Conditions: Scleroderma, Systemic
Keywords: Systemic Sclerosis Repeat-dose Phase IIA GSK2330811 Pharmacodynamics Pharmacokinetics Proof of mechanism study
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
GSK2330811 is a humanized monoclonal antibody which is in development for systemic sclerosis (SSc), a rare autoimmune disease with high morbidity and mortality. Currently, there are no approved disease modifying therapies and it is an area of high unmet medical need. GSK2330811 has been shown to bind and neutralize Oncostatin M (OSM) that has been associated with fibrosis, vasculopathy and inflammation in a number of diseases. This multi-center, randomized, double-blind (sponsor open), placebo controlled, proof of mechanism study will be the first study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of repeat subcutaneous (SC) doses of GSK2330811 in male and female participants with diffuse cutaneous SSc (dcSSc). Participants with active disease and a disease duration of \<= 60 months will be enrolled. Approximately 24 to 40 participants will be randomized across two sequential cohorts. Cohort 1 will evaluate a repeat-dose predicted to provide sub-maximal inhibition of OSM, leading to a dose escalation decision. Cohort 1 is planned to consist of at least 4 participants, randomized such that 3 participants will receive GSK2330811 100 milligram (mg) and 1 will receive placebo. Cohort 2 is planned to consist of at least 20 participants, randomized such that participants will receive GSK2330811 300 mg and placebo in a 3:1 ratio respectively. The duration of the study is up to 34 weeks including a screening period of up to 6 weeks, treatment period of 12 weeks and follow-up period of 16 weeks.

Detailed description:

Arms:
arm 1: During Cohort 1, participants will receive a single dose of GSK2330811 100 mg by SC injection via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197. arm 2: During Cohort 2, participants will receive a single dose of GSK2330811 300 mg by SC injection (3 vials of 1 mL each of GSK2330811 100 mg) via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197. arm 3: During Cohort 1, participants will receive a single dose of placebo by SC injection via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197. arm 4: During Cohort 2, participants will receive a single dose of placebo by SC injection (3 vials of 1 mL each) via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197.

Interventions: intervention 1: GSK2330811 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2330811 will be provided in vials and packed in 1 vial per carton. Each vial will contain 1.2 mL fill with 1 mL extractable volume at 100 mg/mL. intervention 2: Normal saline (0.9 percent weight per volume sodium chloride).

Protocol document:
Prot_000.pdf: 
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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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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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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
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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
% 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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Barksby HE, Hui W, Wappler I, Peters HH, Milner JM, Richards CD, et al. Interleukin-1 
in Combination With Oncostatin M Up-Regulates Multiple Genes in Chondrocytes. 
Arthritis Rheum. 2006;54(2):540-50.
Canady J, Arndt S, Karrer S, Bosserhoff AK. Increased KGF expression promotes 
fibroblast activation in a double paracrine manner resulting in cutaneous fibrosis.  J 
Invest Dermatol. 2013;133(3):647-57.
Clark K, Lopez H, Ahmed Abdi B, Guerra SG, Shiwen X, Khan K, et al. Multiplex 
cytokine analysis of dermal interstitial blister fluid defines local disease mechanisms in 
systemic sclerosis. Arthritis Research & Therapy. 2015;17:73.
Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and 
intraobserver variability of total skin thickness score (modified Rodan TSS) in systemic 
sclerosis. J Rheumatol. 1995;22:1281-5.
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2013;9(8):451-64.
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glycosaminoglycan production by cultured normal dermal fibroblasts: insensitivity of 
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of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, 
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Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety 
and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a 
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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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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201247 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) for Dose Escalation and 
Target Engagement Interims 
 
Title 
: Reporting and Analysis Plan for Dose Escalation and Target 
Engagement Interims for study 201247: 
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. 
Compound Number  : GSK2330811 
Effective Date  
: Refer to Document Date 
 
Description: 
The scope of this version of the RAP is to document the outputs required for the dose 
escalation, first interim analysis (target engagement),second interim (baseline variability) 
and final reporting efforts. 
This RAP describes the planned analyses and output to be included in the Clinical Study 
Report for Protocol 201247. 
This RAP will be provided to the study team members to convey the content of the 
deliverables. 
 
RAP Author(s): 
Author 
Date 
Lead Author 
 
Senior Statistician (Hep/GI Biostatistics) 
NA 
Author 
 
NA 
Director (Hep/GI Biostatistics) 
 
Co-Author 
 
NA 
Quantitative Clinical Pharmacology Director (Hep/GI CPMS) 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201247 
 
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RAP Team Review Confirmations: 
(Method: Email) 
Reviewer 
Date 
 
14-Aug-2020 
Manager Programmer (Clinical Programming) 
 
Discovery Medicine Group Leader (Medical Monitor, CPEM) 
06-Aug-2020 
 
10-Aug-2020 
Clinical Development Manager (GCSD) 
 
GCSP Physician (SERM) 
14-Aug-2020 
 
07-Aug-2020 
Clinical Biomarker Lead (CPEM) 
 
07-Aug-2020 
Discovery Medicine Scientist Director (CPEM) 
 
07-Aug-2020 
Data Manager (blinded) (Clinical Data Management Group, 
Biomedical Data Sciences Dept.) 
 
Senior Director (CPMS) 
14-Aug-2020 
Clinical Statistics and Clinical Programming Delegated Line Approvals: 
(Method: Veeva Clinical Vault eSignature) 
Approver 
 
Statistics Director (Hep/GI Biostatistics) 
 
Programming Leader (Hep/GI Biostatistics) 
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
1.1. 
RAP Amendments ........................................................................................ 8 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Analyses ..................................................................................... 12 
2.4.1. 
Primary endpoints ........................................................................ 12 
2.4.2. 
Secondary endpoints ................................................................... 12 
2.4.3. 
Exploratory biomarker endpoints ................................................. 12 
2.4.4. 
Exploratory efficacy endpoints ..................................................... 12 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
In-stream and Interim Analyses .................................................................. 13 
3.1.1. 
Safety Review Team (SRT) ......................................................... 13 
3.1.1.1. 
Extract from SRT charter: ........................................... 13 
3.1.1.2. 
SRT reporting details .................................................. 13 
3.2. 
Data Review Committee (DRC) .................................................................. 14 
3.3. 
Final Analyses ............................................................................................ 16 
3.3.1. 
DBF timeline ................................................................................ 16 
4. 
ANALYSIS POPULATIONS ................................................................................... 17 
4.1. 
Protocol Deviations ..................................................................................... 18 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 19 
5.1. 
Study Treatment Display Descriptors .......................................................... 19 
5.2. 
Cohort Display Descriptors ......................................................................... 19 
5.3. 
Baseline Definitions .................................................................................... 20 
5.3.1. 
Derivations and Handling of Missing Baseline Data ..................... 21 
5.4. 
Multicentre Studies ..................................................................................... 21 
5.5. 
Examination of Covariates, Other Strata and Subgroups ............................ 21 
5.5.1. 
Covariates and Other Strata ........................................................ 21 
5.5.2. 
Examination of Subgroups ........................................................... 22 
5.6. 
Multiple Comparisons and Multiplicity ......................................................... 22 
5.7. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 22 
6. 
STUDY POPULATION ANALYSES ....................................................................... 23 
6.1. 
Overview of Planned Study Population Analyses ........................................ 23 
7. 
SAFETY ANALYSES ............................................................................................. 24 
7.1. 
Adverse Events Analyses ........................................................................... 24 
7.2. 
Clinical Laboratory Analyses ....................................................................... 24 
7.3. 
Other Safety Analyses ................................................................................ 25 
8. 
IMMUNOGENICITY ANALYSES ............................................................................ 26 
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9. 
PHARMACOKINETIC ANALYSES ......................................................................... 27 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 27 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 28 
10.1. 
Statistical Analyses / Methods .................................................................... 28 
10.1.1. 
Endpoint / Variables ..................................................................... 28 
10.1.1.1. Drug Concentration Measures .................................... 28 
10.1.1.2. Derived Pharmacokinetic Parameters......................... 28 
10.1.2. 
Summary Measure ...................................................................... 28 
10.1.3. 
Population of Interest ................................................................... 28 
10.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 29 
10.1.5. 
Statistical Analyses / Methods ..................................................... 29 
11. PHARMACODYNAMIC ANALYSES....................................................................... 30 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 31 
12.1. 
Statistical Analyses / Methods .................................................................... 31 
13. BIOMARKER ANALYSES ...................................................................................... 32 
13.1. 
Primary Biomarker Analyses ....................................................................... 32 
13.1.1. 
Endpoint / Variables ..................................................................... 32 
13.1.1.1. Systemic: .................................................................... 32 
13.1.1.1.1. Fibrosis markers: .................................... 32 
13.1.1.1.2. Derived fibrosis markers: ........................ 32 
13.1.1.1.3. Inflammation markers: ............................ 32 
13.1.1.1.4. Vascular markers: ................................... 33 
13.1.1.2. Skin Histology ............................................................. 33 
13.1.1.3. Skin Gene expression RNA Sequencing: ................... 33 
13.1.1.3.1. Individual Genes of Interest: ................... 33 
13.1.1.3.2. Derived Gene: ........................................ 33 
13.1.1.3.3. Gene Set Variation Analysis 
(GSVA) Score ......................................... 33 
13.1.1.3.4. Disease signature ................................... 33 
13.1.1.3.5. Lung Fibrosis Signature .......................... 34 
13.1.1.3.6. Cell Module Signatures ........................... 34 
13.1.2. 
Summary Measure ...................................................................... 34 
13.1.3. 
Population of Interest ................................................................... 35 
13.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 35 
13.1.5. 
Statistical Analyses / Methods ..................................................... 35 
13.1.5.1. Model Checking & Diagnostics ................................... 38 
13.2. 
Exploratory Biomarker Analyses ................................................................. 39 
13.2.1. 
Mechanistic Haematology ............................................................ 39 
14. EFFICACY ANALYSES .......................................................................................... 40 
14.1. 
Exploratory Efficacy Analyses ..................................................................... 40 
14.1.1. 
Endpoint / Variables ..................................................................... 40 
14.1.2. 
Summary Measure ...................................................................... 40 
14.1.3. 
Population of Interest ................................................................... 40 
14.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 40 
14.1.5. 
Statistical Analyses / Methods ..................................................... 40 
15. REFERENCES ....................................................................................................... 43 
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16. APPENDICES ........................................................................................................ 44 
16.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 44 
16.1.1. 
Exclusions from Per Protocol Population ..................................... 44 
16.2. 
Appendix 2: Schedule of Activities .............................................................. 45 
16.2.1. 
Protocol Defined Schedule of Activities ........................................ 45 
16.2.1.1. Screening ................................................................... 45 
16.2.1.2. Treatment period and follow-up .................................. 46 
16.3. 
Appendix 3: Assessment Windows ............................................................. 48 
16.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 51 
16.4.1. 
Study Phases .............................................................................. 51 
16.4.1.1. Study Phases for Concomitant Medication ................. 51 
16.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 52 
16.5.1. 
Reporting Process ....................................................................... 52 
16.5.2. 
Reporting Standards .................................................................... 53 
16.5.3. 
Reporting Standards for Pharmacokinetics .................................. 55 
16.6. 
Appendix 6: Derived and Transformed Data ............................................... 56 
16.6.1. 
General ........................................................................................ 56 
16.6.2. 
Study Population .......................................................................... 56 
16.6.3. 
Efficacy ........................................................................................ 58 
16.6.4. 
Safety .......................................................................................... 60 
16.6.5. 
Pharmacodynamic ....................................................................... 61 
16.6.6. 
Biomarkers .................................................................................. 62 
16.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 63 
16.7.1. 
Premature Withdrawals ................................................................ 63 
16.7.2. 
Handling of Missing Data ............................................................. 63 
16.7.2.1. Handling of Missing and Partial Dates ........................ 63 
16.7.2.2. Handling of Missing Data for Statistical 
Analysis ...................................................................... 64 
16.7.2.3. Handling of Missing Data for PK Analysis ................... 64 
16.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 65 
16.8.1. 
Laboratory Values - Haematology ................................................ 65 
16.8.2. 
Laboratory Values – Chemistry and Liver .................................... 66 
16.8.3. 
ECG ............................................................................................. 66 
16.8.4. 
Vital Signs .................................................................................... 67 
16.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 68 
16.9.1. 
Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 68 
16.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Methodology .............. 75 
16.10.1. Systems ....................................................................................... 75 
16.10.2. Data Assembly............................................................................. 75 
16.10.3. Model Development ..................................................................... 75 
16.11. Appendix 11: Abbreviations & Trade Marks ................................................ 77 
16.11.1. Abbreviations ............................................................................... 77 
16.11.2. Trademarks ................................................................................. 78 
16.12. Appendix 12: List of Data Displays.............................................................. 79 
16.12.1. Data Display Numbering .............................................................. 79 
16.12.2. Mock Example Shell Referencing ................................................ 79 
16.12.3. Deliverables ................................................................................. 79 
16.12.4. Study Population Tables .............................................................. 81 
16.12.5. Safety Tables ............................................................................... 85 
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16.12.6. Immunogenicity Tables (may be categorised under Safety 
in HARP folder structure / SAFIRE naming) ................................. 91 
16.12.7. Safety Figures ............................................................................. 92 
16.12.8. Pharmacokinetic Tables ............................................................... 97 
16.12.9. Pharmacokinetic Figures ............................................................. 98 
16.12.10. Pharmacokinetic Population (PopPK) Tables ............................. 100 
16.12.11. Pharmacokinetic Population (PopPK) Figures ........................... 101 
16.12.12. Pharmacodynamic Tables ......................................................... 102 
16.12.13. Pharmacodynamic Figures ........................................................ 103 
16.12.14. Pharmacokinetic / Pharmacodynamic Tables ............................ 105 
16.12.15. Pharmacokinetic / Pharmacodynamic Figures ........................... 106 
16.12.16. Biomarker Tables ....................................................................... 107 
16.12.17. Biomarker Figures ..................................................................... 111 
16.12.18. Exploratory Efficacy Tables ....................................................... 117 
16.12.19. Exploratory Efficacy Figures ...................................................... 119 
16.12.20. ICH Listings ............................................................................... 121 
16.12.21. Non-ICH Listings ........................................................................ 127 
16.13. Appendix 13: List of Gene Modules .......................................................... 130 
16.13.1. Disease Gene Modules .............................................................. 130 
16.13.2. Lung Fibrosis Gene Module ....................................................... 131 
16.13.3. Cell-type specific gene modules ................................................ 132 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Protocol Revision Chronology: 
2016N269831_00 13-Sep-2016 
Original 
2016N269831_01 01-Nov-2016 
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. 
2016N269831_02 12-Dec-2016 
This amendment was primarily executed in response 
to an FDA recommendation for a 30-minute 
observation period after each dose is administered. 
It included a clarification that the DRC may also 
review available data for internal decision making. 
2016N269831_03 20-Jul-2017 
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. It further clarified that the 
'internal decision making' referred to version 2 
would not affect the conduct of the study and may 
involve or be carried out by senior stakeholders. 
In addition, it specified that derived PK parameters 
will not be summarised. PK data will be analysed 
using a Population PK model. Although this will 
provide individual participant parameters, the 
appropriate way of summarising these is by referring 
to the Population PK model itself, not by 
summarising the individual participants’ parameters. 
2016N269831_04 12-Nov-2018 
To clarify that the mycophenolate sodium dose 
allowed is equivalent to the mycophenolate mofetil 
dose, add clarification around use of local labs and 
flexibility to the timing of the interim analyses. 
2016N269831_05 01-Apr-2020 
In response to the COVID-19 pandemic, schedule of 
activities (Section 2 in the protocol) updated to 
extend visit windows, allow virtual/ telephone visits 
and allow safety labs and pregnancy tests to be run 
locally during the off-treatment follow-up period. 
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1.1. 
RAP Amendments 
Revision chronology and planned versions: 
Version  
Status 
Date final 
Scope 
Final 
Final  
20-Feb-2018 
Update from critical components RAP. 
Updated to cover Dose escalation, Extended dose escalation, Interim 
Analysis 1 
Amendment 1 
Final 
14-Dec-2018 Additional detail around Interim Analysis 1 and Interim Analysis 2 
Amendment 2 
Final 
04-Jun-2019 
Additional details added around biomarkers to be explored in Interim 
Analysis 2. Initial details around the outputs for Interim Analysis 3 (if 
occurs) and the Final Analysis.  
Amendment 3 
Planned 
NA 
Removed reference to Interim analysis 3 in alignment with updated 
data review committee (DRC) charter. Added all details required for 
Final Analysis. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. Changes from the DRC charter are outlined in Table 2. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
All available safety, tolerability and 
PK data from cohort 1 will be 
reviewed 
In addition, PD data from cohort 
1 will be reviewed 
The study team has decided 
that an early review of target 
engagement at the low dose 
during the dose escalation 
interim would be beneficial for 
the project. 
Defined enrolled population as all 
subjects who signed the ICF 
Separated out the enrolled 
population into screened 
(signed ICF) and enrolled 
(randomized). 
To allow clearer separation 
between screen failures and 
participants who passed 
screening but did not receive 
study treatment.  
 
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Table 2 
Changes to Analysis Plan defined in DRC charter 
DRC 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
In interim analysis 1, the overview of 
data to be reviewed includes: 
"Safety including Immunogenicity” 
Immunogenicity data will not be 
provided as unavailable at the 
time of reporting and so will not 
form part of reporting effort IA1 
Immunogenicity data is unlikely 
to be conclusive at this early 
interim. If there are unexpected 
PK observations, then the study 
team may request that the 
immunogenicity samples are 
run. 
At interim 2, the question was posed 
‘Does concomitant medication alter 
biomarkers sufficiently to warrant 
changing recruitment strategy?’ 
based on the guideline ‘ 
Exploratory graphical analysis of the 
effect of concomitant medication and 
selected demographic factors on 
baseline levels of key decision-
making biomarkers will be reviewed 
alongside the fitting of a statistical 
model.’ 
The impact of concomitant 
medication on baseline 
biomarkers will not be explored 
at interim 2 and no statistical 
models using concomitant 
medications will be fitted. 
There is no intention to update 
the protocol and change the 
recruitment strategy at this time.  
At interim 2, data planned to be 
reviewed was baseline biomarker, 
safety and population 
In addition to the planned data, 
PK and PD outputs will be 
produced. 
Allow updating of PK/PD 
modelling. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
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 Objectives 
Secondary Endpoints 
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 
Exploratory Objectives 
Exploratory Endpoints 
To explore the pharmacology of repeat 
• 
Endpoints may include (but are not limited to): 
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Objectives 
Endpoints 
subcutaneous doses of GSK2330811 and 
its effects on biomarkers of fibrosis, 
inflammation and vasculopathy in the 
blood and skin of participants with dcSSc 
▪ 
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) 
▪ 
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): 
▪ 
Levels of GSK2330811 in blister fluid measured 
anytime between Day 57 and Day 85 (Week 8 and 
Week 12) 
▪ 
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) 
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. 
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design Features 
o 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. 
o The study has 2 sequential cohorts. A minimum of approximately 24 
participants and a maximum of 40 participants will be randomized 
across two cohorts. Participants will be randomised in a 3:1 ratio 
within each cohort to GSK2330811 and placebo respectively. In 
cohort 1, a minimum of 4 participants and in cohort 2, a minimum of 
approximately 20 participants will be randomized to either 
GSK2330811 or placebo. 
• Cohort 1 will be used to evaluate a repeat-dose, predicted to provide 
sub-maximal inhibition of Oncostatin M (OSM). Once at least 4 
evaluable participants of Cohort 1 have reached the end of the 
treatment period, a dose escalation decision will be made.  If the 
dose is not escalated one pre-defined option is an extension of 
recruitment at the current dose level (extended dose escalation).  If 
the dose is escalated, cohort 2 will then be used to evaluate a 
repeat-dose, predicted to provide maximal inhibition of OSM. In 
cohort 2 treatment allocation will be stratified according to 
mycophenolate concomitant medication status treated or nontreated. 
• 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 participants will then 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. 
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Overview of Study Design and Key Features 
• Participants will enter a follow-up period of approximately 16 weeks, 
after the treatment period. 
• The duration of the study, including screening, will be up to 34 weeks 
for participants. 
Treatment 
Assignment 
• Participants will be randomised in a 3:1 ratio within each cohort to 
GSK2330811 and placebo respectively, in cohort 2 this 
randomisation will be stratified by Mycophenolate use. 
Dosing 
• At least 4 participants in Cohort 1 will be randomised to receive a 
dose of 100 mg GSK2330811 or placebo, recruitment into this dose 
level may be expanded at the recommendation of the Data Review 
Committee (DRC). 
• After these participants have reached the end of the treatment period 
on Day 85, the Data Review Committee (DRC) will review and 
recommend the dose level for the active arm of Cohort 2 as either 
300 mg or >=100 mg and <300 mg.  
Interim Analysis 
See Table 5. 
2.4. 
Statistical Analyses 
2.4.1. 
Primary endpoints 
For the primary endpoints (safety and tolerability) no statistical analysis is planned and 
therefore no formal statistical hypothesis will be tested. 
2.4.2. 
Secondary endpoints 
For the secondary endpoints (PK, PD and Immunogenicity) no statistical analysis is 
planned and therefore no formal statistical hypothesis will be tested. If data allow a 
simultaneous PopPK and PKPD model will be constructed by CPMS to describe PK and 
the relationship between PK and PD. 
2.4.3. 
Exploratory biomarker endpoints 
Exploratory biomarker analysis will take place for final SAC. An estimation approach 
using Bayesian methods will be undertaken.   
Biomarker endpoints are described in Section 13. 
2.4.4. 
Exploratory efficacy endpoints 
Exploratory efficacy analysis will take place for final SAC. An estimation approach using 
Bayesian methods will be undertaken.  
Clinical endpoints are described in Section 14.  
 
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3. 
PLANNED ANALYSES 
3.1. 
In-stream and Interim Analyses 
3.1.1. 
Safety Review Team (SRT) 
In line with routine pharmacovigilance, an internal GSK SRT will review blinded safety 
data at appropriate intervals during the study conduct.  
The following description of data provision and Statistics and Programming (S&P) tasks 
is provided for context: 
3.1.1.1. 
Extract from SRT charter: 
• 
After the week 12 data for 4, 8 and 12 participants have been received, Data 
Management will: 
o Coordinate the loading of data into Spotfire  
o Provide Statistics and Programming with raw data for LAB parameters 
(i.e. the LAB DM dataset).  This will have in-stream QC applied but will 
not be formally cleaned to ensure timeliness. 
• 
Statistics and Programming will provide blinded, grouped graphical representation 
of the restricted/blinded laboratory endpoints as specified in [Appendix 12]  
• In addition, Q2 Solutions will provide results in Result View on an on-going basis 
3.1.1.2. 
SRT reporting details 
• The restricted lab parameters, not available in Spotfire or Result View to those 
with blinded access (an interactive system provided by the contract research 
organisation/ central laboratory for viewing results) are shown in Table 5. 
 
Table 3 
Restricted (blinded) parameters 
Parameter 
Category 
Platelet Count 
Safety 
Haemoglobin 
Safety 
Haematocrit 
Safety 
RBC count 
Safety 
CRP 
Biomarker 
 
• S&P will produce summary tables and Figures for the restricted safety parameters 
(i.e. not CRP), these will be presented blinded (i.e. without revealing treatment 
allocation). Appendix 12 contains details of outputs that will be produced for the 
‘SRT’ reporting effort (see ‘Deliverable’ column). 
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• In addition to the planned reviews in the SRT charter, the study team plan SRTs 
after 4, 8 and 12 participants have reached day 85 and an SRT may be called at 
any time. It is the study team’s intention to time SRT’s as efficiently as possible 
so that the safety review will inform DRC meetings.   
 
• For the purposes of planning, Table 4, below, shows a likely scenario for SRT 
reporting efforts: 
Table 4 
Likely Timing of Initial SRT Reporting Efforts 
 
Reporting effort 
Timing 
SRT 1 
After 4 participants reach week 12 in 
cohort 1 (prior to DEC) 
SRT 2 
After 4 participants reach week 12 in 
cohort 2 (assuming escalation after 4 
participants) 
SRT 3 
After 8 participants reach week 12 in 
cohort 2 (may be timed to coincide with 
IA1) 
SRT 4 
After 12 participants reach week 12 in 
cohort 2 
 
• Note: To ensure study safety, additional SRTs will be conducted during the 
course of the study in line with the scope and frequency of the SRT charter. 
 
• Unless otherwise specified outputs for the SRT will be based on the safety 
population. 
3.2. 
Data Review Committee (DRC) 
Data will be reviewed by a DRC at appropriate intervals throughout the study in order to 
make decisions on study conduct and ensure participant safety, in collaboration with the 
SRT (see Table 4 for details). A DRC charter describes the responsibilities and conduct 
of the DRC and how the integrity of the study, including blinding, will be maintained.  
This RAP describes the details of the analyses and outputs that will be provided for the 
DRC meetings. Table 5 provides an overview of the DRC meetings and the data that will 
be reviewed in them. The paragraphs below describe the interim analyses. A version of 
the RAP covering the outputs for each reporting effort will be agreed prior to interim 
analyses. 
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Table 5 
Summary of Interim Analyses 
Reason for 
analysis 
(reporting effort 
/ deliverable 
title) 
Interim analysis 
trigger 
Data domains included in 
analysis (not all data from 
the domain will be 
reported). 
S&P to 
receive 
unblinded 
(restricted) 
data 
Dose Escalation 
(DE) 
4 evaluable participants 
of Cohort 1 reach week 
12 
• Safety 
• PK 
• Total OSM (serum) 
• Free OSM (serum) 
• Population including 
concomitant medication 
Y 
Expanded Dose 
Escalation 
(Expanded DE, 
will only occur if 
required) 
8 evaluable participants 
of Cohort 1 reach week 
12 (Conditional) 
• Safety  
• PK 
• Total OSM (serum) 
• Free OSM (serum) 
• Population  
Y 
IA1 Target 
Engagement 
(IA1) 
Approximately 8 
participants from Cohort 
2 complete week 8 visit 
• Total OSM in serum, 
and blister fluid, if 
available[1] 
• Free OSM in serum 
• PK in plasma and blister 
fluid, if available[1] 
• Safety 
• Population 
Y 
IA2 Baseline 
Variability (IA2) 
Approximately 16 
participants from Cohort 
2 provide baseline 
sample 
• Total OSM in serum, 
and blister fluid, if 
available[1] 
• Free OSM in serum 
• PK in plasma and blister 
fluid, if available[1] 
• Baseline systemic 
fibrosis and other 
biomarkers 
• Safety  
• Population 
Y 
Additional DRC 
Review Meeting 
 
• Total OSM 
• Free OSM 
• PK in plasma 
• Safety 
• Population 
Y 
1: Note that it is the intention that PK and PD from Blister Fluid will be analysed in 
batches at the same frequency as plasma/serum.  
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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 (IA2) 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. 
The DRC may also review available data at additional points during the study for internal 
decision making. 
An additional DRC was conducted following the request of safety review at the project 
level response to a temporary stopping criterion related to thrombocytopaenia being met 
in another study with GSK2330811 (Study 208564; A phase 1, randomised, double-blind, 
placebo-controlled study of the safety, tolerability, pharmacokinetics and 
pharmacodynamics of single subcutaneous doses of GSK2330811 in healthy Japanese 
participants). 
The population for each output is specified in Appendix 12; unless otherwise specified 
the outputs for the DEC will be based on the safety population whereas the non-safety 
outputs for the later interims will be based on the per-protocol population to provide an 
assessment of repeat dose GSK2330811. 
3.3. 
Final Analyses 
3.3.1. 
DBF timeline 
The final planned analyses will be performed after the completion of the following 
sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3. All criteria for unblinding the randomisation codes have been met.  
4. Randomisation codes have been distributed according to RandAll NG procedures. 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• Comprises of participants who sign the 
Informed Consent 
• Note Re-screened participants will be 
considered only once with their last 
Subject Id. 
• Screen Failures 
Enrolled 
• Comprises of participants who ultimately 
pass screening, even if rescreened. 
• Note that this population includes both 
randomised participants and participants 
where no treatment was assigned (e.g. 
never randomised) even though they 
passed screening. Screen failures are 
excluded from the enrolled population 
unless they are successfully rescreened 
and enrolled. 
• Study Population 
(selected outputs, 
Appendix 12) 
Safety 
• Comprises of all randomised participants 
who receive at least one part of one dose 
of study treatment. 
• This population will be based on the 
treatment the participant actually received. 
• Study Population 
• Safety including 
Immunogenicity 
• PD for IA1 and IA2 
• Systemic biomarkers 
for IA2 
Pharmacokinetic 
(PK) 
• Comprises of participants in the ‘Safety’ 
population who received an active dose 
and for whom a PK sample was obtained 
and analysed. 
• PK  
• PK/PD (including 
PopPK model) 
Per Protocol (PP) 
• Comprises of participants in the ‘Safety’ 
population who comply with the protocol. 
• Protocol deviation that would exclude 
participants from PP population are 
defined in Section 4.1 (Protocol 
Deviations) and Appendix 1 
• PP population will only be derived for SAC. 
• This population will be based on the 
treatment the participant actually received. 
• Study Population 
(selected outputs, 
Appendix 12) 
• PD (not incl. IA1 or 
IA2) 
• Systemic biomarkers 
• Skin Histology 
• Skin Gene Expression 
• Clinical efficacy 
Suction Blister (SB) 
• Comprises of participants in the ‘Safety’ 
population who signed the informed 
consent for Suction Blister, a blister 
sample was obtained and analysed. 
• PK 
• PK/PD 
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Population 
Definition / Criteria 
Analyses Evaluated 
NOTES:  
• 
Please refer to Appendix 12 which details the population to be used for each display being generated. 
• 
The safety population will be used for PD analysis in IA1 and IA2, as there will be limited subject data for the PP 
population due to partial data. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be listed. 
Important deviations which result in exclusion from the per protocol analysis population 
will also be listed if they occur. (Please refer to Appendix 1 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 7, 17 Dec 2019]. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised consistently on the protocol deviations 
dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
A separate table and listing of all COVID-19 related protocol deviations will be provided 
to capture the impact on visits and assessments. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description [3] 
Description [2] 
Order [1] 
A 
GSK2230811 100 mg SC - PARALLEL 
GSK2330811 100 mg 
2 
B 
GSK2230811 300 mg SC - PARALLEL 
GSK2330811 300 mg 
3 
P 
Placebo - PARALLEL 
Placebo 
1 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
2. 
If there is no space for the full drug name, and the full drug name is in the title or elsewhere on the output then the 
dose amount (i.e. 100mg or 300mg) may be used with consultation with statistician 
3. 
This RAP instruction corrects a mistake in the Treatment Description field in the RANDALL NG. 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. 
GSK2330811 100 mg vs Placebo 
2. 
GSK2330811 300 mg vs Placebo 
Or, in short form when full drug name is shown in title or elsewhere on table, listing or 
Figure and after consultation with statistician: 
1. 
100 mg vs Placebo 
2. 
300 mg vs Placebo 
5.2. 
Cohort Display Descriptors 
After the DEC reporting effort has completed, use the RANDALL dataset to create a 
derived variable “cohort” for use with SRT outputs which are blinded. All participants in 
schedules 1 and 2 will belong to cohort 1, all other participants are in cohort 2. 
Cohort Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Randall NG Schedule 
Cohort 
Order [1] 
Schedule 1 
1 
1 
Schedule 2 
1 
1 
Schedule 3 
2 
2 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
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5.3. 
Baseline Definitions 
The column ‘Baseline Label Used in Data Display’ shows the preferred baseline for a 
parameter but if this is missing or a later, unscheduled, assessment exists then the latest 
pre-dose assessment will be used for that participant unless otherwise specified. If time is 
not collected, Day 1 assessments are assumed to be taken prior to first dose and used as 
baseline unless otherwise specified.   
Parameter 
Study Assessments Considered 
as Baseline 
Baseline Label Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
Primary endpoints 
Safety 
12-Lead ECG 
 
X 
Day 1 (Pre-Dose) 
[Note: Triplicate]  
Vital Signs 
 
X 
Day 1 (Pre-Dose)  
Lab 
 
X 
Day 1 (Pre-Dose)  
Urinalysis 
 
X 
Day 1 (Pre-Dose)  
Secondary endpoints 
PD 
Serum OSM free and total 
 
X 
Day 1 (Pre-Dose) 
Blister OSM total 
 
 
No baseline 
PK 
Plasma PK 
 
X 
Day 1 (Pre-Dose) 
Blister PK 
 
 
No baseline 
Immunogenicity 
Immunogenicity 
 
X 
Day 1 (Pre-Dose) 
Exploratory endpoints 
Efficacy 
mRSS 
 
X 
Day 1 (Pre-Dose) 
Respiratory Laboratory FVC 
 
X 
Day 1 (Pre-Dose) 
Home Spirometry FVC 
 
X[1] 
Day 1  
SHAQ /PhGA /PtGA /CRISS[2] 
 
X 
Day 1 (Pre-Dose) 
Disease biomarkers 
CRP 
 
X 
Day 1 (Pre-Dose) 
Blood biomarkers 
 
X 
Day 1 (Pre-Dose) 
Biopsy mRNA 
 
X 
Day 1 (Pre-Dose) 
Biopsy IHC 
 
X 
Day 1 (Pre-Dose) 
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Parameter 
Study Assessments Considered 
as Baseline 
Baseline Label Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
Mechanistic haematology 
 
X 
Day 1 (Pre-Dose) 
NOTES: 
1: The day 1 Home Spirometry FVC (which will be taken on site) is not mandated by the protocol to be pre-dose. If the 
home spirometry is taken post Day 1 dose, then the latest screening observation prior to dosing will be used as 
baseline. 
2: CRISS is a measure of change and events over a time period, starting at Day 1. 
• 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point. 
5.3.1. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit – Baseline) / Baseline] 
Ratio to baseline 
= Post-Dose Visit / Baseline 
Nadir 
= Lowest post-baseline value of endpoint for a participant [1] 
Days to Nadir 
= Study Day of Nadir – 1[1] 
Maximum Change from Baseline = Calculate the change from baseline at each given timepoint  
   and determine the maximum absolute change 
Minimum value at timepoint 
= The lowest value of the parameter in the reported group at 
the specified timepoint. 
NOTES: 
• 
1: When there are multiple instances of the lowest value then the nadir used for reporting will be the earliest 
occurrence of that value. 
• 
Unless otherwise specified, the baseline definitions specified in Section 5.3 Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing. 
• 
The baseline definition will be footnoted on all absolute summary and change from baseline plots. ‘Note: Baseline 
is defined as the pre-dose Day 1 assessment, unless unavailable, in which case it is the latest pre-dose 
assessment.’  
• 
If there are multiple measurements (i.e. ECG) the derivation will be based on the average values where available. 
5.4. 
Multicentre Studies 
In this multicentre global study, it is expected that the number of participants from any 
one site will be low and there are no plans to stratify, summarise or analyse results by 
centres or country. 
5.5. 
Examination of Covariates, Other Strata and Subgroups 
5.5.1. 
Covariates and Other Strata 
• 
The following is a list of covariates that may be used in descriptive summaries 
and statistical analyses, some of which may also be used for subgroup analyses 
(see the statistical analysis sections for each class of data for details).  
• 
Additional covariates of clinical interest may also be considered.  
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Category 
Covariates  
Mycophenolate status: 
• Mycophenolate use 
• No mycophenolate use 
Mycophenolate status on Day 1 will be used as an explanatory 
variable in some analyses of exploratory endpoints (to be specified in 
the relevant statistical analysis sections). This category will not be 
used unless specified for an output. 
 
5.5.2. 
Examination of Subgroups 
There are no planned subgroup analyses due to the small overall study size. 
5.6. 
Multiple Comparisons and Multiplicity 
There is no adjustment for multiplicity in this phase 2a study where the primary endpoint 
of interest is safety and tolerability of the study treatment. 
5.7. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
16.3 
Appendix 3: Assessment Windows 
16.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
16.5 
Appendix 5: Data Display Standards & Handling Conventions 
16.6 
Appendix 6: Derived and Transformed Data 
16.7 
Appendix 7: Reporting Standards for Missing Data 
16.8 
Appendix 8: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the “Safety” population, unless otherwise 
specified. Screen failures will be listed based on the “Screened” population. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, concomitant medications, and 
exposure and treatment compliance will be based on GSK Core Data Standards.  
Concomitant systemic sclerosis and other medications will be summarised separately but 
listed together.  
Bespoke outputs for this population include Systemic Sclerosis Disease and Medication 
History, Mycophenolate use at Day 1 and Autoantibody profiles (Historical collected 
from eCRF and Baseline). 
Historical autoantibodies and positive baseline autoantibodies will be summarized. All 
non-negative data along with collected results for anti-RNAPIII antibody will be listed 
except for Anti-nuclear antibodies which will list both positive (including patterns and 
titres) and negative results. The below table explains the autoantibody labels used for 
displays. 
Sorting 
Order 
Historical 
Autoantibody 
Baseline Autoantibody 
Table/Listing labels 
Plot 
[1] 
1 
ANA (anti-nuclear 
antibodies) 
Anti-nuclear antibody 
Anti-nuclear 
antibodies 
O 
2 
Anti-RNAPIII 
RNA Polymerase III 
Antibody - Standard 
Anti-RNAPIII 
R 
3 
Anti-Scl-70 
Scl-70 Antibody 
Anti-Scl-70 
T 
4 
Anti-centromere 
Anti-centromere 
Antibody 
Anti-centromere 
C 
5 
 
Anti-Smith antibody 
Anti-Smith antibody 
O 
6 
 
Anti-U1 RNP 
Anti-U1 RNP 
O 
7 
 
Jo-1 Antibody  
Jo-1 Antibody 
O 
8 
 
Sjogrens SS-A Antibody Sjogrens SS-A 
Antibody 
O 
9 
 
Sjogrens SS-B Antibody 
Sjogrens SS-B 
Antibody 
O 
Note: [1] Added to subject with positive autoantibodies in the legends of Biomarker and Efficacy 
individual plots. 
Details of the planned displays are presented in Appendix 12. 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the “Safety” population, unless otherwise specified. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs) and Serious 
(SAEs) based on GSK Core Data Standards. The details of the planned displays are 
provided in Appendix 12. 
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 12. 
Summaries of Platelet Count, Haemoglobin, Absolute Neutrophil Count and Red Blood 
Cell (RBC) count Nadir will also be produced to describe the anticipated effect of 
GSK2330811 on these cells. The nadir is defined as the lowest post-baseline value 
observed for each parameter. Correlation analysis will be performed and presented as 
scatter plots including Pearson correlation coefficient for Platelet and Haemoglobin nadir 
by treatment groups. 
Table 6 lists the Haematology parameter groups that will be referenced in Appendix 12. 
These are required because some outputs will only be produced for selected 
haematological/laboratory parameters to monitor potential platelet and RBC effects that 
were observed in the first time in human study (group 1) and to meet the exploratory 
objective ‘To characterise the mechanisms of any observed haematological effects of 
GSK2330811’ (group 2).   
Table 6 
Haematology/Chemistry parameter groups 
Haematology/ Chemistry parameter 
group name 
Parameters 
Reported under 
Additional Chemistry Parameter[1] 
Haptoglobin, Ferritin, Vitamin B12 and 
Folate. 
Safety – 
Chemistry 
Group 1 – Potential Haematology Signal 
Haemoglobin, Red Blood Cells, Platelet 
Count, Reticulocytes, Absolute Neutrophil 
Counts 
Safety – 
Haematology  
Group 2 – Mechanistic Haematology/ 
Chemistry 
Reticulocyte Production Index (See Section 
16.6.4 for derivation), Immature Reticulocyte 
Fraction  
Biomarkers  
Thrombopoietin (TPO) (Collected under 
Coagulation parameter), Erythropoietin 
(EPO), % Transferrin saturation  
Biomarkers 
Note: [1] Summarizes all collected chemistry parameters but Figures are based on only subset of parameters. 
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For the purpose of calculating ‘worst case’ laboratory result summaries, Post-Baseline is 
defined as an occurrence after first dose of the treatment until the final follow up visit, 
see Section 5.3 and Appendix 3 for baseline definition. 
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.  
All ECG summaries and listings will report both QTcF and QTcB which will be derived 
where necessary. If data is captured using another QTc method this will only be reported 
in listings. 
A separate listing to capture the COVID-19 infection assessment of participants based on 
new eCRF page will be provided. 
The details of the planned displays are presented in Appendix 12. 
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8. 
IMMUNOGENICITY ANALYSES 
The Immunogenicity analyses will be based on the “Safety” population, unless otherwise 
specified. The immunogenicity analysis summarises the incidence of anti-drug antibodies 
and lists the titre of immunogenicity results.   
Details of the planned displays are presented in Appendix 12.  
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9. 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.  
Correlation analysis will be performed and presented as scatter plots including Pearson 
correlation coefficient for Measured Steady State Concentration vs Baseline Body 
Weight, Haemoglobin and Platelet Nadirs as Percentage Change from Baseline vs 
Measured Highest Concentration by treatment groups. 
9.1. 
Primary Pharmacokinetic Analyses 
See Section 10 for PopPK analysis and Section 12 for PK/PD analysis. 
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10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
GSK2330811 plasma and Total OSM serum concentration-time data will be analysed by 
population pharmacokinetic/pharmacodynamic (PopPK/PD) methods using a non-linear 
mixed-effects modelling approach. 
The objective of the PopPK analysis is to develop a population PK model that 
characterizes the PK of GSK2330811 following repeat subcutaneous administration in 
patients with dcSSc. The individual participant PK parameters will be estimated and 
documented for the purposes of any subsequent exposure-response (PK/PD) analyses. 
10.1. 
Statistical Analyses / Methods 
See Appendix 10 for details. 
To support this analysis a PK/PD dataset will be generated. The details for the dataset 
specifications are provided in Appendix 9 
10.1.1. 
Endpoint / Variables 
10.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5(Section 16.5.3 Reporting Standards for Pharmacokinetic) 
10.1.1.2. 
Derived Pharmacokinetic Parameters 
In addition to the parameters of the PopPK model itself, individual participant parameters 
will be estimated from the PopPK model i.e. empirical Bayes estimates will be reported 
(also known as post-hoc parameter estimates). 
Parameter 
Parameter Description 
Apparent 
Clearance 
Individual participant estimate of apparent clearance (empirical Bayes estimates) 
Apparent 
Volume of 
Distribution 
Individual participant estimate of apparent volume of distribution (empirical Bayes 
estimates) 
AUC 
Individual model predicted AUC at steady state 
• 
NOTES: Additional parameters may be included as required. 
10.1.2. 
Summary Measure 
The population PK parameter will be used to describe the population so therefore 
parameters will not be summarised across participants.   
10.1.3. 
Population of Interest  
The standalone PopPK analysis will be based on the “Pharmacokinetic” (PK) population, 
unless otherwise specified.  If the simultaneous PopPK/PD model can be developed, 
then the analysis will be based on the PK population. 
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10.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
PK and PK/PD models will use all available data and will not account for intercurrent 
events (i.e. will adopt a ‘while on treatment’ strategy). 
10.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12 and will be based on GSK 
Data Standards and statistical principles. 
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11. 
PHARMACODYNAMIC ANALYSES 
The endpoints OSM Free and OSM Total make up the primary pharmacodynamic 
endpoints in this study. Data will be presented in graphical and/or tabular form and will 
be summarized descriptively. Individual results will be reported in listings and Figures; 
summary results will be reported in tables and Figures. 
 
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12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
OSM Free and OSM Total will be analysed through the PK/PD models specified in 
Appendix 10. 
The objective of this analysis is to develop a population PK/PD model that characterizes 
the PK of GSK2330811 and the total OSM concentration-time profile following repeated 
subcutaneous administration of GSK2330811 in patients with dcSSc.  
Exposure/ response analysis for haematology (platelets and haemoglobin) will be a 
pooled analysis that includes all available clinical data generated with GSK2330811. This 
pooled analysis will be described in a separate document.  
Exposure/ response and or joint analysis for clinical endpoints and biomarkers will be 
done ad-hoc post SAC, based on the results of the statistical analysis.  
 
12.1. 
Statistical Analyses / Methods 
The analysis aims to characterise the relationship between plasma concentrations of 
GSK2330811, and target OSM concentration (total). Predicted TE% will be derived as 
defined in Section 16.6.5. Predicted values for free OSM will be used if measured values 
are below the LLQ of the assay. 
Detailed PK/PD methodology is presented in Appendix 10 
To support this analysis a PK/PD dataset will be generated. The details for the dataset 
specifications are provided in Appendix 9 
Any exposure/ response and or joint analysis for clinical endpoints and biomarkers will 
be initiated post SAC, based on the results ot the statistical analysis. The dataset to 
support this analysis and the analysis plan will be described in a separate document.    
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13. 
BIOMARKER ANALYSES 
Exploratory biomarker analysis will take place at the final SAC.   
13.1. 
Primary Biomarker Analyses 
13.1.1. 
Endpoint / Variables 
The following endpoints will be collected and presented in the outputs. Only systemic 
endpoints will be presented at baseline for IA2. 
13.1.1.1. 
Systemic: 
13.1.1.1.1. Fibrosis markers: 
• Pro-C3  
• C3M  
• Pro-C6 
• C6M 
• PINP 
• C1M (Note: Cohort 1 assay used antibody generated using mouse hybridoma cell 
line (old C1M kit). Cohort 2 assay used recombinant detection antibody, these 
will be summarised and plotted separately) 
• COMP 
• PIIINP 
• HA 
• TIMP-1 
13.1.1.1.2. Derived fibrosis markers: 
• Pro-C3/C3M (ratio) 
• Pro-C6/C6M (ratio) 
• PINP/C1M (ratio) (Note for C1M, Cohort 1 assay used antibody generated using 
mouse hybridoma cell line (old C1M kit). Cohort 2 assay used recombinant 
detection antibody, these will be summarised and plotted separately) 
• Enhanced Liver Fibrosis (ELF) test (a linear combination of hyaluronic acid 
(HA), amino-terminal propeptide of type III Procollagen (PIIINP, a measurement 
of collagen III synthesis) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in 
serum, this derived score will be provided by the vendor 
13.1.1.1.3. Inflammation markers: 
• CRP 
• IL-6 
• MCP-1 (Rename MCP-1 as CCL2 for displays) 
• CCL-18 
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13.1.1.1.4. Vascular markers: 
• vWF 
• VEGF 
• sVCAM-1 
• NT-ProBNP 
13.1.1.2. 
Skin Histology 
• Alpha Smooth Muscle Actin (αSMA)  
(Note: During the review process of Alpha SMA samples, some samples were found to 
have insufficient tissue due to shallow biopsies. Summaries, stats analysis and plots 
exclude those insufficient samples. Additional summary and plots will be produced on 
the full data (including both the sufficient and insufficient samples.) 
13.1.1.3. 
Skin Gene expression RNA Sequencing: 
13.1.1.3.1. Individual Genes of Interest: 
• Inflammation genes: CCL2, CCL18, MS4A4A 
• Fibrosis genes: THBS1, COMP  
• PD marker at the site of action: SOCS3 
• Target expression in skin: OSM, OSMR 
13.1.1.3.2. Derived Gene: 
• 2-gene SSc skin biomarker: 2GSSc (See Section 16.6.6 for derivation) 
13.1.1.3.3. Gene Set Variation Analysis (GSVA) Score 
GSVA (Hanzelmann, 2013) assesses the relative enrichment of a gene set of interest 
across all samples and generates an enrichment score for each gene set per individual 
sample. The algorithm will first calculate expression-level statistic for each gene using all 
the provided samples’ gene expression distribution and subsequently rank the genes. 
Based on the expression-level statistic, the algorithm will then assess if the genes in the 
gene sets of interest are more likely to be enriched at either end of the ranking. The input 
of GSVA will be the rlog normalized and transformed expression matrix and the output 
of GSVA will be enrichment scores bound between 1 and -1 for each individual sample.  
13.1.1.3.4. Disease signature 
A broad set of public microarray datasets were used to create a systemic sclerosis gene 
signature in skin consisting of 251 individual genes, some of which are up-regulated and 
some of which are down-regulated in SSc skin compared to healthy skin (see Appendix 
13 and eLNB reference number N76598-1 Section 2.1 and Section 3.1). The systemic 
sclerosis gene signature will be quantified using GSVA score. 
• Individual Gene Sets: 209 Upregulated Genes and 42 Downregulated Genes 
• Disease Signature: GSVA Scores (Upregulated and Downregulated) 
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13.1.1.3.5. Lung Fibrosis Signature 
A broad set of public microarray datasets were used to create a lung fibrosis signature 
consisting of 42 individual genes. These genes can be detected in the skin and therefore 
lung fibrosis gene dysregulation can be evaluated in the skin biopsies. The lung fibrosis 
signature will be quantified using GSVA score. (see Appendix 13 and eLNB reference 
number N76598-1 Section 2.4 and Section 3.4).  
13.1.1.3.6. Cell Module Signatures 
The aim of the cell modules is to assess the effect of GSK2330811 on different cell-types 
and to compare the effect of GSK2330811 with the published tocilizumab data. The cell 
modules consist of three gene sets derived from Khanna, 2016b: Fibrosis (Table S3), M1-
Macrophage (Table S7) and M2-Macrophage (Table S8). Cell module signatures will be 
quantified using GSVA score. (see Appendix 13) 
• Individual Gene Sets: 37 Fibrosis Genes, 32 M1-Macrophage Genes and 31 M2-
Macrophage Genes. 
• Cell Module Signatures: GSVA Scores (Fibrosis, M1-Macrophage and M2-
Macrophage) 
13.1.2. 
Summary Measure 
Interim 2: 
The baseline values will be summarised without treatment groups using the safety 
population presenting summary statistics assuming a skewed distribution for the systemic 
markers. A scatter plot of the raw baseline values will be presented alongside the 
geometric mean  standard error. 
The Spearman’s and Pearson’s correlations of the baseline values transformed using log 
base 10, will be calculated and presented for each combination of endpoints. The 
correlations will also be presented as scatter plots for each pair of endpoints. Where both 
the correlations are >-0.3 and <0.3 the correlation will be suppressed from the outputs.  
Final analysis 
Standard summaries at each planned timepoint will be used for biomarker endpoints 
assuming a skewed distribution. The ratio of the post-baseline to baseline values and fold 
change (geometric ratio <1 then fold change is -1/geometric ratio otherwise fold change 
is geometric ratio) will also be summarised. 
Systemic biomarkers will be summarised and presented using a log 10 scale while the 
histology and gene sets will be summarised and presented using a log 2 scale. 2GSSc skin 
biomarker and GSVA Scores will be summarised and presented on linear scale. 
Line plots of the unadjusted geometric means  standard error for log transformed data 
and unadjusted means  standard error for linear data will be presented by treatment 
group at each visit. Individual participant plots of the raw values will be presented by 
treatment group and individual plot lines are differentiated by MMF use at Day 1 (solid 
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line denote subjects on mycophenolate at day 1 and dashed line denote subjects not in 
mycophenolate at day 1). Information on positive autoantibodies is added to the subject 
ids in the legend as per Section 6.1. 
13.1.3. 
Population of Interest 
For Interim 2 the summaries will be based on the “Safety” population. 
For other reporting efforts, the primary biomarker analyses will be based on the “Per 
Protocol” analysis population, unless otherwise specified.   
13.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Biomarker analysis will not account for intercurrent events (i.e. will adopt a ‘while on 
treatment’ strategy). 
13.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12 and will be based on GSK 
Data Standards and statistical principles. 
The endpoints / variables defined in Section 13.1.1 will be summarised using descriptive 
statistics, graphically presented (where appropriate) and listed. 
Longitudinal model 
The ratio to baseline for the following systemic biomarkers will be analysed using a 
Bayesian MMRM analysis using the log transformed data including only the placebo and 
GSK2330811 300mg arms: 
• Pro-C3 
• Pro-C6 
• PINP 
• ELF 
• COMP  
• PIIINP  
• IL-6 
• MCP-1 (Rename MCP-1 as CCL2 for displays) 
• CCL-18 
 
Non-informative priors will be used in these analyses, specifically the prior for the 
regression coefficient will be normally distributed with mean 0 and a variance of 106.The 
variance-covariance matrix for the within subject error across the visits will use an 
inverse-Wishart prior distribution, consisting of the identity matrix and the degrees of 
freedom will be the number of visits included in the model.  
The models will be adjusted for the following covariates: MMF use at day 1, baseline 
value, treatment, visit, treatment by visit and baseline by visit interactions. 
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The change from baseline within each treatment group and the difference in the change 
from baseline across the treatment groups (GSK2330811 300mg – placebo) will be 
calculated and are back transformed to give the ratio to baseline and the ratio of the 
change relative to placebo respectively. 
Posterior medians and equal tailed 95% credible intervals will be presented. In addition, 
the probability the ratios are <1 and fold changes (Posterior Medians, as ratio < 1 then 
fold change is -1/ratio otherwise fold change is ratio) will also be calculated. The line plot 
of the adjusted posterior medians ± credible intervals at each visit will be presented.  
ANCOVA 
The ratio to baseline of log transformed and change from baseline of linear data for the 
following skin histology and gene expression mRNA sequencing endpoints will be 
analysed using a Bayesian ANCOVA analysis including only the placebo and 
GSK2330811 300mg arms: 
• Alpha SMA (Excluding Insufficient samples) 
• COMP 
• CCL2  
• 2GSSc 
• Disease Signatures - GSVA Scores (Upregulated and Downregulated) 
• Lung Fibrosis Signature - GSVA Score  
• Cell Modular Signatures - GSVA Scores (Fibrosis, M1-Macrophage and M2-
Macrophage) 
 
Non-informative priors will be used in these analyses, specifically the prior for the 
regression coefficient will be normally distributed with mean 0 and a variance of 106. The 
prior for the variance parameter will be an inverse-gamma (shape=0.001, scale=0.001).  
The models will be adjusted for the following covariates: MMF use at day 1, baseline 
value and treatment. 
Nature of Data 
Output Presentation 
Log 
Transformation 
• The change from baseline and difference in the treatment groups 
(GSK2330811 300mg – placebo) will be back transformed to give ratio 
to baseline and ratio of the change relative to placebo respectively. 
• Posterior medians, equal tailed 95% credible intervals, probability that 
ratios < 1 and fold change (i.e., Posterior Medians, as ratio < 1 then 
fold change is -1/ratio otherwise fold change is ratio) will be presented. 
Linear  
• Change from baseline and the difference in the treatment groups 
(GSK2330811 300mg – placebo) will be calculated. 
• Posterior medians and equal tailed 95% credible intervals will be 
presented. Except for Downregulated GSVA score, the probability that 
difference < 0 will be calculated. For Downregulated GSVA score, the 
probability > 0 will be calculated. 
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The plot of the adjusted posterior medians ± credible intervals along with individual ratio 
to baseline or change from baseline values based on the endpoints will be presented. 
Joint model 
In addition to the Bayesian MMRM analysis, the ratio to baseline or change from 
baseline based on the endpoints for the following four key biomarkers will be modelled 
using a multivariate Bayesian analysis including only the placebo and GSK2330811 
300mg arms: 
• Alpha SMA (Excluding Insufficient samples) 
• CCL2 gene assessed from the skin sample through RNA sequencing 
• PIIINP assessed from the serum sample 
• 2GSSc 
 
Non-informative priors will be used for all parameters. The variance-covariance matrix 
for the within subject error across the endpoints will use an inverse-Wishart prior 
distribution consisting of the identity matrix and 4 degrees of freedom. 
The model will be adjusted for endpoint (allows each endpoint to have their own 
intercept), treatment by endpoint interaction term, MMF use at day 1 by endpoint 
interaction, and baseline by endpoint interaction term. If the model does not converge, the 
covariate for MMF use will be removed from the model.  
Missing baseline covariates will be modelled as part of the MCMC sampling prior to 
fitting the joint model, using non-informative priors. For example, if bi is the baseline of 
the ith endpoint then bi~N(θi, δi) where θi~N(0,sd=100) and δi~iGamma(shape=0.1, 
scale=0.1).   
For modelling purposes, the log transformed endpoints will be back transformed for the 
presentation of results. Fold change will also be presented for only log transformed 
endpoints, posterior medians as, ratio < 1 then fold change is -1/ratio otherwise fold 
change is ratio. 
Heat Plots 
Heat plots will be produced for the gene expression endpoints contributing to a gene 
signature using fold change from baseline. Fold change in Placebo, GSK2330811 100mg 
and GSK2330811 300 mg at day 85 will be presented in three columns using the 3-fold 
change cut off. Plot colour scales from blue to white to red scale, values above 3 or below 
-3 fold change will all be presented using the same colour. 
Heat plots are produced for each individual gene from Disease Signature, Lung Fibrosis 
signature and Cell module signatures as mentioned in Section 13.1.1.3. Within each 
signature, genes are ordered based on ‘Ward’ clustering algorithm. 
For further reference, heat plot with dendogram for full gene panel contributing to the 
different signatures will be produced and saved in Refdata folder. 
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Additional Post SAC transcriptomics analysis will be conducted and the details will be 
documented in a separate analysis plan. 
13.1.5.1. 
Model Checking & Diagnostics 
As an initial model fit 100,000 MCMC samples will be generated with a thin of 10, 
providing 10,000 samples to be used for the estimate of the posterior distribution. A burn-
in of 5,000 samples will be used. Starting values for the parameters will be based on the 
mode of the prior distributions.   
The following list of convergence diagnostics will be applied for each parameter 
(diagnostic checking outputs will be stored in the refdata folder in HARP in the relevant 
reporting effort): 
• The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation of the posterior distribution (SD) to ensure that only a fraction of the 
posterior variability is due to the simulation. The number of samples generated, 
and/or the thinning may be increased to reduce the ratio of the MCSE/SD as 
deemed necessary. 
• Trace plots of samples versus the simulation index will be visually inspected to 
assess some aspects of convergence. The centre of the chain should appear stable 
with very small fluctuations, i.e., the distribution of points should not change as 
the chain progresses and the posterior mean and variance are relatively constant.  
• Autocorrelation plots will be visually inspected to assess degree of autocorrelation 
(should decline rapidly and show no oscillation patterns). 
• Density plots of the posterior for the model parameters will be plotted (should be 
smooth and with a single hump). 
 
If the model is not deemed to have converged the following actions will be taken in the 
order described below: 
• Increasing the number of MCMC samples and/or the thinning will be explored. 
The blocking of the parameters will be considered. 
• For the joint model: 
o The variance of the parameters used to model the baseline data may be 
considered as fixed, based on the observed variance of the parameter 
rather than using δi~iGamma(shape=0.1, scale=0.1). 
o The endpoint with the most missing data will be removed from the model 
and the joint model carried out on the remaining 3 endpoints. 
• For the MMRM model: 
o If missing data at the post-treatment visits are causing the non-
convergence, these visits will be removed and details included in a 
footnote. 
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• Removal of covariates will be considered, starting with MMF use at day1, then 
the baseline by visit interaction (if applicable). 
After which if the model still does not converge, the model results will not be presented. 
13.2. 
Exploratory Biomarker Analyses 
13.2.1. 
Mechanistic Haematology 
Note that the exploratory endpoints that are categorised as ‘blood biomarkers related to 
mechanisms of anaemia and thrombocytopenia’ in the protocol are categorised as ‘Group 
2 – Mechanistic Haematology/chemistry’ in Section 7.2. Reporting of these parameters 
will use the same outputs as other Haematology/ chemistry but will only occur at the end 
of the study. See Appendix 12. No statistical analysis will be performed on these 
endpoints. These displays will use the ‘Safety’ population unless otherwise specified.  
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14. 
EFFICACY ANALYSES 
Exploratory biomarker analysis will take place at the final SAC.   
14.1. 
Exploratory Efficacy Analyses 
14.1.1. 
Endpoint / Variables 
The analyses of clinical disease assessments (preliminary assessment of efficacy in 
Systemic Sclerosis) will be based on the Per Protocol population, unless otherwise 
specified. They will consist of the following endpoints: 
• mRSS  
• HAQ-DI 
• SHAQ VAS scales 
• PhGA 
• PtGA 
• CRISS (derived – non-parametric summaries) 
• Laboratory FVC (L) – (Note: impact of treatment on the rate of change will be 
inferred from the Figures)   
• % predicted laboratory FVC 
• Weekly Home FVC (L) – (Note: impact of treatment on the rate of change will be 
inferred from the Figures)   
14.1.2. 
Summary Measure 
Summary statistics for all endpoints listed in Section 14.1.1 will be presented by visit and 
for the change from baseline at each visit. Line plots of unadjusted means  standard 
error at each visit and individual participant plots of the raw values will be presented by 
treatment groups and individual plot lines are differentiated by MMF use at Day 1 (solid 
line denote subjects on mycophenolate at day 1 and dashed line denote subjects not in 
mycophenolate at day 1). Information on positive autoantibodies is added to the subject 
ids in the legend as per Section 6.1. 
14.1.3. 
Population of Interest  
The efficacy analyses will be based on the “Per Protocol” analysis population, unless 
otherwise specified. 
14.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Exploratory efficacy analysis will not account for intercurrent events (i.e. will adopt a 
‘while on treatment’ strategy). 
14.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12 and will be based on GSK 
Data Standards and statistical principles. 
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The endpoints / variables defined in Section 14.1.1 will be summarised using descriptive 
statistics, graphically presented (where appropriate) and listed. 
 
Longitudinal model 
Longitudinal Bayesian model as specified in Section 13.1.5 will be fitted for the change 
from baseline in the following endpoints: 
• mRSS 
• HAQ-DI 
• Laboratory FVC (L) 
The difference in the differences from baseline will be calculated across the treatment 
groups (GSK2330811 300mg – placebo). 
Posterior means and equal tailed 95% credible intervals will be presented. In addition, 
except for Laboratory FVC, the probability the differences are <0 will be calculated and 
for Laboratory FVC, differences are >0 will be calculated. The line plots of the adjusted 
posterior mean change from baseline  credible intervals at each visit will be presented.  
Non-Parametric Analysis 
The CRISS endpoint is not expected to be normally distributed and so will be analysed 
using Bayesian non-parametric techniques including only placebo and GSK2330811 
300mg arms. 
Observed data from two groups are assumed to come from an underlying latent normal 
distributions with unit variance. Observations from these two latent normal distributions 
are generated from the truncated normal distributions in such a way to maintain the 
ordinality of the data.  The parameter of interest is difference in the two latent means, δ. 
Prior distribution of δ, will be Cauchy distribution with shape parameter 0.5 and scale 
parameter 
. To obtain the posterior distribution for δ, analysis will follow the 
algorithm advocated by van Doorn, 2020. 
Probability difference > 0 will be presented. 
Boxplots of the predicted probability of improvement from baseline in the CRISS 
endpoints at day 85 and day 197 will be presented by treatment group. 
Correlation Analysis 
In addition, correlation analysis will be performed at Day 85 for set of endpoints listed 
below. The correlation will be presented as scatter plots of endpoints for each of the 
treatment groups, including the Pearson correlation coefficient. For ratios, correlations 
will use the log transformed data while the plot will present the untransformed data with 
the appropriate axis presented on the log scale.  
• For each combination of change or ratio of key biomarkers 
• Clinical endpoints vs biomarker endpoints for change or ratio (Following table lists 
the pair of endpoints to be plotted). 
 
 
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 Endpoint 1 
Endpoint 2 
 
Ratio/Change 
FVC (Change) 
1. CCL18 (Serum) 
2. Pro-C6 (Serum) 
Ratio 
3. Disease Signature - GSVA Score (Upregulated 
and Downregulated) 
4. Lung Fibrosis Signature - GSVA Score 
5. Cell Module Signature - GSVA Score (Fibrosis, 
M1-Macrophage and M2-Macrophage) 
Change 
mRSS 
(Change) 
1. Alpha SMA (Excluding Insufficient samples) 
2. COMP (Skin) 
3. CCL2 (Skin) 
4. PIIINP (Serum) 
Ratio 
5. 2GSSc Skin Biomarker 
6. Disease Signature - GSVA Score (Upregulated 
and Downregulated) 
7. Cell Module Signature - GSVA Score (Fibrosis, 
M1-Macrophage and M2-Macrophage) 
Change 
Baseline OSM 
(Skin) 
1. Alpha SMA (Excluding Insufficient samples) 
2. CCL2 (Skin)  
3. PIIINP (Serum) 
Ratio 
4. 2GSSc Skin Biomarker 
5. mRSS 
Change 
 
Model checking and diagnostics will be carried out as described in Section 13.1.5.1. 
 
 
 
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15. 
REFERENCES 
Hanzelmann et al. (2013). GSVA: gene set variation analysis for microarray and RNA-
seq data. BMC Bioinformatics, 14: p. 7. 
J. van Doorn, A. Ly, M. Marsman & E.-J. Wagenmakers (2020): Bayesian rank based 
hypothesis testing for the rank sum test, the signed rank test, and Spearman’s ρ, Journal 
of Applied Statistics. [DOI: 10.1080/02664763.2019.1709053] 
Khanna et al. (2016) The American College of Rheumatology Provisional Composite 
Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis 
Arthritis and Rheumatology, 68 (2), pp. 299-311. 
Khanna et al. (2016b). Safety and efficacy of subcutaneous tocilizumab in adults with 
systemic sclerosis (Fascinate): a phase 2, randomised, controlled trial. Lancet, 
387(10038): p. 2630-2640. 
Reid J., Zamuner S., Edwards K., Rumley S., Sully K., Feeney M., Kumar S., Fernando 
D., Wisniacki N. in vivo affinity and target engagement in skin and blood in a first -time-
in-human study of anti-oncostatin M monoclonal antibody.  Br J Clin Pharmacol 2018 
Oct; 84 (!): 2280-2291 
 
 
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16. 
APPENDICES 
16.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
16.1.1. 
Exclusions from Per Protocol Population 
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population: 
Number 
Exclusion Description 
01 
Participant did not receive at least 4 doses of study treatment 
02 
Placebo participant received active treatment 
03 
Participant did not participate in at least one post-dose assessment 
04[1] 
Participant excluded on basis of final review of inclusion/exclusion criteria 
05[1] 
Participant excluded on basis of final review of the prohibited medication use 
[1] Note: Data reviewed and decisions regarding exclusions from the Per Protocol population will be 
documented in the electronic trial master file. 
 
 
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16.2. 
Appendix 2: Schedule of Activities 
16.2.1. 
Protocol Defined Schedule of Activities 
The following SOA tables are taken from protocol amendment 4 and are included in the 
RAP for convenience. 
Note that baseline ECG is a triplicate measurement; see Appendix 6. 
16.2.1.1. 
Screening 
 
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16.2.1.2. 
Treatment period and follow-up 
 
 
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16.3. 
Appendix 3: Assessment Windows 
Following visit windows are applied for early withdrawal and unscheduled visits. The 
target day is the planned analysis timepoint and windows have been constructed with 
limits approximately equally spaced between visits. If more than one values within 
analysis timepoint with equal distance from the target day then average will be used.  
Table A: 
Domain 
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
All 
Day 1 
Day 1 
Day 1 
Vital Signs, Standard 
Haematology/Clinical Chemistry 
Day 8 
Day 22 
Day 15 
Day 23 
Day 36 
Day 29 
Day 37 
Day 50 
Day 43 
Day 51 
Day 64 
Day 57 
Day 65 
Day 78 
Day 71 
Day 79 
Day 99 
Day 85 
Day 100 
Day 134 
Day 113 
Day 135 
Day 176 
Day 155 
Day 177 
> Day 197 
Day 197 
Additional Haematology, Urinalysis, 
Laboratory FVC, SHAQ-VAS, HAQ-DI, 
PhGA, PtGA and CRISS 
Day 68 
Day 99 
Day 85 
Day 145 
> Day 197 
Day 197 
Immature Reticulocyte Fraction 
Day 37 
Day 50 
Day 43 
Day 68 
Day 99 
Day 85 
Day 145 
> Day 197 
Day 197 
ECG 
Day 8 
Day 22 
Day 15 
Day 50 
Day 64 
Day 57 
Target Engagement (OSM) 
Day 8 
Day 22 
Day 15 
Day 23 
Day 43 
Day 29 
Day 50 
Day 64 
Day 57 
Day 78 
Day 92 
Day 85 
Day 108 
Day 120 
Day 113 
Day 145 
Day 165 
Day 155 
Day 187 
> Day 197 
Day 197 
Blood Biomarkers 
Day 15 
Day 43 
Day 29 
Day 44 
Day 71 
Day 57 
Day 72 
Day 99 
Day 85 
Day 145 
> Day 197 
Day 197 
CRP 
Day 8 
Day 22 
Day 15 
Day 23 
Day 43 
Day 29 
Day 44 
Day 71 
Day 57 
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Domain 
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
Day 72 
Day 99 
Day 85 
Day 100 
Day 127 
Day 113 
Day 145 
> Day 197 
Day 197 
mRSS 
Day 43 
Day 71 
Day 57 
Day 72 
Day 99 
Day 85 
Day 145 
> Day 197 
Day 197 
Skin Biopsy 
Day 55 
Day 99 
Day 85 
Home FVC [1] 
(Target visit -/+ 3 days) 
Day 5 
Day 11 
Day 8 
Day 12 
Day 18 
Day 15 
… 
… 
… 
> Day 194 
 
Day 197 
 [1] Steps for Home FVC Slotting 
• Step 1: Select maximum value within a day. 
• Step 2: After slotting, select the closest target day. 
• Step 3: If more than one value within the analysis timepoint with equal distance 
from the target day, the ‘average of maximum value’ will be used. 
For PK, planned assessments will be summarised, unscheduled assessments will be listed.  
PopPK and PK/PD modelling will use all available data and will use actual relative time, 
not planned relative time. 
Note: Following assessment window followed for all SRT reporting. 
For safety, planned assessments will be summarised. Unscheduled and early withdrawal 
visits are included following the visit slotting algorithm for worst case or CTCAE grade 
summaries and figures. If more than one visit slots to the same analysis timepoint, the 
‘worst’ case will be included in the summary and figure.  
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Table B: 
Analysis Set / 
Domain 
Target 
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Safety/ 
Haematology  
 
The target day is the planned 
analysis timepoint. The windows 
have been constructed with limits 
approximately equally spaced 
between visits 
 
Days less than 0 
 
Screening 
Day 1 
Day 1 
Day 1 
Day 2 
Day 22 
Day 15 
Day 23 
Day 36 
Day 29 
Day 37 
Day 50 
Day 43 
Day 51 
Day 64 
Day 57 
Day 65 
Day 78 
Day 71 
Day 79 
Day 99 
Day 85 
Day 100 
Day 134 
Day 113 
Day 135 
Day 176 
Day 155 
Day 177 
Day 209 
Day 197 
 
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16.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
16.4.1. 
Study Phases 
In general, assessments and events will be classified according to the time of occurrence 
relative to study treatment start date.  Specific rules for Concomitant Medications and 
Adverse Events are specified in the section below. 
Treatment Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start  
On-Treatment 
Study Treatment Start ≤ Date ≤ Study Treatment Stop Date +28 days 
Follow up 
Study Treatment Stop Date +28 days < Date 
 
16.4.1.1. 
Study Phases for Concomitant Medication 
Non-systemic sclerosis medications taken prior to and not ongoing at the screening visit 
were not captured for this study. 
Concomitant Systemic sclerosis medications and systemic sclerosis medication history 
(prior treatments) are captured separately in the eCRF and reported separately.  
 
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16.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
16.5.1. 
Reporting Process 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: \\uk1salx00175.corpnet2.com 
HARP Areas 
Compound: GSK2330811 
Study: MID201247 
Reporting efforts: internal_nn , Final where nn = number of each reporting 
effort, following HARP standard.  The planned identity of each ‘internal’ 
reporting effort is shown in the table below: 
Reporting effort 
(RE) name in RAP 
Type 
HARP folder / RE 
name 
SRT1 
Pre-programming/ dry run srt_01 
SRT1 
Final 
srt_02 
DEC 
Dry run 
data_look_01 
DEC 
Final 
safety_02 
SRT2 
Pre-programming/ dry run data_look_02 
SRT2 
Final 
srt_03 
IA1 
Pre-programming/ dry run data_look_02 
IA1 
Final 
safety_03 
SRT3 
Pre-programming/ dry run data_look_03 
SRT3 
Final 
srt_04 
IA2 
Pre-programming/ dry run data_look_03 
IA2 
Final 
safety_04 
SRT4 
Pre-programming/ dry run data_look_04 
SRT4 
Final 
srt_05 
SRT5 
Final 
srt_06 
SRT6 
Final 
srt_07 
Adhoc DRC 
Final 
safety_05 
SRT7 
Final 
srt_08 
SAC 
Pre-programming/ dry run data_look_04 
SAC 
Final 
Final 
Note: SRTs or DRCs may be called on an ad-hoc basis which will affect the 
numbering in the table above. An up-to-date list of this mapping will be 
maintained by S&P during study conduct and the table above will be updated 
prior to the final reporting effort.  
QC Spreadsheet 
For each reporting effort will be located: 
: \\uk1salx00175.corpnet2.com 
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Reporting Process 
\arenv\arwork\gsk2330811\mid201247\ [reporting effort]\documents 
Analysis Datasets  
• Analysis datasets will be created according to Legacy GSK A&R dataset standards. 
Generation of RTF Files 
• RTF files will be generated for tables at IA2 and Adhoc DRC and final reporting efforts. 
16.5.2. 
Reporting Standards 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
Formats 
• All data will be reported according to the actual treatment the participant received unless 
otherwise stated. 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.  
• Dates will be reported in the format DDMMMCCYY e.g. 01Jan2020 unless otherwise stated. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• Planned time relative to randomisation will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate. 
• Include reference lines at ‘1’ for all change from baseline and at ‘0’ for all ratio to baseline 
plots. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the participant’s listings.  
Visits outside the defined assessment windows specified in Appendix 3 (Table A) will be 
included in listings but omitted from Figures, summaries and statistical analyses. 
Unscheduled Visits 
• Unscheduled visits will be slotted as specified in Appendix 3 Table A.  
• For SRT reporting only, Unscheduled visits will not be included in summary tables apart from 
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Reporting Standards 
any that derive ‘maximum change’ / ‘worst-case’ and CTCAE grade summaries, which will use 
unscheduled results. Assessment windows for the unscheduled visits for the CTCAE grade 
summaries are specified in Appendix 3 Table B. This will not be included in Figures where 
‘visit’ is used on the axis, with the exception of the worst case CTCAE plots. 
Descriptive Summary Statistics 
Continuous Data 
(normally 
distributed) 
Refer to IDSL Statistical Principle 6.06.1 
Descriptive 
Summary Statistics 
(Skewed data)   
N, n, geometric mean, standard deviation (SD) of logged data, between 
geometric coefficient of variation (CVb (%)), median, minimum and 
maximum will be reported. 
Log base e data: CVb (%) = √ (exp(SD^2) - 1) * 100 [NOTE: SD = SD of log base 
‘e’ transformed data] 
Log base 2 data: CVb (%) = √ (exp(loge(2)^2 SD^2) - 1) * 100 [NOTE: SD = SD 
of log base 2 transformed data] 
Log base 10 data: CVb (%) = √ (exp(loge(10)^2 SD^2) - 1) * 100 [NOTE: SD = 
SD of log base 10 transformed data] 
Descriptive 
Summary Statistics 
(Non-parametric 
data)   
N, median, interquartile range (IQR), minimum, maximum 
Categorical Data 
N, n, frequency, %.   
N = the number of participants from the relevant analysis population for the 
group or sub group. 
n = the number of participants counted for the summary statistic. 
Reporting of Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 
Reporting of Pharmacokinetic Parameters 
Descriptive 
Summary Statistics 
(Log Transformed) 
No pharmacokinetic parameters will be summarised in this study, they will 
be produced for each participant from the population PK model and the 
typical value of model parameters is considered the appropriate summary.  
Graphical Displays 
• Refer to IDSL Statistical Principles 7.01 to 7.13. 
• For individual line plots, subjects on MMF at day 1 will be represented with a solid line and 
subjects not on MMF represented with a dashed line. The auto-antibody status of the subject 
will be given in the legend as per Section 6.1. 
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16.5.3. 
Reporting Standards for Pharmacokinetics 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 16.9.1 Pharmacokinetic / Pharmacodynamic Dataset 
Specification  
NONMEM/PK/PD 
File 
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology Modelling 
and Simulation function will be created according to the data specification detailed 
in Section 16.9.1 Pharmacokinetic / Pharmacodynamic Dataset Specification  
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
Highest Concentration – Measured concentration in post dose till the time of nadir. 
Steady State – Measured concentration before the last administered dose. 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
No.  
 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
 
 
 
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16.6. 
Appendix 6: Derived and Transformed Data 
16.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• Where multiple assessments are made, the mean of replicate assessments at any given time 
point will be used as the value for that time point. This derived mean will be reported in the 
listing in addition to the individual assessments. 
• 
If there are two values within a time window the value closest to the target day for that window will be 
used (with the exception of the worst case summaries for parameters detailed in Section 16.3 for SRT 
outputs, where the worst case would be used). If values are the same distance from the target, then the 
mean will be taken. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• Calculated as the number of days from randomisation date: 
• Ref Date = Missing            → Study Day = Missing  
• Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date     
• 
Ref Date ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1  
Actual Relative Time 
• Calculated as the time in days or fraction of a day before or after first dose 
• This will be calculated relative to exposure date and time for both pre- and post- dose 
assessments where relevant. 
• This provides an alternative to ‘Study Day’ with a meaningful value of 0 and is of benefit for 
profile plots showing results before and after dosing. 
 
16.6.2. 
Study Population 
Treatment Compliance 
Total number of doses received and number of doses withheld are summarised for treatment 
compliance. 
Number of doses withheld will be calculated only for subjects who attended the study visit and 
dose was withheld, but will not include the subjects who missed dosing visits. 
Exposure 
Duration of exposure for the treatment phase will be calculated based upon the following formula. If 
a subject has at least 28 days of information after their last dose: 
Duration of exposure in days = treatment stop date – treatment start date + 29 
If a subject withdraws from the study or dies with less than 28 days of information after their last 
dose: 
Duration of exposure in days = Date of withdrawal or death – treatment start date +1  
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This assumes patients are exposed for a 28-day period post-dosing, in-line with the half-life of 
GSK2330811.  
Demographics 
Age 
• 
Only birth year is captured on the eCRF, therefore GSK standard IDSL algorithms will be used for 
calculating age where birth date will be imputed as follows: 
o  The missing date and month will be imputed as ‘30th June’. 
• 
Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) /Height (m)2 
Disease Specific 
Time from onset of the first non-Raynaud’s phenomenon manifestation and Raynaud’s phenomenon 
manifestation 
Time in months calculated as date of first screening visit from onset of the first non-Raynaud’s phenomenon 
manifestation. 
Partial dates will be imputed as follows: 
o Any subject with a missing day will have this imputed as day ‘01’.  
o Any subject with a missing date and month will have this imputed as ‘1st January’. 
Time in months will be rounded up to the nearest whole month for each subject before being summarised. 
Baseline Autoantibody 
Numeric results of RNA Polymerase III Antibody – Standard will be classified as, 
Positive, if numeric values ≥20 and Negative, if numeric values <20. 
DLCO 
During study set-up, the Respiratory Function eCRF screen was set up to collect the screening DLCO 
(uncorrected for Hb) and DLCO (corrected for Hb) values in mL/min/mmHg. However, part way through the 
study, the team became aware that these results were being reported locally in different units (in some 
cases different than the units required per the eCRF), and some sites did not convert the values to the 
required eCRF units.  A note to file in the eTMF documents the corrective and preventative actions.  
DLCO summary tables will present data using ML/MIN/MMHG and therefore data collected using unit 
MMOL/MIN/KPA will be transformed using the following formula: 
ML/MIN/MMHG =MMOL/MIN/KPA x 2.987. 
Based on information from data management (documented in the note to file) sites collected DLCO using 
the following units: 
Site id 
Unit 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
ML/MIN/MMHG 
MMOL/MIN/KPA 
MMOL/MIN/KPA 
MMOL/MIN/KPA 
MMOL/MIN/KPA 
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MMOL/MIN/KPA 
ML/MIN/MMHG 
ML/MIN/MMHG  
16.6.3. 
Efficacy 
Efficacy 
CRISS Composite response index in dcSSc 
CRISS is calculated in a two-step process (formula and text from Khanna, (2016)) and detailed in the 
section below. 
There are two post-baseline assessments of CRISS. Each will use the initial baseline so that, for example, if 
a participant has a scleroderma renal crisis in the first CRISS period between baseline and week 12, they 
will receive a value of 0 for both the first CRISS period (week 12) and the second CRISS period (week 28) 
except for item (b). For item (b) participants will be classified based on their FVC at the current visit FVC 
regardless of their classification at previous assessments. 
Step 1: 
Participants who develop new or worsening cardiopulmonary and/or renal involvement due to systemic 
sclerosis are considered as not improved (irrespective of improvement in other core items) and assigned a 
probability of improving equal to 0.0. Specifically, if a subject develops any of the following: 
a) New scleroderma renal crisis[1] 
b) Decline in FVC % predicted >= 15% (relative to baseline), HRCT to confirm ILD (if previous HRCT 
of chest did not show ILD) and FVC < 80% of predicted[2][3] 
c) New onset of left ventricular failure (defined as left ventricular ejection fraction <= 45%) requiring 
treatment [1] [2] 
d) New onset of PAH on right-sided heart catheterization [1] requiring treatment [1] [2] 
Notes: 
1: Treating physician’s judgement, is recorded directly in eCRF, details in SRM. 
2: Attributable to systemic sclerosis 
3: The three components of item b (FVC % predicted decline, absolute level of FVC % predicted and 
HRCT to confirm ILD) are recorded in the eCRF and will be derived by programming. Note that a 
historic diagnosis of ILD will be recorded in a different variable to one made during the study. 
Items a) c) and d) are captured as part of the eCRF. Item b) the % predicted FVC criteria (>=15% declined 
from baseline and <80% at relevant visit) will be derived programmatically. HRCT is captured as part of the 
eCRF and is requested as required and at the discretion of the investigator.  
• 
If the participant has a HRCT confirming ILD at or prior to the visit (including day 1 and screening 
period or historical diagnosis) they will be considered to have confirmed ILD. Then the % predicted 
FVC results would be used to assess if they meet part b) of step 1. 
• 
If the participant does not have a HRCT confirming ILD or has had a HRCT without presence of 
ILD then they would not meet the criteria for part b) of step 1. 
Step 2:  
For the remaining subjects who do not have a step 1 event a participant’s probability of improving is 
calculated. Step 2 involves computing the predicted probability of improving using the following equation 
(equation to derive predicted probabilities from a logistic regression model): 
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If a participant does not have a step 1 event and is missing any component of step 2, their CRISS predicted 
probability of improving will be set to missing.  
Where:  
Name on 
formula: 
Definition used for 201247 at a given 
timepoint 
Variable name in protocol: 
MRSS 
Change in mRSS total score from 
baseline to timepoint 
mRSS total score change from baseline 
FVC% 
Change in clinic FVC % predicted from 
baseline to timepoint 
% predicted FVC change from baseline 
Pt-glob 
Change in patient global assessment 
from baseline to timepoint 
PtGA change from baseline 
MD-glob 
Change in physician global assessment 
from baseline to timepoint 
PhGA change from baseline 
HAQ-DI 
Change in HAQ-DI from baseline to 
timepoint 
HAQ-DI change from baseline  
(note that the HAQ-DI is a sub-component of 
the SHAQ) 
SHAQ and HAQ-DI 
The Scleroderma Health Assessment Questionnaire (SHAQ) is comprised of:  
• 
The Health Assessment Questionnaire Disability Index (HAQ-DI) (calculated based on 21 items 
across 8 domains) that assess the impact of illness affecting the ability to function in daily life. 
• 
6 individual Visual Analogue Scales assess severity of pain, disease severity and the impact of 
each of the folllowing symptoms on activities of daily living: 
o Intestinal Problems 
o 
Breathing Problems 
o 
Raynaud’s Phenomenon 
o 
Finger Ulcers 
• 
The SHAQ will be completed by the participant during scheduled clinic visits and before any other 
assessments. 
• 
For display purpose use the following terminologies to represent the SHAQ-VAS Questionarrie 
o 
o 
o 
o 
 
o 
o 
HAQ-DI 
There are 8 sections: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 
There are 2 or 3 questions for each section. Scoring within each section is from 0 (
) to 3 
(
). For each section the score given to that section is the worst score within the section, i.e. if 
one question is scored 1 and another 2, then the score for that section is 2. 
In addition, if an aide or devise is used or if help is required from another individual, then the minimum score 
for that section is 2. If the section score is already 2 or more then no modification is made. When there are 
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Efficacy 
no aids or devices or help indicated for a category, the category’s score is not modified. Where the aid or 
device for each section is: 
HAQ-DI Category 
Companion AIDS OR DEVICES item 
DRESSING & 
GROOMING 
Devices used for dressing (button hook, zipper pull, long handled shoe horn 
etc.) 
ARISING  
Special or built up chair 
EATING  
Built up or special utensils 
WALKING  
Cane, walker, crutches, wheelchair 
HYGIENE  
Raised toilet seat, bathtub seat, bathtub bar, long handled appliances in 
bathroom 
REACH  
Long handled appliances for reach 
GRIP 
Jar opener (for jars previously opened). 
If a response to a component question within a section is left blank, then the score for that section is 
determined by the remaining completed question(s) within the section. 
The HAQ-DI is calculated from the taking the 8 scores of the 8 sections are summed and divided by 8. If 
one section is not completed by a participant, then the summed score would be divided by 7. At least 6 
sections must be non-missing for the HAQ-DI to be calculated, else the HAQ-DI is set to missing. 
VAS scales 
VAS scales will be converted to a 0-3 scale before contributing to the SHAQ. The scaled VAS score will be 
calculated as: Scaled score = score*0.03. Scaled VAS scores will be presented in outputs.  
Lab & Home FVC 
Where multiple assessments are taken, the largest of the non-missing values will be used in the analysis.  
16.6.4. 
Safety 
ECG Parameters 
RR Interval 
• If RR interval (msec) is not provided directly, then RR can be derived as: 
(1/HR)/1000(i.e. 1 / heart rate where the heart rate is taken as part of the ECG) 
• If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive. 
Corrected QT Intervals 
• When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.  QTcF or QTcB values entered by the site will always be presented in output.  
• IF RR interval (msec) is provided (or can be derived from HR) then missing QTcB and/or QTcF 
will be derived as:  
 
 
 
 
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Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of decimal places in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 decimal places: ‘< x’ becomes x – 0.01 
o Example 2: 1 decimal places: ‘> x’ becomes x + 0.1 
o Example 3: 0 decimal places: ‘< x’ becomes x – 1     
• Reticulocyte Production Index (RPI) will be calculated, by GSK S&P, as: 
RPI = Reticulocyte Count [%] x [Hematocrit [%] / 45] x 1/RMT 
To use the formula above Hematocrit and Reticulocyte Count must be converted from the SI unit 
(proportion) to a percentage by multiplying by 100 (note that the GSK code describes reticulocyte 
count as a percentage even though it is a proportion). 
Where Normal Hematocrit [%] = 45 and RMT (reticulocyte maturation time) is found from the table 
below: 
Haematocrit 
RMT 
>=40% 
1.0 
30% to 39.9% 
1.5 
20% to 29.9% 
2.0 
<20% 
2.5 
• Corrected calcium will be calculated, by GSK S&P as: 
Corrected Calcium [mmol/L] = Serum Calcium [mmol/L] + 0.02 * (40[g/L] – Serum Albumin[g/L]) 
Where Normal Serum Albumin = 40 [g/L] 
• eGFR (estimated Glomerular Filtration Rate) will be calculated by GSK S&P at all timepoints, 
this will also be provided directly by the vendor at screening. The GSK calculated value at 
screening will be used as primary for reporting (e.g. will be used as baseline if appropriate).   
• The calculation will be as follows: 
SI Results MDRD (GFR) (ml/min/1.73m2) = (175 * (PD9S3/88.4) -1.154) * (Age - 0.203 * Race * Sex)  
Where PD9S3 = Serum Creatinine (UMOL/L), 
Race = 1.212 for Black & 1.000 for other, Sex = 1.00 for males and 0.742 for females. 
16.6.5. 
Pharmacodynamic 
Derived Parameters for Serum Level of OSM 
% Target Engagement (TE%) 
TE (%) = 100*(1- [Free OSM/Baseline Free OSM]) 
Note: predicted value will be presented, this will be derived by CPMS 
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16.6.6. 
Biomarkers 
Derived Parameters for Fibrosis and Histology 
ELF 
The ELF test will be provided by the vendors using on the ADVIA Centaur system. For reference, 
here is the formula as specified in the laboratory manual (Rev. C, 2015-01). 
 
Alpha SMA 
αSMA= αSMA Area (µm²)/(Dermis Area). 
2GSSc Skin Biomarker 
2GSSc = -27.6844 + (4.46*(Baseline THBS1)) + (5.31*∆MS4A4A) + (4.96*∆THBS1) 
Where, ∆MS4A4A and ∆THBS1 are change from baselines and Baseline THBS1 is baseline value 
of THBS1 on log 2 scale 
General 
If biomarker values are below the lower limit of quanitification, data will be imputed as half the lower 
limit of quantification (LLQ). 
If biomarkers are above the upper limit of quantification, data will be imputed as for lab data, where 
the number of decimal places in the observed values will be used to determine how much to add in 
order to impute the corresponding numeric value:  
o Example 1: 2 decimal places: ‘> x’ becomes x + 0.01 
o Example 2: 1 decimal places: ‘> x’ becomes x + 0.1 
o Example 3: 0 decimal places: ‘> x’ becomes x + 1     
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16.7. 
Appendix 7: Reporting Standards for Missing Data 
16.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Participant study completion (i.e. as specified in the protocol) was defined as 
completion of all assessments on Day 197(Week 28).  
• In cohort 1 non-evaluable participants will be replaced. 
• In cohort 2 withdrawn participants are not replaced in the study. 
• All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
Figures, unless otherwise specified. 
 
16.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as reported. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 
16.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4. 
o Missing Stop Day: Last day of the month will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
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Element 
Reporting Detail 
on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
16.7.2.2. 
Handling of Missing Data for Statistical Analysis 
For the joint model, missing baseline data will be modelled as part of the MCMC 
sampling, no post baseline data will be imputed.  For all other models, missing data will 
not be imputed. 
16.7.2.3. 
Handling of Missing Data for PK Analysis 
GSK standards for handling missing PK data will be applied to all PK outputs. 
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16.8. 
Appendix 8: Values of Potential Clinical Importance 
16.8.1. 
Laboratory Values - Haematology 
Haematology parameters will use CTCAE grades (CTCAE criteria, V4.03: June 14, 
2010) to highlight important results based on laboratory value only (i.e. no clinical 
judgement will be applied).  CTCAE grades will replace the category of “values of 
potential clinical importance” for haematology parameters, see table below for reference. 
Parameter 
CTCAE v4.03 
Term for 
Adverse 
Event 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Haemoglobin 
Anemia 
Hemoglobin 
(Hgb)  
<LLN - 100 
g/L 
Hgb  <100 
- 80g/L 
Hgb <80 g/L;  
transfusion 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Haemoglobin 
Hemoglobin 
increased 
Increase in >0 
- 20 g/L above 
ULN or above 
baseline if 
baseline is 
above ULN 
Increase in 
>20 - 40 
g/L above 
ULN or 
above 
baseline if 
baseline is 
above ULN 
Increase in 
>40 g/L 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
 - 
Haptoglobin 
Haptoglobin 
decreased 
<LLN 
 - 
 - 
 - 
Lymphocyte 
count 
Lymphocyte 
count 
decreased 
<LLN - 0.8 
GI/L 
<0.8 - 0.5 
GI/L 
<0.5 - 0.2 
GI/L 
<0.2 GI/L 
Lymphocyte 
count 
Lymphocyte 
count 
increased 
 - 
>4 - 20 
GI/L 
>20 GI/L 
 - 
Neutrophil 
count 
Neutrophil 
count 
decreased 
<LLN - 1.5 
GI/L 
<1.5 - 1.0 
GI/L 
<1.0 - 0.5 
GI/L 
<0.5 GI/L 
Platelet 
count 
Platelet count 
decreased 
<LLN - 75.0 
GI/L 
<75.0 - 
50.0 GI/L 
<50.0 - 25.0 
GI/L 
<25.0 GI/L 
White blood 
cell count 
Leukocytosis 
 - 
 - 
>100 GI/L 
Clinical 
manifestations of 
leucostasis; 
urgent 
intervention 
indicated 
White blood 
cell count 
White blood 
cell 
decreased 
<LLN - 3.0 
GI/L 
<3.0 - 2.0 
GI/L 
<2.0 - 1.0 
GI/L 
<1.0 GI/Lp 
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16.8.2. 
 Laboratory Values – Chemistry and Liver 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
G/L 
 
30 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
µmol/L 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT (SGPT)  
U/L 
High 
 2x ULN 
AST (SGOT) 
U/L 
High 
 2x ULN 
Alkaline Phosphatase 
U/L 
High 
 2x ULN 
T Bilirubin  
µmol/L 
High 
 1.5xULN 
T. Bilirubin + ALT 
µmol/L 
High 
1.5xULN T. Bilirubin 
 
+ 
U/L 
 2x ULN ALT 
16.8.3. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>530 
Absolute PR Interval 
msec 
< 110 
> 220 
Absolute QRS Interval 
msec 
< 75 
> 110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
> 60 
‘QTc’ (corrected QT interval) may be recorded as QTcF, QTcB or another method documented in the SI 
code list. These limits should be applied to both QTcF, QTcB (which will be primary output variables) and 
alternative QTc methods (which will be listed where relevant) 
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16.8.4. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern Range 
An increase or decrease from baseline of the 
following magnitude 
Systolic Blood Pressure 
mmHg 
≥ 40 
Diastolic Blood Pressure 
mmHg 
≥ 20 
Heart Rate 
bpm 
≥ 30 
 
 
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16.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
The details of the PopPK model are specified in Appendix 10 (PopPK/PD model).  The 
first intent is to simultaneously estimate the parameters of the PopPK/PD model, using 
total GSK2330811 and Total OSM data. If a sequential modelling approach (i.e. PopPK 
model and PK/PD separately) is required, the principles and details specified in Appendix 
10 will apply to the PopPK model. Appendix 10 
16.9.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
NONMEM dataset 1: PK/PD 
o To support both the PK and the PK/PD analyses a NONMEM dataset will be 
generated 
o The population PKPD dataset will be used for both the PK and the PK/PD analysis 
selecting the rows which apply.  
o It 
will 
be 
a 
comma 
delimited 
text 
file, 
named 
<“NM.GSK2330811.201247.PKPD.v1.csv”>. 
o This file will include events of dosing or concentration as rows, with the variables in 
the table below as columns. Rows will be in increasing order of unique subject 
identification number; and all events in the same subject must be consecutive and in 
chronological order, ending with the last concentration event (i.e. dosing events that 
occur after the last quantifiable concentration in a subject will not be included in the 
data file). 
o All plasma and blister fluid GSK2330811 and PD (free and total OSM in blister and 
serum) will be included (i.e. all scheduled and unscheduled visits). 
o Non-numerical concentration values (such as missing samples, not assayed samples 
or non-reportable samples) will not be included. Subjects with non-quantifiable 
concentration values will be included. 
Name 
Implicit Unit 
Description  
Derivation 
Format 
ID 
- 
Unique subject 
identification number 
PKCNC.SUBJID for concentration 
events and EXPOSURE.SUBJID 
for dosing events. 
Numeric 
TRFD 
H 
Event time from first 
dose 
(PKCNC.PCSTDM – 
MSTONE.MSTSTDM)/3600 for 
PK concentration events. Similarly 
for PD concentration events and 
EXPOSURE.EXSTDM – 
MSTONE.MSTSTDM)/3600 for 
dosing events. Rounded to 2 
decimal places. 
Numeric 
DV 
PK: ng/mL PD: 
pg/ml for OSM  
For concentration 
events: plasma and 
blister fluid 
concentration of 
GSK2330811, OSM 
free and total in serum 
and blister. For dosing 
events: 0 
PKCNC.PCSTRESN for PK 
concentration events (similarly for 
PD concentration events). "0" for 
dosing events. “0” for non-
quantifiable concentrations 
 
BIOMARK.BIORESN for 
BITESTCD= 
Numeric 
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Name 
Implicit Unit 
Description  
Derivation 
Format 
CONCTSZ (Normal Activity) for 
OSM 
BQL 
Below limit of 
quantification 
concentrations 
1 for non-quantifiable 
concentrations, 0 otherwise 
Note: LLQ=100ng/mL for 
GSK2330811; LLQ=1.4pg/mL for 
Free and Total OSM 
numeric 
AMT 
mg 
For dosing events: 
dose of GSK2330811.  
For concentration 
events: 0 
For dosing events (i.e. EVID=1): 0 
for subjects on Placebo and dose 
for subjects on GSK2330811. For 
concentration events (i.e. EVID=0) 
AMT=0.  
numeric 
MDV 
- 
For concentration 
events: 0 
For non-quantifiable 
concentration values: 
0. 
For dosing events: 1 
Hard coded as description (1 if 
data is from EXPOSURE; 0 if 
PKCNC.PCSTRESN or PD is not 
missing; 0 if PCSTRESN is 
missing and PCORRES is not 
missing, i.e. non-quantifiable 
sample).  
Numeric 
EVID 
For DOSE events: 1, 
for concentration 
events: 0 
CMT 
- 
Compartment: 
For dosing events 1, 
for PK concentration 
events: 2. For PD 
concentration events: 
4 and 5. 
1 in records with LABL= “DOSE”.  
2 in records with LABL= “PK”. 
4 in records with LABL= ”PD” and 
ASSAY_NAME=”Free Oncostatin 
M”. 
5 in records with LABL= ”PD” and 
ASSAY_NAME=”Total Oncostatin 
M” 
. 
Numeric 
NOMT 
H 
Planned PK sample 
time relative to dose 
For dosing events: 0 
For pre-dose 
concentration events: 
0 
Extract numeric part of 
PKCNC.PTM (or format 
PTMNUM). Similarly for PD. For 
dosing events = "0" 
Numeric 
DAY 
- 
Study day 
PKCNC.PCACTSDY for 
concentration events (similarly for 
PD) and EXPOSURE.EXACTSDY 
for dosing events. 
Numeric 
VIS 
- 
Visit number 
PKCNC.VISITNUM  (visit 
sequence number) for PK events 
(similarly for PD) and 
EXPOSURE.VISITNUM for 
dosing events. 
Numeric 
DOSE 
mg 
Dose of GSK2330811 
in mg (for all events) 
AMT added to all records 
Numeric 
STUD 
- 
Numeric part of study 
identifier (i.e. 201247) 
201247 for all records 
Numeric 
BASELINE 
Same unit of 
DV for each 
0 if LABL_NAME=”PK” 
and ”DOSE”, baseline 
Numeric 
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Name 
Implicit Unit 
Description  
Derivation 
Format 
ASSAY_NAME 
otherwise 
SEX 
 
Subject gender 
1 for males and 2 for females 
Numeric 
WT 
kg 
Body weight at 
baseline visit 
VITALS.WEIGHT at baseline visit. 
Numeric 
BMI 
kg/m2 
Body mass index at 
baseline visit 
VITALS.WEIGHT/(VITALS.HEIGH
T/100)^2 
Numeric 
HT 
cm 
Height at baseline visit 
VITALS.HEIGHT 
Numeric 
DATE 
- 
Date of event 
For dosing events, 
EXPOSURE.EXSTDT. For PK 
events, PKCNC.PCSTDT.  
Similarly for PD. 
DD/MM/YYYY 
TIME 
- 
Clock time of event 
For dosing events, 
EXPOSURE.EXSTTM. For PK 
events, PKCNC.PCSTTM. 
Similarly for PD. 
HH:MM 
LLQ 
- 
Lower Limit of 
Quantitation 
. 
Numeric 
FLAG 
1 to 7  
1 in records with LABL= “DOSE”.  
2 in records with LABL= ”PK” and 
MATRIX_NAME=”Plasma”. 
3 in records with LABL= ”PK” and 
MATRIX_NAME=”Blister Fluid”. 
4 in records with LABL= ”PD” and 
ASSAY_NAME=”Free Oncostatin 
M” and MATRIX_NAME=”serum”. 
5 in records with LABL= ”PD” and 
ASSAY_NAME=”Total Oncostatin 
M” and MATRIX_NAME=”Serum”. 
6 in records with LABL= ”PD” and 
ASSAY_NAME=”Free Oncostatin 
M” and MATRIX_NAME=”Blister 
Fluid”. 
7 in records with LABL= ”PD” and 
ASSAY_NAME=”Total Oncostatin 
M” and MATRIX_NAME=”Blister 
Fluid”. 
numeric 
REGIMEN 
Regimen sort order 
numeric 
COHORT 
Cohort sort order 
numeric 
LABL_NAM
E 
- 
Record label 
VARCHAR2(32) 
Maximum 32 characters (numeric 
or text), 
Record identifier:  
In dosing records: “DOSE” 
In PK concentration records “PK” 
varchar 
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Name 
Implicit Unit 
Description  
Derivation 
Format 
in PD concentration records “PD” 
ASSAY_NA
ME 
- 
Used assay 
In records with  
LABL=”DOSE” and ”PK”, use 
“PK_assay” 
In records with LABL=”PD” use 
the appropriate assay: 
 “OSM free etc” 
varchar 
MATRIX_N
AME 
Used matrix (i.e. 
“plasma”, “serum”, 
“blister”) 
. 
varchar 
MRSS 
 
mRSS score 
 
numeric 
 
Dataset 2: PK/PD and Haematology 
The dataset will include exposure, total OSM, Platelets (PLT), Red Blood Cells (RBC), 
Reticulocytes (RET), Haemoglobin (Hb), Immature reticulocyte fraction, Reticulocytes 
(percentage/ratio), erytropoyetin (EPO) and thrombopoietin (TPO) 
• An additional dataset will be generated to support graphical analyses for haematology 
biomarkers 
• It will be a comma delimited text file, named eda-gsk2330811-201247-pkhaem.csv. 
• This file will include time of visits as rows, with the variables in the table below as 
columns. Rows will be in increasing order of unique subject identification number; 
and all events in the same subject must be consecutive and in chronological order. 
• if any variable is missing at a certain time, assign NA.   
• All scheduled and unscheduled visits will be included for plasma GSK2330811, 
serum Total OSM and haematology (Platelets, Red Blood Cells, Reticulocytes, 
Haemoglobin, Immature reticulocyte fraction, Reticulocytes (percentage/ratio), EPO, 
TPO). Only central labs readings will be included. 
• Non-numerical concentration values (such as missing samples, not assayed samples 
or non-reportable samples) will not be included. Subjects with non-quantifiable 
concentration values will be included. 
 
Pseudocode:  
 
Select SUBJID, ELTMSTN, PCSTRESN, PCACTSDY, VISITNUM, PCSTDT from PKCNC where 
PKCNC.PCSPEC='Plasma'. There should be one record per subject per visit. 
Rename NOMT=ELTMSTN, DAY= PCACTSDY, DATE=PCSTDT 
Select SUBJID, ATRGDY, BISTRESN, BIACTDY, VISITNUM, BIDT from BIOMARKER where 
BICATCD in ('TOSM') and AVISIT is not  'DAY 1'. There should be one record per subject per 
visit. 
Mutate ATRTGDY= ATRGDY-1 
Rename NOMT=ATRTGDY, DAY=BIACTDY, DATE=BIDT 
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Select SUBJID, AVISIT, LBSTRESN, LBACTDY, VISITNUM, BIDT (please verify if this is the date 
information) from LABHAEM where LBTESTCD in ('PLT_BLC', HB_BLC, RBC_BLC, RETIC_BLC, 
IRF_BLQ, RETIC_BLQ, EPO_PLC, THROMB_PLC)  
Calculate NOMT as follow: if AVISIT='BASELINE'  then NOMT=0 else NOMT=(numerical part of 
AVISIT). Drop AVISIT. 
Rename DAY= LBACTDY, DATE=BIDT 
Transpose records by SUBID, NOMT DAY,DATE,VISITNUM (var=LBSTRESN, id= LBTESTCD) so 
that there is one record per subject per visit. Each variable in LBTESTCD will be a column.  
Join selected PKCNC and BIOMARKER records by SUBJID, NOMT, DAY, DATE 
Join with LABHAEM dataset by SUBJID, NOMT, DAY, DATE 
Select SUBJID, and information on DOSE, SEX, WT, BMI, HT, REGIMEN and COHORT from 
appropriate dataset and Join by SUBJID 
 
Name 
Implicit Unit 
Description  
Derivation 
Format 
SUBJID 
- 
Unique subject 
identification number 
 
Numeric 
NOMT 
h 
Planned sample time 
relative to dose 
 
 
Numeric 
CONC 
ng/mL 
GSK2330811 plasma 
concentration 
PKCNC.PCSTRESN where 
PKCNC.PCSPEC='Plasma' 
 
if PKCNC.PCSTRESC='NQ' then 
CONC=0 
 
if >1 observation at same 
date/time, take the mean.  
numeric 
TOSM 
pg/mL 
Total OSM serum 
concentration 
BIOMARK.BISTRESN where 
BICATCD in ('TOSM')  and 
AVISIT is not  'DAY 1' 
 
if >1 observation at same 
date/time, take the mean. 
 
PLT 
1E9/L 
platelet count 
LBSTRESN where LBTESTCD in 
('PLT_BLC') 
 
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Name 
Implicit Unit 
Description  
Derivation 
Format 
HB 
g/L 
haemoglobin 
LBSTRESN where LBTESTCD in 
('HB_BLC') 
 
RBC 
TI/L 
red blood cells 
LBSTRESN where LBTESTCD in 
('RBC_BLC) 
 
RETIC 
TI/L 
reticulocytes 
LBSTRESN where LBTESTCD in 
('RETIC_BLC') 
 
IMRETF 
 
immature reticulocyte 
fraction 
LBSTRESN where LBTESTCD in 
('IRF_BLQ') 
 
RETPR 
ratio 
reticulocyte 
(percentage/ratio) 
LBSTRESN where LBTESTCD =’ 
RETIC_BLQ’ 
 
EPO 
 
erithropoietin 
in clinical chemistry 
lbtestcd=”EPO_PLC”.   
 
TPO 
ng/L 
thrombopoietin 
LBSTRESN where LBTESTCD =’ 
THROMB_PLC’ 
 
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Name 
Implicit Unit 
Description  
Derivation 
Format 
DAY 
- 
Study day 
 
Numeric 
VISITNUM 
- 
Visit number 
 
Numeric 
DATE 
- 
Date of event 
 
DD/MM/YYYY 
DOSE 
mg 
Dose of GSK2330811 
in mg  
Numeric 
SEX 
Subject gender 
1 for males and 2 for females 
Numeric 
WT 
kg 
Body weight at 
baseline visit 
VITALS.WEIGHT at baseline visit.  Numeric 
BMI 
kg/m2 
Body mass index at 
baseline visit 
VITALS.WEIGHT/(VITALS.HEIGH
T/100)^2 
Numeric 
HT 
cm 
Height at baseline visit 
VITALS.HEIGHT at baseline 
Numeric 
REGIMEN 
Regimen sort order 
numeric 
COHORT 
Cohort sort order 
numeric 
 
Dataset 3: PK and Clinical efficacy and biomarkers 
The dataset will include exposure-related parameters and clinical efficacy and biomarker 
endpoints. The dataset will be required after SAC, based on the results of the statistical 
analysis.  
 
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16.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Methodology 
Concentration-time profiles of GSK2330811 in plasma and Total OSM in serum, will be 
analysed by population pharmacokinetic/pharmacodynamic (PopPK/PD) methods using a 
non-linear mixed-effects modelling approach. 
The objective of this analysis is to develop population PK/PD models that characterize 
the concentration-time profile of GSK2330811 and total OSM following repeated 
subcutaneous administration of GSK2330811 in patients with dcSSc. 
Concentration-time profiles of GSK2330811 in plasma and platlets and haemoglobin will 
be analysed by PK/PD methods using a non-linear mixed-effects modelling approach. All 
the available exposure haematology clinical data relative to GSK2330811 will be 
combined for the analysis. This pooled analysis will be performed as a separate analysis 
and reported separately.  
Analysis of clinical endpoints and biomarkers could include exposure-response, 
longitudinal exposure-response and joint modelling. This analysis would be performed 
after SAC, based on the results of the statistical analysis.  
16.10.1. 
Systems 
The quantitative analysis will be performed using NONMEM (ICON Solutions) and PsN 
(Perl Speaks NONMEM) or another software platform deemed appropriate. Graphical 
displays and, if needed, modifications of the dataset will be produced using R (The R 
Foundation for Statistical Computing). The analysis will be performed by, or under the 
direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), 
GlaxoSmithKline using the GSK modelling environment MAP (Model-based Analysis 
Platform) using the currently supported versions of all software packages. 
16.10.2. 
Data Assembly 
GSK Stats and Programming will generate the NONMEM input dataset, as detailed in 
Section 16.9.1. 
16.10.3. 
Model Development 
A population PK/PD model for SC single dose of GSK2330811 in healthy volunteers was 
developed [Reid J, 2018] and will be the starting point for the population PK/PD analysis.  
Individual parameters (empirical Bayes estimates) will be derived applying the HV 
popPKPD model to the repeat dose in dcSSc dataset with the MAXEVAL=0 option, if 
$EST METHOD=1, or with the EONLY=1 option, if $EST METHOD=IMP. If the 
corresponding model diagnostics indicate that the HV popPKPD model is appropriate to 
represent the dcSSc PKPD data, then these individual parameters for the dcSSc 
population will be considered adequate to characterise the PK/PD.  
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If the parameter set of the HV popPKPD model applied to the dcSSc data set results in 
substantial bias or if a further exploration of the covariate effect in the dcSSc population 
is deemed necessary, the parameters of the HV popPKPD model will be re-estimated for 
the dcSSc PK/PD data alone and/or for a pooled HV (study 201246, study 208564 cohort 
1) /dcSSc (study 201247) data set. If a pooled analysis is deemed necessary, it will be 
performed as a separate analysis and reported separately. 
 
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16.11. 
Appendix 11: Abbreviations & Trade Marks 
16.11.1. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
A&R 
Analysis and Reporting  
AUC 
Area under the (Concentration-Time) Curve 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CRP 
C-Reactive Protein 
CRISS 
Composite Response Index in diffuse cutaneous Systemic Sclerosis 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBF 
Database Freeze 
DBR 
Database Release 
dcSSc 
Diffuse Cutaneous Systemic Sclerosis 
DOB 
Date of Birth 
DP 
Decimal Places 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
ELF 
Enhanced Liver Fibrosis 
EPO 
Erythropoietin 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
FVC 
Forced Vital Capacity 
GSK 
GlaxoSmithKline 
HAQ-DI 
Health Assessment Questionnaire Disability Index HAQ-DI 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
MMRM 
Mixed Model Repeated Measures 
mRSS 
modified Rodnan skin score 
OSM 
Oncostatin M 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Friderica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
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Abbreviation 
Description 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
RSE 
Relative standard error 
SAC 
Statistical Analysis Complete 
SD 
Standard Deviation 
SE 
Standard Error 
SDTM 
Study Data Tabulation Model 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
TPO 
Thrombopoietin 
16.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
PsN 
 
 
SAS 
 
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16.12. 
Appendix 12: List of Data Displays 
16.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.32 
NA 
Safety (incl. immunogenicity) 
3.1 to 3.36 
3.1 to 3.16 
Pharmacokinetic 
4.1 
4.1 to 4.8 
Population Pharmacokinetic (PopPK) 
5.1 to 5.2 
5.1 to 5.3 
Pharmacodynamic  
6.1 to 6.4 
6.1 to 6.6 
Pharmacokinetic / Pharmacodynamic 
7.1 to 7.2 
7.1 to 7.4 
Biomarker 
8.1 to 8.23 
8.1 to 8.25 
Exploratory Efficacy 
9.1 to 9.22 
9.1 to 9.23 
Section 
Listings 
ICH Listings 
1 to 34 
Other Listings 
35 to 51 
16.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays will be provided in a separate document. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Population Pharmacokinetic (PopPK) 
POPPK_Fn 
POPPK_Tn 
POPPK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PK/PD_Ln 
Biomarker 
BIO_Fn 
BIO_Tn 
BIO_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
16.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
SRT  
Safety Review Team 
DEC 
Dose Escalation 
DECX 
Expanded Dose Escalation [conditional on DEC decision].  Note that all outputs 
created for DEC will also be produced for DECX unless specified.  Depending 
on the reason for expansion this RAP may be further developed for the DECX 
interim. 
IA1 
Interim Analysis 1 Statistical Analysis Complete  
(“Target Engagement” interim) 
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Delivery [Priority] [1] 
Description 
IA2 
Interim Analysis 2 Statistical Analysis Complete 
(“Baseline biomarker” interim) 
Adhoc DRC 
Statistical Analysis Complete at request of the data review committee (DRC) 
SAC  
Final Statistical Analysis Complete 
NOTES: Indicates priority (i.e. order) in which displays will be generated for the reporting effort, priority may not be 
specified 
For interim analyses, not all outputs produced for the interim will automatically be shared 
in the meeting. For example, if it is not necessary to review individual level data then, 
although this may have been produced, it will not be reviewed by the DRC. Also, as 
described above, outputs from the preceding SRT may be shared at any interim but note 
that the data cut for the SRT may be at a different time than the data cut for the DEC and 
that SRT outputs may be produced from data that has not been cleaned by data 
management. 
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16.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
Disposition 
1.1.  
Safety 
ES1 
Summary of Subject Disposition 
Include Total Column 
SAC 
1.2.  
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failures 
 
SAC 
1.3.  
Safety 
SD1 
Summary of Treatment Status and Reason for Discontinuation of Study Treatment 
Include Total Column 
SAC 
1.4.  
Enrolled 
NS1 
Summary of Number of Subjects by Country and Centre ID 
PLS Requirement 
SAC 
1.5.  
Per 
Protocol 
NS1 
Summary of Number of Subjects by Country and Centre ID 
PLS Requirement 
SAC 
Protocol Deviations 
1.6.  
Safety 
DV1 
Summary of Important Protocol Deviations not Related to COVID-19 
 
SAC 
1.7.  
Safety 
DV1 
Summary of Important Protocol Deviations Related to COVID-19 
 
SAC 
Populations Analysed 
1.8.  
Screened 
SP1 
Summary of Study Populations 
 
IA1, IA2, SAC 
1.9.  
Safety 
SP2 
Summary of the Exclusions from the Per Protocol Population 
Include programmatical 
exclusions specified in Section 
16.1.1. 
SAC 
Demography 
1.10. 
Safety 
DM1 
Summary of Demographic Characteristics 
 
IA1, IA2, Adhoc 
DRC, SAC 
1.11. 
Per 
Protocol 
DM1 
Summary of Demographic Characteristics 
Only produce if per-protocol 
population is different from the 
safety population.  
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
1.12. 
Enrolled 
DM11 
Summary of Age Ranges 
 
SAC 
1.13. 
Safety 
DM6 
Summary of Race and Racial Combination Details 
 
IA2, Adhoc 
DRC, SAC 
Disease characteristics 
1.14. 
Safety 
POP_T1 
Summary of Systemic Sclerosis Disease History 
 
IA1, IA2, SAC 
1.15. 
Safety 
POP_T2 
Summary of Systemic Sclerosis Medication History 
 
IA1, IA2, SAC 
1.16. 
Safety 
POP_T2 
Summary of Concomitant Mycophenolate  
 
IA1, IA2, SAC 
1.17. 
Safety 
POP_T3 
Summary of Historical Autoantibody Profile 
 
IA1, IA2, SAC 
1.18. 
Safety 
POP_T3 
Summary of Baseline Autoantibody Profile 
 
SAC 
1.19. 
Safety 
EFF_T1 
Summary of DLCO (mL/min/mmHg) at Screening  
By treatment, Include 
corrected and uncorrected for 
Hb. 
SAC 
1.20. 
Per 
Protocol 
POP_T1 
Summary of Systemic Sclerosis Disease History 
As for Table 1.12. Only 
produce if per-protocol 
population is different from the 
safety population. 
SAC 
1.21. 
Per 
Protocol 
POP_T2 
Summary of Systemic Sclerosis Medication History 
As for Table 1.13. Only 
produce if per-protocol 
population is different from the 
safety population. 
SAC 
1.22. 
Per 
Protocol 
POP_T2 
Summary of Concomitant Mycophenolate  
As for Table 1.14. Only 
produce if per-protocol 
population is different from the 
safety population. 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
1.23. 
Per 
Protocol 
POP_T3 
Summary of Baseline Autoantibody Profile 
As for Table 1.16. Only 
produce if per-protocol 
population is different from the 
safety population. 
SAC 
1.24. 
Per 
Protocol 
EFF_T1 
Summary of DLCO (mL/min/mmHg) at Screening  
By treatment, Include 
corrected and uncorrected for 
Hb. Only produce if per-
protocol population is different 
from the safety population. 
SAC 
1.25. 
Per 
Protocol 
POP_T4 
Summary of Mycophenolate use at Day 1 
If biomarker analysis will be 
done by safety population, use 
safety population here.  
SAC 
Concomitant Medications and Medical Conditions 
1.26. 
Safety 
MH1 
Summary of Current/Past Medical Conditions other than Systemic Sclerosis  
 
SAC 
1.27. 
Safety 
CM8 
Summary of Concomitant Medications by Ingredient and Ingredient Combinations 
 
IA1, IA2, SAC 
1.28. 
Safety 
SU1 
Summary of Smoking History 
 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
Exposure 
1.29. 
Safety 
POP_T5 
Summary of Treatment Compliance 
Add footnotes:  
'[1] Includes subjects who 
attended the study visit and a 
dose was withheld, it does not 
include subjects who missed 
dosing visits.'   
'Note: Percentages use n as 
denominator'. 
SAC 
1.30. 
Per 
Protocol 
POP_T5 
Summary of Treatment Compliance 
Add footnotes:  
'[1] Includes subjects who 
attended the study visit and a 
dose was withheld, it does not 
include subjects who missed 
dosing visits.'   
'Note: Percentages use n as 
denominator'.Only produce if 
per-protocol population is 
different from the safety 
population. 
SAC 
1.31. 
Safety 
POP_T6 
Summary of Exposure to Study Treatment 
 
SAC 
1.32. 
Per 
Protocol 
POP_T6 
Summary of Exposure to Study Treatment 
Only produce if per-protocol 
population is different from the 
safety population. 
SAC 
 
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16.12.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Adverse Events 
3.1.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term, by Treatment Phase 
For IA1, don’t present by phase and 
remove ‘, by Treatment Phase’ from the 
title. 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
IA1, IA2, Adhoc 
DRC, SAC 
3.2.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events, by Treatment 
Phase 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
SAC 
3.3.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
 
SAC 
3.4.  
Safety 
AE5A 
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity, by Treatment Phase 
Add a row to include number of 
participants contributing to treatment 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.5.  
Safety 
AE1 
Summary of Drug-Related Adverse Events, by Treatment Phase 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
SAC 
3.6.  
Safety 
AE5A 
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity, by Treatment 
Phase 
SAC 
3.7.  
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events, by 
Treatment Phase 
SAC 
Serious AEs 
3.8.  
Safety 
AE1 
Summary of Non-Fatal Serious Adverse Events, by System 
Organ Class, by Treatment Phase 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator.  
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
SAC 
3.9.  
Safety 
AE1 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term, by Treatment Phase 
For IA1, don’t present by phase and 
remove ‘, by Treatment Phase’ from the 
title. 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
IA1, IA2, SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.10. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
 
SAC 
3.11. 
Safety 
AE3 
Summary of Serious Drug-Related Adverse Events, by 
Treatment Phase 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
SAC 
3.12. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term, by Treatment Phase 
SAC 
3.13. 
Safety 
AE3 
Summary of Non-Fatal Drug-Related Serious Adverse Events, 
by Treatment Phase 
Add a row to include number of 
participants contributing to treatment 
phase and use as denominator. 
Add footnote ‘Note: On treatment phase 
defined as period from first dose to last 
dose + 28 days. Follow up phase 
defined as period after last dose + 28 
days.’ 
SAC 
3.14. 
Safety 
AE3 
Summary of Fatal Drug-Related Serious Adverse Events, by 
Treatment Phase 
 
Chemistry 
3.15. 
Safety 
LB1 
Summary of Chemistry 
 
IA1, IA2, SAC 
3.16. 
Safety 
LB1 
Summary of Change from Baseline in Chemistry  
 
IA1, IA2, SAC 
3.17. 
Safety 
LB1 
Summary of Percentage Change from Baseline in Chemistry 
 
IA1, IA2, SAC 
3.18. 
Safety 
LB17 
Summary of Worst-Case Chemistry Results Relative to Potential 
Clinical Importance (PCI) Criteria Post-Baseline Relative to 
Baseline 
 
DEC, SAC 
Haematology 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.19. 
Safety 
SAFE_T1 
Summary of Blinded Haematology 
Blinded dataset.  Page by cohort. 
By Parameter, this output should be 
produced for the blinded safety 
parameters (Table 3 in Section 
3.1.1.2).  These are: 
Platelet Count, Haemoglobin, 
Haematocrit, RBC count 
For SRTs, include date of the central 
lab data cut.  
SRT, DEC 
3.20. 
Safety 
SAFE_T1 
Summary of Change from Baseline – Blinded Haematology 
Blinded dataset. Page by cohort. 
By Parameter, this output should be 
produced for the blinded safety 
parameters Table 3 in Section 
3.1.1.2).  These are: Platelet Count, 
Haemoglobin, Haematocrit, RBC count 
For SRTs, include date of the central 
lab data cut. 
SRT, DEC 
3.21. 
Safety 
SAFE_T3 
“[Blinded] Summary of Platelet Count and Anaemia Events by 
CTCAE Grade [and cohort] 
By Parameter / event. Just 
Haemoglobin (anemia) and Platelet 
count decrease 
For SRT use ‘Blinded’ i.e. do not report 
treatment code but do report cohort (i.e. 
cohort 1 and cohort 2) 
For Interims and final do use treatment 
code, do not use cohort. 
SRT 
IA1, IA2, Adhoc 
DRC, SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.22. 
Safety 
SAFE_T4 
Summary of Haematological Limits Crossed During Study 
Haemoglobin, report two events: 
<80 g/L (permanent discontinuation), 
<90g/L (repeat test)  
Platelets, report three events: 
<50 GI/L,(permanent discontinuation)  
>=50 GI/L & <75 GI/L (temporary 
discontinuation)  
and <100 GI/L (repeat test) 
SAC 
3.23. 
Safety 
LB1 
Summary of Haematology 
By parameter 
IA1, IA2, Adhoc 
DRC, SAC 
3.24. 
Safety 
LB1 
Summary of Haematology Change from Baseline 
By parameter 
IA1, IA2, Adhoc 
DRC, SAC 
3.25. 
Safety 
LB1 
Summary of Percentage Change from Baseline in Haematology 
By parameter 
IA1, IA2, Adhoc 
DRC, SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.26. 
Safety 
LB16 
Summary of Haematology Results by Maximum CTCAE Grade 
Increase Post-Baseline Relative to Baseline 
Add Footnote:  
[1] CTCAE grade determined using 
laboratory values only as defined in 
V4.03: June 14, 2010 and does not 
take into account the clinical context. 
Note: Subjects are counted in Increase 
to Grade 1, 2, 3 and 4 by comparing the 
baseline grade to the maximum post 
baseline grade. Increase to Grades 1 to 
4 is by adding number of subjects in 
Increase to Grade 1, 2, 3, and 4. 
Increase to Grades 2 to 4 is by adding 
number of subjects in Increase to 
Grade 2, 3 and 4. Increase to Grades 3 
to 4 is by adding number of subjects in 
Increase to Grade 3 and 4.” 
IA1, IA2, Adhoc 
DRC, SAC 
3.27. 
Safety 
SAFE_T5 
Summary of Nadirs for Selected Haematology Parameters 
Haematology parameter group 1 only.  
by parameter, treatment group. 
Do not produce for Reticulocytes (i.e. 
produce for Haemoglobin, Red Blood 
Cells, Platelets and Absolute Neutrophil 
Counts only). Footnote: “Nadir is the 
lowest post-baseline value of the 
parameter including local lab results. 
Haematology Group 1 Parameters: 
Haemoglobin, Red Blood Cells, Platelet 
Count and Absolute Neutrophil Counts.” 
IA1, IA2, Adhoc 
DRC, SAC 
3.28. 
Safety 
SAFE_T5 
Summary of Nadirs for Selected Haematology Parameters as 
Percent Change from Baseline 
DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
3.29. 
Safety 
SAFE_T6 
Summary of Days to Nadir of Selected Haematology Parameters 
DEC, IA1, IA2, 
SAC 
Urinalysis 
3.30. 
Safety 
 
SAFE_T7 
Summary of Emergent Worst Case Urinalysis Results 
 
IA1, IA2, SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
ECG 
3.31. 
Safety 
EG1 
Summary of ECG Findings 
 
IA1, IA2, SAC 
3.32. 
Safety 
EG2 
Summary of ECG Values 
“Note: If multiple assessments collected 
in any clinical visits then the mean of 
the multiple values within the 
assessments has been used in the 
summary.” 
IA1, IA2, SAC 
3.33. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IA1, IA2, SAC 
Vital Signs 
3.34. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs by Visit 
 
IA1, IA2, SAC 
3.35. 
Safety 
VS7 
Summary of Vital Sign Results Relative to Potential Clinical 
Importance (PCI) Criteria Post-Baseline Relative to Baseline  
 
IA1, IA2, SAC 
 
16.12.6. 
Immunogenicity Tables (may be categorised under Safety in HARP folder structure / SAFIRE naming) 
Immunogenicity: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Immunogenicity 
3.36. 
Safety 
IMM1 
Summary of Positive Immunogenicity results 
Add footnote: 
Note: The denominator for confirmed 
positive is the total number of subjects 
at that visit who have immunogenicity 
data available. 
SAC  
 
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16.12.7. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Adverse Events 
3.1.  
Safety 
AE10 
Plot of Top 20 Adverse Events and Relative Risks 
Top 20 AE by overall number of events. 
Add following footnote and use in 
programming rules: 
“Note: Top 20 Adverse Events by 
overall number of events displayed and 
the AE has to have at least 1 
occurrence in the placebo group for 
relative risk to be calculated. Only AEs 
with calculated relative risk are 
displayed.” 
SAC  
Chemistry 
3.2.  
Safety 
BIO_F2 
Mean Profile for Chemistry Results by Treatment Group  
For Haptoglobin, Ferritin, Vitamin B12 
and Folate. Add footnote “Figure 
displays a subset of Chemistry 
parameters” 
SAC 
 
3.3.  
Safety 
BIO_F4 
Subject Profiles for Chemistry Results by Treatment Group 
SAC 
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Safety: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Haematology 
3.4.  
SRT Safety 
SAFE_F2 
Minimum Value at Each Visit – Blinded Haematology 
By Haematology parameter, this output 
should be produced for the blinded 
safety parameters (Table 3 in Section 
3.1.1.2). These are: Platelet Count, 
Haemoglobin, Haematocrit, RBC count  
Show relevant CTCAE grades as 
reference lines on y axis. 
The relevant boundary is the highest-
grade level that the lowest lab value is 
above (e.g. if the lowest values are just 
above grade 2, then show grade 2). 
Where grade depends on individual 
demographics (e.g. age, sex) show the 
highest boundary that applies to the 
analysis population. 
SRT, DEC 
3.5.  
SRT Safety 
SAFE_F2 
Greatest Reduction from Baseline at Each Visit – Blinded 
Haematology 
By Haematology parameter, this output 
should be produced for the blinded 
safety parameters (Table 3 in Section 
3.1.1.2). These are: Platelet Count, 
Haemoglobin, Haematocrit, RBC count  
Scatter plot, one point per planned visit. 
Include 0 on y-axis 
SRT, DEC 
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Safety: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.6.  
Safety 
201246/final/ 
Figure 3.1 
Participant Profiles of Haematology by Treatment Group 
By Haematology parameter, this output 
should be produced for the blinded 
safety parameters (Table 3 in Section 
3.1.1.2) with the exception of 
Haematocrit. i.e. for: Platelet Count, 
Haemoglobin, RBC count  
Do not show grade 1 boundary. Show 
grade 2 boundary (or higher) as 
described for output 3.2 if any 
participant exceeds grade 1. 
X axis use ‘Actual relative time’ from 
dose. Show all observed values 
including unscheduled. 
Add footnote “Figure displays a subset 
of haematology parameters” 
DEC[1], IA1[1] 
, IA2[1] 
3.7.  
Safety 
BIO_F4 
Subject Profiles for Haematology by Treatment Group 
By Haematology parameter. 
For SAC for Haematology parameter 
group 1, Red Cell Distribution Width 
and mean platelet volume. 
Use rules for CTCAE boundaries for 
Figure 3.7 
X axis use ‘Time (Days)’ from dose.  
Show all observed values including 
unscheduled. 
Add footnote “Figure displays a subset 
of haematology parameters” 
Panel by treatment group 
Adhoc DRC, 
SAC 
3.8.  
Safety 
BIO_F4 
Subject Profiles for Percentage Change from Baseline 
Haematology by Treatment Group 
Adhoc DRC, 
SAC 
3.9.  
Safety 
BIO_F2 
Mean Profile for Haematology by Treatment Group 
By Haematology parameter. 
For IA1 and IA2 for Haematology 
IA1, IA2, Adhoc 
DRC, SAC 
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Safety: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.10. 
Safety 
BIO_F2 
Mean Percentage Change from Baseline for Haematology by 
Treatment Group 
parameter group 1. 
For SAC, Haematology parameter 
group 1, Red Cell Distribution Width 
and mean platelet volume. 
X axis shows visits with approximate 
temporal spacing 
Add footnote “Figure displays a subset 
of haematology parameters” 
IA1, IA2, Adhoc 
DRC, SAC 
3.11. 
Safety 
PK_F1 
Scatter Plot of Platelet Nadir vs. Haemoglobin Nadir 
Panel by treatment group and grouped 
by individual subjects 
X-axis Label: Platelet Nadirs 
Y-axis Label: Haemoglobin Nadirs 
SAC 
Hepatobiliary (Liver) 
3.12. 
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
 
SAC 
3.13. 
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
 
SAC 
3.14. 
Safety 
201246/final/ 
Figure 3.9 
LFT Patient Profiles 
Single plot combining the following 
parameters: ALT = Alanine Amino 
Transferase, AST = Aspartate Amino 
Transferase, Alk. Phos. = Alkaline 
Phosphatase,Total Bili. = Total Bilirubin 
SAC 
ECG 
3.15. 
Safety 
EG7 
Empirical Distribution Function for Maximum Change from 
baseline in QTcF Interval 
All treatments on one plot. Calculate 
maximum change from baseline. 
SAC 
3.16. 
Safety 
EG8 
Distribution of QTcF Change by Visit and Treatment 
 
Use the 0, 30, 60 thresholds following 
shell. 
SAC 
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Safety: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Notes: 
1: Individual figure(s) will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data where possible to reduce 
the degree of unblinding, so this output will only be presented if necessary. 
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16.12.8. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
PK Plasma Concentration  
4.1.  
PK 
PKCT1 
Summary of Plasma GSK2330811 Concentration-Time Data 
(ng/mL)  
Add footnotes “ 
Note: No. of subjects with results below 
the lower limit of quantification, 
assigned 0 (LLQ=100 ng/mL). 
SD is set to missing if No. Imputed/n > 
0.3 
Samples from Day 14 – Day 84 are 
taken at trough (2 weeks after dosing).” 
DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
 
 
 
 
 
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16.12.9. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
PK Plasma Concentration 
4.1.  
PK 
PKCF1P 
Individual GSK2330811 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log) 
Footnote for all PK and PK/PD figures: 
Note: No. of subjects with results below 
the lower limit of quantification, 
assigned 0 (LLQ=100 ng/mL). 
Samples from Day 14 – Day 84 are 
taken at trough (2 weeks after dosing). 
Use actual time (days) as x axis (where 
days is a continuous variable) 
DEC[1], SAC 
4.2.  
PK 
PKCF1P 
Individual GSK2330811 Plasma Concentration-Time Plot by 
Treatment (Linear and Semi-Log) 
Use actual time (days) as x axis (where 
days is a continuous variable) 
[difference between this and 4.1 is that 
all profiles will be on one page for each 
treatment group] 
Note: No. of subjects with results below 
the lower limit of quantification, 
assigned 0 (LLQ=100 ng/mL). 
Samples from Day 14 – Day 84 are 
taken at trough (2 weeks after dosing). 
IA1[1], IA2[1], 
Adhoc DRC, 
SAC 
4.3.  
PK 
PKCF4 
Mean (SD) Plasma GSK2330811 Concentration-Time Plots by 
Treatment (Linear and Semi-log) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Note: No. of subjects with results below 
the lower limit of quantification, 
assigned 0 (LLQ=100 ng/mL). 
Samples from Day 14 – Day 84 are 
taken at trough (2 weeks after dosing). 
IA1, IA2, SAC 
4.4.  
PK 
PKCF5 
Median (Range) Plasma GSK2330811 Concentration-Time Plots 
by Treatment (Linear and Semi-log) 
SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
4.5.  
PK 
201246/adhoc/ 
Figure 4.9 
Mean (SD) Plasma GSK2330811 Concentration-Time Plots 
grouped by Treatment (Linear and Semi-log)  
As Figure 4.3 but on a single page, 
grouped by treatment. Add footnote 
Note: No. of subjects with results below 
the lower limit of quantification, 
assigned 0 (LLQ=100 ng/mL). 
Samples from Day 14 – Day 84 are 
taken at trough (2 weeks after dosing). 
IA1, IA2, Adhoc 
DRC, SAC 
4.6.  
PK 
PK_F1 
Scatter Plot of Individual Measured Steady State Concentration 
vs Baseline Body Weight 
Panel by treatment group and grouped 
by individual subjects. 
X-axis Label: Body Weight (kg) 
Y-axis Label: Measured Steady State 
Concentration (ng/mL) 
Adhoc DRC, 
SAC 
4.7.  
PK 
PK_F1 
Scatter Plot of Individual Platelet Nadirs as Percentage Change 
from Baseline vs Measured Highest Concentration 
Panel by treatment group and grouped 
by individual subjects. 
X-axis Label: Measure Highest 
Concentration (ng/mL) 
Y-axis Label: Percentage Change from 
Baseline of Platelet Nadirs 
Adhoc DRC, 
SAC 
4.8.  
PK 
PK_F1 
Scatter Plot of Individual Hemoglobin Nadirs as Percentage 
Change from Baseline vs Measured Highest Concentration 
Panel by treatment group and grouped 
by individual subjects. 
X-axis Label: Measure Highest 
Concentration (ng/mL) 
Y-axis Label: Percentage Change from 
Baseline of Hemoglobin Nadirs 
SAC 
Notes: 
1: Individual figure(s) will be produced for interim but may not be shared with the study team. Justification: DRCs follow the principle of presenting summary data where 
possible to reduce the degree of unblinding, so this output will only be presented if necessary. 
 
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16.12.10. Pharmacokinetic Population (PopPK) Tables 
Pharmacokinetic Population (POPPK): Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PopPK 
5.1.  
PK 
NA 
Summary of Derived Plasma GSK2330811 Pharmacokinetic 
Parameters from Population PK model 
Produced by CPMS  
Note: this table will contain the 
parameters from the Population PK 
analysis (which already summarise all the 
subjects). It will NOT be a summary of the 
individual subject’s parameters. 
Optional Footnote: Parameters estimated 
from study 201246 
OR Parameters estimated from observed 
data and data from 201246. 
IA1, SAC 
5.2.  
PK 
NA 
Predicted median (95%CI) vs Observed Mean (SE) plasma 
GSK2330811 concentration 
Produced by CPMS 
DEC, IA1, 
SAC 
 
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16.12.11. Pharmacokinetic Population (PopPK) Figures 
Pharmacokinetic Population (POPPK): Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PopPK 
5.1.  
PK 
NA 
Predicted Median (95% CI) vs Mean (SE) of Plasma 
GSK2330811 
Produced by CPMS  
At each dose level 
Footnote: CI = Confidence Interval 
 DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
5.2.  
PK 
NA 
Predicted Median (95% PI) vs Individual Observed Values of 
GSK2330811 
Produced by CPMS 
At each dose level 
Note: May not be shared with the study 
team at interim analyses. 
Footnote: PI = Prediction Interval 
DEC[1], IA1[1] 
SAC 
5.3.  
PK 
NA 
Predicted Median (95% PI) vs Observed Range of GSK2330811 
Produced by CPMS 
At each dose level 
Footnote: PI = Prediction Interval 
DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
Notes: 
1: Individual figure(s) will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data where possible to reduce 
the degree of unblinding, so this output will only be presented if necessary. 
 
 
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16.12.12. Pharmacodynamic Tables 
Pharmacodynamic Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Serum OSM 
6.1.  
Adhoc DRC: 
Safety 
SAC: Per 
Protocol 
PD_T1 
Summary of Log Transformed Serum Level of Free OSM 
(pg/mL) 
Add number imputed,  
Add footnote: [1] No. of subjects with 
results below the lower limit of 
quantification, assigned to half of the 
lower limit of quantification (LLQ = 1.45 
pg/ml) 
 
Adhoc DRC, 
SAC 
6.2.  
IA1, IA2, 
Adhoc DRC: 
Safety 
SAC: Per 
Protocol 
PD_T1 
Summary of Log Transformed Serum Level of Total OSM 
(pg/mL) 
IA1, IA2, Adhoc 
DRC, SAC 
6.3.  
Per Protocol 
PD_T1 
Summary of Ratio of Serum Level of Free OSM (pg/mL) to 
Baseline 
SAC 
6.4.  
IA1, IA2: 
Safety 
SAC: Per 
Protocol 
PD_T1 
Summary of Ratio of Serum Level of Total OSM (pg/mL) to 
Baseline 
IA1, IA2, SAC 
Notes: Will be produced for interim but may not be shared due to small sample size being potentially unblinding.   
 
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16.12.13. Pharmacodynamic Figures 
Pharmacodynamic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Serum OSM 
6.1.  
IA1: Safety 
SAC: Per 
Protocol 
PKCF1P 
Individual Serum Level of Free OSM Concentration-Time Plot by 
Treatment (Linear and Semi-Log) 
Add LLQ reference line 
Page by treatment 
Add Footnote to indicate amount of 
imputed data. 
Add footnote: [1] No. of subjects with 
results below the lower limit of 
quantification, assigned to half of the 
lower limit of quantification (LLQ = 1.45 
pg/ml) 
Use actual time (days) as x axis (where 
days is a continuous variable) 
Note: May not be shared with study 
team at interim. 
IA1[1], SAC 
6.2.  
IA1: Safety 
SAC: Per 
Protocol 
PKCF1P 
Individual Serum Level of Total OSM Concentration-Time Plot 
by Treatment (Linear and Semi-Log) 
Add LLQ reference line. Conditionally 
add ULQ reference line 
Page by treatment 
Add footnote: [1] No. of subjects with 
results below the lower limit of 
quantification, assigned to half of the 
lower limit of quantification (LLQ = 1.45 
pg/ml) 
Use actual time (days) as x axis (where 
days is a continuous variable) 
Note: May not be shared with study 
team at interim. 
Add Footnote to indicate amount of 
imputed data. 
IA1[1], SAC 
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Pharmacodynamic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
6.3.  
IA1, IA2: 
Safety 
SAC: Per 
Protocol 
201246/adhoc/ 
Figure 5.19 
Mean (SD) Serum Level of Total OSM Concentration-Time 
Plots grouped by Treatment (Linear and Semi-log) 
Add LLQ reference line 
Conditionally add ULQ reference line 
Use planned time (days) as x axis 
(where days is a continuous variable) 
IA1, IA2, SAC 
6.4.  
IA1, IA2: 
Safety 
SAC: Per 
Protocol 
201246/adhoc/ 
Figure 5.19 
Median (Range) Serum Level of Total OSM Concentration-Time 
Plots grouped by Treatment (Linear and Semi-log) 
IA1, IA2, SAC 
Three panel PK/PD/Haematology plots 
6.5.  
PK 
201246/Final/
Figure 6.9 
Median Plasma GSK2330811 Concentration, Median Serum 
Level of Total OSM Concentration and Median Platelet Count 
Over Time by Treatment Group 
Page by treatment group 
Title of each panel to include endpoint 
and units, short form endpoint on y axis 
SAC 
6.6.  
PP 
201246/Final/
Figure 6.9 / 
6.20 
Median Serum Level of Total OSM Concentration, Median 
Haemoglobin and Median Reticulocytes by Treatment Group,  
SAC 
Notes: 
1:  Individual figure(s) will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data where possible to 
reduce the degree of unblinding, so this output will only be presented if necessary.  
 
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16.12.14. Pharmacokinetic / Pharmacodynamic Tables 
Pharmacokinetic / Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK/PD 
7.1.  
IA1: Safety 
SAC: Per 
Protocol 
NA 
Parameters from Target Engagement PK/PD Model, [for specify 
model] Model. 
CPMS to produce this output if 
PK/PD model is developed for the 
reporting effort. 
IA1, SAC 
7.2.  
IA1: Safety 
SAC: Per 
Protocol 
NA 
Predicted median (95% CI) vs Mean (SE) Total OSM 
CPMS to produce this 
 
IA1, SAC 
 
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16.12.15. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK/PD 
7.1.  
IA1, IA2, 
Adhoc DRC: 
Safety 
DEC, SAC: 
Per Protocol 
NA 
Predicted median (95% CI) vs Mean (SE) Total OSM 
CPMS to produce this output 
DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
7.2.  
IA1: Safety 
DEC, SAC: 
Per Protocol 
NA 
Predicted target engagement over time 
CPMS to produce this output 
IA1, SAC 
7.3.  
IA1, IA2, 
Adhoc DRC: 
Safety 
DEC, SAC: 
Per Protocol 
NA 
Predicted median and (95% PI) vs Observed range of Total 
OSM 
CPMS to produce this output 
DEC, IA1, IA2, 
Adhoc DRC, 
SAC 
7.4.  
IA1: Safety 
DEC, SAC: 
Per Protocol 
NA 
Predicted median (95% PI) vs Observed Total OSM 
CPMS to produce this output 
Note: Shows individual data points, 
might not be shown to study team at 
interim. 
DEC, IA1, SAC 
 
 
 
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16.12.16. Biomarker Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Systemic biomarkers 
8.1  
Safety 
BIO_T1 
Summary of Baseline Levels of Systemic Biomarkers  
Baseline values only 
No treatment groups. 
Exclude C1M results using mouse 
hybridoma cell line as small 
sample size may be unblinding. 
Add footnote ‘Note: C1M assay 
changed during the study. C1M results 
not presented for samples analysed 
using the old C1M (denoted C1M*) kit 
due to small sample size and potential 
unblinding. New C1M kit denoted as 
C1M+. 
IA2 
8.2  
Per 
Protocol 
BIO_T2 
Summary of Systemic Biomarkers  
By biomarker, by treatment ordered by 
endpoint type (Inflammation, Fibrosis, 
Vascular) 
Note: No. of subjects with results 
below the lower limit of quantification, 
assigned to half of the lower limit of 
quantification. 
Note: C1M assay changed during the 
study. Results using old kit denoted as 
C1M* and new kit denoted as C1M+. 
For only ratio to baseline table, add 
Fold change. 
SAC 
8.3  
Per 
Protocol 
BIO_T2 
Summary of the Ratio to Baseline in Systemic Biomarkers 
SAC 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.4  
Per 
Protocol 
BIO_T3 
Analysis of Systemic Biomarkers 
For endpoints as specified in Section 
13.1.5. 
SAC 
Skin Histology biomarkers 
8.5  
Per 
Protocol 
BIO_T2 
Summary of Alpha SMA Results  
Include both sufficient and insufficient 
tissue samples 
SAC 
8.6  
Per 
Protocol 
BIO_T2 
Summary of Alpha SMA Results Excluding Insufficient Tissue 
Samples 
 
SAC 
8.7  
Per 
Protocol 
BIO_T2 
Summary of the Ratio to Baseline in Alpha SMA Results at Day 
85 Excluding Insufficient Tissue Samples 
Do not include Analysis visit column. 
SAC 
8.8  
Per 
Protocol 
BIO_T7 
Analysis of the Ratio to Baseline in Alpha SMA Results at Day 
85 Excluding Insufficient Tissue Samples 
For endpoints as specified in Section 
13.1.5. 
SAC 
Skin Gene Expression RNA Sequencing 
8.9  
Per 
Protocol 
BIO_T8 
Summary of mRNA Gene Expression Results: Individual 
Genes of Interest 
 
By gene, by treatment.  
SAC 
8.10 
Per 
Protocol 
BIO_T9 
Summary of the Ratio to Baseline in mRNA Gene Expression 
Results at Day 85: Individual Genes of Interest 
SAC 
8.11 
Per 
Protocol 
BIO_T7 
Analysis of the Ratio to Baseline in mRNA Gene Expression 
Results at Day 85: Individual Genes of Interest 
For endpoints as specified in Section 
13.1.5. 
SAC 
8.12 
Per 
Protocol 
BIO_T9 
Summary of Ratio to Baseline in mRNA Gene Expression 
Results at Day 85: Disease Signature Genes 
By gene sets, gene and treatment. 
SAC 
8.13 
Per 
Protocol 
BIO_T9 
Summary of Ratio to Baseline in mRNA Gene Expression 
Results at Day 85: Lung Fibrosis Signature Genes  
By gene, by treatment.  
SAC 
8.14 
Per 
Protocol 
BIO_T9 
Summary of Ratio to Baseline in mRNA Gene Expression 
Results at Day 85: Cell Module Signature Genes  
By gene sets, gene and, by treatment.  
SAC 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.15 
Per 
Protocol 
BIO_T10 
Summary of mRNA Gene Signature Results  
Page by 2GSSc and GSVA scores. 
This include 2GSSc, Disease, Lung 
Fibrosis and Cell module Signatures. 
SAC 
8.16 
Per 
Protocol 
BIO_T10 
Summary of the Change from Baseline in mRNA Gene 
Signature Results at Day 85 
SAC 
8.17 
Per 
Protocol 
BIO_T11 
Analysis of the Change from Baseline in mRNA Gene 
Signature Results at Day 85 
SAC 
Joint model of key biomarkers 
8.18 
Per 
Protocol 
BIO_T5 
Joint Model of Ratio to Baseline in Key Biomarkers at Day 85 
 
SAC 
8.19 
Per 
Protocol 
BIO_T6 
Joint Probabilities for Key Biomarkers at Day 85 
SAC 
Correlation of Biomarkers 
8.20 
Safety 
BIO_T4 
Correlation of Baseline Levels of Systemic Biomarkers 
Baseline values only.  No treatment 
groups. 
Exclude C1M results using mouse 
hybridoma cell line as small 
sample size may be unblinding. 
Add footnote ‘Note: C1M assay 
changed during the study. C1M results 
not presented for samples analysed 
using the old C1M (denoted C1M*) kit 
due to small sample size and potential 
unblinding. New C1M kit denoted as 
C1M+.’ 
IA2 
Mechanistic Haematology/ Chemistry 
8.21 
Safety 
SAFE_T1 
Summary of Mechanistic Haematology/ Chemistry 
Refer to Section 7.2 ‘Group 2’ for 
SAC 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.22 
Safety 
SAFE_T1 
Summary of Change from Baseline in Mechanistic 
Haematology/ Chemistry 
list of endpoints 
SAC 
8.23 
Safety 
SAFE_T1 
Summary of Percentage Change from Baseline in Mechanistic 
Haematology/ Chemistry 
SAC 
 
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16.12.17. Biomarker Figures 
Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Systemic biomarkers 
8.1  
Safety 
BIO_F1 
Panel Plot of Baseline Levels of Systemic Biomarkers  
Baseline values only, jittered scatter 
plot with superimposed geometric 
mean and standard error bars.    
Page 1 (2x4 plot): C3M, C6M, C1M, 
COMP, PINP, Pro-C3, Pro-C6 
Page 2 (2x2 plot): HA, TIMP-1, PIIINP, 
ELF 
Page 3 (1x3 plot): Pro-C3/C3M, Pro-
C6/C6M, PINP/C1M   
Page 4 (2x2 plot): CRP, IL-6, CCL2, 
CCL-18 (PARC1) 
Page 5 (2x2 plot): vWF, VEGF, 
sVCAM-1, NT-ProBNP 
Note: plot using order above. 
Exclude C1M results using mouse 
hybridoma cell line as small 
sample size may be unblinding. 
Add footnote ‘Note: C1M assay 
changed during the study. C1M results 
not presented for samples analysed 
using the old C1M (denoted C1M*) kit 
due to small sample size and potential 
unblinding. New C1M kit denoted as 
C1M+ 
IA2 
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Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.2  
Per 
Protocol 
BIO_F2 
Line Plot of Systemic Biomarkers  
Line plot of three treatment arms. 
page by biomarker, ordered by 
endpoint type (Inflammation, Fibrosis, 
Vascular) 
Y-axis presented to log base 10 scale. 
Note: No. of subjects with results 
below the lower limit of quantification, 
assigned to half of the lower limit of 
quantification. 
Note: C1M assay changed during the 
study. Results using old kit denoted as 
C1M* and new kit denoted as C1M+. 
SAC 
8.3  
Per 
Protocol 
BIO_F2 
Line Plot of Analysis of Ratio to Baseline of Systemic 
Biomarkers  
For endpoints as specified in Section 
13.1.5. 
SAC 
8.4  
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of Systemic Biomarkers  
Panel by treatment, page by 
biomarker, ordered by endpoint type 
(Inflammation, Fibrosis, Vascular)  
y-axis presented to log base 10 scale 
Note: No. of subjects with results 
below the lower limit of quantification, 
assigned to half of the lower limit of 
quantification. 
Note: C1M assay changed during the 
study. Results using old kit denoted as 
C1M* and new kit denoted as C1M+. 
SAC 
Histology biomarkers 
8.5  
Per 
Protocol 
BIO_F2 
Line Plot of Alpha SMA Results  
Include both sufficient and insufficient 
samples. Y-axis presented to log base 
2 scale 
SAC 
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Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.6  
Per 
Protocol 
BIO_F2 
Line Plot of Alpha SMA Results Excluding Insufficient Tissue 
Samples 
Y-axis presented to log base 2 scale 
SAC 
8.7  
Per 
Protocol 
BIO_F6 
Plot of Adjusted Ratio to Baseline of Alpha SMA Result vs 
Individual Ratio to Baseline Values at Day 85 Excluding 
Insufficient Tissue Samples 
SAC 
8.8  
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of Alpha SMA Results 
Include both good and insufficient 
samples. Panel by treatment 
y-axis presented to log base 2 scale 
SAC 
8.9  
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of Alpha SMA Results Excluding 
Insufficient Tissue Samples 
Panel by treatment 
y-axis presented to log base 2 scale 
SAC 
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Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Skin Gene Expression RNA Sequencing 
8.10 
Per 
Protocol 
BIO_F8 
Line Plot of mRNA Gene Expression Results: Individual Genes 
of Interest  
By Panel 1x2 Genes of Interest listed 
in Section 13.1.1.3.1(excluding 
derived gene) y-axis presented to log 
base 2 scale 
SAC 
8.11 
Per 
Protocol 
BIO_F6 
Plots of Adjusted Ratio to Baseline vs Individual Ratio to 
Baseline Values in mRNA Gene Expression Results at Day 85: 
Individual Genes of Interest 
By Panel 1x2. 
y-axis presented to log base 2 scale 
SAC 
8.12 
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of mRNA Gene Expression Results: 
Individual Genes of Interest 
Panel by treatment and page by 
Genes of Interest listed in Section 
13.1.1.3.1(excluding derived gene) 
y-axis presented to log base 2 scale 
SAC 
8.13 
Per 
Protocol 
BIO_F8 
Line Plot of mRNA Gene Signature Results  
Page by signature type.  
Page 1: 2GSSc 
Page 2 (Panel 1x3: Fibrosis, M1 and 
M2 score) 
Page 3 (Panel 1x2: Up/Downregulated 
disease signature score). 
Page 4 (Lung Fibrosis Score) 
 
SAC 
8.14 
Per 
Protocol 
BIO_F6 
Plots of Adjusted Change from Baseline vs Individual Change 
from Baseline Values in mRNA Gene Signature Results at Day 
85 
SAC 
8.15 
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of mRNA Expression Results: 
Disease Signature 
Panel by treatment and page by 
Disease Signature  
SAC 
8.16 
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of mRNA Expression Results: Lung 
Fibrosis Signature 
Panel by treatment  
SAC 
8.17 
Per 
Protocol 
BIO_F4 
Individual Subject Profiles of mRNA Expression Results: Cell 
Module Signature 
Panel by treatment and page by Cell 
module signature 
SAC 
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Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Correlation of Biomarkers 
8.18 
Safety 
BIO_F3 
Correlation of Baseline Levels of Systemic Biomarkers 
Baseline values only. No treatment 
groups. Exclude C1M results using 
mouse hybridoma cell line as small 
sample size may be unblinding. Add 
footnote ‘Note: C1M assay changed 
during the study. C1M results not 
presented for samples analysed using 
the old C1M (denoted C1M*) kit due to 
small sample size and potential 
unblinding. New C1M kit denoted as 
C1M+. 
IA2 
Mechanistic Haematology/ Chemistry 
8.19 
Safety 
BIO_F2 
Mean Profile for Mechanistic Haematology / Chemistry 
Refer to Section 7.2 ‘Group 2’ for list 
of tests. 
Add footnote “Figure displays a subset 
of haematology/chemistry parameters” 
SAC 
8.20 
Safety 
BIO_F2 
Mean Percentage Change from Baseline Profile for 
Mechanistic Haematology / Chemistry 
SAC 
8.21 
Safety 
BIO_F4 
Individual Subject Profiles for Mechanistic Haematology / 
Chemistry 
SAC 
Correlation Analyses of Key Biomarkers 
8.22 
Per 
Protocol 
EFF_F4 
Correlation of Key Biomarkers at Day 85 
Panel by treatment group and grouped 
by individual subjects. 
SAC 
Heat Plots of Skin Gene Expression RNA Sequencing 
8.23 
Per 
Protocol 
BIO_F7 
Heat Plots of Fold Change from Baseline for mRNA Gene 
Expression Results: Disease Signatures 
Pageby Up/Downregulated disease 
signature 
SAC 
8.24 
Per 
Protocol 
BIO_F7 
Heat Plots of Fold Change from Baseline for mRNA Gene 
Expression Results: Lung Fibrosis Signature 
 
SAC 
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Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
8.25 
Per 
Protocol 
BIO_F7 
Heat Plots of Fold Change from Baseline for mRNA Gene 
Expression Results: Cell Module Signatures 
Pageby Fibrosis, M1-Macrophage and 
M2-Macrophage cell module signature 
SAC 
 
 
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16.12.18. Exploratory Efficacy Tables 
Exploratory Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
mRSS 
9.1 
 Per Protocol 
EFF_T1 
Summary of mRSS Total Score  
By treatment, by visit 
SAC 
9.2 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in mRSS Total Score  
By treatment, by visit 
SAC 
9.3 
 Per Protocol 
EFF_T2 
Analysis of Change from Baseline in mRSS Total Score 
By treatment, by visit 
SAC 
FVC and % predicted FVC 
9.4 
 Per Protocol 
EFF_T1 
Summary of Laboratory FVC (L) 
By treatment, by visit 
SAC 
9.5 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in Laboratory FVC (L)  
By treatment, by visit 
SAC 
9.6 
 Per Protocol 
EFF_T2 
Analysis of Change from Baseline in Laboratory FVC (L) 
By treatment, by visit 
SAC 
9.7 
 Per Protocol 
EFF_T1 
Summary of Laboratory Percent Predicted FVC  
By treatment, by visit 
SAC 
9.8 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in Laboratory Percent 
Predicted FVC  
By treatment, by visit 
SAC 
HAQ-DI and SHAQ VAS scales 
9.9 
 Per Protocol 
EFF_T1 
Summary of HAQ-DI 
By treatment, by visit 
SAC 
9.10 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in HAQ-DI 
By treatment, by visit 
SAC 
9.11 
 Per Protocol 
EFF_T2 
Analysis of Change from Baseline in HAQ-DI 
By treatment, by visit 
SAC 
9.12 
 Per Protocol 
EFF_T1 
Summary of SHAQ VAS scales 
By treatment, by visit, by VAS scale 
Add footnote: “Note: US English version of 
SHAQ-VAS Questionnaire presented in the 
output.” 
SAC 
9.13 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in SHAQ VAS scales 
SAC 
PhGA and PtGA 
9.14 
 Per Protocol 
EFF_T1 
Summary of Physician Assessment of Global Disease Activity 
By treatment, by visit 
SAC 
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Exploratory Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
9.15 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in Physician Assessment of 
Global Disease Activity 
By treatment, by visit 
SAC 
9.16 
 Per Protocol 
EFF_T1 
Summary of Patient Assessment of Global Disease Activity 
By treatment, by visit 
SAC 
9.17 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in Patient Assessment of 
Global Disease Activity 
By treatment, by visit 
SAC 
CRISS 
9.18 
 Per Protocol 
EFF_T4 
Summary of CRISS  
Per visit (i.e. 12 weeks and follow up), 
by treatment.  Use non-parametric 
summaries only 
SAC 
9.19 
 Per Protocol 
EFF_T5 
Summary of CRISS Step 1 Events 
 
SAC 
9.20 
 Per Protocol 
EFF_T6 
Analysis of CRISS 
 
SAC 
Home FVC 
9.21 
 Per Protocol 
EFF_T1 
Summary of Weekly Home FVC (L) 
 
SAC 
9.22 
 Per Protocol 
EFF_T1 
Summary of Change from Baseline in Weekly Home FVC (L) 
 
SAC 
 
 
 
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16.12.19. Exploratory Efficacy Figures 
 
Exploratory Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
mRSS 
9.1  
Per Protocol 
EFF_F1 
Line Plot of mRSS Total Score 
Unadjusted Mean  SE 
SAC 
9.2  
Per Protocol 
EFF_F1 
Line Plot of Analysis of Change from Baseline in mRSS Total 
Score  
Posterior Mean  SD 
SAC 
9.3  
Per Protocol 
BIO_F4 
Individual Subject Profiles for mRSS Total Score 
Panel by treatment 
SAC 
FVC and % predicted FVC 
9.4  
Per Protocol 
EFF_F1 
Line Plot of Laboratory FVC (L) 
Unadjusted Mean  SE 
SAC 
9.5  
Per Protocol 
EFF_F1 
Line Plot of Analysis of Change from Baseline in Laboratory 
FVC (L) 
Posterior Mean  SD 
SAC 
9.6  
Per Protocol 
BIO_F4 
Individual Subject Profiles for Laboratory FVC (L) 
Panel by treatment 
SAC 
9.7  
Per Protocol 
EFF_F1 
Line Plot of Laboratory Percent Predicted FVC  
Unadjusted Mean  SE 
SAC 
9.8  
Per Protocol 
EFF_F1 
Line Plot of Change from Baseline in Laboratory Percent 
Predicted FVC 
SAC 
#HAQ-DI and SHAQ VAS scales 
9.9  
Per Protocol 
EFF_F1 
Line Plot of HAQ-DI  
Unadjusted Mean  SE 
SAC 
9.10 
Per Protocol 
EFF_F1 
Line Plot of Analysis of Change from Baseline in HAQ-DI 
Posterior Mean  SD 
SAC 
9.11 
Per Protocol 
EFF_F1 
Line Plot of SHAQ VAS Scales  
Unadjusted Mean  SE. Page by 
scale. 
Add footnote: “Note: US English version of 
SHAQ-VAS Questionnaire presented in the 
output.” 
SAC 
9.12 
Per Protocol 
EFF_F1 
Line Plot of Change from Baseline in SHAQ VAS Scales 
SAC 
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Exploratory Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PhGA and PtGA 
9.13 
Per Protocol 
EFF_F1 
Line Plot of Physician Assessment of Global Disease Activity 
Unadjusted Mean  SE.  
SAC 
9.14 
Per Protocol 
EFF_F1 
Line Plot of Change from Baseline in Physician Assessment of 
Global Disease Activity 
Unadjusted Mean  SE.  
SAC 
9.15 
Per Protocol 
EFF_F1 
Line Plot of Patient Assessment of Global Disease Activity 
Unadjusted Mean  SE.  
SAC 
9.16 
Per Protocol 
EFF_F1 
Line Plot of Change from Baseline in Patient Assessment of 
Global Disease Activity 
Unadjusted Mean  SE.  
SAC 
CRISS 
9.17 
Per Protocol 
EFF_F2 
Box Plots of CRISS 
Panel by Visit (Day 85 and 197) 
SAC 
Home FVC 
9.18 
Per Protocol 
EFF_F3 
Line plot of Weekly Home FVC (L) 
No error bars  
SAC 
9.19 
Per Protocol 
EFF_F3 
Line plot of Change from Baseline in Weekly Home FVC (L) 
No error bars 
SAC 
9.20 
Per Protocol 
BIO_F4 
Individual Subject Profiles for Weekly Home FVC (L) by 
Treatment Group 
 
SAC 
Correlation Analysis 
9.21 
Per Protocol 
EFF_F4 
Correlation of Change in FVC vs Biomarker Endpoints 
Panel by treatment group and grouped 
by individual subjects 
SAC 
9.22 
Per Protocol 
EFF_F4 
Correlation of Change in mRSS vs Biomarker Endpoints 
SAC 
9.23 
Per Protocol 
EFF_F4 
Correlation of Baseline OSM (Skin) vs Biomarker Endpoints and 
Change in mRSS 
SAC 
Notes: 1: Individual figure(s) will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data where possible to 
reduce the degree of unblinding, so this output will only be presented if necessary. 
 
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16.12.20. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Participant Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen failures 
 
SAC  
2.  
Enrolled 
ES2 
Listing of Reasons for Study Withdrawal 
 
SAC  
3.  
Enrolled 
BL1 
Listing of Subjects for whom the Treatment Blind was Broken 
 
SAC  
4.  
Enrolled 
TA1 
Listing of Planned and Actual Treatments 
Add footnote: Subject 600 was 
randomised in error to an incorrect 
strata before the day of dosing. This 
was reversed and they were correctly 
randomised on the day of dosing. 
SAC  
5.  
Enrolled 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
 
Adhoc DRC, 
SAC  
Protocol Deviations 
6.  
Enrolled 
DV2 
Listing of Important Protocol Deviations 
 
SAC  
7.  
Enrolled 
IE3 
Listing of Subjects with Inclusion/ Exclusion Criteria Deviations 
 
SAC  
Populations Analysed 
8.  
Enrolled 
SP3 
Listing of Subjects Excluded from Any Population 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA1, IA2, SAC  
Demography 
9.  
Enrolled 
DM2 
Listing of Demographic Characteristics 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA2, SAC 
10.  
Enrolled 
DM9 
Listing of Race 
IA2, SAC 
Concomitant Medications and Medical Conditions and Smoking History 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
11.  
Enrolled 
CM3 
Listing of Concomitant Medications 
Do not show treatment group at 
interims, output by treatment group at 
final. 
DEC, IA1, IA2, 
SAC 
12.  
Enrolled 
CM6 
Relationship between ATC Level 1, Ingredient and Verbatim 
Text 
 
IA2, SAC 
Exposure 
13.  
Enrolled 
EX3 
Listing of Exposure Data 
See 201246/final/ Listing 2 for the way 
that EX3 has been adapted. Order by 
treatment, subject then list doses in 
chronological order. 
Add summary variable stacked under 
participant details: ‘Cumulative number 
of injections.’ Note: This data would 
only be presented on request for interim 
analyses  
DEC[1], IA1[1], 
IA2[1], SAC  
14.  
Enrolled 
TBC 
Listing of Reason for not Receiving Full Planned Dose 
Listing of verbatim text collected when 
full dose not given as planned at a 
study visit attended by the participant.  
Adhoc DRC, 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Adverse Events 
15.  
Enrolled 
AE8 
Listing of All Adverse Events 
Do not show treatment group at 
interims, output by treatment group at 
final. 
Do use System Organ Class (as in 
AE8CP) 
IA1, IA2, SAC 
16.  
Enrolled 
AE8 
Listing of Adverse Events of Severe Intensity 
Do use System Organ Class (as in 
AE8CP) 
Show frequency. 
SAC 
17.  
Enrolled 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
18.  
Enrolled 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
 
SAC 
Serious and Other Significant AEs 
19.  
Enrolled 
AE8CP 
Listing of Fatal Serious Adverse Events 
 
SAC 
20.  
Enrolled 
AE8CP 
Listing of Non-Fatal Serious Adverse Events 
 
SAC 
21.  
Enrolled 
AE8CP 
Listing of Serious Adverse Events 
 
SAC 
22.  
 Enrolled 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC 
23.  
Enrolled 
AECP8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
Do not show treatment group at 
interims, output by treatment group at 
final. 
Adhoc DRC, 
SAC 
All Laboratory 
24.  
Enrolled 
LB5 
Listing of Haematology Laboratory Values of CTCAE grade 
Order by subject, then lab test 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA1, IA2, SAC 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
25.  
Enrolled 
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance  
Order by subject, then category (e.g. 
Chemistry), then lab test 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA1, IA2, SAC 
26.  
Enrolled 
LB14 
Listing of Laboratory Data with Character Results 
 
SAC 
Haematology 
27.  
Enrolled 
201246/Final/ 
listing 23 
Listing of All Haematology Values and Changes from Baseline 
See listing 23 in 201246. Report: 
Standard result Change from baseline 
and Percent change from baseline.  
Do not flag CTCAE grades 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA1, IA2, SAC 
Hepatobiliary (Liver) 
28.  
Enrolled 
LIVER5 
Listing of Liver Events 
 
SAC  
(may be 
reported at 
interim, 
conditional on 
data) 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Urinalysis 
29.  
Enrolled 
 UR2 
Listing of Urinalysis Results 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
ECG 
30.  
Enrolled 
EG3 
Listing of All ECG Data for Subjects with Any Value of Potential 
Clinical Importance 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA1, IA2, SAC 
31.  
Enrolled 
EG5 
Listing of Abnormal ECG Findings 
IA1, IA2, SAC 
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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Vital Signs 
32.  
Enrolled 
VS4 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 
Immunogenicity 
33.  
Enrolled 
IMM2 
Listing of Immunogenicity Results 
 
SAC 
Other 
34.  
Enrolled 
201246/Final/ 
listing 23 
Listing of Absolute and Changes from Baseline in Weight 
As listing 26 for haematology, show 
standard result, change from baseline 
and % change from baseline 
SAC 
Notes: Listing will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data where possible to reduce the 
degree of unblinding, so this listing will only be presented if necessary.  
16.12.21. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Study Population (Disease Characteristics) 
35.  
Enrolled 
POP_L2 
Listing of Systemic Sclerosis Disease Activity at Screening and 
Day 1 
This requires deriving disease duration 
and combining results from more than 
one dataset. 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA2, SAC 
36.  
Enrolled 
POP_L1 
Listing of Systemic Sclerosis Medication History 
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA2, SAC 
37.  
Enrolled 
POP_L3  
Listing of Systemic Sclerosis Disease History 
IA2, SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
38.  
Enrolled 
POP_L4 
Listing of HRCT 
 
SAC 
39.  
Enrolled 
POP_L5  
Listing of Historical and Baseline Autoantibody  
Do not show treatment group at 
interims, output by treatment group at 
final. 
IA2, SAC 
40.  
Enrolled 
POP_L6 
Listing of mRSS at Skin Biopsy Site 
 
SAC 
Pharmacokinetic 
41.  
Enrolled 
Based on 
PKCL1, see 
output for DEC 
Listing of GSK2330811 Plasma Concentration-Time Data  
Add data dependent footnote: ‘Note: 
NA=Not Available [data dependent], 
NQ=Non-Quantifiable, LLQ 
value=100ng/mL’ 
DEC[1], IA1 
42.  
Enrolled 
PKPL1 
Listing of Derived GSK2330811 Pharmacokinetic Parameters 
per Participant 
CPMS to produce this.  
Footnote:  Parameters for individual 
participants are derived from PopPK 
analysis (empirical Bayes estimates). 
IA1  
43.  
Enrolled 
Based on 
PKCL1, see 
output for DEC 
Listing of GSK2330811 Blister Serum Concentration-Time Data  
Add data dependent footnote: ‘Note: 
NA=Not Available [data dependent], 
NQ=Non-Quantifiable, LLQ 
value=100ng/mL’ 
IA2, SAC 
Pharmacodynamic 
44.  
Enrolled 
Based on 
PKCL1, see 
output for DEC 
Listing of Serum Level of OSM 
By, Parameter (Include both Free and 
Total OSM) then treatment 
Add footnote: 
‘Note:  BLQ = Below the limit of 
quantification which is 1.45 pg/ml for 
both free and total OSM.’ 
DEC[1], IA1, IA2 
45.  
Enrolled 
Based on 
PKCL1, see 
output for DEC 
Listing of Blister Serum Level of OSM 
By, Parameter (Include both Free and 
Total OSM) then treatment 
Add footnote: 
IA2, SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
‘Note: BLQ = Below the limit of 
quantification which is 1.45 pg/ml for 
both free and total OSM.’ 
46.  
PK 
PKPL1 
Listing of Derived Total OSM Parameters per Participant 
CPMS to produce this.  
Footnote:  Parameters for individual 
participants are derived from 
PopPK/PD analysis (empirical Bayes 
estimates). 
IA1  
Biomarkers 
47.  
Enrolled 
BIO_L1 
Listing of Baseline Levels of Biomarkers  
Baseline values only  
Don’t present treatment group.  
By subject then ordered by endpoint 
type (Inflammation, Fibrosis, Vascular) 
IA2 
Patient Profile 
48.  
Enrolled 
ARR1 
Listing of Arrhythmias 
Refer IDSL Standard mock shell under 
Cardiovascular Events 
SAC 
Patient Profile 
49.  
Enrolled 
DV2 
Listing of Subjects with COVID-19 Protocol Deviations 
Do not include ‘exclusion form analyses 
population’ columns. 
SAC 
50.  
Enrolled 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessments 
for Subjects with COVID-19 Adverse Events 
 
SAC 
51.  
Enrolled 
PAN7 
Listing of All Subjects with Visits and Assessments Impacted by 
COVID-19 Pandemic 
Add footnote: 'Note: COVID impact 
forms only collected for missed visits/ 
assessments from Day 113 onwards.' 
SAC 
Notes: 
1:  Listing will be produced for interim but may not be shared. Justification: DRCs follow the principle of presenting summary data for restricted data types where 
possible to reduce the degree of unblinding, so this listing will only be presented if necessary. 
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16.13. 
Appendix 13: List of Gene Modules 
16.13.1. 
Disease Gene Modules 
 
 
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16.13.2. 
Lung Fibrosis Gene Module 
COL6A3
IGHM
UBD
C6
PLA2G2A
LTF
MMP1
CPXM1
SPP1
ADAM12
SFRP4
COL5A1
SULF1
GEM
POSTN
TGFB3
CXCL13
CFI
IGF1
COL5A2
TDO2
PDE1A
ASPN
SERPINE2
THY1
TNC
COL15A1
VCAM1
FNDC1
LAMP5
COL10A1
CPXM2
CTHRC1
THBS4
SAA1
LGI2
IGFBP4
P4HA3
SULF2
DIO2
FAM92B
MMP11
 
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16.13.3. 
Cell-type specific gene modules 
 
201247 | Statistical Analysis Plan  RAP Amendment 3 Final_V1 21 Aug 2020 | TMF-2068612 | 1.0


Signature Page for  201247 TMF-2068612 v1.0
Signature Page for TMF-2068612 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 21-Aug-2020 07:34:46 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 21-Aug-2020 07:39:12 GMT+0000
201247 | Statistical Analysis Plan  RAP Amendment 3 Final_V1 21 Aug 2020 | TMF-2068612 | 1.0
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