 Composite 
Response Index in diffuse 
cutaneous Systemic 
Sclerosis (CRISS).
To enable calculation of the CRISS as 
an exploratory endpoint.
9.8.3 PK and PD in Suction 
Blister Fluid
Refined the duration of the 
blister procedure.
To provide a more accurate 
description of the method. 
10.3.1 Safety Analyses
Updated to remove 'and 
derived pharmacokinetic 
parameters'. 
The individual parameters derived 
from population pharmacokinetic 
models will not be summarised. The 
population-level parameter will be 
used directly where appropriate.
10.3.3 Interim Analyses
Updated text on ‘reviews’ 
of data to clarify that these 
may also be conducted by 
senior managers not 
involved in the conduct of 
the study. Statement 
added to clarify that 
reviews will have no impact 
on the conduct of the 
study.
Clarification
Appendix 1: Abbreviations 
and Trademarks
Minor typographical 
changes.
Clarification
Amendment 2 (12-Dec-2016)
Overall Rationale for the Amendment:  This amendment was primarily executed in 
response to an FDA recommendation for a 30 minute observation period after each dose 
is administered.
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Section # and Name
Description of Change
Brief Rationale
7.1 Treatments 
Administered
Updated to include 30 minute 
observation period after each 
dose.
Response to FDA recommendation
8.1.1 Individual Safety 
Stopping Rules
Reference to criteria for defining 
anaphylaxis has been included 
(Sampson 2006).
Response to FDA recommendation
7.7.1 Permitted 
Medications and Non-
Drug Therapies
7.7.2 
Prohibited Medications 
and Non Drug 
Therapies
Wording clarified to make it clear 
that treatment may be modified 
for an urgent clinical need.
Response to FDA recommendation
10.3.3 Interim 
Analyses
Clarified that DRC may also 
review available data for internal 
decision making.
Clarification
7.1 Treatment 
administered
7.4 Blinding
‘Or designee’ added for the 
unblinded pharmacist role, to 
align with wording in Section 7.5.
Clarification
9 Study Assessments 
and Procedures
12.2 Appendix 2: 
Clinical Laboratory 
Tests
Minor clarification changes.
Clarification
3.3.1 Risk Assessment
Minor typographical changes and 
spaces between words. 
Presentation
Amendment 1 (01-Nov-2016)
Overall Rationale for the Amendment: This amendment was executed in response to 
the FDA request that the participant eligibility criteria be modified to include two forms 
of contraception for males and females of childbearing potential.
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Section # 
and Name
Description of Change
Brief Rationale
6.1. Inclusion 
Criteria
To include 2 forms of contraception 
for male and female participants
Response to FDA request
Appendix 5 
Contraception 
Guidance
To include 2 forms of contraception 
for male and female participants
Response to FDA request
DOCUMENT HISTORY
Document
Date of Issue
Amendment 5
01-Apr-2020
Amendment 4
12-Nov-2018
Amendment 3
20-Jul-2017
Amendment 2
12-Dec-2016
Amendment 1
01-Nov-2016
Original Protocol
13-Sep-2016
Type of Protocol Amendment
Numbering
Type of changes
Global
Amendment 4
New changes for all
Global
Amendment 3
New changes for all
Global
Amendment 2
New changes for all
Global
Amendment 1
New changes for all
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