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
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: 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.
Protocol Number: 208564
Compound Number
or Name:
GSK2330811
Study Phase: Phase 1
Short Title: Safety, tolerability, pharmacokinetics, pharmacodynamics of GSK2330811 
after a subcutaneous dose in healthy Japanese participants.
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual (SRM).
Regulatory Agency Identifying Number(s):
EudraCT:  2019-003042-33
Approval Date: 11-SEP-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Background ................................................................................................12
2.3.
Benefit/Risk Assessment ............................................................................13
2.3.1.
Risk Assessment .........................................................................14
2.3.2.
Benefit Assessment.....................................................................18
2.3.3.
Overall Benefit: Risk Conclusion..................................................18
3.
OBJECTIVES AND ENDPOINTS...........................................................................18
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Number of Participants ...............................................................................20
4.3.
Intervention Groups and Duration ...............................................................20
4.4.
Scientific Rationale for Study Design ..........................................................20
4.5.
Justification for Dose ..................................................................................21
4.6.
End of Study Definition ...............................................................................22
5.
STUDY POPULATION...........................................................................................23
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................24
5.3.
Lifestyle Considerations..............................................................................26
5.3.1.
Meals and Dietary Restrictions ....................................................26
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................26
5.3.3.
Activity .........................................................................................26
5.4.
Screen Failures...........................................................................................26
6.
STUDY INTERVENTION........................................................................................27
6.1.
Study Intervention(s) Administered .............................................................27
6.2.
Preparation/Handling/Storage/Accountability..............................................28
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................29
6.3.1.
Randomisation and Intervention Assignment...............................29
6.3.2.
Blinding........................................................................................29
6.3.2.1.
Risk of Inferred Unblinding .........................................30
6.4.
Study Intervention Compliance ...................................................................30
6.5.
Concomitant Therapy..................................................................................30
6.6.
Dose Modification .......................................................................................31
6.7.
Intervention after the End of the Study........................................................31
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................31
7.1.
Discontinuation of Study Intervention..........................................................31
7.1.1.
Study Stopping Criteria................................................................31
7.1.2.
Liver Chemistry Enhanced Monitoring Criteria .............................32

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7.1.3.
QTc Enhanced Monitoring Criteria...............................................32
7.1.4.
Haematological Enhanced Monitoring Criteria .............................32
7.2.
Participant Withdrawal from the Study ........................................................33
7.3.
Lost to Follow Up........................................................................................33
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
8.1.
Efficacy Assessments.................................................................................34
8.2.
Safety Assessments ...................................................................................34
8.2.1.
Physical Examinations.................................................................34
8.2.2.
Vital Signs....................................................................................34
8.2.3.
ECGs...........................................................................................35
8.2.4.
Clinical Safety Laboratory Assessments ......................................35
8.2.5.
Injection Site Reaction Assessments ...........................................35
8.2.6.
Hypersensitivity Reactions...........................................................36
8.3.
Adverse Events and Serious Adverse Events.............................................37
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................37
8.3.2.
Method of Detecting AEs and SAEs.............................................38
8.3.3.
Follow-up of AEs and SAEs.........................................................38
8.3.4.
Regulatory Reporting Requirements for SAEs .............................38
8.3.5.
Pre-Filled Syringe Deficiencies ....................................................38
8.3.5.1.
Time Period for Detecting Pre-Filled Syringe 
Deficiencies................................................................39
8.3.5.2.
Follow-up of Pre-Filled Syringe Deficiencies...............39
8.3.5.3.
Prompt Reporting of Pre-Filled Syringe 
Deficiencies to Sponsor..............................................39
8.3.5.4.
Regulatory Reporting Requirements for Pre-
Filled Syringe Incidents ..............................................39
8.4.
Treatment of Overdose...............................................................................40
8.5.
Pharmacokinetics .......................................................................................40
8.6.
Pharmacodynamics ....................................................................................41
8.6.1.
Total and Free OSM ....................................................................41
8.6.2.
Erythropoietin (EPO) and Thrombopoietin (TPO).........................41
8.7.
Biomarkers .................................................................................................41
8.8.
Genetics .....................................................................................................42
8.9.
Immunogenicity Assessments.....................................................................42
8.10.
Health Economics.......................................................................................42
9.
STATISTICAL CONSIDERATIONS........................................................................42
9.1.
Statistical Hypotheses.................................................................................42
9.2.
Sample Size Determination ........................................................................42
9.3.
Populations for Analyses ............................................................................44
9.4.
Statistical Analyses.....................................................................................44
9.4.1.
General Considerations ...............................................................44
9.4.2.
Primary Endpoint(s).....................................................................45
9.4.3.
Secondary Endpoint(s) ................................................................45
9.4.3.1.
Pharmacokinetic parameters......................................45
9.4.3.2.
Other secondary endpoints.........................................46
9.4.4.
Exploratory Endpoints..................................................................46
9.5.
Interim Analyses .........................................................................................46
9.6.
Interim Data Review Committee .................................................................46

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................47
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................47
10.1.1.
Regulatory and Ethical Considerations ........................................47
10.1.2.
Financial Disclosure.....................................................................47
10.1.3.
Informed Consent Process ..........................................................48
10.1.4.
Data Protection............................................................................48
10.1.5.
Committees Structure ..................................................................49
10.1.6.
Dissemination of Clinical Study Data ...........................................49
10.1.7.
Data Quality Assurance ...............................................................49
10.1.8.
Source Documents ......................................................................50
10.1.9.
Study and Site Start and Closure.................................................50
10.1.10. Publication Policy.........................................................................51
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................52
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................54
10.3.1.
Definition of AE............................................................................54
10.3.2.
Definition of SAE..........................................................................55
10.3.3.
Recording and Follow-Up of AE and SAE....................................56
10.3.4.
Reporting of SAE to GSK.............................................................58
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................59
10.5.
Appendix 5: Genetics..................................................................................60
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................61
10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................63
10.7.1.
Definition of AE and ADE.............................................................64
10.7.2.
Definition of SAE, SADE and USADE..........................................64
10.7.3.
Definition of Device Deficiency.....................................................65
10.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies .................................................................................65
10.7.5.
Reporting of SAEs .......................................................................67
10.7.6.
Reporting of SADEs.....................................................................68
10.8.
Appendix 8: Country-specific requirements.................................................69
10.9.
Appendix 9: Abbreviations and Trademarks................................................70
11. REFERENCES.......................................................................................................74

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: 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.
Short Title: Safety, tolerability, pharmacokinetics, pharmacodynamics of GSK2330811 
after a subcutaneous dose in healthy Japanese participants.
Rationale:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity after single subcutaneous (SC) doses of 
GSK2330811 administered to healthy Japanese participants. This information is intended 
to enable future efficacy studies in Japanese patients with relevant diseases, and to 
support defining the optimal SC dose for future studies in this population.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary

To evaluate the safety and tolerability of a 
single SC dose of GSK2330811 in 
healthy Japanese participants

Number of participants reporting adverse 
events (AEs).

Number of participants reporting serious 
adverse events (SAEs).

Number of participants with vital signs 
(blood pressure, heart rate, body 
temperature) reaching a threshold of 
potential clinical importance.

Number of participants with treatment 
emergent abnormal electrocardiogram 
(ECG) findings.

Number of participants with Common 
Terminology Criteria for Adverse Events 
(CTCAE) grade 1 or higher safety 
laboratory results (clinical chemistry, 
haematology values where CTCAE
grading applies).

Number of participants with treatment 
emergent abnormal urinalysis findings
Secondary
Secondary

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Objectives
Endpoints

To evaluate the pharmacokinetic (PK) 
profile of a single SC dose of 
GSK2330811 in healthy Japanese 
participants

Pharmacokinetic parameters (Cmax, 
AUC, CL/F, Tmax, t1/2, Vss/F)

To assess the potential for anti-drug 
antibody (ADA) formation following a 
single SC dose of GSK2330811 in 
healthy Japanese participants

Number of participants with anti-
GSK2330811 antibodies

To assess effects of GSK2330811 on 
platelets and haemoglobin in healthy 
Japanese participants

Platelet nadir

Time to platelet nadir

Haemoglobin nadir

Time to haemoglobin nadir
Overall Design:
This is a randomised, double-blind (sponsor-open), placebo-controlled, single-centre 
study with single SC doses of GSK2330811 administered to healthy male Japanese 
participants.

Participants will attend a screening visit at the clinical unit within 30 days of 
Study Day 1. If eligible for the study, participants will return on Day -1 for 
overnight admission to the unit.

Participants will be randomized to either GSK2330811 or placebo in an 
approximate ratio of 7:3.

Approximately 10 eligible participants will be admitted to the clinical unit on the 
day prior to dosing (Day-1). On Day 1, each participant will receive a single SC
dose of GSK2330811 or placebo, administered as three separate SC injections. 
Participants will then remain as an in-patient until discharged on Day 2 after 
assessments have been performed.

Participants will then return to the clinical unit for outpatient visits as per the 
Schedule of Activities (SoA).

The final follow up visit will be at the clinical unit on Day 126.

The maximum dose will not exceed 450 mg SC.
Disclosure Statement: 
This is a 2-arm, double-blind, parallel group, safety and PK study.

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Number of Participants:
Approximately ten participants will be enrolled and dosed (7 GSK2330811: 3 Placebo) 
with a view to ensuring 8 are evaluable (6 GSK2330811: 2 Placebo). 
Up to a maximum of 14 participants may be enrolled and dosed.
Intervention Groups and Duration:
This study will include a single cohort of approximately 10 participants randomised to a 
single dose of 450mg SC GSK2330811 or placebo in a 7:3 ratio (active: placebo).
The study duration, including screening and follow-up, is not expected to exceed 163 
days for any participant in the study.
1.2.
Schema

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1.3.
Schedule of Activities (SoA)
Screening Period
Screening Procedure
Screening (up to 30 days prior to Day 1)
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Exam (incl. weight and height)
X
Medical History and current medical conditions1
X
Concomitant Medication Review
X
12 lead ECG in triplicate
X
Vitals (blood pressure, heart rate, body temperature)2
X
Breath Alcohol Screen
X
Urine Drug Screen
X
Human Immunodeficiency Virus (HIV), Hepatitis B virus
(HBV) and Hepatitis C virus (HCV) Screen
X
Tuberculosis (TB) Screening QuantiFERON 
X
Haematology/Clinical Chemistry/Urinalysis/Clotting
X
SAE Review
X
1.
To include substance usage, family history of premature cardiovascular disease, medication, drug/alcohol history
2.
Vital signs are to be taken before blood collection for laboratory tests.

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Treatment and Follow-Up Period
Procedure
Day-
1
Day 1
Day 
2
Day 
3
Day 
5
Day 
7
Day 
10 
Day 
14
Day 
21
Day 
28
Day 
42
Day 
56
Day 
84
Day 126 
(follow-up 
visit)/Early 
Withdrawal
+/- 1 
day
+/- 1 
day
+/- 1 
day
+/- 1 
day
+/- 2 
days
+/- 2 
days
+/- 7 
days
+/- 7 days
Admission
X
In-patient Stay
X
X
Discharge
X
Outpatient Visit
X
X
X
X
X
X
X
X
X
X
X
Inclusion and Exclusion Criteria
X
Breath Alcohol Screen
X
Urine Drug Screen
X
Pre-
dose
0h
1h
4h
8h
24h
Dosing3
X
Injection Site Reaction Assessment
X5
X5
X5
X5
X5
Brief Physical Exam
X
X1
Full Physical Exam6
X
Haematology/Clinical Chemistry
X
X2
X1
X
X
X
X
X
X2
X
X
X
X
X
Urinalysis
X
X
X
X
X
12 lead ECG (triplicate)
X
X
X
X
X
Vitals (blood pressure, heart rate, 
body temperature)4
X
X
X1
X1
X1
X1
X
X
X
X
X
X
X
X
X
X
X
PK Sampling
X
X1
X1
X
X
X
X
X
X
X
X
X
X
X
Free & Total OSM Sampling
X
X1
X1
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sampling
X
X
X
X
TPO Sampling
X
X
X
X
X
EPO Sampling
X
X
X
X
X

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Procedure
Day-
1
Day 1
Day 
2
Day 
3
Day 
5
Day 
7
Day 
10 
Day 
14
Day 
21
Day 
28
Day 
42
Day 
56
Day 
84
Day 126 
(follow-up 
visit)/Early 
Withdrawal
Concomitant Medication Review
Monitored from screening until end of follow-up visit
SAE/AE Review
SAEs collected from signing of consent form, AEs collected continuously from time of dose
AE= adverse event; ECG= Electrocardiogram; EPO= Erythropoietin; TPO = Thrombopoietin; OSM= Oncostatin M; PK= 
pharmacokinetic; SAE= serious adverse event
Footnotes: 
1.
All post dose time points are in reference to the first injection of IMP.
2.
Day 1 Pre-dose sample and Day 21 sample will be fasted for approximately 12 hr and will include lipids
3.
IMP administration consists of 3 syringes, all 3 syringes are to be administered as closely together in time as possible 
4.
Vital signs are to be taken before blood collection for laboratory tests.
5.
Assessments should be conducted immediately before first injection (pre-dose) and immediately after last injection (0h). Post dose assessments  (4h and 24h) to be conducted in 
reference to the last injection of IMP. Any injection site reactions to be captured through AE reporting.
6.
Full physical exam at follow-up will not include height

The timing and number of planned study assessments may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation.

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2.
INTRODUCTION
GSK2330811 is a first in class, humanised IgG1 monoclonal antibody that binds and 
inhibits the action of Oncostatin M (OSM) and is being developed for the treatment of 
Crohn’s disease (CD) and Systemic sclerosis (SSc). 
The current strength of the liquid formulation is 150 mg/mL and is presented as a pre-
filled syringe (PFS) assembled in a safety syringe device for SC administration.
2.1.
Study Rationale
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity after single SC doses of 450 mg 
GSK2330811 administered to healthy Japanese participants. This information is intended 
to enable future efficacy studies in Japanese patients with relevant diseases, and to 
support defining the optimal SC dose for future studies in this population.
2.2.
Background
GSK2330811 is a humanised monoclonal antibody that binds and neutralises OSM and is 
being developed for the treatment of SSc and CD.
OSM is a member of the IL-6 family of cytokines, which is produced by a variety of 
immune cells including macrophages, activated T-cells and neutrophils in response to 
infection and tissue injury. OSM signalling on a variety of cell types, including
fibroblasts, epithelial, endothelial, smooth muscle cells and hematopoietic cells, drives 
inflammation, fibrosis and vasculopathy [Hermanns, 2015; Ayaub, 2017].
The safety profile of GSK2330811 has been evaluated in repeat-dose SC 13 and 26-week 
monkey toxicity studies. The key findings were of a reduction in red cell parameters in 
the peripheral blood and bone marrow with evidence of a regenerative reticulocyte 
response and of a transient reduction in platelet counts which showed partial to complete 
recovery by week 13. In the 13-week toxicity study, the no observed adverse effect level 
(NOAEL) was considered to be 300 mg/kg/week (the highest dose tested). In the 26-
week toxicity study, because of the magnitude of the pharmacology related effects on red 
blood cell parameters noted the NOAEL was not identified.  Of note, for non-
pharmacology related findings the NOAEL is considered to be 300 mg/kg/week (highest 
dose tested). Detailed information can be found in the Investigator’s Brochure (IB) for 
GSK2330811 [GlaxoSmithKline Document Number 2016N284919_02, 2019].
The safety, tolerability and PK of GSK2330811 has been evaluated in a Phase 1 single-
dose escalation study in healthy volunteers (201246, NCT02386436, [Reid, 2018]). 
Thirty participants were exposed to GSK2330811 at doses ranging from 0.1 mg/kg to 6.0 
mg/kg. GSK2330811 was well-tolerated, with no 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 reversible reduction in platelet count was observed at dose levels of 1 

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mg/kg and above, and a low-grade reduction in haemoglobin and red cell count was 
observed at the highest dose level (6 mg/kg).  Both these effects are consistent with the 
inhibition of the known pharmacology of OSM by GSK2330811. Detailed information 
can be found in the IB for GSK2330811 [GlaxoSmithKline Document Number 
2016N284919_02, 2019].
A repeat dose, proof of mechanism study (201247, NCT03041025) with GSK2330811 in 
participants with SSc is ongoing, dosing up to 300 mg every two weeks for 6 doses.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2330811 may be found in the Investigator’s 
Brochure.

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2.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention GSK2330811
Thrombocytopaenia

OSM has been shown to modulate haematopoiesis through an effect on 
bone marrow stromal cells, haematopoietic progenitors and bone marrow 
microenvironment [Wallace, 1995; Miyajima, 2000; Tanaka, 2003].

In the 13 and 26 week repeat dose monkey toxicology studies transient 
reduction in platelet counts were observed which showed partial to 
complete recovery by week 13.  In the 13 week repeat dose study, platelet 
counts were comparable to vehicle control monkeys following clearance of 
GSK2330811 (at the end of an 18 week off drug period).  Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

A First Time in Human (FTIH) study of single doses of GSK2330811 in 
healthy participants demonstrated a dose-dependent, reversible reduction 
in platelet count at doses between 1 mg/kg and 6 mg/kg. Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

Only participants with platelet count LLN will be 
included in the study. 

Participants with any history of known bleeding 
or coagulation disorders will be excluded.

The use of anti-platelet medications, other than 
occasional use of non-steroidal anti-inflammatory 
drugs (NSAIDs), will not be permitted. 

Platelet count will be tested at each scheduled 
visit, until the end of the follow-up period, to 
ensure careful monitoring. 

Haematological Study Stopping criteria and 
Individual participant enhanced monitoring 
criteria will be implemented.  

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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Anaemia

OSM has been shown to modulate haematopoiesis through an effect on 
bone marrow stromal cells, haematopoietic progenitors and bone marrow 
microenvironment [Wallace, 1995; Miyajima, 2000; Tanaka, 2003].

In the 13 and 26 week repeat dose monkey toxicology study progressive 
decreases in red cell parameters and bone marrow myeloid to erythroid 
ratios with a compensatory increase in reticulocyte count were noted 
correlates. In the 13 week repeat dose study there was partial to complete 
recovery of red cell parameters and reticulocytes following clearance of 
GSK2330811 (at the end of an 18 week off drug period). Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

A FTIH study of single doses of GSK2330811 in healthy participants 
showed a reduction in haemoglobin / red cell count at 6 mg/kg. A 
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_02, 2019].

Only participants with haemoglobin LLN will be 
included in the study. 

Participants with any history of known bleeding 
or coagulation disorders will be excluded.

Participants will not receive anti-coagulant 
medications during the study. 

Haemoglobin will be tested at each scheduled 
visit, until the end of the follow-up period, to 
ensure careful monitoring. 

Haematological Study Stopping criteria and 
Individual participant enhanced monitoring 
criteria will be implemented.  
Infection including 
reactivation of 
Mycobacterium 
tuberculosis

OSM contributes to immunity in synergy with other cytokines such as TNF 
and IL-1 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.

In the 26-week cynomolgus monkey toxicology study decreases in 
neutrophils (associated with left shift) and eosinophils were noted.  Also 
observed were increases in total lymphocyte count, which was attributed to 
increased T helper and T cytotoxic cell numbers. Refer to IB for details 
[GlaxoSmithKline Document Number 2016N284919_02, 2019].

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. Refer to IB for details [GlaxoSmithKline Document Number
2016N284919_02, 2019].

Participants will be screened for HIV, HBV, HCV
and TB and excluded if positive.

Participants with prior opportunistic or recurrent 
infection, or evidence of recent or ongoing 
infection, will be excluded; refer Section 5.2 for 
details.

Participants planning travel to regions of high 
endemic infection during the study will be 
excluded.

Participants will be monitored closely for 
infection, through regular review of symptoms, 
signs and laboratory tests during the study.

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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Vaccination

Since an immunosuppressive effect of GSK2330811 cannot be excluded, 
there is a theoretical possibility that GSK2330811 could decrease an 
individual’s immune response to vaccines administered while on therapy

In the monkey 6 month repeat dose study, the antibody response to
Keyhole Limpet Hemocyanin (KLH) immunization (anti KLH IgM and IgG) 
was assessed. Although a delay in the antibody response following primary 
KLH immunisation was noted, these data are not considered indicative of 
an inability to mount a T cell dependent B cell response since an antibody 
response was observed. Refer to IB for details [GlaxoSmithKline 
Document Number 2016N284919_02, 2019].

Participants will not be allowed to receive live 
vaccines within the 4 weeks prior to Day 1, until 
the end of follow-up. 

Investigators should consider the benefit-risk of 
administering any non-live vaccines during the 
study.
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 hypersensitivity / 
allergy that may put them at increased risk of a 
hypersensitivity reaction will be excluded; refer 
Section 5.2 (eligibility) for details.

GSK2330811 will be administered by trained 
clinical staff and participants will be appropriately 
monitored after dosing in a setting with the 
capacity to manage any immediate 
hypersensitivity reactions.

Participants will be educated on the potential for 
hypersensitivity reactions and the appropriate 
emergency care.
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.The risk of developing ADA and their 
clinical consequences are mitigated given that GSK2330811 is a 
humanized monoclonal antibody against a soluble target

Serum samples will be collected for detection of 
ADA at timepoints aligned with regulatory 
guidelines [EMA, 2017;FDA, 2019].

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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 [Nakamura, 
2004]. Administration of OSM ameliorated liver injury in wild-type mice.

However, in the 13- and 26-week toxicity studies in healthy cynomolgus 
monkeys, treatment with GSK2330811 was not associated with any 
observed liver effects. Refer to IB for details [GlaxoSmithKline Document 
Number 2016N284919_02, 2019]

Mild, isolated, transient elevations in Alanine aminotransaminase (ALT), 
Aspartate Aminotransferase (AST) and 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_02, 2019].

Participants will be screened for HCV and HBV
and excluded if positive.

Participants will be excluded if ALT or bilirubin 
1.5x upper limit of normal (ULN) (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%), 

Standard GSK phase 1 monitoring of liver 
chemistry and criteria for enhanced liver 
chemistry monitoring and follow up Assessments 
will be implemented.
Reproductive Toxicity

Animal reproductive toxicity studies have not yet been carried out with 
GSK2330811.

Animal reproductive toxicity studies have been carried out for GSK315234, 
another IgG anti-OSM monoclonal antibody. GSK2330811 and 
GSK315234 antibodies bind different epitopes but have similar affinity for 
OSM in the animal model used. No GSK315234 related effects on 
pregnancy, embryofoetal 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.

The study will only recruit male participants. 

There are no specific contraception requirements 
for males participating in this study.
Carcinogenicity

There is conflicting evidence for the role of OSM in cell proliferation in 
metastatic cancer. Data are 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 
certain exceptions as described in Section 5.2.

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2.3.2.
Benefit Assessment
There will be no direct benefit to the healthy participants in this study. However, 
information obtained in this study will inform the conduct of future clinical studies to 
contribute to the process of developing new therapies for diseases where there is unmet 
medical need, including CD and SSc.
2.3.3.
Overall Benefit: Risk Conclusion
The safety of each individual participant has been prioritised and the eligibility, 
monitoring, enhanced monitoring and study level stopping criteria described in Section 7
have been designed to minimise risks to participants associated with exposure to 
GSK2330811. Taking into account these measures designed to minimise risks, the 
potential risks identified in association with GSK2330811 are justified.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Primary

To evaluate the safety and tolerability of a 
single SC dose of GSK2330811 in healthy 
Japanese participants

Number of participants reporting AEs.

Number of participants reporting SAEs.

Number of participants with vital signs (blood 
pressure, heart rate, body temperature) 
reaching a threshold of potential clinical 
importance.

Number of participants with treatment 
emergent abnormal ECG findings.

Number of participants with CTCAE grade 1 
or higher safety laboratory results (clinical 
chemistry, haematology values where 
CTCAE grading applies).

Number of participants with treatment 
emergent abnormal urinalysis findings.
Secondary
Secondary

To evaluate the pharmacokinetic (PK) profile 
of a single SC dose of GSK2330811 in 
healthy Japanese participants

Pharmacokinetic parameters (Cmax, AUC, 
CL/F, Tmax, t1/2, Vss/F).

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Objectives
Endpoints

To assess the potential for anti-drug 
antibody (ADA) formation following a single 
SC dose of GSK2330811 in healthy 
Japanese participants

Number of participants with anti-
GSK2330811 antibodies

To assess effects of GSK2330811 on 
platelets and haemoglobin in healthy 
Japanese participants

Platelet nadir

Time to platelet nadir

Haemoglobin nadir

Time to haemoglobin nadir
Tertiary/Exploratory
Tertiary/Exploratory

To explore the PD and the PK/PD 
relationship for GSK2330811 in the blood of 
healthy Japanese participants

Serum levels of free OSM

Serum levels of total OSM

Levels of Thrombopoietin (TPO)

Levels of Erythropoietin (EPO)
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind (sponsor-open), placebo-controlled, single-centre 
study with single SC doses of GSK2330811 administered to healthy male Japanese 
participants.

Participants will attend a screening visit at the clinical unit within 30 days of 
Study Day 1. If eligible for the study, participants will return on Day -1 for 
overnight admission to the unit.

Participants will be randomized to either GSK2330811 or placebo in an 
approximate ratio of 7:3.

Approximately 10 eligible participants will be admitted to the clinical unit on the 
day prior to dosing (Day-1). On Day 1, each participant will receive a single SC
dose of GSK2330811 or placebo, administered as three separate SC injections. 
Participants will then remain as an in-patient until discharged on Day 2 after 
assessments have been performed.

Participants will then return to the clinical unit for outpatient visits as described in 
the SoA.

The final follow up visit will be at the clinical unit on Day 126.

The maximum dose will not exceed 450 mg SC.

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4.2.
Number of Participants
Approximately ten participants will be enrolled and dosed (7 GSK2330811: 3 Placebo) 
with a view to ensuring 8 are evaluable (6 GSK2330811: 2 Placebo). See Section 9.2 for 
details. Evaluable is defined as a participant who has received a full dose and has 
attended all visits up to Day 56 and at least one of Day 84 or Day 126.
In rare instances, a participant may not be able to receive all 3 required injections and 
will receive a partial dose. In such circumstances, the participant will not be considered 
evaluable, but will be encouraged to remain in the study for the planned duration.
If any participant is non-evaluable for any reason, the participant may be replaced at the 
discretion of the sponsor in consultation with the investigator and assigned to the same 
treatment. 
Up to a maximum of 14 participants may be enrolled and dosed.
4.3.
Intervention Groups and Duration
This study will include a single cohort of approximately 10 participants randomised to a 
single dose of 450 mg SC GSK2330811 or placebo in a 7:3 ratio (active: placebo).
The study duration, including screening and follow-up, is not expected to exceed 163 
days for any participant in the study. The follow-up may be extended if a SAE has not 
resolved by the final scheduled visit (see Section 8.3.3 and Section 10.3.3).
4.4.
Scientific Rationale for Study Design
The proposed 450 mg single SC dose in Japanese participants is anticipated to result in 
exposure comparable to the 6 mg/kg (average 417 mg, range 375-443 mg) single SC dose 
tested in Caucasian participants in the FTIH study 201246 allowing a comparative 
assessment of ethnic sensitivity in terms of safety, tolerability and PK and PD in a 
Japanese population. Furthermore, a dose of 450 mg SC aligns with the highest 
anticipated dose to be administered in the global clinical studies with GSK2330811.
In addition, this study will be conducted in healthy male participants for the following 
reasons:

Patients with inflammatory and fibrotic diseases may have existing comorbidities 
or be taking concomitant medications that may confound the analysis.

It is anticipated that patients would derive little or no benefit from a single dose of 
GSK2330811, but that taking part in the study might interfere with their ability to 
receive other potentially efficacious therapies.

Animal reproductive toxicity studies have not yet been carried out with 
GSK2330811 and therefore the benefit-risk of enrolling women of child-bearing 

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potential in this study, where they are unlikely to derive any direct benefit from a 
single dose of GSK2330811, does not support their inclusion. Moreover, enrolling 
only male participants will facilitate comparison with data from study 201246, a 
single-dose FTIH study of GSK2330811 in predominantly male Caucasian 
participants [Reid, 2018].
This study will include a placebo arm to ensure that the treatment-attribution of adverse 
events (AEs) is appropriately blinded and to provide control data for the PD and safety 
laboratory assessments.
The duration of follow-up will be about 126 days, which will be approximately 5 half-
lives of GSK2330811 (half-life of between 19 to 25 days) [GlaxoSmithKline Document 
Number 2016N284919_02, 2019].
Exploratory endpoints have been chosen to confirm target engagement and further 
investigate PK/PD relationships in the blood.
4.5.
Justification for Dose
To date, GSK2330811 has been administered as single SC doses to healthy participants 
(0.1-6 mg/kg) in the FTIH study 201246. In the highest dose cohort in study 201246, the 
average administered dose was 417 mg (range 375-443 mg). GSK2330811 is currently 
being tested in a repeat SC dose study (201247) of participants with systemic sclerosis 
(100 and 300 mg every other week for 6 doses).
The 450 mg single SC dose proposed for this study in healthy Japanese participants is 
anticipated to result in exposure comparable to the 6 mg/kg single SC dose tested in 
healthy Caucasian participants in study 201246. The 450 mg single SC dose is 47x lower 
than the NOAEL dose for non-pharmacology-related findings (300 mg/kg/week, highest 
dose tested) observed in the 26-week toxicity study in monkeys. Safety margins for 
predicted exposure in this study are summarised in Table 1. Predicted exposure was 
simulated using the minimal Physiologically Based Pharmacokinetic (mPBPK) model 
developed from data from study 201246 [Reid, 2018]. Clearance and volume were 
allometrically scaled assuming median body weight for Japanese living in the Western 
hemisphere equal to 64.2 kg (based on 15 Japan PK studies run by GSK in the Western 
hemisphere) and minimum body weight equal to 45 kg, as per study inclusion criteria.
Allometric scaling is likely to over-predict exposure.

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Table 1
Safety margins for predicted exposure for 450 mg SC single dose vs 
measured exposure in Study 201246 and 26-weeks toxicology study
Body 
weight (kg)
Predicted 
for 450 mg 
SC SD
Observed in 
2012461
Fold difference: observed 
in 2012462/ Predicted for 
450 mg SC SD
NOAEL3
Fold difference: 
NOAEL3/Predicted 
for 450 mg SC SD
Parameter: Cmax (ug/mL)
64.2
33
36.4 (28.7-48.9)
1.1x
9710
294x
45
39
0.9x
249x
Parameter: AUC (mg.hr/mL) 4
64.2
33
27.7 (19.8-37.7)
0.8x
1390
42x
45
43
0.6x
32x
1 Shown are observed geomean (range) for 6 mg/kg single dose (SD) SC.  2 Calculated using geomean 
observation in 201246.  3 NOAEL for non-pharmacodynamic related findings is 300 mg/kg/wk SC, which is 
the highest dose tested in the 26-weeks toxicology study in monkey. Shown are mean, gender averaged, 
exposures at Week 25.  4 Note that different AUCs are shown: Predicted for 450 mg SC SD: AUC(0-inf)-;
201246: AUC(0-inf); NOAEL: AUC(0-tau), where tau is 1 week.
The safety and tolerability of ascending single SC doses of GSK2330811 in the range of 
0.1 mg/kg to 6 mg/kg were studied in study 201246. GSK2330811 at these doses was 
generally well tolerated in healthy participants. Reversible, dose-dependent decreases in 
platelet counts were observed from the 1 mg/kg to the 6 mg/kg dose levels with recovery 
evident between Days 28 to 35. A reduction in haemoglobin from baseline values was 
observed in the GSK2330811 6 mg/kg group with all participants returning to within the 
normal range by Day 133. Further details can be found in Section 5 of the IB 
[GlaxoSmithKline Document Number 2016N284919_02, 2019].
The effect of GSK2330811 on platelets and haemoglobin is anticipated to be comparable 
in Japanese and Caucasian participants, since average exposure and target engagement 
are predicted to be comparable in the two populations. At the 6 mg/kg (average 417 mg) 
dose studied in study 201246, median maximum target engagement (TE) was 90% in 
serum. Therefore, a dose of 450 mg SC is appropriate to investigate the saturated PK/TE 
relationship. Furthermore, a dose of 450mg SC is the highest dose to be administered in 
the global clinical studies with GSK2330811.
4.6.
End of Study Definition
A participant is considered to have completed the study if he has completed the treatment 
and follow-up phases of the study including the last scheduled procedure shown in the 
SoA.

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The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participants must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests and 12-lead ECGs
3.
A participant with a clinical abnormality or laboratory parameter(s) outside the 
reference range for the healthy population being studied that is not specifically listed 
in the inclusion or exclusion criteria may be included if the investigator and GSK 
Medical Monitor agree and document that the finding is unlikely to introduce 
additional risk factors and will not interfere with the study procedures or 
interpretation.
Weight
4.
Body weight 45 kg and body mass index (BMI) within the range 18.5-29.9 kg/m2
(inclusive).
Sex
5.
Male
Informed Consent
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
Geographical Ancestry
7. Japanese ancestry, defined as having been born in Japan, being descendants of four 
ethnic Japanese grandparents and two ethnic Japanese parents, holding a Japanese 
passport or identity papers, and being able to speak Japanese. Participants should 
have lived outside Japan for less than 10 years at the time of screening.

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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Sensitivity to any of the study treatments or components there of (including 
humanised monoclonal antibodies) or history of severe post treatment 
hypersensitivity reactions including erythema multiforme major, linear 
immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis and exfoliative 
dermatitis. 
2. Any other history of significant allergy that in the opinion of the investigator 
contraindicates their participation in this study. 
3. An active infection or a history of serious infections as follows:
a.
Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic 
agents) for an infection within 30 days prior to Day 1. Topical treatments may 
be allowed at the Investigator’s discretion (in consultation with the Medical 
Monitor).
b. A history of opportunistic or recurrent infections, as determined by the 
investigator. 
c.
Currently active or unresolved infection. Participants with ‘trivial’ infections 
such as tinea pedis may be eligible at the discretion of the investigator.
d. Symptomatic herpes zoster within 3 months prior to screening.
e.
History of TB (active or latent) irrespective of treatment status. 
f.
A positive diagnostic TB test at screening (defined as a positive 
QuantiFERON test).
NOTE: In cases where the QuantiFERON test is indeterminate, the participant 
may have the test repeated once and will be eligible if the second test is 
negative. 
4. Any planned major surgical procedure during the study. 
5. A history of haematological disease, for example (but not limited to): significant 
anaemia, platelet disorders including drug-induced thrombocytopaenia or primary 
immune thrombocytopaenia and coagulation disorders including von Willebrand’s 
disease.
6. A history of carcinoma in situ and malignant disease, with the exception of 
adequately treated non-metastatic basal or squamous cell cancer of the skin that has 
been fully treated and shows no evidence of recurrence after 3 years. 

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7. QTc >450 msec at screening. 
NOTE: The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), or another method, machine-read or manually over-read. The same 
correction is to be used throughout the study.
Prior/Concomitant Therapy
8.
Use of prescription or non-prescription drugs (including recreational drugs and 
herbal medications) within 7 days or 5 half-lives (whichever is longer) prior to Day 1
unless in the opinion of the investigator (in consultation with the GSK Medical 
Monitor) the medication will not interfere with the study or compromise participant 
safety.
NOTE: Paracetamol at doses of 4 grams/day, and occasional use of NSAIDs at 
licensed doses, are permitted.
9.
Received live vaccination within 4 weeks prior to Day 1, or any plan to receive a live 
vaccination during the study (i.e. up to and including to the last follow-up visit).
Prior/Concurrent Clinical Study Experience
10. Participation in a clinical trial and has received an investigational medicine product
(IMP) within the following time period prior to Day 1: 3 months, 5 half-lives, or 
twice the duration of the biological effect of the IMP (whichever is longer).
11. Exposure to more than 4 new chemical entities within 12 months prior to Day 1.
12. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months.
Diagnostic assessments
13. Platelet count or haemoglobin below the normal range at any time during screening.
14. ALT >1.5x ULN at any time during screening. 
15. Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at any time during screening.
16. Presence of Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody 
(HBcAb), or positive HCV antibody result at screening
NOTE: Participants with positive HCV antibody due to prior resolved disease can be 
enrolled only if a confirmatory negative HCV RNA test is obtained.
17. Positive HIV antibody test at screening.
18. Positive pre-study drug/alcohol screen.
NOTE: Retesting of diagnostic assessments in the case of potentially spurious results 
or sample handling errors is allowed during the screening period. See Section 5.4 for 
details.

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Other Exclusions
19. History of regular alcohol consumption within 6 months of the screening visit in 
excess of an average weekly intake of >21 units. One unit is equivalent to 8 g of 
alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 
(25 mL) measure of spirits. 
20. Planning to travel to regions of high endemic infection, as determined by the 
investigator, for the duration of the study.
21. Unstable lifestyle factors, to the extent that in the opinion of the investigator they 
would interfere with the ability of a participant to complete the study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Participants will be required to fast for approximately 12 hours (no food or drink, 
except water) prior to collection of the Day 1 and Day 21 clinical chemistry blood 
sample. There will be no other caffeine, xanthine or dietary restrictions for the rest of 
the study.
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches and other delivery devices such as 
vaporizers) will not be permitted while they are in the clinical unit. Participants will 
abstain from alcohol for 24 hours prior to clinic visits. Thereafter a weekly intake of 
21 Units of alcohol is permitted. 
5.3.3.
Activity

Participants will abstain from strenuous exercise 24 hours prior to each blood 
collection for clinical laboratory tests. 
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled (randomized). A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations
and any SAEs.
Repeat assessments during the 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 

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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. Rescreened 
participants will be assigned a new participant number.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
This study will use a pre-filled syringe (PFS): Becton Dickinson’s UltraSafe Plus Safety 
Syringe Device. Instructions for use of the PFS medical device are provided in the Study 
Reference Manual (SRM).  
Intervention Name
GSK2330811
Placebo
Type 
Drug
Placebo
Dose Formulation
50mM Sodium Acetate Trihydrate, 
51mM Sodium Chloride, 1% (w/v) 
L-Arginine, 0.05mM Edetate Disodium 
Dihydrate (EDTA) and 0.02% 
Polysorbate 80 in Water for Injection 
USP, pH 5.5
Normal saline (0.9% sodium 
chloride)
Unit Dose Strength(s)
150mg/ml
N/A
Dosing Instructions
Administered by study personnel.  
3 injections to be used to provide 
450mg SC dose.
Administered by study 
personnel.  3 injections will be 
used to match active doses 
administered.
Route of 
Administration
SC injection to abdomen
SC injection to abdomen
IMP and Non-
investigational 
medicinal product
(NIMP)
IMP
NIMP

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Intervention Name
GSK2330811
Placebo
Sourcing
Provided by the Sponsor
Provided by the Sponsor
Packaging and 
Labelling
Study intervention will be provided in a 
pre-filled safety syringe.  Label content 
will be in accordance with the
country’s regulatory requirements
Study intervention will be 
provided in a pre-filled safety 
syringe.  Label content will be in 
accordance with the country’s 
regulatory requirements
[Current/Former 
Name(s) or Alias(es)]
Anti-OSM
N/A
GSK2330811 is a humanised monoclonal antibody and all formulation ingredients have 
been previously used in the clinic. 
SC GSK2330811 is administered as multiples of 150 mg injections, each provided as a 
pre-filled safety syringe. 
In an individual participant, injections should be administered into the abdomen and 
should be separated by a minimum of 2 cm. The location of the injections (abdominal 
quadrant) will be recorded.
6.2.
Preparation/Handling/Storage/Accountability
Each syringe will be supplied as a single PFS within a labelled carton, detailing the 
appropriate content according to the country’s regulations.
Study treatment will be stored in the refrigerator. The PFS must be allowed to come up to 
room temperature for at least 30 minutes after taking out of the refrigerator prior to use. 
Refer to the SRM for further details.
Any malfunctions of the PFS must be documented and reported throughout the study (see 
Section 10.7 for reporting of syringe deficiencies and malfunctions).
The following will also apply in the study:
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.

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3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Randomisation and Intervention Assignment
Participants who meet the screening eligibility criteria will be randomised to a treatment 
group through the Interactive Web Response System (IWRS). Before the study is 
initiated, the log in information and directions for the IWRS will be provided to the site. 
Once assigned, a randomisation number must not be reassigned to another participant in 
the study
6.3.2.
Blinding
This will be a double blind (sponsor-open) study with both the investigator and 
participant blinded to study treatment. Site personnel will remain blinded.
The following will apply:

The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. 

If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact GSK prior to unblinding a participant’s intervention 
assignment unless this could delay emergency intervention of the participant. 

If a participant’s intervention assignment is unblinded, GSK must be notified 
within 24 hours after breaking the blind.

The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable.

A participant may continue in the study if that participant’s intervention
assignment is unblinded. 

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
GSK’s Safety and Medical Governance (SMG) staff may unblind the intervention
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.

Sponsor-open refers to the potential need of the sponsor to unblind single or 
multiple participants at the request of the GSK2330811 Safety Review Team
(SRT) (see Section 10.1.5) to investigate important safety concerns. This would 
be done in accordance with GSK standard operating procedures, is expected to be 
very uncommon, and will be implemented in such a way as to maintain the 
integrity of the study as much as possible. 
6.3.2.1.
Risk of Inferred Unblinding
The treating physician and/or delegate (including the study nurse) will have sight of 
safety laboratory results to fulfil their responsibility for the medical care of study 
participants. Therefore, in this study there is a risk that the physician and/or delegate may 
infer a participant’s treatment allocation through this knowledge. 
Sites will be required to make every effort to ensure that the results of study laboratory 
tests are not proactively communicated to participants during the study unless essential 
for clinical care.
Study monitors, through their review of safety laboratory results, are also at risk of 
inferring a participant’s treatment.
PK and Free and Total OSM results that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, 
under medical supervision. The date and time of the dose administered in the clinic will 
be recorded in the source documents. The dose of study intervention and study participant
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention.  
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrolment or receives during the study must be 
recorded along with:

reason for use

dates of administration including start and end dates

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
dosage information including dose and frequency
The GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. Participants will be questioned about concomitant 
medication at each study visit.
Paracetamol (acetaminophen) at doses of 4 grams/day, and occasional NSAIDs at 
licensed doses, are permitted for use. 
Otherwise, participants must abstain from taking prescription or non-prescription drugs 
(including vitamins and dietary or herbal supplements) within 7 days or 5 half-lives 
(whichever is longer) before the start of study intervention until completion of the follow-
up visit unless, in the opinion of the investigator and GSK Medical Monitor, the 
medication will not interfere with the study. 
Live vaccination is prohibited within 4 weeks of Day 1 until after the Follow-Up visit.
6.6.
Dose Modification
No dose modifications are planned.
6.7.
Intervention after the End of the Study
This is a single dose study in healthy participants. No study intervention will be provided 
following the end of the study.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
This is a single dose study. In rare instances a participant may not be able to receive all 3 
injections and it may be necessary for the participant to permanently discontinue study 
intervention. If study intervention is discontinued, the participant will remain in the study 
for the planned duration. 
7.1.1.
Study Stopping Criteria
If any of the following occur, the study will be temporarily halted:

Any participant experiences a SAE that can be reasonably attributed to 
GSK2330811.

Two or more participants experience a severe adverse event that can be 
reasonably attributed to GSK2330811. 

Any participant experiences a CTCAE Grade 3 or greater reduction in platelet 
count (< 50x109/L) or haemoglobin (< 80 g/L). This should be confirmed by a 
repeat blood sample if there is any concern that the result may be spurious.

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The Competent Authority and the Ethics Committee will be notified of a Temporary Halt. 
No further participants will be dosed until a full safety review by relevant GSK personnel 
has taken place.  If, following the safety review, a decision is made to restart dosing, this 
will be based on an updated assessment of the benefit risk and will only occur after 
Competent Authority and Ethics Committee approval via a substantial amendment.
7.1.2.
Liver Chemistry Enhanced Monitoring Criteria
Phase 1 Liver chemistry increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event aetiology.

Refer to Section 10.4 for liver safety required actions and follow-up assessments. 

Any participant meeting the liver chemistry criteria (ALT 3x ULN) will have 
enhanced monitoring as detailed in Section 10.4. The participant should continue 
in the study, given this is a single dose study.

Liver events meeting SAE criteria will be managed as detailed in Section 7.1.1
Study Stopping Criteria.
7.1.3.
QTc Enhanced Monitoring Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility and for all monitoring throughout the study. The formula must not 
be changed or substituted once the participant has been enrolled. 
For participants that meet either of the bulleted criterion below, additional monitoring 
will be undertaken until the QTc value is no longer clinically significant. The frequency 
of this monitoring and the decision as to when the QTc value is no longer clinically 
significant will be at the discretion of the investigator. The participant should continue in 
the study, given this is a single dose study.

QTc >500 msec.

Change from baseline: QTc >60 msec.
The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief recording period.
7.1.4.
Haematological Enhanced Monitoring Criteria
Any participant with platelet count <75x109/L (CTCAE Grade2) must have platelet count 
assessed at least weekly until platelet count is ≥75x109/L. This may necessitate 
unscheduled assessments.
Any participant with a haemoglobin <100 g/L (CTCAE Grade2) must have haemoglobin 
assessed at least weekly until haemoglobin is ≥100g/L. This may necessitate unscheduled 
assessments.

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7.2.
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his own request or
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of withdrawal from the study, if possible, an early withdrawal visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of study withdrawal and follow-up and for any further 
evaluations that need to be completed.

The participant will be permanently withdrawn from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
Discontinuation of the study as a whole is handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

The actual date and time of each blood sample collection will be recorded. The 
collection, sample handling, processing, storage and shipping procedures are 
provided in the SRM.
8.1.
Efficacy Assessments
Efficacy assessments are not applicable to this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height (at screening only) 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).
8.2.2.
Vital Signs

Temperature (tympanic), pulse rate and blood pressure will be assessed.

Vital signs will be measured in a semi-supine position after 5 minutes rest in a 
quiet setting without distractions.

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
Vital signs will be measured with a completely automated device. Manual 
techniques will be used only if an automated device is not available.

Vital signs are to be taken before blood collection for laboratory tests.
8.2.3.
ECGs

Triplicate 12-lead ECGs will be obtained in a semi-supine position as outlined in 
the SoA (see Section 1.3) using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section  
7.1.3 for additional QTc readings that may be necessary.

The same QT correction formula must be used for each individual participant to 
determine study eligibility and enhanced monitoring, and this formula may not 
be changed or substituted once the participant has been screened.

Three individual ECG tracings should be obtained as closely as possible in 
succession, but no more than 2 minutes apart. 
8.2.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the case report form (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 
within 126 days after the last dose of study intervention should be repeated 
periodically until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or Medical Monitor. This 
monitoring may extend beyond the final scheduled follow-up visit. Also see 
Section 7.1.2 and Section 7.1.4 for protocol defined enhanced monitoring
requirements for specific assessments.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified, and the 
sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Injection Site Reaction Assessments
Trial staff will apply light pressure at the injection site and record any tenderness, 
erythema and induration in accordance with the SoA and SRM.

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8.2.6.
Hypersensitivity Reactions 
As GSK2330811 is a humanized monoclonal antibody, it is considered unlikely that 
acute allergic reactions will occur in response to exposure; however, all participants 
should be monitored carefully for evidence of allergic response. 
Participants should be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, vomiting, or other symptoms that may represent a hypersensitivity 
reaction to study intervention. It is important to recognize early signs of a 
hypersensitivity reaction and prevent progression to a severe reaction. In the case of a 
mild local reaction during dosing, study intervention administration may be reinitiated 
(with appropriate pre-medication if thought necessary) at the discretion of the 
investigator. 
In the event of a suspected severe acute hypersensitivity reaction or anaphylaxis, sites 
should manage this in accordance with relevant local or national guidelines (for example, 
the Resuscitation Council (UK) Emergency Treatment of Anaphylactic Reactions 
Guidelines for Healthcare Providers (2008). In particular sites should:
Discontinue administration of study intervention (if still ongoing), and not delay 
initial treatment due to an indefinite diagnosis.
Ensure adrenaline, chlorphenamine, hydrocortisone, and a resuscitation trolley are 
immediately available.
Assess the participant using the Airway, Breathing, Circulation, Disability, 
Exposure approach. In the event of a cardiac arrest, initiate cardiopulmonary 
resuscitation.
Provide adrenaline according to relevant local/national guidelines if there is any 
compromise of the participant’s airway, breathing or circulation: 
Provide high concentration oxygen via a non-rebreather mask; fluid resuscitation; 
initiate ECG monitoring and pulse oximetry; and monitor blood pressure.
Administer an appropriate antihistamine (e.g., chlorphenamine maleate 10 mg by 
slow intravenous injection, or intramuscularly).
Administer hydrocortisone 200 mg by slow intravenous injection, or 
intramuscularly.
Acquire two blood samples for serum tryptase analysis:
o As soon as possible after the onset of symptoms, and
o Within 1-2 hours (but no later than 4 hours) from the onset of symptoms.

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Discuss the clinical situation with the relevant hospital medical and/or intensive 
care team and arrange transfer to hospital for further treatment and observation as 
indicated.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
For the purpose of reporting safety events related to the PFS, the definitions of device-
related safety events, (adverse device effects (ADEs) and serious adverse device effects 
(SADEs), can be found in Section 10.7, (Appendix 7). PFS deficiencies are covered in 
Section 8.3.5.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative) and identified by the 
investigator/designee through clinical examination and review of laboratory 
investigations.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to withdraw from the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the final follow-up 
visit.

All AEs will be collected from the start of intervention until the final follow-up 
visit (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section. The exceptions are 
SAEs, which must be recorded in the CRF AE/SAE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.

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8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). This may require follow-up beyond the final scheduled follow-up 
visit. Further information on follow-up procedures is given in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pre-Filled Syringe Deficiencies
PFS are being provided for use in this study for administering the study treatment. In the 
event that a deficiency or a malfunction occurs with the PFS, in order to fulfil regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of PFS deficiencies that occur during the study.
For the purpose of reporting deficiencies and malfunctions, the definition of a Medical 
Device Deficiency can be found in Appendix 7.

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NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol. 
8.3.5.1.
Time Period for Detecting Pre-Filled Syringe Deficiencies

PFS deficiencies will be detected, documented, and reported during all periods 
of the study in which the medical device is used. 

The method of documenting PFS deficiencies or malfunctions is provided in 
Appendix 7.
8.3.5.2.
Follow-up of Pre-Filled Syringe Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the deficiency.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
8.3.5.3.
Prompt Reporting of Pre-Filled Syringe Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor within 72 hours after the 
investigator becomes aware of a deficiency or malfunction.

The PFS Deficiency/Malfunction Report Form will be sent to the sponsor.

The sponsor will be the contact for the receipt of PFS deficiency reports.
8.3.5.4.
Regulatory Reporting Requirements for Pre-Filled Syringe Incidents

The PFS to be used in the study is a combined medicinal product/medical 
device. The investigator will promptly report all deficiencies occurring with any 
medical device component provided for use in the study in order for the sponsor 
to fulfil the legal responsibility to notify appropriate regulatory authorities and 
other entities about certain safety information relating to medical devices being 
used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of any medical device component 
deficiencies to the IRB/IEC.

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

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
The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
8.4.
Treatment of Overdose
For this study, any potential dose of GSK2330811 greater than 450 mg 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 immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities weekly for 
at least 4 weeks or as otherwise advised by the Medical Monitor.
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
As this is a single dose study, in the event of an overdose no further study treatment will 
be administered to the participant.
8.5.
Pharmacokinetics

Approximately 2 mL EDTA blood will be collected at the time-points listed in 
the SOA for determination of GSK2330811 plasma concentrations.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

GSK2330811 plasma concentration analysis will be performed under the control 
of In Vitro/In Vivo Translation/Bioanalysis, Immunogenicity, Biomarkers
(IVIVT/BIB), GlaxoSmithKline.  Plasma concentrations of GSK2330811 will 
be determined using approved bioanalytical methodology.  The bioanalytical site 
will be detailed in the SRM and raw data will be archived by the bioanalytical 
site listed in the SRM.

Once the plasma has been analysed for GSK2330811, with the participant’s 
consent (see Section 10.1.3), residual samples may be stored and used for 
research to develop methods and assays including potential diagnostics related 
to targeting OSM in a range of potential conditions or to further understand the 
mechanism of action of GSK2330811.

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8.6.
Pharmacodynamics
8.6.1.
Total and Free OSM
Pharmacodynamic parameters of GSK2330811 target engagement with OSM will be 
assessed by measuring free and total OSM in serum.

Approximately 2 mL blood will be collected and processed to serum at the time-
points listed in the SOA for determination of total and free OSM.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Sample analysis will be performed under the control of In Vitro/In Vivo 
Translation/Third Party Resourcing (IVIVT/TPR), GlaxoSmithKline.  Plasma 
concentrations of GSK2330811 will be determined using approved bioanalytical 
methodology.  The bioanalytical site will be detailed in the SRM and raw data 
will be archived by the bioanalytical site listed in the SRM.

In addition, with the participant’s consent (see Section 10.1.3), residual samples 
may be stored and used for research to develop methods and assays including 
potential diagnostics related to targeting OSM in a range of potential conditions
or to further understand the mechanism of action of GSK2330811.
8.6.2.
Erythropoietin (EPO) and Thrombopoietin (TPO)
Blood samples will be collected for biomarker assessments related to the mechanism of 
anaemia and thrombocytopenia. These may include (but are not restricted to) EPO and 
TPO.

Approximately 2 mL blood will be collected for each biomarker listed above at 
the time-points listed in the SOA to evaluate their association with the observed 
clinical responses to GSK2330811.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The date of each sample will be recorded.

In addition, with the participant’s consent, residual samples may be stored and 
used for research to develop methods and assays including potential diagnostics 
related to targeting OSM in a range of potential conditions or to further 
understand the mechanism of action of GSK2330811.
8.7.
Biomarkers
No additional samples other than those detailed in Section 8.6 will be analysed.

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8.8.
Genetics
Genetics are not evaluated in this study.
8.9.
Immunogenicity Assessments
Blood samples will be collected for immunogenicity assessment.

Approximately 4 mL blood will be collected and processed to serum at the time-
points listed in the SOA for the determination anti-GSK2330811 antibodies.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The date of each sample will be recorded.

Sample analysis will be performed using a tiered approach involving screening, 
confirmation and titration [EMA, 2017;FDA, 2019] under the control of 
IVIVT/BIB, GlaxoSmithKline. The bioanalytical site will be detailed in the 
SRM and raw data will be archived by the bioanalytical site listed in the SRM.

If sera contain potential anti-GSK2330811 antibodies in the screening 
assessment, they will be confirmed by immune-competition 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). 
8.10.
Health Economics
Health Economics parameters are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary objective of this study is to assess the safety, and tolerability of single SC
doses of GSK2330811 in healthy Japanese participants. No formal hypotheses are being 
tested in this study. 
9.2.
Sample Size Determination
There will be a minimum of 10 Japanese participants. The participants will be 
randomised in the ratio 7:3 to GSK2330811 (450 mg) or placebo.
From the number of adverse events of a specific type observed in 7 participants receiving 
GSK2330811, statistical inferences can be made about the 95% Credible Interval of the 
true event rate, as shown in Table 2, specifying a prior distribution (Beta [1,1]). The 95%
CrI for 6 participants is also presented, as the sample size was defined with a view to 

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ensuring at least 6 participants receiving GSK2330811 are evaluable. Table 2 shows that 
if 0 particular safety events are observed out of 7 participants in the GSK2330811 group, 
the upper limit of the 95% Credible Interval indicates that a true event rate of 37% could 
not be ruled out.
Table 2
Upper 95% Credible Limit of the True Event Rate based on 7 
participants on GSK2330811 completing the study
Observed events / participants 
in cohort
Lower 95% Credible Limit of 
true event rate
Upper 95% Credible Limit of 
true event rate
0/7
0.3%
37%
1/7
3.2%
53%
2/7
8.5%
65%
0/6
0.4%
41%
1/6
3.7%
58%
2/6
9.9%
71%
The values in Table 3 are the geometric means of PK parameters observed in the FTIH 
study 201246 following GSK2330811 SC administration:
Table 3
AUC and Cmax Geometric Means and Percent Coefficient of 
Variation (%CVb) Observed in Caucasian PK Study 201246
Treatment group
Value (%CVb)
AUC (0-inf) 
(h*ug/mL)
Cmax
(ug/mL)
0.1 mg/kg
615 (26.2)
0.6 (32.3)
0.3 mg/kg
1605 (21.6)
1.5 (42.7)
1 mg/kg
5316 (42.5)
5.7 (43.5)
3 mg/kg
14656 (21.6)
19.0 (42.7)
6 mg/kg
27681 (23.3)
36.4(22.9)
The mean baseline weight in the 201246 study was 69.5kg and so the 6 mg/kg dose 
corresponds to an average dose of 417 mg; therefore, the PK parameters and CVb %’s 
presented in Table 3 for the 6 mg/kg group are a good approximation for a dose of 450 
mg.
Simulations were performed to determine the sample size based on comparing PK 
exposure in Japanese to PK exposure in Caucasians. The simulations were based on the 
data from the 6 participants who received 6 mg/kg of GSK2330811 in 201246, whose 
geometric mean of AUC(0-inf) was 27681 h*g/mL (95% Confidence interval (CI): 21748 
to 35233). Assuming the true AUC(0-inf) for the Japanese participants is the same as that 
of the 6 mg/kg dose from 201246 and a standard deviation on the loge scale of 0.23, the 
probability that the observed median will be within the 95% CI of the 6 mg/kg group is 
97.5% for 6 evaluable participants receiving GSK2330811 and 97.8% for 7 evaluable 
participants receiving GSK2330811. The probability that the median AUC(0-inf) will be 
within 0.5-2 fold change of the geometric mean from the 6 mg/kg group (13841 to 55363 
h*ug/mL) is 100% for either 6 or 7 evaluable participants receiving GSK2330811.

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Additional simulations were performed factoring in the effect of body weight on 
exposure utilising the mPBPK model developed using data from study 201246. If the true 
AUC(0-inf) is affected by body weight according to allometric scaling and intra-individual 
variability is 30% (as estimated by the mPBPK model), the probability that the geometric 
mean of AUC(0-inf) is within 0.5-2 fold compared to that observed in study 201246 
remains 100% for 6 evaluable participants receiving GSK2330811.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Screened
All participants who signed the ICF and were screened for eligibility.
Enrolled
All participants who signed the ICF and are randomized into the study.
Safety
All randomized participants who received at least one dose of study 
treatment.
Participants will be analysed according to the treatment they 
received.
Note: In the very unlikely case a participant is not randomized but 
receives at least one dose of study treatment, these participants will 
be listed separately.
Pharmacokinetic
All participants in the Safety population who received at least one
active dose of study treatment and had at least 1 non-missing PK 
assessment (Non-quantifiable values will be considered as non-
missing values).
Participants will be analysed according to the study treatment they 
received.
9.4.
Statistical Analyses
The Reporting Analysis Plan (RAP) will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and 
secondary endpoints.
9.4.1.
General Considerations
No formal hypothesis testing will be performed in this study. Summary statistics and 
graphs will be presented where appropriate.
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 (or 

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Day -1 where applicable) assessments are assumed to be taken prior to first dose and used 
as baseline.
If baseline data is missing, no derivation will be performed, and baseline will be set to 
missing.
9.4.2.
Primary Endpoint(s)
Analysis
Details
Endpoints

Number of participants reporting AEs and SAEs

Number of participants with vital signs (blood pressure, heart 
rate, body temperature) reaching a threshold of potential clinical 
importance

Number of participants with treatment emergent abnormal ECG 
findings.

Number of participants with CTCAE grade 1 or higher safety 
laboratory results (clinical chemistry, haematology values 
where CTCAE grading applies).

Number of participants with treatment emergent abnormal 
urinalysis findings.
Analysis

For count data, the number and percentage of participants will 
be presented.

In addition, where continuous data is available, descriptive 
statistics (i.e. n, arithmetic mean, standard deviation, minimum, 
median, and maximum) of both raw and change from baseline 
data will be also presented.

CTCAE criteria (version 5) will be used to categorise laboratory 
safety data.

Statistical 
Analysis 
(Modelled)

No statistical modelling is planned.
9.4.3.
Secondary Endpoint(s)
9.4.3.1.
Pharmacokinetic parameters
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population. 
Individual plasma concentration-time data will be graphically displayed and summary 
statistics will be produced by time point. Plasma GSK2330811 concentration-time data 
will be analysed by non-compartmental methods.  Calculations will be based on the 
actual sampling times recorded during the study. From the plasma concentration-time 
data, the following pharmacokinetic parameters will be determined, as data permit: 
maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the 
plasma concentration-time curve (AUC[0-t], AUC[0-inf]), terminal half-life (t1/2), apparent 
volume of distribution at steady state (Vss/F) and apparent systemic clearance (CL/F).
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum,) will be calculated for all pharmacokinetic parameters. In addition, for 

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loge-transformed variables geometric mean, 95% confidence interval, standard deviation 
on the log scale and %CVb will be provided.
Full details of planned secondary analysis will be specified in the RAP.
9.4.3.2.
Other secondary endpoints
The number and percentage of participants with confirmed positive anti-GSK2330811
antibodies will be presented.  Where applicable the titres will be listed.
Descriptive statistics (n, arithmetic mean, standard deviation, median, minimum and 
maximum) will be calculated for nadirs (for platelet count and haemoglobin).
Descriptive statistics (n, median, minimum, maximum and range) will be calculated for 
time to nadir (for platelet count and haemoglobin).
Full details of planned secondary analysis will be specified in the RAP.
9.4.4.
Exploratory Endpoints

Summary statistics will be produced where appropriate by time point and 
treatment group. 

Graphical displays will be produced over time for serum free and total OSM, TPO 
and EPO levels.

Exploratory PK/PD analyses, if data permit, may be completed on selected free 
and total OSM measurements to examine the relationship between plasma 
concentrations of GSK2330811, and target OSM concentration (free and total). 

Exploratory PK/PD analyses, if data permit, may be conducted on the platelet 
endpoint to examine the relationship between plasma concentrations of 
GSK2330811, and platelet count.  
Full details of planned exploratory analysis will be specified in the RAP.
9.5.
Interim Analyses
No interim analyses are planned.
9.6.
Interim Data Review Committee
An interim data review committee will not be required.

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

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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, where applicable, 
and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
Participants who are rescreened are required to sign a new ICF.
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK2330811 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have the GSK2330811 approved 
for medical use or approved for payment coverage.
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 

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
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
In line with routine pharmacovigilance, oversight of study safety will be provided by the 
GSK2330811 Safety Review Team (SRT). The SRT will conduct in-stream periodic 
review of blinded safety data including AEs, SAEs, vital signs and laboratory data. Ad 
hoc reviews may be scheduled if required and under certain circumstances the SRT may 
request unblinding of events to address an emerging safety concern (see Section 6.3.2). 
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized participant-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.

A manuscript will be progressed for publication in the scientific literature.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

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
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic case report form (eCRF)
that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement. 
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 

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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant follow-up
10.1.10.
Publication Policy

The results of this study will be progressed for publishing and may be 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 multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Reticulocyte
% Reticulocytes
Clinical 
Chemistry1
Urea
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein  
Albumin         
Glucose3
Calcium
Alkaline 
phosphatase
Lipids (fasted)2:
Total Cholesterol
HDL
LDL
Triglycerides
INR4
APTT4
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)

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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Breath alcohol and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody [HBcAb], and HCV antibody) 

QuantiFERON test for TB
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Blood for lipids (fasted) will be taken at pre-dose on day 1 and at day 21  
3.
Non-fasting sample except for pre-dose on day 1 and day 21. 
4.
Blood for INR and APTT will be taken at screening.

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

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

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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.

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

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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Not applicable.

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10.5.
Appendix 5: Genetics
Not applicable.

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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria and required follow up assessments have been 
designed to assure participant safety and to evaluate liver event etiology
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, as soon as possible and at 
least within 7 days of liver event4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form

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Liver Chemistry Stopping Criteria 
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week)
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that 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, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; HCV RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.

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10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

The device to be used in this study is a combination medicinal product; the PFS

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155. 

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements.

The detection and documentation procedures described in this protocol apply to 
the PFS provided for use in this study.

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10.7.1.
Definition of AE and ADE
AE and ADE Definition 

An AE is defined as any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device. This definition includes events related to the investigational medical 
device or comparator and events related to the procedures involved except for events 
in users or other persons, which only include events related to investigational 
devices.

An adverse device effect (ADE) is defined as an adverse event related to the use of 
an investigational medical device. This definition includes any adverse events 
resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational 
medical device as well as any event resulting from use error or from intentional 
misuse of the investigational medical device.
10.7.2.
Definition of SAE, SADE and USADE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is an AE that:
a.
Led to death 
b.
Led to serious deterioration in the health of the participant, that either resulted in:
1. A life-threatening illness or injury. 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
2. A permanent impairment of a body structure or a body function,
3. Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
c.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
SADE definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.

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USADE definition

A USADE is a serious adverse device effect which by its nature, incidence, severity 
or outcome has not been identified in the current version of the risk analysis report 
(see Section 2.3).
10.7.3.
Definition of Device Deficiency
Device Deficiency definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate labelling.
10.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies
AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice, and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the sponsor AE/SAE/device 
deficiency CRF page.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. 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 the sponsor.

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.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent recurrence.

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Assessment of Intensity

The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs 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.

Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment.

For each AE/SAE/device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/device deficiency and has provided an 
assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AE/SAE/device deficiency

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/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.7.5.
Reporting of SAEs
SAE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

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 GSK medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.

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10.7.6.
Reporting of SADEs
SADE Reporting to GSK
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to GSK
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency.

GSK shall review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These shall be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations.

Contacts for SAE reporting can be found in the SRM.

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10.8.
Appendix 8: Country-specific requirements
Non applicable

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10.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
ADA
Anti-drug antibody
ADE
Adverse Device Effect
AE
Adverse event(s)
ALT
Alanine aminotransaminase 
ANOVA
Analysis of variance 
AST
Aspartate Aminotransferase
AUC
Area under the curve 
AUC(0-inf)
Area under the plasma concentration time-curve from time zero to infinity
AUC(0-t)
Area under the plasma concentration-time curve from time zero to the time of last 
quantifiable concentration
BMI
Body Mass Index
CA
Competent Authority
CD
Crohn’s Disease
CIOMS
Council for International Organizations of Medical Sciences 
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase 
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events 
CVb
Coefficients of variation 
EC
Ethics committee
ECG
Electrocardiogram

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eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EPO
Erythropoietin
F
Bioavailability 
FTIH
First Time In Human
GCP
Good Clinical Practice 
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody 
HBsAg
Hepatitis B surface antigen 
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
IB
Investigator(‘s) Brochure
ICF
Informed Consent Form
ICH
International Council of Harmonization
IDRC
Interim Data Review Committee
IEC
Independent Ethics Committees 
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
INR
International normalized ratio 
IRB
Institutional Review Boards
IVIVT/BBI
In Vitro/In Vivo Translation/ Bioanalysis, Immunogenicity, Biomarkers
IVIVT/TPR
In Vitro/In Vivo Translation/Third Party Resourcing
IWRS
Interactive Web Response System
KLH
Keyhole Limpet Hemocyanin 

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LDH
Lactate dehydrogenase 
LLN
Lower Limit of Normal
MCH
Mean Corpuscular Haemoglobin
mPBPK
minimal Physiologically Based Pharmacokinetic
MSDS
Material Safety Data Sheet
NIMP
Non-investigational medicinal product
NOAEL
No Observed Adverse Effect Level
NSAID
Non-steroidal anti-inflammatory drug
OSM
Oncostatin M
PD
Pharmacodynamic
PK
Pharmacokinetic
QTc
Corrected QT interval
QTcF
Corrected QT interval (Fridericia’s formula)
RAP
Reporting Analysis Plan 
RBC
Red Blood Cell
SADE
Serious adverse device effect
SAE
Serious adverse event(s)
SC
Subcutaneous
SD
Single dose
SMG
Safety and Medical Governance 
SoA
Schedule of Activities 
SRM
Study Reference Manual
SSc
Systemic Sclerosis
SUSAR
Suspected unexpected serious adverse reactions
TB
Tuberculosis

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TE
Target Engagement
Tmax
Time of occurrence of Cmax
TMDD
Target-mediated drug disposition 
TPO
Thrombopoietin
ULN
Upper limit of normal
USADE
Unexpected serious adverse device effect
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON
UltraSafe Plus

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11.
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