A Randomised, Double Blind (Sponsor Unblinded), Placebo-controlled, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a IV Dose of GSK2831781 in Healthy Volunteers and Patients With Plaque Psoriasis
Phase: PHASE1
Conditions: Psoriasis
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, double blind (sponsor unblinded), placebo 
controlled, single ascending dose study to investigate the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of a IV 
dose of GSK2831781 in healthy volunteers and patients with 
plaque psoriasis.
Compound Number:
GSK2831781
Development Phase: 
I
Effective Date:
24-JUL-2017
Protocol Amendment Number:  10
Author (s):
 (EDL, II TAU); 
 (CPMS); 
 (Biol); 
 (Biol); 
 (Biol); 
 (Biol); 
 (GCSP); 
 (QSci); 
 (CIL II TAU); 
 (CPSSO); 
 
 (QSci); 
 (II TAU); 
 (Medical Monitor, II TAU) 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N192690_01
2014-FEB-28
Original
2014N192690_02
2014-MAR-27
Amendment No. 1
To respond to comments from MHRA
2014N192690_03
2014-JUN-06
Amendment No. 2
To include a test at screening to only allow ADA- subjects to be included in Parts A and 
B of the study.  
Changes to correct inconsistencies and clarifications for exploratory assays.
2014N192690_04
2014-NOV-07
Amendment No. 3
To remove eligibility criteria regarding vaccinations and amend criteria regarding 
tuberculosis history.
Changes to correct text that was not logistically possible, or required clarification.
2014N192690_05
2014-NOV-27
Amendment No. 4
To reinstate eligibility criteria regarding vaccinations at MHRA request, and to enable 
this, to add potential to vaccinate during screening and potential to use serology.
2014N192690_06
2015-MAR-25
Amendment No. 5
To replace 2 Healthy volunteer DTH challenge cohorts with Healthy Volunteer No DTH 
challenge cohorts and improve flexibility for vaccinations. Changes to correct text no 
longer accurate due to improved assays. Eligibility criteria text updated to meet country 
specific ethics requirements.
2014N192690_07
2015-JUL-30
Amendment No. 6
Exclusion criteria and text to provide greater clarity regarding the composition of Dose 
Escalation Committee and DEC decision making updated to meet country specific 
regulatory and ethics requirements.
2014N192690_08
2015-SEP-22
Amendment No. 7
To modify study design to enable assessment of the impact of pre-existing anti-drug 
antibodies in healthy volunteers and psoriasis subjects.
To clarify estimation of body surface area, extend review of psoriasis clinical response, 
define duration of extended screening for subjects undergoing vaccination and add 

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flexibility to assays for ex vivo antigen stimulation and transcriptomics.
2014N192690_09
2016-MAY-18
Amendment No. 8
Part B, Psoriasis: To include females of reproductive potential (FRP) and to modify other 
eligibility criteria (age, BMI, BSA, vaccination and liver function tests). Addition of 
causality requirement to adverse event reporting for safety review criteria.
2014N192690_10
2017-MAR-09
Amendment No. 9
Remove requirement for 3 ADA+ve patients in Cohorts 8 and 9.  Update Time and 
Events Table 9 and Table 10 to reflect: adjustment of PK schedule (one new visit for 
Cohort 8 [Day 36] and Cohort 9 [Day 71]; introduction of efficacy assessments at Day 
85; removal of Ex vivo Antigen/Cytokine Stimulation Test and in vitro LAG-3+ activity 
assay; to state immunophenotyping methodology as chip cytometry; photography moved 
prior to biopsy; introduce possibility for additional interim analyses to inform internal 
development decisions, update medical monitor.
2014N192690_11
2017-JUL-24
Amendment No. 10
Update pharmacokinetic predictions and data. Consolidate the follow-up and surveillance 
visits for subjects in Part B who have not already completed follow up, into a 6-month
final visit and incorporate assessment of clinical response (Section 6.3.5.3). An 
additional PGA endpoint added to secondary endpoints. Minor corrections to Time and 
Event Tables. Update medical monitor details.

P P D
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
Experimental Medicine Unit, 
Immuno-inflammation 
Therapy Unit
GlaxoSmithKline Medicines 
Stevenage Hertfordshire 
SG1 2NY, UK
Secondary 
Medical 
Monitor
as above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  EudraCT Number 2014-000312-33
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200630
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................11
1.
INTRODUCTION....................................................................................................15
1.1.
Study Rationale ..........................................................................................15
1.2.
Brief Background ........................................................................................15
1.2.1.
GSK2831781...............................................................................15
1.2.2.
LAG-3 biology..............................................................................16
1.2.3.
Psoriasis......................................................................................17
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................18
3.
STUDY DESIGN ....................................................................................................21
3.1.
Study Schematic.........................................................................................21
3.1.1.
PPD injection sites.......................................................................22
3.1.2.
Study Design Summary ...............................................................23
3.2.
Study Design Detail ....................................................................................24
3.2.1.
Healthy Volunteer to Patient Switching ........................................27
3.3.
Discussion of Study Design ........................................................................27
3.3.1.
Design Rationale .........................................................................27
3.3.2.
Dose Rationale ............................................................................30
3.3.2.1.
Human PK prediction..................................................30
3.3.2.2.
Starting dose determination (Minimum 
Anticipated Biologically Effective Level 
[MABEL] approach) ....................................................33
3.3.2.3.
Assessment of GSK2831781 pharmacology in 
healthy volunteers ......................................................34
3.3.2.4.
Potential therapeutic dose determination....................35
3.4.
Risk Management.......................................................................................35
4.
STUDY POPULATION...........................................................................................40
4.1.
Number of Subjects ....................................................................................40
4.2.
Eligibility Criteria .........................................................................................40
4.2.1.
Inclusion Criteria..........................................................................41
4.2.2.
Exclusion Criteria.........................................................................42
4.3.
Lifestyle Restrictions...................................................................................45
4.3.1.
Dietary requirements ...................................................................45
4.3.2.
Alcohol.........................................................................................45
4.3.3.
Activity .........................................................................................45
4.4.
Screen and Baseline Failures .....................................................................45
4.5.
Withdrawal Criteria and Procedures............................................................45
4.6.
Subject Completion.....................................................................................46
5.
STUDY TREATMENT ............................................................................................47
5.1.
Investigational Product and Other Study Treatment....................................47
5.2.
Challenge Agents .......................................................................................47
5.3.
Treatment Assignment................................................................................48
5.4.
Planned Dose Adjustments.........................................................................49
5.5.
Dose Adjustment/Stopping/Monitoring Criteria............................................51

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5.6.
Subject Specific Dose Adjustment/Stopping Safety/Monitoring 
Criteria........................................................................................................53
5.6.1.
Liver Chemistry Monitoring Criteria..............................................53
5.6.2.
QTc Monitoring Criteria................................................................53
5.6.3.
Renal Function Monitoring Criteria...............................................53
5.6.4.
Haematological Monitoring Criteria ..............................................53
5.6.5.
Febrile Monitoring Criteria............................................................54
5.6.6.
Other Dose Adjustment/Stopping Safety Criteria .........................54
5.7.
Dose Adjustment/Stopping Pharmacokinetic Criteria ..................................54
5.8.
Blinding.......................................................................................................54
5.9.
Packaging and Labelling.............................................................................55
5.10.
Preparation/Handling/Storage/Accountability..............................................55
5.10.1.
PPD 2TU and 10TU Dose............................................................56
5.11.
Assessment of Compliance ........................................................................56
5.12.
Treatment of Study Treatment Overdose....................................................56
5.13.
Treatment After the End of the Study..........................................................56
5.14.
Concomitant Medications and Non-Drug Therapies....................................57
5.14.1.
Permitted Medications .................................................................57
5.14.1.1.
Part A and Part B .......................................................57
5.14.1.2.
Part B.........................................................................57
5.14.2.
Prohibited Medications and Non-Drug Therapies.........................57
5.14.2.1.
Part A.........................................................................57
5.14.2.2.
Part A and B...............................................................57
5.14.2.3.
Part B.........................................................................58
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................60
6.1.
Time and Events Table...............................................................................61
6.2.
Demographic/Medical History Assessments ...............................................76
6.3.
Safety .........................................................................................................76
6.3.1.
Physical Exams ...........................................................................76
6.3.2.
Vital Signs....................................................................................76
6.3.3.
Electrocardiogram (ECG).............................................................76
6.3.4.
Infusion-related Reactions and Hypersensitivity Reactions ..........77
6.3.5.
Immunosuppression, Infections and Malignancies.......................77
6.3.5.1.
Progressive Multifocal Leukoencephalopathy 
(PML) .........................................................................78
6.3.5.2.
Follow-up of healthy volunteers who exhibit 
reduction of PPD challenge ........................................78
6.3.5.3.
Follow-up of subjects with psoriasis............................78
6.3.6.
Autoimmunity...............................................................................78
6.3.6.1.
Monitoring for thyroid complications and other 
endocrine complications .............................................78
6.3.6.2.
Monitoring for colitis....................................................79
6.3.7.
Clinical Laboratory Assessments .................................................79
6.3.8.
Vaccination..................................................................................80
6.3.8.1.
Part A: Healthy Volunteers .........................................80
6.3.8.2.
Part B: Psoriasis subjects...........................................81
6.4.
Efficacy.......................................................................................................81
6.4.1.
Body Surface Area (BSA) ............................................................81
6.4.2.
Psoriasis Area and Severity Index (PASI) Assessment................81
6.4.3.
Physician Global Assessment (PGA)...........................................82

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6.4.4.
Plaque Lesional Severity Score (PLSS) and index plaque 
selection ......................................................................................83
6.4.5.
Photograph of the psoriasis plaques............................................83
6.4.6.
Histology-Psoriasis skin biopsy evaluation and scoring................83
6.5.
Other measures of clinical response...........................................................83
6.5.1.
PPD Intradermal injections ..........................................................83
6.5.1.1.
Bleb............................................................................84
6.5.1.2.
ILH .............................................................................84
6.5.2.
DTH.............................................................................................84
6.5.2.1.
Ball Point Pen Technique ...........................................84
6.5.2.2.
Photograph of DTH reaction.......................................85
6.6.
Pharmacokinetics .......................................................................................85
6.6.1.
Blood Sample Collection..............................................................85
6.6.2.
Sample Analysis ..........................................................................85
6.7.
Immunogenicity...........................................................................................85
6.7.1.
Blood Sample Collection..............................................................85
6.7.2.
Sample Analysis ..........................................................................85
6.8.
Biomarkers/Pharmacodynamic Markers .....................................................86
6.8.1.
LAG-3+ cells in DTH challenge site skin biopsies (Part A) ...........86
6.8.2.
LAG-3+ cells in psoriasis lesion biopsies (Part B) ........................86
6.8.3.
Immune Cell Phenotyping............................................................86
6.8.4.
LAG-3 Cell Receptor Occupancy .................................................87
6.8.5.
NK CD16 Cell Receptor Occupancy ............................................87
6.8.6.
Serum Protein Analysis................................................................87
6.8.6.1.
Assessment of serum cytokines .................................87
6.8.6.2.
Assessment of sLAG-3 receptor occupancy ...............87
6.8.7.
Novel Biomarkers ........................................................................87
6.8.7.1.
RNA Transcriptome Research....................................88
6.8.7.2.
RNA Expression Research of a Subset of RNA 
Species ......................................................................88
6.9.
Pharmacogenetics......................................................................................88
7.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................89
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................89
7.1.1.
Time period for collecting AE and SAE information......................89
7.1.2.
Method of Detecting AEs and SAEs.............................................89
7.1.3.
Definition of Adverse Events........................................................90
7.1.4.
Definition of Serious Adverse Events...........................................91
7.1.5.
Cardiovascular Events.................................................................92
7.1.6.
Death Events...............................................................................92
7.1.7.
Prompt Reporting of SAEs to GSK...............................................93
7.1.8.
Regulatory Reporting Requirements For SAEs............................93
8.
DATA MANAGEMENT ...........................................................................................93
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................93
9.1.
Hypotheses and Treatment Comparisons...................................................93
9.2.
Sample Size Considerations.......................................................................94
9.2.1.
Sample Size Assumptions ...........................................................94
9.2.2.
Sample Size Sensitivity................................................................95
9.2.3.
Sample Size Re-estimation..........................................................96
9.3.
Data Analysis Considerations .....................................................................96

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9.3.1.
Interim Analysis ...........................................................................96
9.3.2.
Final Analyses .............................................................................97
9.3.2.1.
Safety Analyses..........................................................97
9.3.2.2.
Pharmacokinetic Analyses..........................................97
9.3.2.3.
Pharmacokinetic/Pharmacodynamic Analyses ...........99
9.3.2.4.
Pharmacodynamic/Biomarker Analyses .....................99
9.3.2.5.
Efficacy Analyses .......................................................99
9.3.2.6.
Immunogenicity Analyses...........................................99
10. STUDY GOVERNANCE CONSIDERATIONS......................................................100
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........100
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................100
10.2.1.
Urgent Safety Measures ............................................................101
10.3.
Quality Control (Study Monitoring) ............................................................101
10.4.
Quality Assurance.....................................................................................101
10.5.
Study and Site Closure .............................................................................101
10.6.
Records Retention....................................................................................102
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............102
11. REFERENCES.....................................................................................................104
12. APPENDICES......................................................................................................107
12.1.
Appendix 1: Liver Safety Process .............................................................107
12.2.
Appendix 2: Pharmacogenetic research ...................................................109
12.3.
Appendix 3: Cytokine Release Syndrome AE Grading..............................115
12.4.
Appendix 4: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of Adverse Events and Medical Device Incidents .....................117
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................120
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............120
12.5.2.
Collection of Pregnancy Information ..........................................120
12.6.
Appendix 6: Protocol Amendment Changes..............................................122

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LIST OF ABBREVIATIONS
%AUCex
Percentage of AUC(0-) obtained by extrapolation
µg
Microgram
ABC
airway, breathing, and circulation from Basic Life Support
aCCR4
Anti C-C chemokine receptor type 4
ADA
Anti-drug antibodies
ADCC
Antibody Dependent Cell Cytotoxicity
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to last 
time of quantifiable concentration within a subject across all treatments
AUC(0-x)
Area under the concentration-time curve from zero (pre-dose) to some 
fixed nominal time x
BCG
Bacillus Calmette Guérin vaccine
BMI
Body mass index
BSA
Body Surface Area
BUN
Blood urea nitrogen
CI
Confidence Interval
CIL
Clinical Investigator Lead
CL
Systemic clearance of parent drug
Cmax
Maximum observed concentration 
CMV
Cytomegalovirus
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling and Simulation
CPR
Cardio-Pulmonary Resuscitation 
CPSSO
Clinical Pharmacology Sciences and Study Operations
CRF
Case Report Form
CRP
C-Reactive Protein
CSR
Clinical Study Report
CTLA
Cytotoxic T-Lymphocyte Antigen
CXCR
CXC Chemokine Receptor
DC
Dendritic Cells
DEC
Dose Escalation Committee
DMPK
Drug Metabolism and Pharmacokinetics 
DPT
Diphtheria, pertussis, tetanus
DTH
Delayed type hypersensitivity
EBV
Epstein-Barr Virus
EC50
Median Effective Concentration
EC90
90% Effective Concentration
ECG
Electrocardiogram
ECL
Immunoelectrochemiluminescent 

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eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic acid
FCS
Foetal Calf Serum 
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time In Human
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factor 
GGT
Gamma glutamyltransferase
GI
Gastrointestinal
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
HBcAb
Hepatitis B core antibody
Hep B
Hepatitis B
Hep C
Hepatitis C
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
HSV
Herpes Simplex Virus
IB 
Investigator’s Brochure
IBS
Irritable Bowel Syndrome
ICU
Intensive Care Unit
ID
Intradermal
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
Ig
Immunoglobulin
IgM
Immunoglobulin M
IHC
Immunohistochemistry
ii TAU
Immuno-Inflammation Therapeutic Area Unity
IL2R
Interleukin 2 Receptor
ILH
Immediate local hypersensitivity
INR
International Normalised Ratio
IRB
Institutional Review Board
IV
Intravenous
KD
Dissociation constant
kg
Kilogram
L
Litres
LAG-3
Lymphocyte Activation Gene 3
LDH
Lactate dehydrogenase
LFA
Lymphocyte Function-associated Antigen
LLQ
Lower Limit of Quantification
mAb
Monoclonal Antibody

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MABEL
Minimum Anticipated Biological Effect Level 
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
mg
Milligram
MHCII
Major Histocompatability Complex II
MlU/mL
milli-international units per millilitre
ml
Millilitre
mm
Millimetre
MMR
Measles, mumps, rubella
mRNA
Messenger Ribonucleic Acid
MRT
Mean Residence Time
MSDS
Material Safety Data Sheet 
MTB
Mycobacterium tuberculosis
NK
Natural Killer
nM
Nanomolar
NOAEL
No Observed Adverse Effect Level
OSL
Operations and Science Lead
PASI
Psoriasis Area Severity Index
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamic
PGA
Physicians Global Assessment
PGx
Pharmacogenetics
PK
Pharmacokinetic
PLSS
Plaque Lesional Severity Score 
PML
Progressive Multifocal Leukoencephalopathy 
PPD
Tuberculin Purified Protein Derivative
PTS
Platform Technologies and Science
QSci
Quantitative Sciences
QTc
Electrocardiogram QT interval corrected for heart rate 
QTcF
Electrocardiogram QT interval corrected for heart rate using Fridericia’s 
formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
RO
Receptor Occupancy
RT-PCR
Reverse transcription polymerase chain reaction
SAE
Serious adverse event(s)
SC
Subcutaneous
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
sLAG-3
Soluble Lymphocyte Activation Gene 3
SPC
Summary of Product Characteristics
SPM
Study Procedures Manual
t½
Terminal phase half-life

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TB
Tuberculosis
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
TNF
Tumour necrosis factor alpha
Tregs
Regulatory T cells
TU
Tuberculin Unit
UK
United Kingdom
USA
United States of America
Vss
Volume of distribution at steady state
VZV
Varicella Zoster Virus 
WBC
White blood cells
λz
Terminal elimination rate
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
InForm
Phoenix

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1.
INTRODUCTION
1.1.
Study Rationale
This study is the first administration of GSK2831781 in humans and will evaluate in two 
parts the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and 
immunogenicity of single intravenous (IV) doses of GSK2831781 administered to 
healthy volunteers (Part A), including a cohort of those previously vaccinated with 
Bacillus Calmette Guérin (BCG) (Part A delayed type hypersensitivity [DTH] cohort) 
and patients with plaque psoriasis (Part B). Single dose escalation will allow for the 
identification of any immediate dose-limiting toxicities. Investigation of pharmacology 
in healthy subjects in the Part A DTH cohort will confirm whether the selected dose is  
likely to result in pharmacodynamic effects in immune-inflammatory diseases associated 
with the target Lymphocyte Activation Gene 3+ (LAG-3+) T cells, which are then tested 
in Part B. As there are very low levels of LAG-3+ T cells in blood it is necessary to 
monitor LAG-3+ cells at the site of antigen challenge or the disease site. The use of a 
DTH in healthy subjects in Part A allows investigations into the impact of GSK2831781 
on immunological endpoints after a controlled challenge. The switch to patients with 
psoriasis in Part B, at a dose by which effects would be expected, then allows 
investigations of higher doses in a chronic disease setting. Measuring the pharmacology 
of GSK2831781 using the depletion of LAG-3+ T cells in skin biopsies from Tuberculin 
Purified Protein Derivative (PPD) skin challenge and lesional skin biopsies from patients 
with psoriasis, is an important component of the study and for the latter may enable an 
understanding of the dose response relationship, which will be important for decision 
making and the design of future studies in immuno-inflammatory diseases, including 
psoriasis. The use of DTH and psoriasis subjects to explore the mechanism in biopsies 
and clinical response endpoints in these populations, as well as investigate systemic 
biomarkers will also provide useful information before conducting studies in other 
immune-inflammatory disease where more invasive tissue biopsies would be required. 
1.2.
Brief Background
1.2.1.
GSK2831781
GSK2831781 is a humanised Antibody Dependent Cell Cytotoxicity (ADCC) enhanced 
monoclonal afucosylated antibody (mAb) that is specific to the LAG-3 protein, and has 
demonstrated depletion of LAG-3+ cells ex vivo and in vivo. LAG-3 is predominantly 
expressed on recently activated T cells upon T cell receptor engagement. 
In vitro pharmacology studies conducted with GSK2831781 demonstrate high binding 
affinity of GSK2831781 to LAG-3 (dissociate constant (KD) = 0.218 nanomolar [nM]) 
(GlaxoSmithKline Document Number 2011N130304_00). The biological activity of 
GSK2831781 was demonstrated in vitro showing ADCC activity on ARH-77, a human 
LAG-3 expressing cell line with median effective concentration (EC50) for killing 
activity 8.4 ng/ml. A 4 week IV or subcutaneous (SC) good laboratory practice (GLP) 
toxicity study in cynomolgus monkeys was used to provide the safety profile. In this 
study there were no consistent GSK2831781 related changes in plasma cytokine levels 6 
or 24 hours after administration of GSK2831781 relative to baseline. Adverse 

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GSK2831781 related effects were limited to a marked decrease in absolute neutrophil 
count for two males given 100 mg/kg/week (one animal by each route of administration). 
Based on the GLP toxicity study, the no observed adverse effect level (NOAEL) for 
monkeys in this study was considered to be 30 mg/kg/week given intravenously. 
However, in two investigative studies, a reduction in neutrophil counts was observed in 1 
monkey from each study dosed intravenously at 30mg/kg (n=7) but was not observed in 
monkeys dosed at 3 mg/kg (n=7). 
Pre-existing anti-drug antibodies (ADA) that bind GSK2831781 have been noted in 36% 
and 37.5% of sera from healthy and psoriatic human subjects respectively. Analysis of 
ADA to GSK2831781 indicated they are generally low titre and low affinity, based on 
the IgM isotype. The relevance of pre-existing ADAs for biotherapeutics in general is 
poorly understood, but they may have an effect on pharmacological and clinical 
parameters (Xue et al, 2013).  
Detailed information can be found in the Investigators Brochure (IB) for GSK2831781 
[GlaxoSmithKline Document Number 2013N175515_01 and GlaxoSmithKline 
Document Number 2014N201916_00]
1.2.2.
LAG-3 biology
The mode of action of GSK2831781 utilises the specific expression of LAG-3 on 
recently activated T cells as target to specifically deplete these potentially pathogenic T 
cells. This approach that has been utilised in the past with other agents, alefacept, that 
targets CD2 and denileukin diftitox which targets CD25+ T cells (Chaarani et al, 2010; 
Martin et al, 2001).   In vivo, LAG-3 is a negative co-stimulatory receptor that modulates 
T cell homeostasis, proliferation and activation via its interaction with major 
histocompatability complex class II (MHCII). GSK2831781 is designed not to interfere 
with the MHCII binding of LAG-3 and does not increase T cell proliferation ex vivo. A 
monomeric soluble form of LAG-3 (sLAG-3) also exists and occurs at low levels in 
serum of healthy donors and patients.
LAG-3 is predominantly expressed on a low number of recently activated T cells (<1% in 
healthy volunteers) upon T cell receptor engagement, with very low expression on resting 
and naive/memory T cells and regulatory T cells (Tregs) in blood and secondary 
lymphoid tissue. This is supported by immunohistochemistry (IHC) data which 
demonstrate increased expression of LAG-3 on T cells in human tissue during the 
immune response to challenge antigens and in a growing number of immuno-
inflammatory disorders, including psoriasis [GlaxoSmithKline Document Number 
2013N184876_00]. It is hypothesised that in T cell driven immuno-inflammatory 
disorders, LAG-3+ T cells are pathogenic (having recently encountered self-antigen), and 
hence their depletion will reduce disease activity. The low level of expression of LAG-3 
on other T cell sub-types (naive and memory) should allow preferential targeting of 
pathogenic/effector T cells while sparing memory and naive T cells and Tregs, which are 
key for the normal immune response to pathogens and immune homeostasis. 
The key attribute of LAG-3 as a target antigen for an enhanced lymphocyte depletion 
agent is its relatively selective expression profile compared with other agents currently in 

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the clinic, i.e. Campath (T/B cells), alefacept (most CD45RO+ T cells) or rituximab (B-
cells). 
Data to support the hypothesis that depletion of LAG-3+ activated T cells will produce an 
inhibition of the immune response was generated by Immutep, the inventors of the 
parental non-enhanced mAb, IMP731. In a baboon tuberculin skin challenge model, 
IMP731 mediated depletion of LAG-3+ T cells, both in the periphery, including the 
lymph nodes and at the skin challenge site, and demonstrated a reduction in the 
tuberculin skin challenge response. LAG-3+ activated T cells have been quantified in 
biopsies of a delayed type hypersensitivity reaction following challenge with tuberculin 
purified protein derivative (PPD) in human healthy volunteers, at a time when the 
induration and erythema from the DTH reaction can also be measured (GSK unpublished 
data). 
1.2.3.
Psoriasis
Plaque psoriasis vulgaris is a chronic inflammatory skin disorder, affecting 1-3% of the 
population in Europe and the United States of America (USA) and represents one of the 
most prevalent immunoinflammatory diseases. The spread of psoriasis across the body 
can vary from minimal on elbows, knees and scalp (mild disease) to covering the entire 
body (severe).   
There are two key abnormalities in psoriasis, hyperproliferation of keratinocytes and an 
inflammatory cell infiltrate, which includes; dendritic cells (DCs), macrophages, NK T 
cells, mast cells, T cells and neutrophils. There is strong evidence that T cells have an 
important role in psoriasis (Cai et al, 2012); this is supported by the clinical activity of 
multiple T cell targeted agents including: cyclosporine, anti-CD4 antibodies, anti-
Cytotoxic T-Lymphocyte Antigen 4 Immunoglobulin (anti-CTLA4 Ig), alefacept 
(lymphocyte function-associated antigen 3 (LFA3)/CD2 fusion protein), efalizumab 
(anti-CD11a), siplizumab (anti-CD2) and DAB389IL-2 (diphtheria toxin-Interleukin 2 
receptor fusion protein) (Kircik et al, 2009).   
The number of T cells expressing LAG-3 are increased in lesional skin biopsies from 
patients with plaque psoriasis, when compared to non-involved skin from the same 
patients (GSK unpublished data). This increased LAG-3 expression, linked to the clear 
role of T cells in the pathogenesis of psoriasis warrant further investigation of 
GSK2831781 in patients with psoriasis.    

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2.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
To assess the safety and tolerability of 
single IV doses of GSK2831781 in healthy 
volunteers and psoriasis patients.

Laboratory safety data (haematology, 
clinical chemistry, urinalysis)

Vital signs (blood pressure, heart rate, 
body temperature)

12-lead ECGs

Adverse events

Inflammatory cytokine levels
Secondary
To evaluate the pharmacology and clinical 
effect of a single IV dose of GSK2831781 
in a DTH model in healthy volunteers.

Change from baseline (PPD 1st 
challenge) of induration diameter from 
re-challenge at 3 days post-dose

Duration of induration in the re-
challenge

Change from baseline (PPD 1st 
challenge) of LAG-3+ cells in biopsies 
of re-challenged skin at 3 days post-
dose, measured by IHC
To evaluate the pharmacology of a single 
IV dose of GSK2831781 in psoriasis 
patients.

Change from baseline in LAG-3+ cells 
in lesional biopsies at Day 29 
measured by IHC
To evaluate the pharmacokinetics of single 
IV doses of GSK2831781 in healthy 
volunteers and psoriasis patients.

GSK2831781 PK parameters 
following single intravenous dose: 
AUC(0-∞), AUC(0-t), AUC(0-
Week4), %AUCex, Cmax, tmax, tlast, 
CL, Vss, MRT, λz and t ½ when 
assessable 
To evaluate the immunogenicity of 
GSK2831781 administered as a single IV 
dose in healthy volunteers and psoriasis 
patients.

Antibodies to GSK2831781 in serum
To evaluate the effect of a single IV dose 
of GSK2831781 on disease activity in 
psoriasis patients.

Change from baseline and actual PASI 
scores at Day 15, 29, 43, 85, 121 and
follow up

Proportion of subjects who achieve 
≥50% and ≥75% improvement from 
baseline in PASI score at Day 15, 29, 

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Objectives
Endpoints
43, 85,121 and follow up (PASI 50 and 
PASI 75)

Change from baseline and actual PLSS 
scores at Day 15, 29, 43, 85 ,121 and
follow up

Change from baseline and actual PGA 
scores at Day 15, 29, 43, 85 and 121

Proportion of subjects in each PGA 
score category at Day 15, 29, 43, 85 
and 121

Proportion of subjects achieving PGA 
0/1 and at least a 2 point improvement
at Day 15, 29, 43, 85 and 121
Exploratory
To evaluate the effect of a single IV dose 
of GSK2831781 in psoriasis patients on 
biomarkers.

Histopathological scoring of psoriatic 
lesional biopsies in patients with 
psoriasis - Ki67, CD3 and epidermal 
thickness

Transcriptomic analysis of psoriatic 
lesional biopsies in patients with 
psoriasis
To evaluate the effect of a single IV dose 
of GSK2831781 in healthy volunteers and 
psoriasis patients on pharmacodynamic 
biomarkers.

Proof of pharmacology biomarker 
endpoints may include, but not be 
limited to, the following as data 
permit:

LAG-3 expression on different 
blood immune cell populations 
including T cells

Transcriptomic profiling to assess 
mRNA levels in peripheral blood

Quantification of LAG-3 mRNA 
in whole blood

Inflammatory cytokine levels

Free and GSK2831781 bound 
sLAG-3 concentrations

NK cell CD16 receptor occupancy 
in whole blood

NK cell activation marker 
expression in whole blood

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Objectives
Endpoints
To explore the impact of pre-existing 
ADAs on the PK of GSK2831781

GSK2831781 PK parameters 
following single intravenous dose: 
AUC(0-∞), AUC(0-t), AUC(0-
Week4), %AUCex, Cmax, tmax, tlast, 
CL, Vss, MRT, λz and t ½ when 
assessable 

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3.
STUDY DESIGN
3.1.
Study Schematic

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3.1.1.
PPD injection sites
Day 1
Right forearm
Left   forearm
2 or 10 TU PPD ID 
injection site 
2 or 10 TU PPD ID 
injection site
Day 30
2 or 10 TU PPD ID 
injection site
Right forearm
Left   forearm
2 or 10 TU PPD ID injection 
site
2 or 10 TU PPD ID 
injection site
2 or 10 TU PPD ID 
injection site
All injection sites should be 4 cm apart from each other and from Day 1 injection sites

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3.1.2.
Study Design Summary
Table 1
Dose escalation/Cohort Structure and Safety review periods
Planned 
Doses
Number of 
subjects 
(active:placebo)
Safety Follow-up 
period to progress 
to next 
subjects/cohorts
PPD DTH 
Challenge if 
Healthy 
volunteer/ Biopsy 
if patient
Follow-up and end of 
exclusion of systemic 
immunosuppressives
Healthy Volunteers
0.0003mg/kg
1:1
1:1 wait 28 days post-
dose
No DTH
Day 29 ± 1 day
(28 days post-dosing)
0.0015mg/kg
Day 43 ± 1 day
(42 days post-dosing)
0.0075mg/kg
6:2
1:1 wait 48 hours 
post-dose
5:1 wait 28 days post-
dose
No DTH
Day 85 ± 2 days
(84 days post-dosing)
0.04mg/kg
Day 147 ± 3 days
(146 days post-dosing)
0.15mg/kg
6:6
1:1 wait 48 hours 
post-dose
5:5 wait 28 days post-
dose
DTH
Day 219 ± 7 days
(190 days post-dosing)
0.15mg/kg*
6:2
1:1 wait 48 hours 
post-dose
5:1 wait 28 days post-
dose
No DTH
Day 189 ± 7 days
(190 days post-dosing)
Note: Cohort with a DTH starts dosing on Day 29
*Note: No DTH cohort at dose level 0.15mg/kg is in subjects with pre-existing ADA. All previous cohorts are in subjects 
without pre-existing ADA
Maximum dose for healthy volunteers may change based on emerging exposure (See Section 3.2.1)
Psoriasis Patients (Pre-existing ADA- and ADA +) 
0.5mg/kg
6:3(ADA-ve 4:2
ADA+ve: 2:1)
1:1 ADA-ve wait 48 
hours post-dose
5:2 wait 28 days post-
dose*
Biopsy
230 days post-dosing ± 7†
days
1.5mg/kg
6:3
Sentinel 1:1 - wait 48 
hours post-dose
5:2  - then wait 28 
days post-dose*
Biopsy
183 days post-dosing ± 7†
days (prior to Amendment 10 
was 270 days)

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Planned 
Doses
Number of 
subjects 
(active:placebo)
Safety Follow-up 
period to progress 
to next 
subjects/cohorts
PPD DTH 
Challenge if 
Healthy 
volunteer/ Biopsy 
if patient
Follow-up and end of 
exclusion of systemic 
immunosuppressives
5mg/kg
6:3
Sentinel 1:1 - wait 48 
hours post-dose
5:2
Biopsy
183 days post-dosing ± 7†
days (prior to Amendment 10 
was 300 days)
Note: All follow-up days may be increased or decreased during the study based on emerging data (See Section 3.3.1)
*Note: Progression to the next psoriasis cohort will be based on safety data and clinical measures of response at 28 
days post-dose for a minimum of 8 out 9 subjects plus a minimum of 72 hours post-dose for all subjects.
† All subjects in Cohort 7 have already completed the day 230 ± 7 follow up visit. Any subjects in Cohort 7 who have 
not had a 12-month surveillance visit when the amendment is approved should instead have a surveillance telephone 
call as their last study visit (see Table 6), as soon as practically possible after the amendment is approved, rather than 
waiting to month 12 after dosing. Subjects in Cohort 8 who have already completed their follow up visit should also 
have a surveillance telephone call as soon as the protocol amendment is approved. Subjects in Cohort 8 and Cohort 9 
who have not yet had a follow up visit when the protocol amendment is approved should have a combined follow 
up/surveillance visit at day 183 ± 7, or as soon as practically possible if they have already been monitored for longer 
than 183 ± 7 days after dosing.
3.2.
Study Design Detail
This is a FTIH, phase I, randomised, double-blind (sponsor unblind), placebo-controlled, 
single ascending dose study in healthy volunteers and patients with plaque psoriasis.  In 
Parts A and B of the study subjects will be screened for pre-existing ADA status and 
initially in Part A only subjects who do not have pre-existing ADAs will be randomised. 
A cohort (cohort 6) of subjects positive for pre-existing ADA at the maximum healthy 
volunteer dose of 0.15mg/kg will then be dosed.  Part B will include subjects with both 
negative and positive pre-existing ADA status.  In Cohort 7,  randomisation  was 
stratified by  ADA status. as outlined in Table 1.  In subsequent cohorts, the remaining 
subjects may be ADA+ve or ADA-ve.  
The planned dosing schedule is provided in Table 1 to aid understanding, although this is 
subject to change dependent on emerging study data and DEC decisions after each dosing 
session (See Section 5.4). In summary the doses planned are 0.0003, 0.0015, 0.0075, 
0.04, 0.15, 0.5, 1.5 and 5mg/kg.
The first healthy volunteer cohort will begin with the lowest dose. Healthy volunteers 
will be dosed up to a maximum dose of 0.15mg/kg (unless criteria in Section 3.2.1 are 
met). Once the last healthy volunteer cohort data has been reviewed by the DEC, the 
dose escalation will continue in patients with plaque psoriasis. The first cohort of patients 
with plaque psoriasis will begin at the next dose level after the maximum dose 
administered to healthy volunteers. The dose escalation will not exceed the maximum 
planned dose.
Based on the criteria which are defined in Section 5.4, ‘Planned Dose Adjustments’, 
Section 5.7 ‘Dose Adjustment/Stopping Pharmacokinetic Criteria’ and the DEC Charter, 
the DEC may recommend that doses and intervals between dose levels are changed 

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within these limits based on any of the following emergent data: safety and tolerability, 
PK, clinical measures and PD. 
All IV doses will be administered for 2 hours. However, dosing duration may be 
modified based on safety data with the approval of the PI and sponsor.  
PART A
Healthy volunteers without DTH
In cohorts 1 and 2, one active and one placebo subject will be recruited. 
For cohorts 3, 4 and 6, one active and one placebo subject will be recruited initially. 
After the GSK medical monitor and investigator have reviewed the safety data up to 48 
hours post dose, an additional 5 active and 1 placebo subjects will be dosed (no more 
than 2 subjects per day with dosing separated by at least 1 hour).  
After the DEC have reviewed the safety data up to 28 days on all subjects within the 
cohort along with the available PK data, a dose escalation may occur to the next planned 
dose. If safety findings are noted in the active subjects in cohorts with 2 subjects, the 
cohort may be expanded to a maximum cohort size of 6:3 (active:placebo) or the 
escalation stopped (See Section 5.5). Once data up to 28 days post dose has been 
collected for all subjects within cohort 6, the DEC will review the safety data along with 
the available PK data, available PD data from cohort 6 and also the DTH clinical 
response data from the Healthy Volunteer (DTH) cohort 5 (below), before switching to 
patients with plaque psoriasis.
A study schematic giving an overview of the visits is in Section 3.1.
Screening – Subjects will attend screening up to 35 days before dosing.
Day -1 – Day 4 – Subjects will attend the unit on Day -1 and will remain 
resident in the unit until Day 4. Provided that there are no safety issues on 
Day 4 (72 hours post dose) and there are no clinically significant 
haematology results from the 72 hour post-dose safety sample the subject 
will be discharged from the unit.
Days 8 and beyond - Subjects will attend the unit as an out-patient.
Follow-up - Subjects will return for a follow-up as specified in Table 1.
All subjects in cohorts 1, 2, 3 and 4 will attend a surveillance visit at 6 and 12 months. As 
the follow-up visit is at approximately 6 months (190 days post-dose, as per Table 1), 
subjects in the 0.15mg/kg cohort 6 do not require an additional post-dose surveillance 
visit at 6 months and will only attend a surveillance visit at 12 months.
Healthy volunteers with DTH
One active and one placebo subject will be recruited initially. After the GSK medical 
monitor and investigator have reviewed the safety data up to 48 hours post dose, an 

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additional 5 active and 5 placebo subjects will be dosed (no more than 2 subjects per day 
with dosing separated by at least 1 hour). Once data up to 28 days post dose has been 
collected for all subjects within the cohort, the DEC will review the safety data along 
with the available PD data, before dosing a cohort of healthy volunteers with pre-existing 
ADA, at the same dose, without DTH.
A study schematic giving an overview of the visits is in Section 3.1.
Screening - Subjects will attend screening up to 35 days before the first 
PPD challenge. 
Day 1 to Day 3 - Subjects will attend the unit on Day 1 and will receive 
ID injections of PPD as per Section 5.10.1 and Section 6.5.1. A skin 
biopsy will be taken from one of the DTH sites as detailed in Section 
6.8.1. 
Day 28 to Day 32 - After a period of at least 28 days (3 days) from the 
first challenge, subjects will return to the unit and will remain resident in 
the unit from Day 28 (3 days) until at least 72 hours after dosing. 
Subjects will receive ID injections of PPD as per Section 5.10.1 and 
Section 6.5.1. A skin biopsy will be taken from one of the DTH sites as 
detailed in Section 6.8.1. Provided there are no safety issues and there are 
no clinically significant haematology results on Day 32 (72 hours post 
dose) the subject will be discharged from the unit. 
Days 36 and beyond dependent on dose group - Subjects will attend the 
unit as an out-patient.
Follow-up - Subjects will return for a follow-up as specified in Table 1
As the follow-up visit is at approximately 6 months (190 days post-dose, as per Table 1), 
subjects in the 0.15mg/kg cohort do not require an additional post-dose surveillance visit 
at 6 months and will only attend a surveillance visit at 12 months.
PART B
Psoriasis patients
At the beginning of  Cohort 7, sentinel dosing in subjects without pre-existing ADA will 
occur such that one subject will receive active and one subject will receive placebo. After 
review of the two sentinel subjects’ safety data (Cohort 7) at 48 hours post-dose, an 
additional 5 active (3 without and 2 with pre-existing ADA) and 2 placebo subjects (1 
with and 1 without pre-existing ADA) will be dosed (no more than 2 subjects per day 
with dosing separated by at least 1 hour).
All subsequent cohorts do not require stratification for pre-existing ADAs.
Once safety data and clinical measures of response (e.g. PASI) at 28 days post-dose have 
been completed for a minimum of 8 out of 9 subjects within the cohort and all subjects 

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have completed dosing and the inpatient monitoring until Day 4, the DEC will review the 
safety data, available PK data and clinical response data, and may consider the available 
PD data before proceeding to the next dose level.  
A study schematic giving an overview of the visits is in Section 3.1.
Screening - Patients will attend screening up to 35 days before dosing.
Day -1 to Day 4 - Patients will attend the unit on Day -1. Two psoriatic 
plaques (index lesion and biopsy lesion) will be identified as per Section 
6.4.4 and Section 6.8.2. The biopsy lesion will be photographed prior to 
biopsy.  Patients will remain resident in the unit for at least 72 hours after 
dosing. Provided there are no safety issues and there are no clinically 
significant haematology results at 72 hours post-dose the patient will be 
discharged from the unit.
Day 8 and beyond - Patients will return to the unit as an out-patient. The 
biopsy lesion will again be photographed prior to biopsy on Day 29 (as 
specified in Section 6.8.2).
Follow-up and Surveillance - Patients will have a final combined follow-
up and surveillance visit as specified in Table 1 and associated footnote.
3.2.1.
Healthy Volunteer to Patient Switching
When the switch to psoriasis patients is made, no further dosing of healthy volunteers 
will occur.  If the understanding of EC50 for LAG-3+ T cells depletion change and/or 
emerging PK profiles differs markedly from prediction, the maximum dose for healthy 
volunteers may also change.  If GSK2831781 exposure is substantially less than 
predicted the maximum dose into healthy subjects would be increased to a dose predicted 
by the emerging pharmacokinetic data to provide a similar exposure as currently 
predicted at 0.15mg/kg (i.e. a target AUC of ~1800µg*h/mL [See Table 2]).  If a dose 
switch then occurs later, psoriasis cohorts would start one dose higher than the last dose 
used in healthy volunteers.  Details of dose adjustment can be found in Section 5.4.
3.3.
Discussion of Study Design
3.3.1.
Design Rationale
This study has been designed to be a 2-part study. Firstly, in Part A, a single ascending 
dose escalation will enrol healthy volunteers and then Part B will enrol patients with 
psoriasis.  
The assessment of GSK2831781 pharmacology in healthy subjects is challenging due to 
the low numbers of LAG-3+ T cells in the blood of healthy volunteers which makes the 
monitoring of the depletion of this cell population technically difficult.  To circumvent 
this issue, the last cohort of Part A of the study will employ a DTH model of a PPD 
intradermal injection, in healthy volunteers previously vaccinated with BCG to induce a 
DTH skin reaction and an increase of LAG-3+ T cells in the skin.  GSK2831781 

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mediated LAG3+ T cell depletion can then be monitored.  Intradermal DTH challenge 
results in accumulation of LAG-3+ T cells in the DTH site, as measured in biopsies from 
healthy volunteers previously vaccinated with BCG (GSK unpublished results).  The 
acute synchronous activation of T cells in a DTH challenge site may facilitate the 
demonstration of GSK2831781 pharmacology by monitoring the LAG-3+ T cell 
depletion in vivo, using a single ascending dose design.  By contrast, this T cell activation 
is likely to be chronic and asynchronous and hence potentially more difficult to detect 
after a single dose in an immuno-inflammatory condition like psoriasis.  
In addition the DTH reaction will be used as a proof of mechanism, to test whether 
GSK2831781 affects the clinical immune response, as measured by the induration 
diameter.  DTH skin reactions to intradermal injections of specific antigens have been 
used for decades in clinical studies to measure immune function.   DTH reactions are 
strongly driven by T cells (Ahmed et al, 1983) and so are very suited for measuring the 
proposed mode of action of GSK2831781.   Patient and healthy volunteer studies have 
demonstrated inhibition of the clinical induration response with T cell targeted agents 
such as cyclosporine, efalizumab, fingolimod and anti-IFNγ mAb (Palestine et al, 1985; 
Amlot et al, 1986; Ellis et al, 1991; Rentenaar et al, 2002; Krueger et al, 2008; Boulton
et al, 2012; Dumont et al, 2005).  By contrast, patient and healthy volunteer studies have 
demonstrated that inhibition of the B-cell immune response (Bingham et al, 2010) and 
the innate immune system (anti-Tumor Necrosis Factor alpha [TNFα] mAbs) have little 
or no effect on clinical DTH response (Moreland et al, 2002; Hatemi et al, 2007; Joven et 
al, 2006).  In addition, LAG-3 T cell depletion with the parental molecule of 
GSK2831781 - IMP731- has demonstrated inhibition of the tuberculin DTH response in 
baboons (Poirier et al, 2011).  Furthermore, a study with PPD ID challenge performed by 
GSK (GlaxoSmithKline Document Number 2012N150273_03) has demonstrated that the 
PPD challenge response has the operating characteristics to allow detection of a treatment 
response as well as showing the presence of LAG-3 cells at the challenge site by IHC 
(GSK unpublished data).  It is therefore hypothesised that a DTH challenge should allow 
the assessment of both the pharmacology and the mechanism of action of GSK2831781.
A healthy volunteer population is believed to be the appropriate population for the initial 
(Part A) investigations of GSK2831781 to explore the safety and tolerability in a 
population not currently receiving concomitant therapeutic treatments, and in whom the 
impact on immune function could be assessed in a controlled manner (i.e. under 
controlled challenge conditions).  The healthy volunteer population offers the potential to 
confirm the pharmacology observed in the baboon tuberculin skin challenge study with 
the parent mAb by using a well described PPD DTH challenge (Vukmanovic-Stejic et al,
2006).  Furthermore, assessment of the pharmacokinetics and pharmacodynamics across 
a wide dose range is not practical in a patient population especially given the requirement 
for the patient population to be treatment free of systemic immunosuppressives, due to 
the theoretical risk of synergistic or additive immunosuppressive effects, or confounding 
of the results.  In addition the recruitment of healthy volunteers at lower dose cohorts will 
mean that recruitment of patients with psoriasis will be focused on doses more likely to 
demonstrate clinical activity.  These considerations justify clinical investigations in 
healthy subjects before dosing patients with psoriasis.

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Proof of pharmacology and mechanism will be tested in healthy subjects up to 0.15mg/kg 
(to limit duration of exposure above the in vitro EC50 ADCC killing activity) before 
switching to psoriasis patients for further evaluation of pharmacology and mechanism 
(see Section 3.3.2.3 for dose rationale). This dose of 0.15 mg/kg might be altered if 
emerging PK profiles differ markedly from predictions (See Section 3.2.1).  A number of 
factors support the selection of patients with psoriasis as the population for Part B of the 
study.  It is well described that skin resident T cells are important drivers of psoriasis 
pathogenesis (Cai et al, 2012) and this has been demonstrated therapeutically, with a 
range of T cell targeted agents.  In addition data generated in-house, has shown that 
LAG-3+ T cells are present in increased numbers in psoriatic plaques from patients with 
psoriasis and that LAG-3+ cells can be used as a biomarker in a first time in human 
(FTIH) study to measure depletion of LAG-3+ T cells in psoriatic lesions. 
Measuring depletion of LAG-3+ T cells in psoriasis lesional biopsies is anticipated to be 
more challenging than in a PPD DTH challenge as T cell activation is asynchronous, 
hence the study in patients will be focused on doses at or above doses that are anticipated 
to demonstrate pharmacology in healthy volunteers following a DTH challenge. 
Test of proof of mechanism in psoriasis patients will be carried out using psoriasis 
disease endpoints such as lesional plaque biomarkers like epidermal thickness and CD3+ 
T cell numbers.  Clinical response in psoriasis patients will be measured using PASI and 
PLSS.  
Dose escalation in psoriasis patients will be started at one dose higher than the maximum 
dose investigated in healthy volunteers following a DTH challenge.  The overall total 
number of LAG-3+ cells in the whole body is not anticipated to be markedly different 
between healthy volunteers with a DTH challenge and patients with mild to moderate 
psoriasis. However, LAG3+ T cells in skin  lesions of psoriasis patients are likely to be 
higher and that could result in the need for higher doses compared to the dose showing 
pharmacological activity in healthy volunteers following a DTH challenge.  Dose 
escalation will therefore continue in psoriasis subjects until a significant clinical response 
is seen (Section 5.4) or the maximum dose is achieved.
Due to the presence of pre-existing ADA in a variable percentage in sera from both 
healthy and psoriatic human subjects, the initial investigation of GSK2831781 will be 
carried out initially in ADA negative subjects in Part A of the study to minimise the 
potential for diluting/confounding a signal of pharmacological or clinical response.  
However, for GSK2831781 to have development potential, it will need to be used in a 
mixed ADA population.  Therefore, after initial 28 day safety information is available for 
the DTH cohort at the highest dose for healthy volunteers, an additional cohort of healthy 
volunteers (without DTH) with pre-existing ADA will be dosed at the same dose level.  
Subjects in the psoriasis Cohort 7 will be recruited according to the following 
stratification: 4 ADA negative on active: 2 ADA negative on placebo and 2 ADA positive 
on active: 1 ADA positive on placebo.  Stratification for pre-existing ADAs in 
subsequent cohorts is not required. Subject follow-up visits will occur when 
GSK2831781 plasma concentrations are on average around the EC50 value of the in vitro
depletion assay in human plasma (See Table 1 and Figure 1).  This criteria was selected 
based on the theoretical possibility that GSK2831781 may still be able to deplete LAG-

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3+ T cells and affect the immune system, requiring monitoring of infection risk and 
applying restrictions for immunosuppressives use and travelling to endemic areas. Thus 
the period between final dosing and follow up will vary depending on the dose received.   
The time of the follow-up may be revised based on emerging data collected during the 
study. 
In addition, it is not known whether there will be any long term PD  effect, beyond the 
follow-up time at which levels of GSK2831781 would be negligible, for example by 
prolonged activity due to slow repletion of LAG-3+ cells.  Therefore all subjects in Part 
A will have a 12 month long term surveillance visit for assessment of safety and 
tolerability, as well as repeat of immune cell phenotyping and other pharmacodynamic 
assessments, which are still considered clinically abnormal at the follow-up visit. 
Subjects on lower doses, where follow-up is less than 6 months, will also have an interim 
6 month long term surveillance visit.  See Section 6.3.5.2 for repeat PPD challenge for 
subjects with persistent reduction of the DTH challenge.  
In Part B, psoriasis patients will be assessed for clinical response to determine long term 
effect up to Day 121.  Emerging pharmacokinetic data from subjects in Part A and in Part 
B (0.5 and 1.5mg/kg dose cohort) demonstrated a much more rapid clearance of 
GSK2831781 than previously predicted (see Figure 1 and Table 1).  At the highest dose 
delivered (5mg/kg), levels of GSK2831781 are expected to be below the lower limit of 
quantitation by Day 85. Subjects in Part B receiving 1.5mg/kg and 5.0mg/kg will 
therefore have a combined final follow-up and surveillance visit at 6 months (183 days ± 
7). If a follow-up visit has already taken place, a final surveillance telephone call will 
take place as soon as practically possible after the introduction of Amendment 10 (see 
Table 1). Lifestyle and medication restrictions are not mandated between the follow-up 
visit and final long-term surveillance visit, but use of any immunosuppressant or 
experimental medicine during this time, will be assessed for likelihood of confounding 
results.  Subjects with abnormalities at the final study visit that can be reasonably 
attributed to GSK2831781, will be asked to return for continued surveillance visits until 
the abnormality has resolved or is no longer clinically significant.
3.3.2.
Dose Rationale
3.3.2.1.
Human PK prediction
The human PK profile of GSK2831781 was predicted using the monkey pharmacokinetic 
data collected during the safety assessment study, excluding the PK profiles with 
suspected immunogenicity. Analysis of the monkey pharmacokinetic data using a 2-
compartment PK model provided estimates of PK parameters in this species. In these 
conditions, the clearance of GSK2831781 in the monkey was 0.000533 L/h or 4.42 
mL/day/kg, the volume of distribution was 0.190 L or 65.6 mL/kg and the half-life was 
approximately 11 days. An allometric scaling approach was used to predict the PK 
parameters in humans, with powers of unity for volume and 0.75 for clearance. Assuming 
a bodyweight of 70 kg for humans, the predicted human clearance (CL) is 0.00581 L/h or 
1.99 mL/day/kg, the volume of distribution (Vss) is 4.59 L or 65.6 mL/kg and the plasma 
elimination half-life is approximately 23 days, in the absence of target mediated 
disposition. Predicted human exposure at the proposed different doses (Figure 1), 
assuming a 2-hour infusion duration, as well as the comparison with monkey (cross-

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reactive species) exposure was determined assuming no target mediated disposition and 
in the absence of soluble LAG-3 (most conservative case) (Table 2). Due to the small 
expected amount of target, target mediated disposition is not anticipated to be prominent 
even at the low doses.  Furthermore, internalisation of the complex drug-LAG-3 receptor 
was found to be limited in vitro.  The anticipated level of soluble LAG-3 in the plasma is 
also low.
The proposed dose escalation scheme used a cautious approach in light of the enhanced 
ADCC mechanism, the nature of the target and the observed neutropenia in monkeys 
with larger dose increments at the beginning after the starting dose has been tested and 
when the doses investigated are still low. Lower dose increments are then implemented 
when getting closer to the maximum dose to be tested in this study.  
Table 2
Predicted human exposure versus monkey exposure at 30 mg/kg 
(cross-reactive species) at the proposed GSK2831781 doses 
administered IV with emerging actual exposure data and updated 
predictions also presented
Predicted Human Cmax and AUC
Comparison vs. Monkey (30 
mg/kg)
Ratio of 
predicted
human
Cmax/EC50*
Updated actual 
or predicted
human Cmax 
and AUC values 
based on 
emerging data**)
Dose 
(mg/kg)
Cmax 
(µg/mL)
AUC 
(µg*h/mL)
Dose 
ratio
Cmax 
ratio
AUC 
ratio
Cmax 
(µg/m
L)
AUC 
(µg*h/
mL)
0.0003
0.00763
3.61
100000x
171791x
36802x
0.908x
NA
NA
0.0015
0.0381
18.1
20000x
34358x
7360x
4.54x
NA
NA
0.0075
0.191
90.3
4000x
6872x
1472x
22.7x
0.152
1.38
0.04
1.02
482
750x
1288x
276x
121x
0.861
25.4
0.15
3.81
1807
200x
344x
73.6x
454x
3.22
208
0.5
12.7
6023
60x
103x
22.1x
1514x
8.48
903
1.5
38.1
18069
20x
34.4x
7.4x
4541x
40.1
8250
5
127
60232
6.0x
10.3x
2.2x
15136x
95.6†
30700†
* EC50 = 8.4 ng/mL for depletion of LAG-3 + cells in human plasma
** For doses up to and including 1.5mg/kg calculations are based on actual PK interim data from dose 
escalation meetings (all concentrations, except for one, were below LLOQ of 10ng/mL after 0.0003 and 
0.0015mg/kg, and therefore PK parameters could not be derived). For 5mg/kg dose: Cmax and AUC shown 
are predicted using a population PK model that was developed with data from 0.0075-1.5mg/kg 
GSK2831781
† Predicted values

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Figure 1
Predicted human GSK2831781 PK profiles at the proposed doses 
administered IV; predictions at beginning of study (a), and after 
1.5mg/kg cohort, with preliminary PK data (b)
a)
b)
Note: symbols are actual subject PK measurements observed during the study. Lines represent median drug 
concentrations per cohort based on the model predictions, and the shaded areas indicate the 95% confidence 
intervals of the model predications.

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3.3.2.2.
Starting dose determination (Minimum Anticipated Biologically 
Effective Level [MABEL] approach)
In order to investigate the pharmacology aspect of GSK2831781, predicted receptor 
occupancy (RO) in the plasma of healthy subjects, based on the binding affinity of the 
drug for its target and LAG-3 receptor concentration in the blood (Ganusov et al, 2007) at 
the predicted Cmax (assuming no target mediated disposition and in the absence of 
soluble LAG-3) of the proposed doses, were estimated and summarised in Table 3 below.
Table 3
Predicted receptor occupancy in the plasma at Cmax of the 
proposed GSK2831781 doses
Dose (mg/kg)
Cmax (µg/mL)
RO
0.0003
0.00763
19%
0.0015
0.0381
54%
0.0075
0.191
86%
0.04
1.02
97%
0.15
3.81
99%
0.5
12.7
100%
1.5
38.1
100%
5
127
100%
Furthermore, to incorporate the dynamic aspect, a drug-receptor binding PKPD model 
was developed incorporating the major elements believed to be involved in the drug 
disposition process (e.g. target load, number of LAG-3 receptors on T cells, 
internalisation rate and shedding rate of the LAG-3 receptors (soluble LAG-3)), based on 
pre-clinical data (in vitro and in vivo) generated in house, and assumptions supported by 
published data in the literature. The model simulates the predicted level of receptor 
occupancy achieved over time and the number of LAG-3+ T cells. Predicted Cmax and 
receptor occupancy at the proposed GSK2831781 doses are presented in Table 4 below. 
Prediction incorporates the presence of soluble LAG-3.
Table 4
Predicted receptor occupancy in the plasma at Cmax of the 
proposed GSK2831781 doses from the drug-receptor binding PKPD 
model
Dose (mg/kg)
Cmax (µg/mL)
RO
0.0003
0.00707
18%
0.0015
0.0375
52%
0.0075
0.184
84%
0.04
1.05
97%
0.15
3.67
99%
0.5
12.5
100%
1.5
37.7
100%
5
131
100%

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Selection of starting dose:
In consideration of the enhanced ADCC mechanism of action of GSK2831781, the 
novelty of the target and the cell expressing the target (T cells), a starting dose (MABEL) 
at which the PK profile remains below the in vitro EC50 for depleting activity in human 
plasma was selected. A starting dose of 0.0003 mg/kg is therefore proposed (Figure 1). 
This dose is predicted to provide 18% receptor occupancy at Cmax in the plasma which 
is expected to translate into the depletion of approximately 10% of the LAG-3 + T cells 
in the systemic circulation. The proposed starting dose is in the same range as the starting 
dose investigated by another competitor ADCC enhanced molecule (e.g. siplizumab 
0.0004mg/kg) albeit with different target.  The proposed starting dose of 0.0003 mg/kg is 
100000-fold lower than the 30 mg/kg dose investigated in the GLP toxicity study in 
monkey and the predicted AUC 36800-fold lower than the exposure observed at that 
dose. The predicted AUC would be 4081-fold lower than the exposure at the highest dose 
(3mg/kg) without neutropenia in the investigative study P70263N.
3.3.2.3.
Assessment of GSK2831781 pharmacology in healthy volunteers
It is hypothesised that LAG-3+ T cells drive the clinical DTH response in humans, 
therefore an adequate depletion of LAG-3 expressing T cells by GSK2831781 should 
translate in the reduction of DTH induration. There is evidence in the literature that 
molecules with enhanced ADCC mechanism show pharmacology at very low doses (i.e. 
0.03 mg/kg and below (benralizumab [Busse et al, 2010])).  
To assess the pharmacology of GSK2831781 in healthy volunteers and confirm the 
findings in the baboon study conducted with the parent molecule IMP731 where a 
depletion of peripheral LAG-3 expressing T cells was associated with an inhibition of a 
DTH response (Poirier et al, 2011), a DTH challenge will be conducted at the 0.15 mg/kg 
proposed dose. 
The difference in potency between the parent molecule IMP731 used in the baboon 
experiment and GSK2831781 using EL4 cells expressing human LAG-3 incubated with 
human peripheral blood mononuclear cells (PBMC) was about 20-fold in favour of 
GSK2831781.  Assuming the same fold difference would also apply in the baboon in 
vivo, as inhibition of the DTH response was observed at a Cmax of 2.5 µg/mL with 
IMP731 (highest Cmax observed at 0.1 mg/kg), it could be reasonable to assume that an 
effect on the PPD challenge could be observed at a concentration around 0.125 µg/mL 
(2.5/20) with GSK2831781.  At the proposed highest dose of 0.15 mg/kg in healthy 
subjects, human predicted concentrations are expected to be above 0.125 µg/mL for 98 
days.
From the drug-receptor binding PKPD model adjusted for the DTH challenge component, 
a dose of 0.15 mg/kg is predicted to confer at least on average 80% RO in the skin over 
approximately 28 days which is expected to translate into a reduction in the DTH 
response.    
There will be a maximum dose for healthy subjects of 0.15mg/kg (dose could be altered 
dependent on emerging PK data and/or PD data), to limit the duration of exposure above 
the in vitro EC50 ADCC killing activity (where there are lifestyle and medication 
restrictions), to no more than approximately 6 months (See Section 3.2.1 and Section 5.4
Planned Dose Adjustments).

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3.3.2.4.
Potential therapeutic dose determination
From the drug-receptor binding PKPD model, considering the presence of soluble LAG-3 
and a skin compartment, doses in the range of 0.5-2 mg/kg, depending on the blood:skin 
ratio assumed for a monoclonal antibody and the body surface area involved with 
psoriasis, are anticipated to confer at least 90% RO in the skin over 28 days (an 
acceptable dosing interval). These doses would also provide a concentration in the skin 
above the EC90 from the assay depletion of LAG-3 + cells in human plasma.  The 
maximum dose to be investigated in this study will not exceed 5 mg/kg. The decision to 
progress up to 5 mg/kg will be based on the emerging safety, tolerability, 
pharmacokinetic, pharmacodynamic data and clinical activity (PASI score and PLSS).  If 
significant clinical activity is seen (see Section 5.4 Planned Dose Adjustments), but with 
no safety and tolerability signals, dose will be increased to one higher level than the dose 
with clinical activity, but not beyond the maximum 5mg/kg dose.  The maximum dose is 
based on the predicted therapeutic dose range of 0.5-2 mg/kg in psoriasis patients derived 
from the receptor binding PKPD model, while also taking into account the maximum 
dose that can be delivered every 4 weeks by one subcutaneous injection and to also allow 
a fold factor above it to gather additional safety information.
The maximum dose proposed in this study is 6-fold lower than the 30 mg/kg dose 
investigated in the GLP toxicity study in monkey and the predicted AUC 4.3-fold lower 
than the exposure observed at that dose.  The maximum dose proposed would be 1.7-fold 
higher than the dose (3 mg/kg) without neutropenia in the investigative study P70263N 
and the AUC 2-fold higher than the AUC at that dose. Although the maximum proposed 
dose exceeds the highest dose and exposure without neutropenia findings in the 
investigative monkey study, it will only be assessed providing the extensive within study 
monitoring has shown no clinically relevant safety findings at the lower doses.
3.4.
Risk Management
Consistent with GlaxoSmithKline guidance for early phase studies, GSK2831781 will be 
administered in an in-patient setting (with sufficient overnight facilities) with appropriate 
monitoring. 
In order to minimise the risk of the initial human administration of GSK2831781 
monoclonal antibody, at the beginning of each cohort, 1 subject will receive 
GSK2831781 and 1 subject will receive placebo. After the GSK medical monitor and 
investigator have reviewed the safety data up to 48 hours, the remaining subjects (where 
appropriate) from that cohort will be dosed (see Section 3.2).  Once safety data and 
clinical measures of response (e.g. DTH induration for healthy volunteers, PASI for 
psoriasis patients) at 4 weeks post-dose have been completed for all subjects in each 
cohort (Part B: minimum 8 of 9 subjects, but with all subjects completing 72 hours post 
dose), the DEC and the investigator will review the data along with the available PK data 
before proceeding to the next dose level. In Part A and B of the study, the in-house safety 
monitoring will be at least 72 hours after dosing. 
A number of potential risks have been identified.  Details of these risks and the proposed 
strategy to mitigate/monitor these risks are described in Table 5.

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Table 5
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk
Summary of data
Impact eligibility criteria
Strategy-monitoring criteria
IP risk
Infusion-
reaction/hypersensitivity
The first study in 
humans will be 
conducted by IV 
administration.
Subjects will be excluded 
if history of severe allergic 
reaction. (Exclusion #4)
Initial cohorts (1-5) will 
exclude subjects with pre-
existing ADA (Exclusion 
criteria #8)
Subjects will be in a phase 1 unit 
and closely monitored for 72 
hours post dosing. 
IV doses will be administered for 
2 hours.  However, dosing 
duration may be modified based 
on safety data with the approval 
of the PI and sponsor.
Guidelines for monitoring 
relevant adverse events 
encompassing hypersensitivity, 
angioedema and anaphylaxis 
and for management of acute 
anaphylactic shock and minor 
allergic episodes will be in place 
at investigational sites. 
Study sites will include facilities 
and expertise for emergency 
care/resuscitation, including 
access to hospital and Intensive 
Care Unit (ICU).
Pre-medications are permitted at 
investigator’s discretion (Section 
6.3.4).
Cytokine release
Hyper-immune 
activation leading to 
activation of the innate 
immune system is only 
a theoretical safety 
concern, as there is no 
in vitro and in vivo
evidence of cytokine 
release associated with 
LAG-3+ and T cell 
depletion mechanism, 
in the presence or 
absence of pre-existing 
ADA.
Initial cohorts (1-5) will 
exclude subjects with pre-
existing ADA (Exclusion 
criteria #8)
Study sites will include facilities 
and expertise for emergency 
care/resuscitation, including 
access to hospital and ICU.
Monitoring for clinical symptoms 
associated with cytokine release 
such as fever, nausea, chills, 
hypotension, tachycardia, 
asthenia, headache, rash, 
tongue and throat swelling, and 
dyspnea. 
Standard safety haematology 
and clinical chemistry 
assessments to include CRP will 
be performed.
In addition limited cytokine 
analysis will be performed within 
24 hours if any clinical signs 
suggest cytokine release 
syndrome (See Section 6.3.7)

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Potential risk
Summary of data
Impact eligibility criteria
Strategy-monitoring criteria
Type III Hypersensitivity 
(Immune complex 
deposition in kidney, liver, 
skin)
Reactions due to 
immune complexes
formed from pre-
existing ADA and 
GSK2831781 are a 
theoretical risk. Risk is 
assessed as low as 
pre-existing ADAs are 
predominantly of low 
titre.
Initial cohorts (1-5) will 
exclude subjects with pre-
existing ADA (Exclusion 
criteria #8)
Targeted clinical monitoring will 
include physical examination,  
urinalysis to detect haematuria 
and proteinuria, and clnical 
chemistry to monitor renal and 
liver function. 
Risk of infection
No specific studies 
have been conducted in 
nonclinical species to 
investigate the effect of 
GSK2831781 on 
response to viral or 
bacterial infection.
A significant proportion 
of newly activated T 
cells express LAG-3, 
and therefore T cell 
proliferation upon 
encounter with an 
infectious agent may be 
inhibited by 
GSK2831781 if 
exposure is at the same 
time. 
However, it has been 
demonstrated that in 
healthy volunteers only 
a small proportion of 
central memory T cells 
express LAG-3, so 
there is low risk of 
eliminating central 
memory of anti-
infectious immune 
response against future 
encounter.
Subjects to be screened 
for HIV, Hep C and B prior 
to enrolment and 
excluded if positive.
(Exclusion #13 and 15)
Subjects with a history of 
tuberculosis (TB) 
(screening for latent 
infection included) or 
other relevant chronic 
diseases will be excluded. 
(Exclusion #2 and 7)
Healthy volunteer 
subjects will need to be 
vaccinated against 
infectious agents 
(Inclusion #8).
Psoriasis subjects: 
investigators are expected 
to assess vaccination 
status, according to local 
and/or national guidelines 
for patients with psoriasis 
during screening.
Subjects with an acute 
illness or evidence of 
significant active infection, 
such as fever, will not be 
allowed on the study.
(Exclusion #7)
Subjects will be advised not to  
travel to infection endemic 
countries up to the follow-up 
visit.
Serology for Cytomegalovirus 
(CMV), and Epstein-Barr Virus 
(EBV) will be tested at baseline. 
Samples for CMV, EBV, Herpes 
Simplex Virus (HSV) and 
Varicella Zoster Virus (VZV) will 
be taken and stored at baseline. 
If signs or symptoms consistent 
with viral reactivation occur 
during the study further samples 
will be taken and analysed 
together with the baseline 
sample.
Other immunosuppressive 
concomitant medications (See 
Section 5.14 are excluded  up to 
follow-up  (exposure above in 
vitro EC50 level for LAG-3 
depletion) though low dose 
background therapies may be 
allowed depending on the 
immunosuppressive risk at the 
time of FTIH.
Close monitoring of subjects for 
infections to follow-up visit with 
targeted surveillanceas specifed 
in the protocol.
Subjects will not be allowed to 
receive live (attenuated) vaccine 
within the 4 weeks prior to Day 1 
or during the study until the end 
of follow-up.
A biomarker approach will be 
used to measure the duration of 
action of GSK2831781 in 
inhibiting the response to PPD 
challenge repeated at 3 month 

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Potential risk
Summary of data
Impact eligibility criteria
Strategy-monitoring criteria
intervals until recovery of 
response, in healthy volunteers.
Risk of autoimmune-like 
reactions
Theoretical risk only. 
There are publications 
demonstrating a small 
subset of T-regulatory 
cells being LAG-3 
positive.
Excluded: patients with 
history of other immune 
disorders.
(Inclusion #3 and 
Exclusion #24)
Excluded: patients with 
any acute or chronic 
clinical, even mild, GI 
upset. (Exclusion #6)
Targeted clinical monitoring of 
possible autoimmune-reactions, 
especially GI tract and thyroid 
diseases will be conducted at 
every visit.
See Section 6.3.6.
Neutropenia
In the 1 month GLP 
toxicology study 
clinically significant 
decreases in neutrophil 
count, which were 
considered adverse, 
were observed in 2/12 
monkeys which were 
administered 100 
mg/kg/week SC or IV.
Including separate 
single and repeat dose 
pharmacology studies, 
decreases in neutrophil 
count of a similar 
magnitude occurred in 
2/15 animals at 30 
mg/kg but not in 7 
animals administered at 
3 mg/kg.
Exclude subjects with 
neutrophils below normal 
range. (Exclusion # 5)
Neutrophil count is readily 
measurable in the clinic and both 
trends and changes outside 
normal range will be monitored 
as part of laboratory safety 
assessments. 
Subjects developing neutrophil 
counts <1.5x109/L will be 
followed up until levels are not 
clinically significant. Study 
stopping criteria are also in place 
(see Section 5.5).
Supportive therapy (growth 
factors, transfusions, antibiotics, 
monitoring and active treatment 
of infections) may be provided if 
neutropenia is seen.
Hepatotoxicity
Minimal to mild Kupffer 
cell activation at doses 
>30mg/kg in primates.
Only subjects with  liver 
chemistry results within 
the limits specified in the 
inclusion and exclusion 
criteria will be included 
(Inclusion #10; Exclusion 
#10, #25)
Standard GSK liver stopping 
applied for dosing new subjects,  
and monitoring guidance (See 
Section 5.5 and Section 5.6.1)
PPD ID risk
Potential events 
associated with PPD ID 
injection: 
1.
Systemic 
Hypersensitivity 
(Anaphylaxis) for 
PPD
2.
Immediate local 
hypersensitivity (ILH) 
after secondary 
intradermal 
1 and 2 likely to occur 
<30 minutes post 
immunisation.  
1. Systemic 
anaphylaxis’ is 
characterised by any of 
the following: difficulty 
in breathing, stridor, 
hoarse voice, flushing, 
wheezing, rash, itching, 
Subjects with a prior 
medical history of 
anaphylaxis, severe 
adverse reaction to 
vaccines, or history of 
sensitivity to any of the 
study challenge agents, or 
components thereof or a 
history of drug or other 
allergy will be excluded if 
in the opinion of the 
Subjects will be observed for 30 
minutes after the administration 
of PPD at the study unit at the 
investigators discretion.  
The study will be conducted in a 
unit where personnel is trained 
in immediate management of 
anaphylaxis
Immediate assessment and 

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Potential risk
Summary of data
Impact eligibility criteria
Strategy-monitoring criteria
immunisation with 
PPD
3.
Excessive DTH
4.
Necrotic skin reaction
swelling of the lips or 
tongue, hypotension, 
confusion, diarrhoea).
2. ILH post challenge is 
defined as a wheal that 
is at least 5 mm larger 
than the original bleb
3. Excessive DTH: 30 
mm or larger induration 
between 24-48 hours 
associated with 
inflammation and 
itching. Vesiculation is 
possible. Pain is 
possible with large 
reactions but significant 
pain is unlikely.
4. Necrotic skin 
reaction: characterised 
by severe pain, 
swelling, induration and 
possibly haemorrhage 
and necrosis.
investigator or GSK 
Medical Monitor, it 
contraindicates their 
participation.
management will be conducted 
according to the current 
guidelines from the 
Resuscitation Council (UK) on 
Emergency Treatment of 
Anaphylactic Reactions.
Any subject requiring treatment 
for suspected anaphylaxis will be 
transferred to an acute medical 
unit for further observation as 
judged necessary by the medical 
team in charge of the clinical 
emergency situation
Subjects will be advised to seek 
immediate medical attention if 
they develop these symptoms 
after leaving the unit and they 
will be issued with an information 
leaflet that details what these 
symptoms are. 
Any subject that exhibits an ILH 
after secondary ID immunisation 
can be reassured that their 
symptoms are likely to settle 
within a few hours, but if they 
consider this unacceptable they 
may be offered antihistamines at 
the discretion of the attending 
physician. Subjects receiving 
antihistamines will be continued 
in the trial but note will be made 
of their antihistamine use at the 
analysis stage. 
An excessive DTH or necrotic 
skin reaction in extreme cases 
and at the discretion of the 
attending physician treatment 
with glucocorticoids could be 
offered according to best clinical 
practice. 
Procedure risk
Punch Biopsy
Possible risks of the 
procedure are pain for 
the subject, a small 
infection risk after the 
Punch Biopsy and 
possible scarring, these 
will be minimised 
considerably by 
following the study 
procedures.
Subjects with keloids or a 
history of keloids will be 
excluded. (Exclusion #19 
and 24)
Three mm (DTH) and 6 mm 
(Psoriasis plaques) punch skin 
Punch Biopsies will be 
performed under a local 
anaesthetic to reduce any 
discomfort for the subjects.
The small risk of infection after 
Punch Biopsy will be minimised 
by cleaning of the site before 
Punch Biopsy and the addition of 
a steri-strip if required (or 

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Potential risk
Summary of data
Impact eligibility criteria
Strategy-monitoring criteria
similar) on top of the Punch 
Biopsy site. 
For the 3mm biopsy a minute 
scar will be visible and will be 
minimised. Stitching and a small 
scar will occur for the 6mm 
biopsy.
Vaccination 
As per Boostrix-IPV 
and/or M-M-RVAXPRO 
or equivalent SPC.
Subjects in Part A who 
are ineligible due to lack 
of history of vaccinations 
for diphtheria, tetanus, 
pertussis, measles, 
mumps or rubella, who 
consent to vaccination 
may only be vaccinated in 
accordance with the 
restrictions for these 
vaccines in the SPC. If 
such subjects are unable 
to be vaccinated, they will 
be ineligible for the study.
As per Boostrix-IPV and/or M-M-
RVAXPRO or equivalent SPC.
4.
STUDY POPULATION
4.1.
Number of Subjects
Approximately 67 subjects will be enrolled to complete dosing and critical assessments.  
The subject numbers will be split to approximately 40 healthy volunteers and 27 patients 
with psoriasis.
Additional subjects/cohorts may be enrolled between the 0.0003mg/kg and 5mg/kg doses 
to allow for evaluation of additional dose levels but they will not exceed 5mg/kg (see 
Section 5.4). 
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects at the discretion of the Sponsor in consultation with the investigator.
4.2.
Eligibility Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigators Brochure 
[GlaxoSmithKline Document Number 2013N175515_01 and GlaxoSmithKline 
Document Number 2014N201916_00].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

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4.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1.
Part A males aged between 18 and 65 years of age and Part B males and females 
aged between 18 and 75 years of age inclusive at the time of signing the informed 
consent.
2.
Part A: A body weight ≤120 kg and BMI within the range 19 – 32 kg/m2 (inclusive). 
For healthy volunteer subjects participating in Germany the BMI must be within the 
range of 19 – 30 kg/m2 (inclusive).  Part B: BMI within range 19-35 kg/m2
(inclusive).
3.
Part A only: Healthy as determined by a responsible and experienced physician, 
based on a medical evaluation including medical history, physical examination, 
laboratory tests and 12-lead ECGs. A subject with a clinical abnormality or 
laboratory parameter(s) which is/are not specifically listed in the inclusion or 
exclusion criteria, outside the reference range for the population being studied may 
be included only if the Investigator in consultation with the GSK Medical Monitor, if 
required, agree and document that the finding is unlikely to introduce additional risk 
factors and will not interfere with the study procedures.
4.
Part A DTH cohort only: Subjects with a history of BCG vaccination as evidence 
by either:

A BCG scar and verbal confirmation of BCG vaccination

Or documented medical history of a BCG vaccination with or without a BCG 
scar
5.
Part B only: Subject has psoriasis covering BSA ≥3% as assessed at Screening and 
Day -1.
6.
Part B only: Subject has had a confirmed diagnosis of chronic plaque-type psoriasis 
(without recent documented flare within 30 days prior to screening) for at least 6 
months.
7.
Part B only: Subject has at least 2 stable plaques assessed at Screening and Day -1. 
One of a suitable size and in a site suitable for repeat biopsy, and one for index 
lesion PLSS scoring. Both must have a PLSS lesional score of ≥2 for the induration 
component (moderate or above), ≥1 for erythema and scaling with a total score of 
≥5. The biopsy lesion must not be on the face, groin or scalp and must be protected 
from the sun.
8.
Part A only: Subjects with a history of vaccination for Tetanus, diphtheria, measles, 
pertussis, mumps and rubella.
9.
Part B only: A female subject is eligible to participate if she is not pregnant (as 
confirmed by a negative serum human chorionic gonadotrophin (hCG) test at 
screening and negative urine hCG test at Day -1 for FRP), not lactating, and at least 
one of the following conditions applies:
a.
Non-reproductive potential defined as:

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Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-
up confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will 
be required to use one of the highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrolment.
b.
Reproductive potential and agrees to use a barrier method (male condom or 
female diaphragm) plus to follow one of the options listed in the Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP) (see Appendix 5) from 28 days prior to the first dose of study 
medication and until completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception. The investigator or designee should remind the 
subjects of the need to comply with these requirements approximately monthly, 
either at study visits or by telephone call until the follow-up visit.
10. ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
11. Based on single or averaged QTc values of triplicate ECGs obtained over a brief 
recording period:
-QTcF < 450 msec
12. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form, and has provided written 
informed consent. 
4.2.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Received live vaccine(s) (attenuated or recombinant) within 4 weeks of Day 1 or 
plan to receive a live vaccination during the study until follow-up.
2.
Subjects who have history of tuberculosis or have close family members with 
confirmed MTB infection or who are positive at screening by Quantiferon testing.

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3.
Subject is unable to abstain from travelling to areas with high endemic rates of 
infectious diseases until the end of the follow up period.
4.
A medical history of severe allergic reaction, angio-edema, anaphylaxis or 
immunodeficiency.
5.
Subjects with neutrophil results below the normal range at screening and baseline.
6.
Subjects with any clinical, even mild, GI upset such as, but not limited to, diarrhea or 
abdominal cramping during the previous week before dosing, as well as history of 
more chronic GI upset, e.g. IBS
7.
Current evidence of ongoing or acute infection within 3 months prior to the first dose 
of study drug, such as:

Serious local infection (e.g. cellulitis, abscess)

Systemic infection (e.g. pneumonia, septicaemia, TB)
8.
Part A (only cohorts, 1-4 without DTH challenge, and DTH cohort 5) only: 
Subjects who test positive for pre-existing ADA to GSK2831781 at screening.
9.
History of malignancy.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).  Part A 
only: Subjects with an aspartate aminotransferase and/or gamma glutamyltransferase 
level above the upper limit of normal at screening and/or baseline will be excluded.
11. History of regular alcohol consumption within 6 months of the study defined as: 
an average weekly intake of >21 units for males or >14 units for females. One unit is 
equivalent to 8g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 
1 (25 ml) measure of spirits. 
12. History of sensitivity to any of the study medications or PPD challenge agent, or 
components thereof or a history of drug (or IgG therapeutic antibodies) or other 
allergy that, in the opinion of the investigator or GSK Medical Monitor, 
contraindicates their participation.
13. A positive pre-study Hepatitis B surface antigen or Hepatitis B core antibody, or 
positive Hepatitis C antibody result within 3 months of screening.
14. A positive pre-study drug/alcohol screen.
15. A positive test for HIV antibody.
16. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period.
17. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
18. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.

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19. Part A (only cohort with DTH challenge) only: Presence of tattoos, naevi or other 
skin abnormalities such as keloids (or a history of keloids) that may, in the opinion 
of the investigator, interfere with DTH assessments.
20. Part A (only cohort with DTH challenge) only: Use of nicotine patches on the arm 
at screening that would interfere with the injection sites.
21. Part A (only cohort with DTH challenge) only: Subjects participating, within 
seven days of screening, in recreational sun-bathing, or the use of a sun-bed, on the 
area of the skin from the wrist to the shoulder (inclusive).
22. Part A only: Use of prescription drugs or non-prescription drugs, if in the opinion of 
the investigator (in consultation with the GSK medical monitor), the medication will 
interfere with the study procedures or compromise subject safety.
23. Part A only: Subjects must not currently be taking any of the following: topical 
steroids on the arms, oral or systemic steroids or any other immune-modulators (the 
washout period will be determined, on a case by case basis, by the investigator in 
consultation with the GSK medical monitor).
24. Part B only: History of significant cardiac, endocrinologic, haematologic, 
pulmonary, metabolic, renal, hepatic, immunologic (excluding psoriasis and psoriatic 
arthritis), urologic, neurologic, dermatologic (except psoriasis), psychiatric or 
gastrointestinal conditions that, in the opinion of the investigator and/or GSK 
medical monitor, places the subject at unacceptable risk.
25. Part B only: Clinically significant abnormalities of laboratory assessments (not 
related to disease) as judged by the investigator and/or GSK medical monitor.
26. Part B only: All systemic psoriasis medications, including psoralen long-wave 
ultraviolet radiation treatments, or other systemic immunosuppressives, are not 
allowed within 5 half lives prior to Day -1 (Methotrexate and cyclosporin are not 
allowed within 8 weeks of Day -1; Psoralen long-wave UV is not allowed within 4 
weeks of Day-1). Subjects should not be included if the investigator considers that 
the subject is at high risk of requiring rescue with prohibited medication (see Section 
5.14.2.3) for duration of study up to follow-up. This assessment should be based on 
current disease activity or a history of frequent and/or severe flares requiring 
systemic immunosuppression.
27. Part B only: The use of single treatment phototherapy (ultraviolet B or self 
treatment with tanning beds) is not allowed within 14 days prior to Day -1.
28. Part B only: The use of topical therapies for psoriasis are not allowed with 7 days 
prior to Day -1 on the index lesion or biopsy plaque.
29. Part B only: Previous treatment with anti-TNF/IL-12/IL-23 or any other monoclonal 
antibodies is not allowed within 12 weeks prior to Day -1.
30. Part B only: Patients that require narrow therapeutic index medications from 
Screening to Follow-up.
31. Vulnerable subjects (e.g. person kept in detention).

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32. Subjects who are not able to understand and communicate in the native language of 
the country where the study is conducted.
33. Subjects who work for the Sponsor or CRO.
4.3.
Lifestyle Restrictions
4.3.1.
Dietary requirements
Subjects must fast overnight before screening for the glucose blood test. If the subject 
has not fasted then they may return before baseline to have the glucose blood test taken.
4.3.2.
Alcohol
Subjects will abstain from alcohol for 24 hours prior to each visit to the clinical unit.  
Additionally they should refrain from alcohol for 7 days after dosing. Thereafter an 
average weekly intake of <21 units alcohol.
4.3.3.
Activity
Part A and B: Subjects will abstain from strenuous exercise for 48 hours prior to dosing 
and prior to each blood collection for clinical laboratory tests.  Subjects may participate 
in light recreational activities during studies (e.g., watch television, read).
Part B: Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) 
whilst taking the study medication and until Day 43. Subjects will be advised that when 
they are outdoors they should wear protective clothing (e.g. sun hat, long sleeves) and use 
a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
4.4.
Screen and Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including, but not limited to, Demography, 
Screen Failure details, Eligibility Criteria, and any Serious Adverse Events.
4.5.
Withdrawal Criteria and Procedures
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons.
Refer to Section 5.4 or planned dose adjustment and Section 5.5 for subject specific dose 
adaptation including Liver Chemistry and QTc. 

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Liver chemistry threshold monitoring criteria have been designed to assure subject safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). See Section 5.6.1 for details.
4.6.
Subject Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit (which will be a combined 
follow-up/surveillance visit or a surveillance telephone call if the subject has already 
completed Follow Up, as specified in Table 1).

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5.
STUDY TREATMENT
5.1.
Investigational Product and Other Study Treatment
Study Treatment
Product name:
GSK2831781
Diluent
Placebo
Formulation 
description:
50mM Na Acetate, 
51mM NaCl, 0.05mM 
EDTA, 0.02% 
Polysorbate 80, and 
57mM Arginine at pH 
5.5
0.9% NaCl solution 
containing 0.015% PS80
Commercial saline solution
Dosage form:
Solution
Solution
Commercial saline solution
Unit dose 
strength(s)/Dosage 
level(s):
100mg/mL
SD of 0.0003-5mg/kg
N/A
Saline Placebo
Route/
Administration/
Duration:
IV over approximately 2 
hours
N/A
IV over approximately 2 
hours
Dosing 
instructions:
Infuse over 
approximately 2 hours 
via an infusion pump
N/A
Infuse over approximately 2 
hours via an infusion pump
Physical 
description:
Clear or opalescent, 
colourless, yellow to 
brown liquid that is 
essentially free from 
particles.  
Clear, Colourless to pale 
yellow, sterile solution
Commercial presentation
Manufacturer/
source of 
procurement:
GSK Parma, Italy
GSK Parma, Italy
Supplied by site
5.2.
Challenge Agents
Challenge Agent
Product name:
Challenge agent PPD
Formulation description:
Tuberculin PPD RT23
Dosage form:
Solution 
Unit dose strength(s)/Dosage 
level(s):
ID 2TU / 0.04g
ID 10TU / 0.2g
Route/
Administration/
Duration:
Part A DTH cohorts:
1x ID injection/single dose

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Challenge Agent
Dosing instructions:
Part A DTH cohorts: 
1 x ID injection left forearm
1 x ID injection right forearm
Followed by 4x ID injection 28 days later:
2 x ID injection left forearm
2 x ID injection right forearm
Manufacturer/
source of procurement:
Staten Serum Institut
5.3.
Treatment Assignment
Subjects will be assigned to receive GSK2831781 or placebo in accordance with the 
randomisation schedule generated by Clinical Statistics, prior to the start of the study, 
using the validated internal software RandAll NG.
The randomisation schedule will be generated to account for the sentinel subjects. Where 
the first two subjects dosed for any given cohort will be randomised so that 1 subject will 
receive GSK2831781 and 1 subject will receive matching placebo. In Part B, the sentinel 
subjects will be required to be ADA negative and subsequent subjects will be stratified by 
ADA status (ADA negative or ADA positive) as applicable (see Section 3.1.2).
Eligible subjects will receive a unique subject number which will be assigned in 
chronological order. Once a subject number has been assigned to a subject, it cannot be 
reassigned to another subject.
Each subject scheduled to receive study drug will also receive a treatment allocation 
number when randomised. The treatment number will indicate if the subject is to receive 
the scheduled dose of GSK2831781 or placebo at each dosing occasion.
A description of the projected regimens based on available data is provided in the table 
below: 

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Regimen
Description
Ratio (Active:Placebo)
A
0.0003mg/kg GSK2831781 IV single dose
1:1
B
0.0015mg/kg GSK2831781 IV single dose
1:1
C
0.0075mg/kg GSK2831781 IV single dose
3:1
D
0.04mg/kg GSK2831781 IV single dose
3:1 
E
0.15mg/kg GSK2831781 IV single dose
1:1 for HV DTH (ADA-)
3:1 for HV No DTH 
(ADA +)
F
0.5mg/kg GSK2831781 IV single dose
4:2 for psoriasis (ADA-)
2:1 for psoriasis (ADA+)
G
1.5mg/kg GSK2831781 IV single dose
6:3 for psoriasis
H
5mg/kg GSK2831781 IV single dose
6:3 for psoriasis 
P
Placebo IV single dose
N/A
5.4.
Planned Dose Adjustments
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum single dose will not exceed 5 mg/kg (to ensure about a 2.2 fold ratio with 
regard to the exposure (AUC) observed at 30 mg/kg in the cynomolgus monkey GLP 
toxicity study).  The maximum dose exceeds the highest dose without neutropenia 
findings in the investigative monkey study, but will only be assessed providing the 
extensive within study monitoring has shown no clinically relevant safety findings at the 
lower doses.
Safety/tolerability data monitoring and the decision to proceed to the next dose level of 
GSK2831781 will be made by the DEC, consisting of the Principal Investigators (or 
appropriate designees), GSK Medical Monitor, GSK Study Team Leader (either Clinical 
Investigator Lead [CIL] and/or Operations and Science Lead [OSL]), GSK CPMS 
representative, a GSK GCSP representative, GSK Statistician and an independent GSK 
expert on FTIH studies.  The DEC may also call on ad hoc internal/external members 
with specific expertise. DEC meetings will have open and closed sections.  During the 
open section, the Principal Investigators will be present to provide additional information 
on patient assessment if required, and the data will be blinded. In the closed section, the 
Principal Investigators will not be present and if required data will be presented in an 

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unblinded manner.  A DEC charter will be agreed between GSK and the principal 
investigator before the first DEC meeting.  
For healthy volunteer cohorts, once safety data up to 28 days post-dose has been 
collected in all subjects for that cohort, the DEC will review the safety/tolerability data 
(including trends in neutrophil counts), the available PK data and for the DTH cohort, the 
clinical DTH response (induration diameter), before proceeding to the next dose level 
(See Section 3.2.1).  The DEC may also consider available biomarker/PD data (including 
immune cell phenotyping) in considering the escalation.  Outcomes of DEC review 
include escalation to the next dose, stopping the escalation, switching escalation to 
psoriasis patients, altering the next dose level, altering the subject numbers in a cohort.  If 
emerging PK data departs from prediction, outcomes may also include continuing dose 
escalation in healthy volunteers beyond the maximum of 0.15mg/kg up to a maximum 
duration of exposure above EC50 of approximately 6 months, if there are no other 
safety/tolerability findings or reduction of DTH response (See Section 3.2.1).  
For the psoriasis cohorts, once safety data and clinical measures of response (PASI and 
PLSS) at 28 days post-dose have been completed for a minimum of 8 out of 9 subjects, 
and all subjects have completed dosing and the inpatient monitoring until Day 4, the DEC 
will review the safety/tolerability data (including trends in neutrophil counts), the 
available PK data and the clinical response (PASI and PLSS) before proceeding to the 
next dose level. The DEC may also review the other measures of clinical response and 
available biomarker/PD data (including immune cell phenotyping) in considering the 
escalation.  Outcomes of DEC review include escalation to the next dose, stopping the 
escalation, altering the next dose level or altering the subject numbers in a cohort.  
Definition of significant change in PLSS and/or PASI or strong trends in clinical 
response, leading to stopping of dose escalation at same or one higher dose will be 
discussed in the DEC Guidance/Charter document.
Apart from stopping of the dose escalation, alterations to the planned dose levels and 
intervals between dose levels will be limited to the following.  Other changes will require 
a substantial amendment:

Reduction in the dose increment to the next dose level (based on higher 
exposure than predicted and/or safety data of clinical significance).

Introduction of an additional dose level cohort between the current and next 
planned dose level (based on higher exposure than predicted and/or safety data 
of clinical significance).

Replacement of the highest dose level in psoriasis cohorts with a lower dose 
than the scheduled starting dose for psoriasis cohorts
For both healthy volunteers and psoriasis patients, the DEC will ensure that data from the 
ongoing cohort as well as accumulated data from all previous cohorts is reviewed.  
Decisions may be modified if subjects on placebo have findings.  The dosing schedule 
may also add cohorts to evaluate 2 additional dose levels.  The study procedures for these 
additional subject(s) or cohort(s) will be the same as that described for other study 
subjects.

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5.5.
Dose Adjustment/Stopping/Monitoring Criteria
If one or more subject experiences an Serious Adverse Event (SAE) that can be 
reasonably attributed to GSK2831781, the dose escalation will be halted and no further 
subject will be dosed until a full safety review of the data has taken place. Relevant 
reporting and discussion with the DEC, (which must include the GSK medical monitor), 
relevant GSK personnel, and with the Ethics Committee and Regulatory Agency will 
then take place.  If following the safety review a decision is made to restart dose 
escalation, this may be allowed after approval of a substantial amendment.
If two or more subjects experience a severe or significant non-serious AE that can be 
reasonably attributed to GSK2831781, the dose escalation will be halted and no further 
subject will be dosed until a full safety review of the study has taken place. Relevant 
reporting and discussion with the DEC (which must include the GSK medical monitor), 
relevant GSK personnel, and with the Ethics Committee and Regulatory Agency will 
then take place.  If following the safety review a decision is made to restart dose 
escalation, this may be allowed after approval of a substantial amendment.
Events of note across the cohorts (unless otherwise stated) that will also result in the 
study being temporarily halted and reviewed by the DEC include:
NOTE: If any of the below occur in the single active subject in the first 2 healthy 
volunteer cohorts the study will also be reviewed by the DEC.
1.
Infusion Reaction/Hypersensitivity: Infusion reactions requiring termination of 
infusion/dosing in 2 or more subjects. 
2.
Cytokine Release Syndrome (CRS): Evidence of CRS leading to moderate clinical 
symptoms in 2 or more subjects, based on modified NCI-CTC Criteria (see Section 
12.3, Appendix 3). Symptoms include: Headache, fever, chills/rigors, nausea, 
vomiting, diarrhoea, arthalgia, myalgia, hypotension. 
3.
Neutropenia (the following must be confirmed by repeat samples): 

If one subject experiences neutrophil count <1.5 x 109/L for >7 days for the first 
28 days for the first 2 healthy volunteer cohorts.

If one or more subjects experiences neutrophil count <0.5 x 109/L for >7 days 

If 2 or more subjects experience neutrophil count <0.5 x 109/L for <7 days. 

If 2 or more subjects experience clinically significant neutropenia for >7 days.
4.
Infections: If one or more subjects experiences an infection SAE, regardless of initial 
assessment of causality. 
5.
Liver event in one or more subjects:

a  Hy’s law liver SAE as characterised by  ALT ≥ 3xULN and total bilirubin ≥ 
2xULN (>35% direct bilirubin*); or ALT ≥ 3xULN and INR** > 1.5 (*serum 
bilirubin fractionation should be performed if testing is available; if unavailable, 
withdraw subject (if ALT ≥ 3xULN and total bilirubin ≥ 2xULN) and measure 
urinary bilirubin via dipstick.** INR testing not required per protocol and the 

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threshold value does not apply to subjects receiving anticoagulants). The study 
will be also put on hold if one subject experiences

ALT ≥ 5xULN.

ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness or jaundice) or hypersensitivity (such as fever, rash or 
eosinophilia).

ALT ≥ 3xULN persists for ≥ 4 weeks.
QTC criteria:  if 2 or more subjects demonstrate 

QTcF > 500 msec or,

QTcF increase >60 msec from baseline
This assessment is to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief 
period of time and then use the averaged QTc values of the 3 ECGs to determine 
whether the subject should meet these criteria. 
If safety findings are noted in the active subject in cohorts with a single active subject, 
the cohort may be expanded to a maximum cohort size of 6:3 (active:placebo) or the 
escalation stopped.
To enable appropriate investigation of potential issues, the DEC will review data prior to 
continued dosing, if any of the following occur:
1.
PPD challenge; if one or more subjects experience persistent reduction of the PPD 
challenge for ≥3 months after rechallenge.
2.
Moderate or severe adverse events of the same nature (including infections) in 2 or 
more subjects in the same cohort which can be reasonably attributed to dosing with 
GSK2831781, within 28 days of dosing (Appendix 4 and specific criteria at 
individual subject level in Section 5.6).
3.
For a cohort of patients with psoriasis, if 2 or more subjects in a dose cohort 
experience a worsening of their psoriasis symptoms which can be reasonably 
attributed to dosing with GSK2831781, which requires treatment with prohibited 
concomitant medication. 
The above criteria will apply regardless of whether pharmacokinetics are less than the PK 
stopping criteria described in Section 5.7 and every effort will be made to take a blood 
sample at the time of the event for pharmacokinetics analysis in the presence of any of 
the above events.

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5.6.
Subject Specific Dose Adjustment/Stopping 
Safety/Monitoring Criteria
5.6.1.
Liver Chemistry Monitoring Criteria
Liver chemistry threshold monitoring criteria have been designed to assure subject safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). 
In addition to any liver safety criteria (Section 5.5, bullet point 5), subjects meeting the 
following liver chemistry criteria will have enhanced monitoring: 

ALT 3xULN
NOTE: Refer to Appendix 1 for details of the required assessments if a subject meets the 
above criteria.
5.6.2.
QTc Monitoring Criteria
For subjects that meet either criterion below, additional monitoring will be required.  The 
same QT correction formula, QTcF, should be used to determine inclusion and enhanced 
monitoring for any individual subject throughout the study.

QTcF > 500 msec,

Change from baseline: QTcF >60 msec
Monitoring of subjects is to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTc values of the 3 ECGs to determine whether the 
subject should return for further monitoring of ECG one week later, and should be 
followed up until values are not clinically significant.
If an abnormality is noted during dosing the infusion may be halted.
5.6.3.
Renal Function Monitoring Criteria
If a subject experiences a serum creatinine increase of ≥30% from baseline (Pre-dose Day 
1) the patient should be followed up until values are not clinically significant.
5.6.4.
Haematological Monitoring Criteria
If any of the following haematological criteria is met the patient should be followed up 
until values are not clinically significant:
•
Haemoglobin <10 g/dL or an absolute decrease of ≥3 g/dL from baseline (pre-
dose Day 1)
•
White blood count <2.5 x 109/L
•
Neutrophils <1.5 × 109/L

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•
Lymphocytes <0.85 × 109/L
•
Platelets <125 × 109/L
5.6.5.
Febrile Monitoring Criteria
Any unexplained febrile illness/episode will be considered a significant medical event.  
The patient should be followed up until the event is resolved.   If the subject demonstrates 
any clinical symptoms consistent with viral reactivation e.g. fever, a blood sample will be 
taken and analysed for viral reactivation and/or other appropriate medical investigations 
as suggested by the clinical context.
5.6.6.
Other Dose Adjustment/Stopping Safety Criteria
Symptoms of hypersensitivity which require stopping of infusion, together with 
appropriate management are described in Section 6.3.4.
The reason(s) for discontinuation of the study treatment must be recorded in the subject’s 
electronic case report form (CRF). Subjects whose infusion is terminated prematurely 
will be expected to complete the remainder of the study visits so that study data are 
collected.
5.7.
Dose Adjustment/Stopping Pharmacokinetic Criteria
Pre-defined dose will be altered or dose escalation stopped if the average predicted 
exposure AUC and/or Cmax at the next dose reaches 66.5 mg.hr/mL and/or 0.66 mg/mL 
respectively (AUC and Cmax values 2-fold lower than the observed values at the 30 
mg/kg dose from the GLP repeat dose toxicity study in monkey).
See also Section 3.3.2.4 for comparisons with predicted exposure at maximum dose.
5.8.
Blinding
This will be a double-blind (sponsor unblind) study. 
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, or in the event of a serious medical condition when 
knowledge of the study treatment is essential for the appropriate clinical management or 
welfare of the subject as judged by the investigator. Investigators have direct access to 
the subject’s individual study treatment. It is preferred (but not required) that the  
investigator  first contact  the GSK Medical Monitor or appropriate GSK study personnel 
to discuss options before unblinding the subject’s treatment assignment. If GSK 
personnel are not contacted before the unblinding, the investigator must notify GSK as 
soon as possible after unblinding. The date and reason for the unblinding must be fully 
documented in the appropriate data collection tool.
A subject may continue in the study if that subject’s treatment assignment is unblinded as 
subjects will only receive a single dose.

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GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff will unblind the 
treatment assignment for any subject 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 subject’s treatment assignment, may be sent to clinical investigators in
accordance with local regulations and/or GSK policy.
When the DEC convenes the investigator will only attend the open (blinded) portion of 
the meeting.  
5.9.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
5.10.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2831781 can 
be found in the Technical Terms of Supply document.
Study treatment must be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study may receive study treatment.  Only authorized 
site staff may supply or administer study treatment.  An un-blinded pharmacist will 
perform the dilutions and preparation of the IV bags for active and placebo subjects.  The 
un-blinded pharmacist must ensure that the blind is maintained.  All study treatment must 
be stored in a secure area with access limited to the investigator and authorized site staff.  
Study treatment is to be stored at -40C (±10oC) and protected from light.  Maintenance 
of a temperature log (manual or automated) is required.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance.  
The investigator or the head of the medical institution (where applicable), or designated 
site staff (e.g., storage manager, where applicable) must maintain study treatment 
accountability records throughout the course of the study.  The responsible person(s) will 
document the amount of study treatment received from GSK and destroyed by the site 
and the amount administered to the subjects.  The required accountability unit for this 
study will be a vial.  Discrepancies are to be reconciled or resolved.  Procedures for final 
disposition of unused study treatment are listed in the SPM.
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration.  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 study 
manager.  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.

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Precaution will be taken to avoid direct contact with the investigational product.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator.
5.10.1.
PPD 2TU and 10TU Dose
In Part A Healthy volunteers DTH cohort only
See PPD injection sites diagram in Section 3.1.1.
In the Part A DTH cohort, on Day 1, 0.1ml of PPD 2 TU (0.04 µg/0.1ml) will be injected 
intradermally into the volar aspect of the left forearm and the volar aspect of the right 
forearm. On Day 3 the injection sites will be inspected. If the induration is less than 6mm 
on Day 3, the subject will be re-challenged with 10 TU PPD in both arms (0.2 µg/0.1ml).
The subject will then return 48 hours later and the Day 3 assessments will be repeated. If 
subjects do not have an induration of 6mm or more after the 10 TU ID PPD dose on day 
3, they will be withdrawn and replaced.
On Day 30, 0.1ml of PPD 2 or 10 TU will be injected intradermally into the volar aspect 
of the left forearm and the volar aspect of the right forearm, twice in each forearm (at 
least 4cm apart from each other and the Day 1 injection sites).
5.11.
Assessment of Compliance
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects are dosed at the study site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
5.12.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2831781 > the planned single dose for that cohort will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose.  The investigator or 
physician in charge of the subject at the time will use clinical judgment to treat any 
overdose.
5.13.
Treatment After the End of the Study
Healthy volunteers will not receive any additional treatment from GSK after completion 
of the study nor will the patients with psoriasis because the indication being studied is not 
life threatening or seriously debilitating and/or other treatment options are available

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The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition, whether or not GSK is providing specific 
post-study treatment.
5.14.
Concomitant Medications and Non-Drug Therapies
It is recommended that a subject’s vaccination record and the need for immunisation 
prior to Day 1 should be carefully investigated in all subjects prior to entering the study. 
In those who are likely to require immunisation in the period up to the follow up visit for 
non-study reasons, such as subjects requiring vaccinations or boosters for their 
professional activity, the administration of any required vaccination/booster should be 
given at least 4 weeks prior to Day 1. For subjects with psoriasis, if indicated as part of 
standard of care, non live vaccines (e.g., inactivated influenza vaccines) may be 
administered during the study based on an assessment of the benefit:risk (e.g. risk of 
theoretical decreased responsiveness).
5.14.1.
Permitted Medications
5.14.1.1.
Part A and Part B
Occasional paracetamol or NSAIDs, at prescribed doses, are permitted for use during the 
study. Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
5.14.1.2.
Part B
Medicinal shampoos that contain tar and/or salicylic acid, but not corticosteroid 
containing, are permitted at any time during the study for use on the scalp area.
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
5.14.2.
Prohibited Medications and Non-Drug Therapies
5.14.2.1.
Part A
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of 
study medication until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor the medication will not interfere with the study.
Exceptions to the above are detailed in Section 5.14.1.
5.14.2.2.
Part A and B
Live vaccine(s) (attenuated or recombinant) within 4 weeks of Day 1 and until 
completion of the follow up visit.

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5.14.2.3.
Part B
Use of the following prescription and non-prescription drugs are not permitted for the 
following periods a detailed below:
Restricted Medication
Restricted Time 
Period
Details
Low potency local corticosteroid 
“rescue” treatment for psoriasis 
flares may be used, but not at or 
near the index plaque being used to 
assess efficacy or the biopsy 
plaque.  Worsening of the psoriasis 
may, if needed, be managed by 
introducing topical steroid therapy 
(if not already in use) or increasing 
the strength of topical steroid 
being used or using a higher 
potency steroid.
7 days prior to Day -
1  to Day 43
As a rescue medication only 
upon discussion with 
investigator.  
Example medications:
Weak topical steroids (class 
VI or VII only) for use 
limited to the face, axillae, 
or genitalia as required 
except on the lesions of 
interest. 
Alclometasone dipropionate 
0.05% cream and 0.05% 
ointment 
Desonide 0.05% cream, 
0.05% foam, 0.05% gel and 
0.05% lotion 
Fluocinolone acetonide 
0.01% shampoo and 0.01% 
solution 
Flurandrenolide 0.025% 
cream 
Triamcinolone acetonide 
0.025% cream and 0.025% 
lotion 
Over-the-counter non-medicated, 
topical emollients/moisturizers
24hr prior to Day -1 
to Day 43
Not allowed within 24hrs 
before assessment visit
Topical Vitamin D analogues
High dose topical corticosteroids
Topical coal tar 
7 days prior to Day -
1 to Day 43
Always
Single-treatment phototherapy 
(ultraviolet B or self-treatment 
with tanning beds).
14 days prior to Day-
1 to Day 43
Always
Anti-TNF/IL12/23 or other 
monoclonal antibodies.
12 weeks prior to 
Day -1 to Follow up1
Always

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Restricted Medication
Restricted Time 
Period
Details
Systemic therapies including oral 
steroids, Fumaric acid esters, Oral 
retinoids  Acitretin, Oral steroid.
Methotrexate and Cyclosporine
PUVA with psoralen 
5 half lives prior to 
Day -1 to Follow-up1
8 weeks prior to Day 
-1 to Follow-up1
4 weeks prior to Day 
-1 to Follow-up1
Always
Narrow therapeutic index 
medications
Screening to Follow-
up1
Always
1.
Follow-up varies with dose (See Table 1).

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6.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 6.1. 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic/biomarker or others 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. The change in timing or 
addition of time points for any planned study assessments must be approved and 
documented in a Note to File which is approved by the relevant GSK study team member 
and then archived in the study sponsor and site study files, but this will not constitute a 
protocol amendment. The IRB/IEC will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the Informed Consent Form. 
No more than 600 mL of blood will be collected over the duration of the study, including 
any extra assessments that may be required.

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6.1.
Time and Events Table
Informed consent for optional PGx (pharmacogenetics) research must be obtained before collecting a sample
Table 6
Screening and Follow-Up
Protocol Activity
Screeningf
Combined Follow Up/Surveillance Visita
Surveillance telephone callb
Up to 35 Days prior to Day 1
Day 183+/-7 days
Informed Consent Process
X
Subject Demography
X
Full Physical Exam
X
X
Medical/Disease History
X
Urine Drug and Alcohol Screen
X
Quantiferon TB Test
X
Pregnancy Test (FRP)
X (serum)
X (urine)
Safety Assessments
Vital Signs
X
X
12 - Lead ECG
Xc
X
Concomitant Medications
X
X
Xd
Adverse Events Assessment / SAE's
X
X
Xe
Laboratory Assessments
Haematology
X
X
Chemistry
X
X
Urinalysis
X
X
Hep B(HBsAg), Hep C (HCVAb) and HIV Ab Screen
X
Serology to confirm vaccination status (if required)
Xg
Thyroid Function Test
X
Vaccination for MMR and/or DPT (only if required)g
Xf
Identify 2 target psoriatic lesions
Xi

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Protocol Activity
Screeningf
Combined Follow Up/Surveillance Visita
Surveillance telephone callb
Up to 35 Days prior to Day 1
Day 183+/-7 days
Psoriatic Body Surface Area
Xi
Xh
Psoriatic Lesion Severity Score
Xi
Xh
Psoriasis Area Severity Index
Xh
Immune Cell Phenotyping
X
Immunogenicity Sample
X
X
PK Sample
X
G-CSF Sample
X
sLAG-3 Sample
X
Blood transcriptomics sample
X
a.
Required for subjects who have not yet had a follow-up visit at the time of approval of Protocol Amendment 10. If the subject has already been monitored for more than 183 
days at the time of the Protocol amendment, but have not yet had a follow-up visit, this combined follow-up/surveillance visit should be conducted as soon as practically 
possible.
b.
Required for subjects who completed their follow-up visit prior to amendment 10, but have not completed a 12-month surveillance visit.  This call should be conducted as soon 
as practically possible.
c.
Triplicate.
d.
Only immunosuppressants and experimental medicines will be collected.
e.
Only relevant AEs and SAEs as defined in Section 7.
f.
Screening can be longer, up to a maximum of 42 days if vaccinations are required prior to dosing.
g.
Part A only: See Section 6.3.8 for more details.
h.
Subjects with psoriasis will be assessed for BSA, PASI and for index lesion PLSS at follow-up (See Section 6.3.5.3 and Table 1)
i.
Psoriasis patients only.

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Table 7
Healthy Volunteers (No DTH)
Protocol Activity Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1 Pre-
dose 0 hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
hour 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25a
Day 
29k
Day 
43
Day 
57 l
Day 
85
Day 
121
Window
1d
1d
1d
1d
1d
1d
1d
2d
2d
2d
3d
Admission to the 
unit
X
Discharge from 
the unit
X
Brief physical
X
Urine Drug and 
Alcohol Screen
X
Administer IV 
Dose (2 hour 
infusion)
◄----------►i
Safety Assessments
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 - Lead 
ECG
Xj
X
◄---------►b
X
X
Concomitant 
Medications
◄------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Adverse 
Events 
Assessment 
/ SAE'sc
◄-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Laboratory Assessments
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
Xd
Xd
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X

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Protocol Activity Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1 Pre-
dose 0 hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
hour 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25a
Day 
29k
Day 
43
Day 
57 l
Day 
85
Day 
121
Window
1d
1d
1d
1d
1d
1d
1d
2d
2d
2d
3d
CMV and 
EBV 
serology 
sample
X
Viral load 
sample 
(CMV, EBV, 
HSV, VZV)e
X
PK Samplef
◄-----------------------------------------------------------------------------------------------------►
Immunogenicity 
Sample
X
X
X
X
Immune Cell 
Phenotypingg
X
X
X
X
X
X
X
X
X
X
CD16 and LAG-3 
Receptor 
occupancy
X
X
X
X
X
X
X
X
X
X
Cytokine Sample
X
X
X
X
X
G-CSF Sample
X
X
X
X
X
X
X
X
X
X
X
sLAG-3 Sample
X
X
X
X
X
X
X
X
X
X
X
Blood 
Transcriptomics 
Sample
X
X
Ex Vivo 
Antigen/Cytokine 
Stimulation Test
X
X

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Protocol Activity Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1 Pre-
dose 0 hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
hour 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25a
Day 
29k
Day 
43
Day 
57 l
Day 
85
Day 
121
Window
1d
1d
1d
1d
1d
1d
1d
2d
2d
2d
3d
In vitro LAG-3+ 
activity
X
X
X
PGx Sample
Xh
a.
Cohort 0.0003mg/kg last out patient visit will be on Day 25.
b.
Continuous 2-lead ECG during infusion. Only significant abnormalities during this time will be databased.
c.
A targeted physical examination may take place if guided by AE reporting relating to Section 6.3.4, Section 6.3.5 and Section 6.3.6..
d.
Liver Chemistry and CRP only
e.
Viral load sample for storage as baseline.  If symptoms suggestive of viral infection develop then a sample will be taken and analysed with the baseline sample (See Section 6.3).
f.
See Pharmacokinetic time and events table for dose specific timepoints.
g.
Additional blood samples may be taken during the study if subject develops infection in order to measure LAG-3+ cells or other parameters as may be clinically or immunologically 
indicated.
h.
Pharmacogenetics sample can be taken any time after consent is signed.
i.
To calculate the correct dose, weight must be measured on Day -1 or Day 1 pre-dose.
j.
Triplicate.  Only required if screening ECG not within 35 days of Day 1.
k.
Cohort 0.0015mg/kg last out patient visit will be on Day 29.
l.
Cohort 0.0075mg/kg last out patient visit will be on Day 57.

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Table 8
Healthy Volunteers (DTH)
Protocol Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 3 Day 
28
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 
hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 
85 
(Day 
57 
post-
dose)
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
3d
1d 1d 1d 1d 1d 1d 1d 2d
2d
2d 3d
Admission to the 
unit
X
Discharge from 
the unit
X
Brief Physical
X
X
Urine Drug and 
Alcohol Screen
X
Administer IV 
Dose (2 hour 
infusion)
◄------------►
n
Safety Assessments
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 - Lead 
ECG
Xa
X
◄-----------►b
X
X
Concomitant 
Medications ◄-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Adverse 
Events 
Assessment 
/ SAE'sc
◄------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►

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Protocol Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 3 Day 
28
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 
hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 
85 
(Day 
57 
post-
dose)
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
3d
1d 1d 1d 1d 1d 1d 1d 2d
2d
2d 3d
Efficacy Assessments
Visual Arm 
Inspection
Xd
Xe
ID PPD 
Challenge
Xf
Xf
Bleb/ILH 
Assessment
Xe
Xe
Ball Point 
Pen 
Technique
X
X
X
X
X
Skin Biopsy
Xg
Xg

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Protocol Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 3 Day 
28
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 
hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 
85 
(Day 
57 
post-
dose)
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
3d
1d 1d 1d 1d 1d 1d 1d 2d
2d
2d 3d
Laboratory Assessments
Haematology Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
Xh
X
Xi
Xi
X
X
X
X
X
X
X
X
X
Urinalysis
Xh
X
X
X
X
X
X
X
X
X
X
X
X
CMV and 
EBV 
serology 
sample
X
Viral load 
sample 
(CMV, EBV, 
HSV, VZV)j
X
Immunogenicity 
Sample
X
X
X
X
PK Samplek
◄------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Immune Cell 
Phenotypingl
X
X
X
X
X
X
X
X
X
X
CD16 and LAG-3 
Receptor 
occupancy
X
X
X
X
X
X
X
X
X
X
Cytokine Sample
X
X
X
X
X
G-CSF Sample
X
X
X
X
X
X
X
X
X
X
X

2014N192690_11
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Protocol Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 3 Day 
28
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 
hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 
85 
(Day 
57 
post-
dose)
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
3d
1d 1d 1d 1d 1d 1d 1d 2d
2d
2d 3d
sLAG-3 Sample
X
X
X
X
X
X
X
X
X
X
X
Blood 
Transcriptomics 
Sample
X
X
Ex vivo 
antigen/cytokine 
stimulation
X
X
In vitro LAG-3+ 
activity
X
X
X
PGx Sample
Xm

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a.
Triplicate. Only required if screening ECG not within 35 days of Day 1.
b.
Continuous 2-lead ECG during infusion. Only significant abnormalities during this time will be databased.
c.
A targeted physical examination may take place if guided by AE reporting relating to Section 6.3.4, Section 6.3.5 and Section 6.3.6..
d.
Must be performed before ID PPD Challenge
e.
Bleb is assessed 5 minutes after ID injection and the immediate local hypersensitivity assessment 15-30 minutes after ID injection.
f.
See Section 5.10.1 for details.
g.
Only biopsy from one of the PPD sites preferably from the subjects non-dominant arm.
h.
If safety labs have been taken ≤7 days prior to challenge then these safety labs are not required. These samples can be taken on Day 1 or Day -1.
i.
Liver Chemistry and CRP only
j.
Viral load sample for storage as baseline.  If symptoms suggestive of viral infection develop then a sample will be taken and analysed with the baseline sample (See Section 
6.3).
k.
See Pharmacokinetic time and events table for dose specific timepoints.
l.
Additional blood samples may be taken during the study if subject develops infection in order to measure LAG-3+ cells or other parameters as may be clinically or 
immunologically indicated.
m.
Pharmacogenetics sample can be taken any time after consent is signed.
n.
To calculate the correct dose, weight must be measured on Day 28 or Day 29 pre-dose.

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Table 9
Psoriasis Patients
Protocol Activity Base-
line
In Clinic Period
Out Patient Visits l
Day 1
Day 2
Day 3
Day 4
Day 8
Day -
1
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
36 n
Day 
43
Day 
57
Day 
71 n
Day 
85
Day 
121
Window
1d
1d 1d 1d 1d 1d 1d 1d 2d 2d 2d 2d 3d
Admission to the 
unit
X
Discharge from 
the unit
X
Reassess 2 target 
lesions for 
suitability
X
Brief physical
X
Urine Drug and 
Alcohol Screen
X
Administer IV 
Dose (2 hour 
infusion)
◄------►j
Safety Assessments
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 - Lead ECG
X k
X
◄------►a
X
X
Concomitant 
Medications
◄-----------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Adverse Events / 
SAEs b
◄-----------------------------------------------------------------------------------------------------------------------------------------------------------------------►

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Protocol Activity Base-
line
In Clinic Period
Out Patient Visits l
Day 1
Day 2
Day 3
Day 4
Day 8
Day -
1
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
36 n
Day 
43
Day 
57
Day 
71 n
Day 
85
Day 
121
Window
1d
1d 1d 1d 1d 1d 1d 1d 2d 2d 2d 2d 3d
Efficacy Assessments
Psoriatic 
Body 
Surface Area
X
X
X
X
X
X
Psoriasis 
Area 
Severity 
Index
X
X
X
X
X
X
Psoriatic 
Lesion 
Severity 
Score
X c
X c
X c
X d
X d
X d
Phys. Global 
Assessment 
Scale
X
X
X
X
X
X
Skin Biopsy
X
X
Photograph 
of index 
lesion
X
X
X
X
X
X
Photograph 
of biopsy 
lesion e
X
X

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Protocol Activity Base-
line
In Clinic Period
Out Patient Visits l
Day 1
Day 2
Day 3
Day 4
Day 8
Day -
1
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
36 n
Day 
43
Day 
57
Day 
71 n
Day 
85
Day 
121
Window
1d
1d 1d 1d 1d 1d 1d 1d 2d 2d 2d 2d 3d
Laboratory Assessments
Haematology
Xo
X
Xo
Xo
Xo
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X f
X f
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine 
Pregnancy 
Test (FRP)
X
X
X
X
X
CMV and 
EBV 
serology 
sample
X
Viral load 
sample 
(CMV, EBV, 
HSV, VZV) g
X
Immunogenicity 
Sample
X
X
X
X
PK Sample h
◄----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
Immune Cell 
Phenotyping i 
(Flow)
X
X
X
X
X
X
X
X
X
X
X
Immune Cell 
Phenotyping m 
(Chip) 
X
◄------------------------------------------------------------------------------------ m -----------------------------------------------------------------------------------►
CD16 and LAG-3 
Receptor 
occupancy
X
X
X
X
X
X
X
X
X
X
X

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Protocol Activity Base-
line
In Clinic Period
Out Patient Visits l
Day 1
Day 2
Day 3
Day 4
Day 8
Day -
1
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
36 n
Day 
43
Day 
57
Day 
71 n
Day 
85
Day 
121
Window
1d
1d 1d 1d 1d 1d 1d 1d 2d 2d 2d 2d 3d
Cytokine Sample
X
X
X
X
X
G-CSF Sample
X
X
X
X
X
X
X
X
X
X
X
sLAG-3 Sample
X
X
X
X
X
X
X
X
X
X
X
Blood 
Transcriptomics 
Sample
X
X
PGx Sample
X
a.
Continuous 2-lead ECG during infusion. Only significant abnormalities during this time will be databased.
b.
A targeted physical examination may take place if guided by AE reporting relating to Section 6.3.4, Section 6.3.5 and Section 6.3.6..
c.
PLSS will be recorded for the index lesion and the biopsy lesion (prior to the biopsy being performed).
d.
Index lesion only.
e.
Photographs of the biopsy lesion will be taken before the skin biopsy.
f.
Liver Chemistry and CRP only
g.
Viral load sample for storage as baseline.  If symptoms suggestive of viral infection develop then a sample will be taken and analysed with the baseline sample (See Section 
6.3).
h.
See Pharmacokinetic time and events table for dose specific timepoints.
i.
Additional blood samples may be taken during the study if e.g. subject develops infection (measure LAG-3+ cells), hypersensitivity reactions (serum tryptase), signs/symptoms 
suggestive of viral reaction, or other parameters as may be clinically or immunologically indicated (See Section 6.3).
j.
To calculate the correct dose, weight must be measured on Day -1 or Day 1 pre-dose.
k.
Triplicate.  Only required if screening ECG not within 35 days of Day 1.
l.
Investigator/designee should remind subjects to comply with contraception requirements on an ~ monthly basis until Follow-Up (either at study visits or by telephone call).
m.
Immune Phenotyping (Chip) Cohort 7: at Baseline, 6 hours post-start of infusion, Day 8 and 15. Cohorts 8 and 9: at Baseline, 6 hours post start of infusion, Day 43 and 85.
n.
Additional visit introduced at Day 36 (Cohort 8 only) and Day 71 (Cohort 9 only).
o.
Samples taken for haematology at Day -1, 12 hours, 72 hours and 168 hours are to include analysis for CD3, CD4 and CD8 lymphocyte subsets.

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Table 10
Pharmacokinetics
In-clinic period a
Out-patient visits a
Dose Level  
Cohort
Day 1
Day 2
Day 3
Day 4
Day 
8
Day 
11
Day  
15
Day 
18
Day 
22
Day 
29
Day 
36
Day 
43
Day 
57
Day 
71
Day 
85
Day 
121
Pre-
dose
0.5 h 
1 h 
2 h b
4 h
6 h 
8 h
12 h
24 h
48 h
72 h
1d 1d 1d 1d 1d 1d 1d 2d 2d 2d 2d 3d
◄-------------------------------------hours post-start of infusion------------------------------►
◄--------------------------visit window-----------------------------►
0.0003mg/kg 
Cohort 1
X
X
X
X
X
X
X
X
X
0.0015mg/kg 
Cohort 2
X
X
X
X
X
X
X
X
X
X
X
0.0075mg/kg 
Cohort 3
X
X
X
X
X
X
X
X
X
X
X
X
X
0.04mg/kg 
Cohort 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
0.15mg/kg 
Cohort 5 & 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
0.5mg/kg 
Cohort 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.5mg/kg 
Cohort  8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5mg/kg 
Cohort  9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
When PK is taken in the healthy volunteer DTH cohort all PK times are relative to the start of the infusion on Day 29.
b.
The PK sample taken at the time coinciding with the end of infusion should be collected just before the end of the infusion. Timing for PK collection post infusion may be 
adjusted in particular if the infusion duration were to be modified during the course of the study.

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6.2.
Demographic/Medical History Assessments
The following demographic parameters will be captured: year of birth, gender, race and 
ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 4.2.  Cardiovascular medical history/risk factors including height, 
weight, blood pressure, smoking history, medical conditions will also be assessed at 
baseline.
6.3.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Table 
(Section 6.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
6.3.1.
Physical Exams

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  Height and weight will also be measured and 
recorded.

A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).

A targeted physical examination may take place if guided by AE reporting relating to 
Section 6.3.4, Section 6.3.5 and Section 6.3.6.
6.3.2.
Vital Signs

Vital sign measurements to be measured in semi-supine position after 5 minutes rest 
will include systolic and diastolic blood pressure, pulse rate and temperature.
6.3.3.
Electrocardiogram (ECG)

Triplicate 12-lead ECGs will be obtained at screening and single 12-lead ECGs will 
be obtained thereafter during the study, using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.  Refer to 
Section 5.6.2 for QTc monitoring criteria and additional QTcF readings that may be 
necessary.

ECG to be measured in semi-supine position after 5 minutes rest.

2-lead ECG will be measured continuously during the IV infusion (0-2 hours).  Only 
abnormalities during this time will be databased.  If abnormalities are detected a 12-
lead ECG will be obtained.

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6.3.4.
Infusion-related Reactions and Hypersensitivity Reactions
Subjects with a history of allergies or urticaria, allergic responses to foods, drugs, or 
insects may receive diphenhydramine and paracetamol (acetaminophen) prior to dosing at 
the discretion of the Principal Investigator or as a result of emerging data.  
Subjects will be closely monitored for signs of infusion-related reactions and acute 
allergic reactions and/or anaphylaxis following the administration of GSK2831781.  If an 
infusion-related reaction occurs during administration, the infusion rate will be reduced 
or halted.  The subject will receive appropriate medical treatment.  When the subject’s 
condition is stable, the infusion may be restarted and the infusion rate will be half of the 
infusion rate at the time the infusion was paused.  Severe hypersensitivity reactions such 
as anaphylaxis, will result in immediate termination of the infusion and the infusion will 
not be restarted.
As GSK2831781 is a fully humanized monoclonal antibody, it is considered unlikely for 
acute allergic reactions to occur in response to GSK2831781 exposure; however, all 
subjects will be monitored carefully for evidence of allergic response.  A subject that 
exhibits signs or symptoms of severe hypersensitivity or anaphylaxis will receive 
appropriate medical treatment and remain on study at the discretion of the investigator 
and after discussion with the GSK medical monitor.  In the event of a suspected acute 
hypersensitivity reaction a blood sample should be taken between 30 minutes – 3 hours of 
the event for serum tryptase analysis.
In accordance with the preparedness for treatment of anaphylaxis, emergency 
resuscitation equipment, advanced cardiac life support equipment, and medications must 
be readily accessible during GSK2831781 administration.
If more severe clinical signs arise, immediate assessment of the ABC's (airway, 
breathing, and circulation from Basic Life Support) will be done in all suspected 
anaphylactic reactions. Cardio-Pulmonary Resuscitation (CPR) will be initiated if 
needed.  Epinephrine will be given by injection without delay.  Emergency interventions 
may include endotracheal intubation or tracheostomy.  Treatment for shock will include
IV fluids and medications that support the actions of the heart and circulatory system. 
6.3.5.
Immunosuppression, Infections and Malignancies
As with other immunomodulating agents, the mechanism of action of GSK2831781 could 
increase the possibility of immunosuppression resulting in an increase in the frequency 
and/or severity of infection and/or an increased risk of malignancy.  Therefore, the 
protocol will exclude subjects who may be at increased risk of infection or malignancy 
based on medical/medication history and screening physical examination or laboratory 
findings.  During the trial, subjects will be questioned at all study visits about adverse 
events and results recorded in the electronic case report form (eCRF).  Specific attention 
will be given to monitoring for infection, although the single dose design with limited 
follow-up means that specific monitoring for malignancies is not supported. 
Examinations and laboratory evaluations will be performed routinely and the results, 
including markers of potential immunosuppression, will be reported to the investigators.  
Blood samples may be collected from subjects with infections, including flu like 

2014N192690_11
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symptoms, during the study for analysis of LAG-3+ cells.  Serology for CMV and EBV 
will be performed at baseline to identify subjects with potential risk of viral reactivation 
for these viruses.  Blood samples for viral load monitoring (CMV, EBV, HSV, VZV) will 
be taken at baseline and archived.  If the subject demonstrates any clinical symptoms 
consistent with viral reactivation e.g. fever, then another sample would be taken and this 
and the baseline sample sent for analysis and/or other appropriate medical investigations 
as suggested by the clinical context.
6.3.5.1.
Progressive Multifocal Leukoencephalopathy (PML)
PML has been found as a very rare occurrence in certain other immunosuppressive agents 
with different mechanisms of action.  The most common signs and symptoms of PML 
include visual disturbances, ocular movements, ataxia, and mental status changes such as 
disorientation or confusion.  If these are found, the investigator must exercise best 
judgment in further workup and clinical intervention as appropriate.  If PML is suspected 
this should be promptly reported to the sponsor.
6.3.5.2.
Follow-up of healthy volunteers who exhibit reduction of PPD 
challenge
Healthy volunteers will undergo a first PPD DTH ID challenge on Day 1 and then on Day 
30 (24 hours post GSK2831781 infusion) as described in Section 3.2. Healthy volunteers 
who produce an induration of ≥ 6 mm in the post dose challenge, will not require further 
PPD DTH ID re-challenges.  However, subjects who produce a DTH induration of < 6 
mm (i.e. exhibit reduction), will have a PPD DTH ID re-challenge after a further 3 
months.  If they still produce an induration of < 6 mm, it is likely that they will be PPD 
ID re-challenged every 3 months until the DTH induration is ≥ 6 mm dependent on 
review by the DEC. 
6.3.5.3.
Follow-up of subjects with psoriasis
All subjects in Part B will have assessments of clinical response (BSA, PASI, PLSS) 
carried out on Day 121 and follow-up visits.
6.3.6.
Autoimmunity
There is a theoretical risk that subjects could develop autoimmunity following 
GSK2831781 as there are a small percentage of T-regulatory cells which are LAG-3+ 
(Gagliani et al., 2013; Camisaschi et al, 2010; GSK internal data).  Subjects will 
therefore be monitored for evidence of possible auto-immune reactions.
6.3.6.1.
Monitoring for thyroid complications and other endocrine 
complications
Subjects will be excluded with a history of other significant immune disorders (apart 
from psoriasis), including diabetes, if places subject at unacceptable risk.  Investigators 
and subjects will be told to monitor for constant or unusual headaches, fatigue or the 
subjects feeling cold at all the time, dizziness, as well as for weight, change in mood and 
personality and change in the pattern of your bowel movements. Subjects will be tested 
for thyroid function at screening for comparison, if thyroid clinical symptoms occur 
during the study. 

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6.3.6.2.
Monitoring for colitis
Subjects will be excluded, and/or not be dosed if they experience gastrointestinal (GI) 
upset, but not limited to diarrhoea or abdominal cramping, during the previous week 
before dosing, as well as if they have a history of more chronic GI upset e.g. Irritable 
Bowel Syndrome (IBS). Investigators and subjects will be told to monitor GI symptoms 
and to seek medical advice as soon as these symptoms appears, including continuous 
abdominal pain, fever, blood in the stools, or dark coloured stools.  
6.3.7.
Clinical Laboratory Assessments
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below.  Details for the preparation and shipment of samples will be provided by the 
local laboratory. Reference ranges for all safety parameters will be provided to the site 
by the laboratory.
If additional non-protocol specified laboratory assessments are performed at the site’s 
local laboratory and result in a change in subject management or are considered clinical 
significant by the Investigator (for example SAE or AE or dose modification) the results 
must be captured and sent to GSK along with other study data as defined in Appendix 4.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Haematology
Platelet Count 
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes***
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST (SGOT)**
Total and direct bilirubin**
Creatinine
Chloride
ALT (SGPT)**
Uric Acid
Glucose, fasting*
Bicarbonate
GGT**
Albumin
Sodium
Calcium
Alkaline phosphatase**
Total Protein
C-reactive protein 
(CRP)
*Fasting glucose only screening.  Glucose non-fasting at all other timepoints. 
** Liver Chemistry parameters
*** CD3, CD4 and CD8 lymphocyte subsets will be analysed for subjects in Part B at Day -1, 12, 72 and 168 
hours

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Cytokines for safety assessment may include but are not limited to IL-6, TNFα, IL-8, 
IFN-γ. Analysis will be performed within 24 hours if any clinical signs suggest cytokine 
release syndrome. 
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.6.1
Routine Urinalysis (minimum requirements)
Specific gravity
pH, glucose, protein, blood, leucocytes, nitrites and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urine pregnancy test
Other screening tests
HIV
Hepatitis B (HBsAg, HBcAb)
Hepatitis C (Hep C antibody)
FSH and estradiol (as needed in women of non-child bearing potential only)
Serum pregnancy test
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).
Thyroid Function Test
Quantiferon test
Serology to confirm vaccination status (if required)
Baseline only tests
CMV, EBV serology
Viral load: CMV, EBV, HSV, VZV (sample for storage only unless clinical symptoms during study)
All laboratory tests with values that are significantly abnormal during participation in the 
study should be repeated until the values return to normal or baseline.  If such values do 
not return to normal within a period judged reasonable by the investigator, the aetiology 
should be identified and the sponsor notified.
6.3.8.
Vaccination
6.3.8.1.
Part A: Healthy Volunteers
Subjects who have no history of vaccination for diphtheria, pertussis, and tetanus may 
consent to receive a booster of an appropriate licensed combined vaccine at least  2 
weeks prior to dosing (If a suitable serology test is available to confirm vaccination status 
then this may be used prior to vaccinating).
Subjects who have no history of vaccination for measles, mumps and rubella may consent 
to receive a booster of an appropriate licensed combined vaccine (M-M-RVAXPRO or 
similar) at least 4 weeks prior to dosing which will be given after serology results are 
available to assess levels of antibodies.  

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It has been reported that live attenuated measles, mumps, and rubella virus vaccines 
given individually may result in a temporary depression of tuberculin skin sensitivity 
(PPD challenge). Therefore, for this study, vaccination using M-M-RVAXPRO (or 
similar) should be administered a minimum of 28 days (4 weeks) before the first PPD 
challenge (based on advice in SPC). When a serology sample to assess MMR vaccination 
status is taken, results must be obtained and interpreted prior to administering MMR 
vaccination. If required, MMR vaccination will be administered at a separate visit during 
the screening period.
For further details refer to the SPM.  
6.3.8.2.
Part B: Psoriasis subjects
Investigators are expected to assess vaccination status according to local and/or national 
guidelines for patients with psoriasis during screening.
6.4.
Efficacy
6.4.1.
Body Surface Area (BSA)
This should be performed by the same qualified dermatologist at all timepoints as 
detailed in the Time and Events table.
The BSA will be estimated by the ‘palm method’ whereby the palm to the proximal 
interphalangeal (PIP) joints, including the thumb, of the patient represents 1% of the total 
BSA) (Christensen et al, 2006).
Calculate the number of palm areas affected for the following areas: 

Head

Upper extremities

Trunk 

Lower extremities
The sum of these areas is the % BSA affected.
6.4.2.
Psoriasis Area and Severity Index (PASI) Assessment
The PASI assessment will be performed by the investigator or a suitably trained delegate, 
and whenever possible, the PASI assessments for an individual subject will be completed 
by the same assessor at all time-points. 
Each area of the body (head, upper extremities, trunk, lower extremities) will be assessed 
for the following symptoms: erythema, induration, scaling.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.

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After calculating the BSA as detailed above, use the multiplier for that body region to 
calculate the area score for each region as detailed below:
The area of psoriatic involvement for each area of the body (head, upper extremities, 
trunk, lower extremities) will be assessed using a 0–6 point rating scale, as follows:
Further details including the formula for calculating the PASI are included in the SPM.
6.4.3.
Physician Global Assessment (PGA)
Psoriatic lesions will be assessed using the PGA (Langley et al, 2004). The PGA 
assessment will be performed wherever possible by the same qualified dermatologist at 
all timepoints (either the investigator or a suitably trained delegate).
A 7-point scoring system will be used to measure the severity of psoriatic lesions over the 
whole body, at the time of the evaluation:
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by
third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by
third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by
third party copyright laws and therefore have been excluded.

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6.4.4.
Plaque Lesional Severity Score (PLSS) and index plaque 
selection
Two plaques will be selected at Day -1, one for clinical assessment (index plaque) and 
one for biopsy.  Ideally the index plaque should be the most severe plaque.  At a 
minimum each plaque will have an induration score of ≥2 (moderate or above) and a 
score of ≥1 in erythema and scaling, as detailed in the scoring list below.  Each lesion 
must have a PLSS score of ≥5.  The PLSS is the sum of the erythema, scaling and 
induration. The PLSS assessment will be performed by the same qualified dermatologist 
throughout, wherever possible and will be scored using the same scale (0-4 point rating 
scale) as the PASI (Section 6.4.2). 
6.4.5.
Photograph of the psoriasis plaques
A photograph of the index lesion and the biopsy lesion will be taken at each timepoint as 
detailed in the Time and Events table (Section 6.1).
6.4.6.
Histology-Psoriasis skin biopsy evaluation and scoring
Skin biopsies will be analysed histologically for psoriasis disease activity biomarkers by 
a central reader. The biopsy tissue may be evaluated for general appearance, epidermal 
thickness, total inflammatory infiltrate, expression of Ki67. Specific cell numbers may 
also be analysed (which may include but not limited to CD163+ monocytes, CD11c+ 
dendritic cells, CD83+and/or CD206+ cells, and CD3+ T cells).
6.5.
Other measures of clinical response
6.5.1.
PPD Intradermal injections
Healthy volunteers will receive one PPD injection into each forearm on Day 1 and 2 
injections into each forearm on Day 30.   

0.1mL is administered with a 1mL graduated syringe fitted with a short bevel needle.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by
third party copyright laws and therefore have been excluded.

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
The injection should be given strictly intra-dermally in the middle third of the 
forearm. Administration near the wrist or the elbow joint may weaken the reaction.

The skin is slightly stretched, and the needle is held almost parallel with the skin 
surface with bevel upwards. The tip of the needle is inserted into the superficial layer 
of the dermis.

The needle should be visible through the epidermis during insertion. The 0.1mL is 
slowly injected and a small blanched papule of 8 – 10 mm in diameter appears. This 
papule will disappear after approximately ten minutes.

If a papule does not appear, the injection has been given too deep, and the skin test 
should be repeated on the other arm or on the same arm, separated at least 4 cm from 
the first injection site.
Subjects will be observed at the research unit for 30 minutes after any administration of 
PPD (ID).
6.5.1.1.
Bleb
In order to assess whether a negative DTH reaction is due to a poor intradermal 
technique, a bleb assessment will be made within 5 minutes of administering a challenge 
agent. The length (diameter) and width of the bleb (raised area) that develops following 
an ID injection will be measured with a plastic flexible millimetre (mm) ruler.
6.5.1.2.
ILH
An immediate local hypersensitivity assessment will take place 15-30 minutes after each 
ID challenge immunisation. The assessment will involve examining the injection site for 
evidence of immediate local hypersensitivity/wheal (erythema or induration will not be 
taken into consideration for this assessment).   The diameter of the wheal (central 
swelling/raised skin) at the immunisation site, if that is present at the time of the 
hypersensitivity assessment, will be measured in the vertical and horizontal plane using a 
plastic flexible millimetre (mm) ruler. The 2 measurements will be added and divided by 
2 to get the diameter value.
The recognition and management of immediate local hypersensitivity is summarised in 
Section 3.4.
6.5.2.
DTH
6.5.2.1.
Ball Point Pen Technique
PPD induced DTH response will be assessed by the ball point pen technique. The 
induration of wheals (defined as elevation and induration that are palpable in the skin) 
that develop as a result of intradermal immunisation with PPD will be measured in the 
vertical and horizontal plane using the ball point pen technique.
Only the induration, which is a hard, dense, raised formation, will be measured, even if 
there is soft swelling or redness (erythema). The diameter of the induration is measured 
by rolling a medium ball point pen from 10 to 20 mm outside the edge of the induration 
and toward the centre with just enough pressure to indent the skin slightly. When the 

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induration is met the investigator (or designee) will feel a change in resistance as the biro 
is advanced. At this point they should immediately remove the biro from the surface of 
the skin.
6.5.2.2.
Photograph of DTH reaction
Photographs of any abnormal skin reactions may be taken if they are clinically 
significant.
6.6.
Pharmacokinetics
6.6.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK2831781 will be collected at the time 
points indicated in Section 6.1, Time and Events Table.  The actual date and time of each 
blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
Processing, storage and shipping procedures are provided in the SPM.
6.6.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SPM.  Concentrations of 
GSK2831781 will be determined in plasma samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site (detailed 
in the SPM).
6.7.
Immunogenicity
6.7.1.
Blood Sample Collection
Serum samples for determination of anti-GSK2831781 antibodies will be taken from all 
subjects in this study at the time-points specified in the Time and Events Tables in 
Section 6.1.
In Parts A cohorts 1-5, only subjects with a negative pre-existing ADA status at screening 
will be included.
6.7.2.
Sample Analysis
Immunogenicity assays will be performed by Clinical Immunology, GSK.  ADAs to 
GSK2831781 will be detected using a validated bridging electrochemiluminescent (ECL) 
immunoassay. This assay will be used both to prospectively define subjects’ pre-existing 
ADA status and to evaluate post-dose ADA responses.  The bioanalytical cut points of 
screening and confirmation for a positive antibody response will be determined 
statistically during ADA assay validation from drug-naive human serum samples.  
Samples will be directly tested in confirmatory ADA assay to define subjects’ pre-
existing ADA status for subject screening if required. An ADA assay involving 

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screening, confirmation and titration steps (tiered-testing approach) will be adopted for 
study samples. Confirmed positive samples will be titrated to obtain the titre of the anti-
GSK2831781 antibodies.  Samples testing positive for anti-GSK2831781 antibodies may 
be further characterised for the presence of GSK2831781 neutralizing activity (NAb) 
using a validated ADCC reporter gene assay, if needed. Details on sample preparation, 
storage and analysis will be given in the SPM.
6.8.
Biomarkers/Pharmacodynamic Markers
6.8.1.
LAG-3+ cells in DTH challenge site skin biopsies (Part A)
A punch biopsy will be taken from one of the challenge sites after each challenge.  A 
3mm skin punch biopsy will be taken from all subjects at the timepoints specified in 
Section 6.1, under local anaesthetic.
Biopsies will be taken from the middle of the induration as detailed in the SPM.
Biopsies will always be taken after the relevant DTH assessments have been completed.
The biopsy will be placed in formalin and subsequently processed for analysis by 
immunocytochemistry or other techniques to characterise and count the LAG-3+ and 
CD3+ cells in the biopsy.  These sections may also be analysed for histology including 
but not limited to the number of perivascular infiltrates and mRNA transcriptome 
analysis for novel biomarkers (see Section 6.8.7 and SPM).
6.8.2.
LAG-3+ cells in psoriasis lesion biopsies (Part B)
At baseline (pre-dose Day 1), a target lesion suitable for repeat biopsies will be identified 
on the trunk or extremities that protected from the sun. The same target lesion will be 
used for the baseline lesion biopsy and post treatment biopsy.  Lesions on palms, soles, 
face and groin will not be used as the target biopsy lesion site.  Ideally the most severe 
plaque, after the index lesion, should be selected and the severity of the erythema, scaling 
and induration of the plaque will be assessed as detailed in the PLSS scoring (Section 
6.4.4).  
Six mm punch biopsies will be taken from the active leading edge of the lesion using 
standard methodology.  Local anaesthetic will be administered before each biopsy, and 
only suitably experienced personnel, trained in aseptic technique, will take the biopsies.    
The 6mm biopsy will be split with a scalpel into 2, one sample will be placed in formalin 
and used to quantify CD3+ and LAG-3+ immune cells by IHC or similar techniques and 
also for histology assessment (see SPM).  The 2nd half of the biopsy will be frozen for 
mRNA transcriptome analysis for novel biomarkers (see Section 6.8.7 and SPM).
6.8.3.
Immune Cell Phenotyping
To address the effects of GSK2831781 on the LAG-3 expressing cells in the T cell 
compartment, regulatory, memory and effector T cells may be assessed.

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Markers may include but are not restricted to: CD3, CD4, CD8, CD14, CD16, CD19, 
CD25, CD45, CD56, CD45RA, CD95, CD127, CD197 (CCR7), CCR6, CXCR3 and 
LAG-3 as data permit.
CD107a, CD69, CD11b expression may be explored on NK cells to investigate the effect 
of GSK2831781 on NK cell function.
To monitor effects on specific blood leukocytes absolute counts for T, B and NK cells 
may be measured by flow cytometry or other technologies (e.g. chip cytometry).
6.8.4.
LAG-3 Cell Receptor Occupancy
The binding of GSK2831781 to cell surface LAG-3 may be measured (bound and free) 
using competitive and non-competitive anti-LAG3 antibodies.
6.8.5.
NK CD16 Cell Receptor Occupancy
The binding of GSK2831781 to CD16 may be measured (bound and free).
6.8.6.
Serum Protein Analysis
6.8.6.1.
Assessment of serum cytokines
Pro- and anti-inflammatory cytokine production will be assessed at the end of the study 
or may be assessed at the end of each cohort. 
Granulocyte-Colony Stimulating Factor [G-CSF] samples may be taken and analysed as 
an exploratory biomarker.
6.8.6.2.
Assessment of sLAG-3 receptor occupancy
Levels of sLAG-3 bound and unbound to GSK2831781 may be measured using ECL 
assays.
6.8.7.
Novel Biomarkers
With the subject’s consent, skin tissue and blood sample(s) will be collected during this 
study and may be used for the purposes of measuring novel biomarkers to identify factors 
that may influence psoriasis or the DTH challenge immune response, and/or medically 
related conditions, as well as the biological and clinical responses to GSK2831781.  If 
relevant, this approach will be extended to include the identification of biomarkers 
associated with adverse events.
Samples will be collected at the timepoints indicated in Section 6.1. The timing of the 
collections may be adjusted on the basis of emerging PK or PD data from this study or 
other new information in order to ensure optimal evaluation of the PD endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with psoriasis or the DTH challenge immune response or medically 
related conditions and/or the action of study treatment may be identified by application of 

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
RNA transcriptome analysis of blood and skin tissue samples.

Measurement of the levels of a subset of RNA species on blood and skin tissue 
samples.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
6.8.7.1.
RNA Transcriptome Research
An exploratory whole human genome expression array analysis may be conducted on 
blood and the punch skin biopsies from the DTH biopsies and from psoriasis patients 
using RNA sequencing, microarray, and/or alternative equivalent technologies, which 
facilitates the simultaneous measurement (and confirmation) of the relative abundances 
of thousands of RNA species resulting in a transcriptome profile for each skin sample. 
That will enable the evaluation of changes in transcriptome profiles that may correlate 
with biological response relating to the DTH immune challenge or psoriasis (Part A and 
Part B respectively) or the action of GSK2831781. 
The same samples may also be used to confirm findings by application of alternative 
technologies.
6.8.7.2.
RNA Expression Research of a Subset of RNA Species
RNA expression studies may be conducted using quantitative RT-PCR, and/or alternative 
equivalent technologies, which can facilitate the simultaneous measurement of the 
relative abundances of hundreds of RNA species resulting in a RNA expression profile 
for each blood and skin tissue sample. The RNAs assayed may include LAG-3 itself and 
other mRNAs that maybe involved with the pathogenesis of psoriasis or the DTH 
challenge immune response, the absorption, distribution, metabolism, or excretion of 
GSK2831781, or in the subject’s response to GSK2831781. In addition continuing 
research may identify other proteins or regulatory RNAs that may be involved in 
response to GSK2831781 or the pathogenesis of psoriasis or the DTH challenge immune 
response. The RNAs that code for these proteins and/or regulatory RNAs may also be 
studied. This will enable the evaluation of changes in RNA expression profiles that may 
correlate with biological response relating to psoriasis or the DTH challenge immune 
response and medically related conditions or the action of GSK2831781.
In part B the samples expression of specific genes  may include, but not limited to, Ki67, 
K16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INF-γ, TNF-α, iNOS, IL-1R 
antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPARα, PPAR-delta, and p53. 
6.9.
Pharmacogenetics
Information regarding pharmacogenetic (PGx) research is included in Appendix 2
Pharmacogenetic research.  The IRB/IEC and, where required, the applicable regulatory 
agency must approve the PGx assessments before these can be conducted at the site.  In 
some cases, approval of the PGx assessments can occur after approval is obtained for the 
rest of the study.  If so, then the written approval will clearly indicate approval of the 
PGx assessments is being deferred and in most cases, the study, except for PGx 

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assessments, can be initiated.  When PGx assessments will not be approved, then the 
approval for the rest of the study will clearly indicate this and therefore, PGx assessments 
will not be conducted.
7.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.1.
Time period for collecting AE and SAE information
AEs will be collected from the start of Study Treatment and until the follow-up contact.
Between follow-up and the surveillance visits only listed targeted medical events (see 
Section 3.4) will be reported and databased as SAEs/AEs.  
Subjects will be issued with a diary to record adverse events and concomitant 
medications during the study. This document will be used to assist subject recall in 
discussions with the investigator, for site staff to then enter as appropriate into the eCRF.
Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical Conditions 
CRF.
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study up to and including any 
follow-up contact.  All SAEs will be recorded and reported to GSK within 24 hours, as 
indicated in Appendix 4.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator would promptly 
notify GSK.
NOTE: The method of recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

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
“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.1.3.
Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
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 medicinal product.  
Events meeting the definition of an AE include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

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
Situations where 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.
7.1.4.
Definition of Serious Adverse Events
If an event is not an AE per Section 7.1.3, 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, etc).
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  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 or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 

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dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or 

ALT 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported 
as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 1 for the required liver chemistry follow-up instructions.
7.1.5.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization
This information should be recorded within one week of when the AE/SAE(s) are first 
reported.
7.1.6.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and non-
cardiovascular death.
This information should be recorded within one week of when the death is first reported.

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7.1.7.
Prompt Reporting of SAEs to GSK
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to GSK within 24 hours.  Any follow-up information on a 
previously reported SAE will also be reported to GSK within 24 hours.
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
appropriate data collection tool.  The investigator will always provide an assessment of 
causality at the time of the initial report as described in Appendix 4.
7.1.8.
Regulatory Reporting Requirements For SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs/IECs and investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug.  eCRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.  Subject initials will not be collected or transmitted to 
GSK according to GSK policy.
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses and Treatment Comparisons
The primary objective is to determine the safety and tolerability of single IV Doses of 
GSK2831781 in healthy volunteers and in patients with mild to moderate psoriasis. 

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There are no formal hypotheses planned.  
An assessment of dose proportionality of AUC and Cmax, following single dosing, will 
be conducted separately for healthy volunteers and patients with psoriasis.
Where appropriate, an estimation approach will be used to address the study objectives 
where point estimates and corresponding confidence intervals will be constructed to 
provide a plausible range of values for the comparison of interest.
Exploratory comparisons will be conducted to investigate the effect of ADA status at 
baseline on the pharmacokinetics of GSK2831781.
9.2.
Sample Size Considerations
The sample size is based on feasibility, and therefore there have been no formal sample 
size calculations
9.2.1.
Sample Size Assumptions
The sample size is based on feasibility, and therefore there have been no formal sample 
size calculations conducted. 
It is anticipated that sufficient number of healthy volunteers and patients will be enrolled 
in the study so that data are obtained from approximately 40 healthy subjects (26 on 
active, 14 on placebo) and approximately 27 psoriasis patients (18 on active, 9 on 
placebo).    
Part A and Part B - Safety
The primary objective of the study is safety, where a number of safety events are of 
interest.  A maximum of 6 subjects will receive each active dose and therefore if 0/6 of a 
particular safety event in the GSK2831781 group is observed, the upper limit of the exact 
95% Confidence Interval (CI) indicates that a true incidence rate of 46.5% could not be 
ruled out. Whereas if 1/6 of the same safety event in the GSK2831781 group is observed, 
the upper limit of the exact 95% CI indicates that a true incidence rate of 62.9% could not 
be ruled out. 
Using a Bayesian approach to determine the confidence interval around an observed 
safety event, we would assume a flat Beta (1,1) prior, and if we were to observe 1 safety 
event in 6 then the posterior distribution would be Beta (2, 6), as outlined below:

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Where we can be 95% certain that the true probability of the safety event lies between 
0.04 and 0.58.
Efficacy Assessment in Psoriasis Patients
The percentage change from baseline in PLSS in psoriasis patients can vary, with 
standard errors ranging from 6.9% to 11.1% (Boy et al, 2009). Assuming the greatest 
variability from this tofacitinib data and a sample size of 6 for each cohort, the 95% CI 
around the percentage change from baseline in PLSS point estimate would be plus or 
minus 26%, assuming a standard deviation of 24.8%.
9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates. If the number of subjects who completed each 
active dose is lower than 6, then the true incidence rates of safety events that could not be 
ruled out (as outlined in Section 9.2.1) would change. These changes are outlined in the 
table below:
N 
completing 
cohort
Number of particular a 
safety event observed with 
GSK2586184
Upper limit of exact 95% CI indicating 
that a true incidence rate of x% could 
not be ruled out
6
2 / 6
75.2%
6
3 / 6
84.9%
5
0 / 5
51.8%
5
1 / 5
69.1%
4
0 / 4
58.4%
4
1 / 4
76.4%
4
2 / 4
88.6%

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N 
completing 
cohort
Number of particular a 
safety event observed with 
GSK2586184
Upper limit of exact 95% CI indicating 
that a true incidence rate of x% could 
not be ruled out
2
0 / 2
76.8%
2
1 / 2
93.4%
9.2.3.
Sample Size Re-estimation
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
Statistical analyses will be performed by, or under the auspices of, Clinical Statistics, 
QSci, GlaxoSmithKline.
Complete details of the planned statistical analyses will be provided in the Reporting and 
Analysis Plan (RAP).
9.3.1.
Interim Analysis
Dependant on the dose cohorts reached in the escalation, formal interim analyses may be 
performed after the last subject in the Healthy Volunteer DTH cohort has completed their 
4 week post dose assessment visit, and also after the last subject in the Psoriasis group 
has completed the final PK assessment visit, to inform internal development decisions. If 
required, additional interim analyses  to contribute to internal development decisions may 
also be performed during Part B (psoriasis cohorts).  Full details of interim analysis will 
be documented in a RAP addendum.
For Parts A and B of the study, review of safety, tolerability, available pharmacokinetic 
and DTH induration for healthy volunteers or PASI and PLSS for psoriasis patients will 
be performed by DEC to aid decisions to proceed to higher dose strengths or, between 
cohorts 5 and 6 to subjects with pre-existing ADA. This analysis can include review of 
individual subject data, summaries, graphical presentations and/or statistical analysis. 
Owing to the modest time intervals involved, all data to be used for dose escalation 
decisions will be preliminary, non-quality-controlled (non-QC’ed), data.
Safety/tolerability data monitoring and the decision to proceed to the next dose level of 
GSK2831781 will be made by the DEC (see Section 5.4 for more details).
The GSK Clinical Pharmacology Modeling and Simulation (CPMS) representative will 
extract PK data (including treatment information) from SMS2000 using unscrambled 
subject IDs. PK data will provide supporting evidence for each dose modification 
decision. Importantly, if the emerging PK data is significantly different from the 
predicted values, adjustment may have to be made to the planned doses (see Section 5.4). 
Dose modification decisions will take into account the emerging PK data, new PK 
prediction for the next dose and thus the expected safety cover for the next dose.

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Standard Pharmacokinetic parameters will be derived for each subject by the GSK CPMS 
representative when possible. These parameters will be summarised by planned dose.
The criteria for switching from healthy volunteers to psoriasis patients are outlined in 
Section 3.2.1.
9.3.2.
Final Analyses
Final analysis for all endpoints will be reported when all subjects in all groups have 
completed their final scheduled visits (Table 6).
9.3.2.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.3.2.2.
Pharmacokinetic Analyses
Raw Plasma Concentrations
Blood sampling time will be related to the start of dosing. Linear and semi-logarithmic 
individual plasma concentration-time profiles and mean and median profiles by 
GSK2831781 dose will be plotted for each population (healthy volunteers or patients). 
Plasma concentrations of GSK2831781 will be listed and summarised by dose and 
nominal time for each population.
Derived Plasma Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, QSci, GSK. Plasma concentration time data for 
GSK2831781 will be analyzed by non-compartmental methods according to 
GlaxoSmithKline guidance document, GUI_00000051487 and using Phoenix.
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, for each dose of GSK2831781 and for each subject in both 
population:
• maximum observed plasma concentration (Cmax)
• time to Cmax (tmax)
• area under the plasma time curve [AUC(0-t), AUC(0-week4) and AUC(0-∞)]
• %AUCextrapolated
• Last time point where the concentration is above the limit of quantification (tlast)
• Systemic clearance (CL)
• Volume of distribution at steady state (Vss)
• Mean residence time (MRT)

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• terminal phase elimination rate constant (λz)
• the number of points used to determine λz
• the terminal phase half-life (t1/2).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline.
Descriptive statistics (n, arithmetic mean, standard deviation, 95%CI, minimum, median 
and maximum,) will be calculated for all pharmacokinetic parameters by treatment and 
pre-existing ADA status, where applicable. 
In addition, for loge-transformed variables geometric mean, 95% confidence interval and 
%CVb (100 * √ (exp(SD2) -1)) will be provided, where the SD is the standard deviation 
of log-transformed data.
Dose Proportionality
Separately for Parts A and B, dose proportionality across the single dose cohorts of loge-
transformed parameters AUC(0-) (or if not available AUC(0-t)) and Cmax will be 
assessed using the power model for of data permit, as described below:
y = * dose
where y denotes the PK parameter being analysed and depends on subject.  Dose 
proportionality implies that =1 and will be assessed by estimating along with its 
confidence interval.  The exponent, , in the power model will be estimated by regressing 
the loge-transformed PK parameter on loge dose:
log(y) = log() + log(dose)
The power model will be fitted by restricted maximum likelihood (REML), for all groups 
across the single dose cohorts. Both the intercept and slope will be fitted as random 
effects. If this model fails to converge, the model will be refitted with slope as a fixed 
effect. If the mixed effects model does not converge then a fixed effects power model 
will be fitted. The slope will be estimated from the power model and the corresponding 
90% confidence interval calculated. 
If the log transformed models are not proportional and sufficient data are available, loge 
transformed dose-normalised AUC(0-) (or if not available AUC(0-t)) and Cmax will be 
analysed using a suitable mixed effects model, fitting regimen as a fixed effect and 
subject as a random effect.  Point estimates and corresponding 90% confidence intervals 
for the ratios of each dose level to the reference dose will be determined.

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All other data will be summarised and listed.
9.3.2.3.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory plots will be presented for individual and/or pooled plasma GSK2831781 
concentrations versus serum soluble LAG-3 and/or drug bound soluble LAG-3 levels, if 
appropriate. 
Exploratory plots for PD/clinical activity variables (e.g. receptor occupancy, LAG3+ 
cells count and PASI, PLSS and PGA scores in patients) will be presented for individual 
and/or pooled plasma GSK2831781 concentrations and/or exposure versus corresponding 
PD/clinical activity variables. If deemed appropriate, further PK/PD modelling might be 
performed on those PD/clinical activity variables selected based on the results of the 
exploratory graphical analysis showing obvious relationships or trends between plasma 
GSK2831781 concentration/exposure and corresponding PD/clinical activity variables. 
The choice of the structural pharmacokinetic/pharmacodynamic models will be 
dependent on the emerging data. More details of any exploratory 
pharmacokinetic/pharmacodynamic analysis will be provided in the RAP.
9.3.2.4.
Pharmacodynamic/Biomarker Analyses
For Parts A and B, descriptive statistics, where appropriate, (n, arithmetic mean, 
geometric mean, standard deviation, minimum, median and maximum) will be calculated 
for the pharmacodynamic endpoints and the biomarkers and summarized by time for 
GSK2831781. Graphical displays will be produced over time if deemed appropriate. All 
data will be listed.
For Parts A and B, appropriate secondary pharmacodynamic/biomarker endpoints will be 
separately analysed using suitable mixed models repeated measures (MMRM) analysis, if 
deemed appropriate. Point estimates and their associated 95% confidence intervals will 
be constructed for the adjusted mean differences between “GSK2831781-placebo”. 
Further details of the model terms (random and repeated effects), possible covariates and 
interactions between treatment and covariates will be included in the RAP. 
Additional exploratory statistical analyses may also be performed to further characterise 
the pharmacodynamic/biomarker endpoints. Further details of the analyses will be 
provided in the RAP.
9.3.2.5.
Efficacy Analyses
For Part B, secondary endpoints including those related to PASI, PGA and PLSS will be 
summarised and graphically represented appropriately. Formal statistical analysis may be 
conducted if deemed appropriate. Further details are outlined in the RAP. All data will be 
listed appropriately.
9.3.2.6.
Immunogenicity Analyses
For Parts A and B, the immunogenicity assessment will include the incidence (confirmed 
positive results only) and titres of anti-GSK2831781 binding antibodies at each time 

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point and at any time point post baseline. Further details of the statistical analyses will be 
provided in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 1996 
(Germany) and 2008 (UK) Declaration of Helsinki.  This includes, but is not limited to, 
the following:

IRB/IEC review and favourable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject 
before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.
Information regarding pharmacogenetic research is included in Appendix 2)  .  In 
approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency must also approve the PGx assessments (i.e., approval of Appendix 
2)), unless otherwise indicated.  Where permitted by regulatory authorities, approval of 
the PGx assessments can occur after approval is obtained for the rest of the study.  If so, 
then the written approval will clearly indicate approval of the PGx assessments is being 
deferred and the study, except for PGx assessments, can be initiated.  When PGx 
assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, PGx assessments will not be conducted.

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10.2.1.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 
study treatment, and this new event is likely to affect the safety of subjects, the sponsor 
and the investigator will take appropriate urgent safety measures to protect subjects 
against any immediate hazard.
The sponsor will work with the investigator to ensure the IEC/IRB and regulatory 
authorities are notified, according to local regulatory requirements.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK requirements.  When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the CRF 
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures.
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 

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severe non-compliance. For multicenter studies, this can occur at one or more or at all 
sites.  If GSK determines such action is needed, GSK will discuss this with the 
investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, GSK will provide advance notification to 
the investigator or the head of the medical institution, where applicable, of the impending 
action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the investigator or 
the head of the medical institution (where applicable) must inform the IRB/IEC promptly 
and provide the reason for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
investigator must assure that all reproductions are legible and are a true and accurate copy 
of the original, and meet accessibility and retrieval standards, including re-generating a 
hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions.
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or GSK standards/procedures; otherwise, the 
retention period will default to 15 years.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator leaves the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 

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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.

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12.
APPENDICES
12.1.
Appendix 1: Liver Safety Process
The procedures listed below are to be followed if a subject meets the liver chemistry 
monitoring criteria defined in Section 5.5 and Section 5.6.1:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 7.1.4), the SAE data collection tool will be completed separately 
with the relevant details.

Refer to the Flow chart for a visual presentation of the procedures listed below.
Safety Follow-Up Procedures for subjects with ALT 3xULN:

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3xULN and total bilirubin 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR1 > 1.5:

This event is considered an SAE (see Section 7.1.4).  Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3xULN, every attempt must be made to also 
obtain the following:

Viral hepatitis serology including:

Hepatitis A IgM antibody.

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 

Hepatitis C RNA. 

Cytomegalovirus IgM antibody.
                                                
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.

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
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within one week of the 
liver event. Record the date/time of the PK blood sample draw and the date/time of 
the last dose of study treatment prior to blood sample draw on the CRF.  If the date or 
time of the last dose is unclear, provide the subject’s best approximation.  If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected within a week of the liver event, do not obtain a PK sample.  Instructions 
for sample handling and shipping are included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE CRF.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF.

Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week [James et al, 2009]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.

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12.2.
Appendix 2: Pharmacogenetic research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene 
Variant
Outcome
Abacavir
HIV [Hetherington et 
al, 2002; Mallal et al, 
2002; Mallal et 
al, 2008]
HLA-B* 
57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01 
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbama
zepine
Seizure, Bipolar 
disorders & 
Analgesia [Chung et 
al, 2010; Ferrell et al, 
2008]
HLA-
B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02 
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.

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Drug
Disease
Gene 
Variant
Outcome
Irinotecan
Cancer [Innocenti et 
al, 2004; Liu et al, 
2008; Schulz et al, 
2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to GSK2831781. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
GSK2831781.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK2831781 the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.

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Study Assessments and Procedures
Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
In addition to any blood samples taken for the clinical study, a whole blood sample 
(~6ml) will be collected for the PGx research using a tube containing EDTA.  It is 
recommended that the blood sample be taken at the first opportunity after a subject has 
been randomised and provided informed consent for PGx research, but may be taken at 
any time while the subject is participating in the clinical study.

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
GSK2831781 has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to 
GSK2831781.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 

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when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to GSK2831781.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood/saliva being 
taken for PGx research.

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Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.

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References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.

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12.3.
Appendix 3: Cytokine Release Syndrome AE Grading

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Modified from NCI-CTC.

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12.4.
Appendix 4: Procedures for Detection, Evaluation, Follow-
Up and Reporting of Adverse Events and Medical Device 
Incidents
Recording of AEs and SAEs
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) relative 
to the event.  The investigator will then record all relevant information regarding an 
AE/SAE in the appropriate data collection tool.
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE data collection tool.  
However, there may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to submission 
to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
Subject-completed health outcomes questionnaires and the collection of AE data are 
independent components of the study.  Responses to each question in the health outcomes 
questionnaire will be treated in accordance with standard scoring and statistical 
procedures detailed by the scale’s developer.  The use of a single question from a 
multidimensional health survey to designate a cause-effect relationship to an AE is 
inappropriate.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities.
Severe:  An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE.  Severity 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 one of the pre-
defined outcomes as described in the definition of an SAE.

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Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence 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 natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of 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 when 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 prior to the initial 
transmission of the SAE data to GSK.  The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool 
accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All AEs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.   The 
investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.  If a subject 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 data collection 
tool.  The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Reporting of SAEs to GSK
The primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.  If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor or protocol 

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contact.  Then the site will enter the serious adverse event 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 (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to their 
GSK protocol contact by telephone.
GSK contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
Facsimile transmission of the SAE data collection tool is the preferred method to transmit 
this information to the project contact for SAE receipt.  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.  Initial notification via the telephone 
does not replace the need for the investigator to complete and sign the SAE data 
collection tool within the designated reporting time frames.

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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher et al, 2011])
4.
Injectable progestogen [Hatcher et al, 2011]
5.
Contraceptive vaginal ring [Hatcher et al, 2011]
6.
Percutaneous contraceptive patches [Hatcher et al, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher et al, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

Will be withdrawn from the study.
REFERENCES
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 
2011: 50.  Table 3 2

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12.6.
Appendix 6: Protocol Amendment Changes
AMENDMENT 10
Summary and rationale for the changes
1. Additional sub-analysis of PGA scores added to secondary endpoints (see 
Section 2).
2. Including emerging PK data into the Study Design explanation (see Section 
3.3.2, Table 2 and Figure 1).
a.
Pre-clinical pharmacokinetic (PK) data generated in non-human primates 
had predicted the half-life of GSK2831781 was such that at the highest 
dose (5mg/kg), the time taken for drug levels to drop below the lower limit 
of quantitation (LLOQ, 10ng/ml) would be approximately 300 days.  
Preliminary human PK data from Cohorts 1-8 has now been included in 
the protocol, together with updated predictions for Cohort 9 (5mg/kg), in 
which drug plasma concentration is predicted to drop below the LLOQ by 
Day 85 (Table 2 and Figure 1).
3. Changing the study duration and structure to take account of this emerging
PK data (see Section 3.1.2, Section 3.3.1, Table 1 and Table 6)
a.
The duration of subject participation in the Phase I study was based on 
predictions, from non-human primate data, of the time taken to clear 
GSK2831781 from the circulation. As human PK has dramatically 
reduced these predictions, duration of subject participation has been 
amended
b. Psoriasis patients in 0.5mg/kg, 1.5mg/kg and 5mg/kg dosing cohorts (7-9) 
will have a final combined follow-up and surveillance visit at Day 183± 7 
due to emerging PK data that demonstrated more rapid clearance of 
GSK2831781 than previously predicted. Some subjects in Part B treated 
prior to Amendment 10 will have progressed beyond Day 183 ± 7.  If they 
have already had their follow-up visit, they should have a final 
surveillance telephone call as soon as practically possible after 
Amendment 10 regulatory approval. If they have not already had their 
follow-up visit, a combined follow-up and surveillance visit should be 
completed as soon as practically possible after Amendment 10 regulatory 
approval. to reflect this change.
4. Consolidation of previously enacted File Notes since Protocol Amendment #9 
(See Time and Events Table 9).
a.
File Note [Jun 9th 2017] – In Section 6.3.5.3, the protocol originally 
stated that clinical response would be assessed at follow-up and 
surveillance if clinical response was maintained at Day 121. This was 
amended via the file note to mandate response assessment (BSA, PASI, 
PLSS) at follow and surveillance visits for cohort 7, 8 and 9 subjects 

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irrespective of clinical response on Day 121. Protocol amendment 10 will 
include response assessments at follow-up visits (for some subjects, the 
follow-up and surveillance visit will occur at the same time, as detailed in 
Table 1).
b. File Note [Jun 9th 2017] (2) – Table 6 corrected, by removing ex vivo 
Antigen Stimulation Testing for cohorts 8 and 9, to reflect approved 
Protocol Amendment 09 text. Table 9 corrected to include assessment of 
CD16 and LAG3 receptor occupancy at Day 43 as per approved Protocol 
Amendment 09 text. Table 9 updated to clarify and reflect the routine 
analysis of CD3, CD4 and CD8 lymphocyte subsets for cohorts 7, 8 and 9 
on samples taken for haematology at Day -1, 12h, 72h (Day 4) and 168h.
5. Updating medical monitor details

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AMENDMENT 9
Summary and rationale for the non-substantial changes
Amendment 9 consolidates non-substantial changes to date. It serves to 1) remove the 
requirement for 3 ADA +ve patients in Cohorts 8 and 9,  2) introduce flexibility to 
conduct additional analyses to enable internal development decisions and 3) to 
incorporate previously enacted non-substantial changes captured in File Notes (8th Aug 
2016, 7th Nov 2016 and 12th Dec 2016) so as to ensure clarity of and adherence to the 
protocol (detailed below). 
The primary objectives and endpoints of the protocol remain unchanged and none of the 
changes were/are considered to impact on either safety or safety management or were/are 
considered to affect the overall scientific value of the study.  
Briefly:-
1. Removal of the stratification of psoriasis patients according to their pre-existing anti-
drug antibody (ADA) status, and to recruit “all-comers” into the remainder of Cohort 
8 and into Cohort 9.  The justification is based upon de-escalation of concerns 
regarding the theoretical impact of pre-existing ADAs following the review of Cohort 
7 data and their substantially lower frequency in the patient population than predicted 
(patient pool has been screened to exhaustion).  None of the events listed here have 
been observed following a single 0.5 mg/kg intravenous infusion: serious adverse 
event, immediate hypersensitivity, infusion reaction, cytokine release syndrome, type 
III hypersensitivity any other safety concern or any impact of ADA on 
pharmacokinetics. Importantly, enrolling patients at higher doses (1.5 or 5.0 mg/kg) is 
no longer considered necessary to test for overt risk of immediate hypersensitivity, 
infusion reactions, cytokine release or type III hypersensitivity.
2. Introduce the possibility of additional Interim Analyses to enable internal 
development decisions (See Section 9.3.1)
3. Consolidation of previously enacted File Notes since Protocol Amendment #8 (See 
Time and Events Table 9 and Table 10).
a. File Note [12th Dec 2016] - Following the blinded review of Cohort 7 data, the 
following changes (permitted by the protocol) were deemed necessary to both 
bridge the anticipated shortfall in the critical portion of the kinetic profile and to 
secure the utility of this study to inform the next steps in rational clinical 
development (e.g. definition of the dose regimen):-

Adjustment of the pharmacokinetic sampling schedule (additional sample 
Days 29 and 57).

Introduction of one new (different) visit per each Cohort 8 [Day 36] and 
Cohort 9 [Day 71] to enable capture of important pharmacokinetic time 
points.

Adjustment to the timing of immunophenotyping (chip cytometry).

Introduction of psoriasis efficacy assessments at Day 85 (non-invasive).
The overall blood volume (484 mL) remains below that approved (600 mL).

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b. File Note [7th Nov 2016] - Downward adjustment of the overall blood volume 
(minus 44 mL) as a result of the following:-
i)
Difficulty in the development of bioanalytical assays for two exploratory 
pharmacodynamic biomarker objectives/endpoints (Ex vivo Antigen/Cytokine 
Stimulation Test and in vitro LAG-3+ activity), justified that blood should no 
longer be collected for such purposes in Cohorts 8 and 9.   
ii) Adjustment of the blood volume for immunophenotyping (chip cytometry),  
as permitted by the protocol.
c.
File Note [8th Aug 2016] – Change the timing of photography of the biopsy 
lesion from post- to pre-biopsy.
AMENDMENT 8
Summary of Amendment Changes with Rationale
This amendment has been introduced to make the eligibility criteria more suitable for 
recruitment for psoriasis subjects in Part B of this study. This includes permitting the 
inclusion of females of reproductive potential (FRP) and modification of other eligibility 
criteria including age, BMI, BSA, vaccination and liver function tests that are more 
appropriate for the recruitment of psoriasis patients. The addition of a causality 
requirement to adverse event reporting for safety review criteria has also been introduced.
This amendment will also aim to improve operations by reducing number of biopsies 
required (from 3 to 2) in psoriasis subjects and modifying requirements for DEC review 
of psoriasis cohorts. Indeed dose escalation to the next psoriasis cohort will be based on 
safety data and clinical measures of response at 28 days post-dose for a minimum of 8 out 
9 subjects plus a minimum of 72 hours post-dose for all subjects.
List of Specific Changes
CHANGE 1
Synopsis, 2nd and 3rd paragraph 
REVISED/ADDED TEXT
Part A of the study will be a single dose escalation in healthy volunteers. The first 4 
cohorts will be given an intravenous (IV) dose of GSK2831781 or placebo over 
approximately 2 hours on Day 1. The last 5th healthy volunteer cohort will receive a skin 
challenge of 2 Tuberculin Unit (TU) or 10TU Purified Protein Derivative (PPD) on Day 
1. Twenty-eight days later the subjects will be given an intravenous (IV) dose of 
GSK2831781 or placebo over approximately 2 hours. Twenty-four hours after dosing 
they will be re-challenged with either 2TU or 10TU PPD. Biopsies will be taken from 
one of the challenge sites after each challenge for measurement of LAG-3+ T cells. A 
cohort (cohort 6) of subjects positive for pre-existing anti-drug antibodies (ADA) at 
the maximum healthy volunteer dose will then be dosed.

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Part B of the study will be a single dose escalation in patients with plaque psoriasis. Two 
lesions with a plaque lesional severity score (PLSS) of ≥5 will be identified. One will be 
used as an index lesion and the other will be used for skin biopsies on Day -1, Day 15 and 
Day 29. The biopsies will be used to quantify CD3+ and LAG-3+ immune cells. On Day 
1 patients will be given an intravenous (IV) dose of GSK2831781 or placebo over 
approximately 2 hours. Part B cohorts will be stratified to include subjects with 
negative or positive pre-existing ADA.
CHANGE 2
Objectives and Endpoints table
REVISED TEXT
Change from baseline in LAG-3+ cells in lesional biopsies at Day 15 and 29 measured by 
IHC
CHANGE 3
3.1. Study Schematic
REVISED SCHEMATIC
Day 15 skin biopsy removed.
CHANGE 4
3.1.2. Study Design Summary
Footnote added to psoriasis section: *Note: Progression to the next psoriasis cohort 
will be based on safety data and clinical measures of response at 28 days post-dose 
for a minimum of 8 out 9 subjects plus a minimum of 72 hours post-dose for all 
subjects.
CHANGE 5
Section 3.2. Study Design Detail, Part B, Psoriasis Patients, 1st paragraph, 6th line
REVISED TEXT
Once safety data and clinical measures of response (e.g. PASI) at 28 days post-dose have 
been completed for a minimum of 8 out of 9 subjects all subjects within the cohort and 
all subjects have completed dosing and the inpatient monitoring until Day 4, the 
DEC will review the safety data, available PK data and clinical response data, and may 
consider the available PD data before proceeding to the next dose level.
CHANGE 6

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Section 3.4. Risk Management, 2nd paragraph
ADDED TEXT
Once safety data and clinical measures of response (e.g. DTH induration for healthy 
volunteers, PASI for psoriasis patients) at 4 weeks post-dose have been completed for all 
subjects in each cohort (Part B: minimum 8 of 9 subjects, but with all subjects 
completing 72 hours post dose), the DEC and the investigator will review the data along 
with the available PK data before proceeding to the next dose level.
CHANGE 7
Section 3.4. Risk Management, Table 5
AMENDED TEXT
Risk of infection section: Healthy volunteer subjects will need to be vaccinated against 
infectious agents (Inclusion #8).
Psoriasis subjects: investigators are expected to assess vaccination status, according 
to local and/or national guidelines for patients with psoriasis during screening.
Neutropenia section: Exclude subjects with neutrophils outside of below normal range. 
(Exclusion # 5).
Hepatotoxicity section: Only subjects with  liver chemistry results within the limits 
specified in the inclusion and exclusion criteria will be included (Inclusion #10; 
Exclusion #10, #25)
Punch biopsy section: For the 3mm biopsy a minute scar will be visible and will be 
minimised as it will not require stitching. Stitching and a small scar will occur for the 
6mm biopsy.
Vaccination section: Subjects in Part A who are ineligible due to lack of history of 
vaccinations for diphtheria, tetanus, pertussis, measles, mumps or rubella, who consent to 
vaccination may only be vaccinated in accordance with the restrictions for these vaccines 
in the SPC. 
CHANGE 8
Section 4.2.1. Inclusion Criteria
AMENDED TEXT
1. Part A males aged between 18 and 65 years of age only and Part B males and 
females of non-child bearing potential aged between 18 and 6575 years of age
inclusive at the time of signing the informed consent.

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2. Part A: A body weight ≤120 kg and BMI within the range 19 – 32 kg/m2 (inclusive). 
For healthy volunteer subjects participating in Germany the BMI must be within the 
range of 19 – 30 kg/m2 (inclusive).  Part B: BMI within range 19-35 kg/m2
(inclusive).
5.
Part B only: Subject has psoriasis covering BSA ≥310% as assessed at Screening 
and Day -1.
6.
Part A only: Subjects with a history of vaccination for Tetanus, diphtheria, measles, 
pertussis, mumps and rubella.
7.
Part B only: A female subject is eligible to participate if she is of: not pregnant (as 
confirmed by a negative serum human chorionic gonadotrophin (hCG) test at 
screening and negative urine hCG test at Day -1 for FRP), not lactating, and at 
least one of the following conditions applies:
9.
Non-childbearing potential defined as pre-menopausal females with a documented 
tubal ligation or hysterectomy [for this definition, “documented” refers to the 
outcome of the investigator's/designee’s review of the subject's medical history for 
study eligibility, as obtained via a verbal interview with the subject or from the 
subject’s medical records]; or postmenopausal defined as 12 months of spontaneous 
amenorrhea [in questionable cases a blood sample with simultaneous follicle 
stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is 
confirmatory]. [Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 
weeks will elapse between the cessation of therapy and the blood draw; this interval 
depends on the type and dosage of HRT. Following confirmation of their post-
menopausal status, they can resume use of HRT during the study.]
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with 
follow-up confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle 
stimulating hormone (FSH) and estradiol levels consistent with 
menopause (refer to laboratory reference ranges for confirmatory 
levels)].  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly 
effective contraception methods if they wish to continue their HRT 
during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrolment.

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b. Reproductive potential and agrees to use a barrier method (male condom or 
female diaphragm) plus to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 5) from 28 days prior to the 
first dose of study medication and until completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception. The investigator or designee 
should remind the subjects of the need to comply with these requirements 
approximately monthly, either at study visits or by telephone call until the 
follow-up visit.
CHANGE 9
Section 4.2.2. Exclusion Criteria
AMENDED TEXT
1. Received live vaccine(s) (attenuated or recombinant) within 4 weeks of Day 1 or 
plan to receive a live vaccination during the study until follow-up.
5.
Subjects with neutrophil results outside of below the normal range at screening and 
baseline.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).  Part A 
only: Subjects with an aspartate aminotransferase and/or gamma glutamyltransferase 
level above the upper limit of normal at screening and/or baseline will be excluded.
26. Part B only: All systemic psoriasis medications, including psoralen long-wave 
ultraviolet radiation treatments, or other systemic immunosuppressives, are not 
allowed within 5 half lives prior to Day -1 (Methotrexate and cyclosporin are not 
allowed within 8 weeks of Day -1; Psoralen long-wave UV is not allowed within 4 
weeks of Day-1).  Subjects should not be included if the investigator considers 
that the subject is at high risk of requiring rescue with prohibited medication  
(see Section 5.14.2.3) for duration of study up to follow-up. This assessment 
should be based on current disease activity or a history of frequent and/or 
severe flares requiring systemic immunosuppression.
CHANGE 10
Section 5.4. Planned Dose Adjustments, 2nd paragraph, 10th line
ADDED TEXT
In the closed section, the Principal Investigators will not be present and if required data 
will be presented in an unblinded manner.
CHANGE 11
Section 5.4. Planned Dose Adjustments, 4th paragraph, 1st line

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AMENDED TEXT
For the psoriasis cohorts, once safety data and measures of clinical response (PASI and
PLSS) up to 28 days post-dose have been completed for a minimum of 8 out of 9 
subjects, and all subjects have completed dosing and the inpatient monitoring until 
Day 4,has been collected in all subjects for that cohort, the DEC will review the 
safety/tolerability data (including trends in neutrophil counts), the available PK data and 
the clinical response (PASI and PLSS) before proceeding to the next dose level. 
CHANGE 12
Section 5.5. Dose Adjustment/Stopping/Monitoring Criteria
ADDED TEXT
2.
Moderate or severe adverse events of the same nature (including infections) in 2 or 
more subjects in the same cohort which can be reasonably attributed to dosing 
with GSK2831781, within 28 days of dosing (Appendix 4 and specific criteria at 
individual subject level in Section 5.6).
3.
For a cohort of patients with psoriasis, if 2 or more subjects in a dose cohort 
experience a worsening of their psoriasis symptoms which can be reasonably 
attributed to dosing with GSK2831781, which requires treatment with prohibited 
concomitant medication. 
CHANGE 13
Section 5.14. Concomitant Medications and Non-Drug Therapies, 6th line
ADDED TEXT
For subjects with psoriasis, if indicated as part of  standard of care, non live 
vaccines (e.g., inactivated influenza vaccines) may be administered during the study 
based on an assessment of the benefit:risk (e.g., risk of theoretical decreased 
responsiveness).
CHANGE 14
Section 5.14.2.2 Part A and B
ADDED TEXT
Live vaccine(s) (attenuated or recombinant) within 4 weeks of Day 1 and until 
completion of the follow up visit.

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CHANGE 15
Section 6.1. Time and Events table
AMENDED TEXT
Table 6 - Pregnancy test added to screening and follow-up table.
Table 6 - Footnote J. Part A only: See Section 6.3.8 for more details.
Table 9 – Day 15 skin biopsy and photograph of biopsy lesion timepoints removed.
Table 9 – Pregnancy test added at Day-1, Days 29, 57, 85 and 121
Table 9 – Footnote L. The investigator or designee should remind subjects of the 
need to comply with contraception requirements on an approximately monthly basis 
until Follow-Up (either at study visits or by telephone call).
Table 10 – PK timepoints on Day 29 and 57 removed and added on Day 11 and 18 (for 
healthy volunteer Cohorts 5 & 6 and all psoriasis cohorts).
CHANGE 16
Section 6.3.7. Clinical Laboratory Assessments
Reason for cytokine change due to assay and validation availability.
AMENDED TEXT
Cytokines for safety assessment may include but are not limited to IL-6, TNFα, IL-8, IL-
1b IFN-γ.  Analysis will be performed within 24 hours if any clinical signs suggest 
cytokine release syndrome. 
CHANGE 17
Section 6.3.7. Clinical Laboratory Assessments
ADDED TEXT
Urine pregnancy test added to Routine Urinalysis table.
Serum pregnancy test added to Other Screening Tests table.
CHANGE 18
Section 6.3.8. Vaccination
ADDED HEADINGS AND TEXT
Section 6.3.8.1 Part A: Healthy Volunteers

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Section 6.3.8.2 Part B: Psoriasis subjects
Investigators are expected to assess vaccination status according to local and/or 
national guidelines for patients with psoriasis during screening.
CHANGE 19
Section 6.8.1. 4th paragraph
ADDED TEXT
The biopsy will be placed in formalin and subsequently processed for analysis by 
immunocytochemistry or other techniques to characterise and count the LAG-3+ and 
CD3+ cells in the biopsy.  
CHANGE 20
Section 6.8.3. Immune Cell Phenotyping, final paragraph
AMENDED TEXT
To monitor effects on specific blood leukocytes absolute counts for T, B and NK cells 
will may also be measured by flow cytometry or other technologies.
CHANGE 21
Section 9.3.2. Final Analyses
TEXT REMOVED
Final analysis of Part A will be reported when after all subjects in Part A have completed 
their follow-up visit. Final analysis for all endpoints will be reported when all subjects in 
all groups have completed their 12 month surveillance visit.
CHANGE 22
Section 12.5. Appendix 5
APPENDIX ADDED
Appendix 5: Modified List of Highly Effective Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information
Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)

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The list does not apply to FRP with same sex partners or for subjects who are and 
will continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the 
female subject's entry into the study, and this male is the sole partner for that
subject [Hatcher, 2011]. The documentation on male sterility can come from 
the site personnel’s: review of subject’s medical records, medical examination
and/or semen analysis, or medical history interview provided by her or her 
partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE 
or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported 
as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 

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GSK as described in Appendix 4. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn 
of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating 

Will be withdrawn from the study.
REFERENCES
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, 
Inc., 2011: 50.  Table 3 2

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AMENDMENT 7
Summary of Amendment Changes with Rationale
This amendment has been introduced to modify the study design to enable assessment of 
the impact of pre-existing anti-drug antibodies in healthy volunteers and psoriasis 
subjects.
The opportunity has been taken to modify text on BSA and screening requiring 
clarification, maximize utility of psoriasis clinical response assessments and add 
flexibility to assays for exploratory biomarkers.
List of Specific Changes
CHANGE 1
Change to describe rationale to including subjects with pre-existing ADAs
Section 1.2.1 GSK2831781, 3rd paragraph
REVISED/ADDED TEXT
Pre-existing anti-drug antibodies (ADA) that bind GSK2831781 have been noted in 
approximately 10-32 36% and 6 – 45 37.5% of sera from healthy and psoriatic human 
subjects respectively.  Analysis of ADA to GSK2831781 indicated they are generally 
low titre and low affinity, based on the IgM isotype.  The relevance of pre-existing 
ADAs for biotherapeutics in general is poorly understood, but they may have an effect on 
pharmacological and clinical parameters (Xue et al, 2013). 
Section 2 Objective(s) and Endpoint(s). Exploratory. 4nd row
ADDED TEXT
To explore the impact of pre-existing 
ADAs on the PK of GSK2831781

GSK2831781 PK parameters 
following single intravenous dose: 
AUC(0-∞), AUC(0-t), AUC(0-
Week4), %AUCex, Cmax, tmax, 
tlast, CL, Vss, MRT, λz and t ½ 
when assessable 

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Section, 3.3.1 Design Rationale, 9th paragraph
ADDED TEXT
Due to the presence of pre-existing ADA in a variable percentage in sera from both 
healthy and psoriatic human subjects, the initial investigation of GSK2831781 will be 
carried out initially in ADA negative subjects in Part A of the study to minimise the 
potential for diluting/confounding a signal of pharmacological or clinical response.  
However, for GSK2831781 to have development potential, it will need to be used in 
a mixed ADA population.  Therefore, after initial 28 day safety information is 
available for the DTH cohort at the highest dose for healthy volunteers, an 
additional cohort of healthy volunteers (without DTH) with pre-existing ADA will 
be dosed at the same dose level.  Subjects with psoriasis in Part B of the study will 
then be from a mixed population with and without pre-existing ADAs, after initial 
sentinel dosing in subjects without pre-existing ADA.  Subjects in the psoriasis 
cohorts will be recruited according to the following stratification: 4 ADA negative 
on active: 2 ADA negative on placebo and 2 ADA positive on active: 1 ADA positive 
on placebo. This will support a comparison of the effects of GSK2831781 at each 
dose level irrespective of ADA status, and will allow an exploration of the effect of 
ADA on PK across the dose levels.
CHANGE 2
To correct typographical  error  in assessment day for an endpoint.
Section 2 Objective(s) and Endpoint(s). Secondary. 2nd row
REVISED TEXT
To evaluate the pharmacology of a single 
IV dose of GSK2831781 in psoriasis 
patients.

Change from baseline in LAG-3+ cells 
in lesional biopsies at Day 1415 and 29 
measured by IHC
CHANGE 3
Change to indicate change in study design - that subjects with pre-existing ADA will now 
be recruited. 

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Section 3.1 Study Schematic
REVISED/ADDED TEXT

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Section 3.1.2 Study Design Summary, Table 1
REVISED/ADDED TEXT
Planned 
Doses
Number of 
subjects 
(active:placebo)
Safety Follow-up 
period to progress 
to next 
subjects/cohorts
PPD DTH 
Challenge if 
Healthy 
volunteer/ Biopsy 
if patient
Follow-up and end of 
exclusion of systemic 
immunosuppressives
0.15mg/kg
6:6
1:1 wait 48 hours 
post-dose
5:5 wait 28 days post-
dose
DTH
Day 219 ± 7 days
(190 days post-dosing)
0.15mg/kg*
6:2
1:1 wait 48 hours 
post-dose
5:1 wait 28 days 
post-dose
No DTH
Day 189 ± 7 days
(190 days post-dosing)
Note: Cohort with a DTH starts dosing on Day 29
*Note: No DTH cohort at dose level 0.15mg/kg is in subjects with pre-existing ADA. All previous cohorts are in 
subjects without pre-existing ADA
Maximum dose for healthy volunteers may change based on emerging exposure (See Section 3.2.1)
Psoriasis Patients (Pre-existing ADA- and ADA +)
0.15mg/kg
6:23
(ADA-ve 4:2
ADA+ve: 2:1)
1:1 ADA-ve wait 48 
hours post-dose
5:12 wait 28 days 
post-dose
Biopsy
190 days post-dosing ± 7 days
0.5mg/kg
230 days post-dosing ± 7 days
1.5mg/kg
270 days post-dosing ± 7 days
5mg/kg
300 days post-dosing ± 7 days
Section 3.2 Study Design Detail. 1st paragraph 2nd and 3rd sentences
ADDED TEXT
In Parts A and B of the study subjects will be screened for pre-existing ADA status and 
initially in Part A only subjects who do not have pre-existing ADAs will be randomised. 
A cohort (cohort 6) of subjects positive for pre-existing ADA at the maximum 
healthy volunteer dose of 0.15mg/kg will then be dosed.  Part B will include subjects 
with both negative and positive pre-existing ADA status, stratified by their ADA 
status, as outlined in Table 1. 

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Section 3.2 Study Design Detail. 3rd paragraph 4th sentence
REVISED TEXT
The first cohort of patients with plaque psoriasis will begin at the same dose asnext dose 
level after the maximum dose administered to healthy volunteers.
Section 3.2 Study Design Detail. PART A Healthy volunteers without DTH, 2nd
paragraph 1st sentence, 3rd paragraph 3rd  sentence, 10th paragraph 1st and 2nd
sentences
REVISED
For cohorts 3 and,4 and 6, one active and one placebo subject will be recruited initially.
ADDED TEXT
Once data up to 28 days post dose has been collected for all subjects within cohort 6, 
the DEC will review the safety data along with the available PK data, available PD
data from cohort 6, and also the DTH clinical response data from the Healthy 
Volunteer (DTH) cohort 5 (below), before switching to patients with plaque 
psoriasis.
REVISED/ADDED TEXT
All subjects in cohorts 1, 2, 3 and 4 will attend a surveillance visit at 6 and 12 months. 
As the follow-up visit is at approximately 6 months (190 days post-dose, as per Table 
1), subjects in the 0.15mg/kg cohort 6 do not require an additional post-dose 
surveillance visit at 6 months and will only attend a surveillance visit at 12 months.
Section 3.2 Study Design Detail. PART A Healthy volunteers with DTH, 1st
paragraph 3rd sentence
REVISED/ADDED TEXT
Once data up to 28 days post dose has been collected for all subjects within the cohort, 
the DEC will review the safety data along with theavailable PK data, the DTH clinical 
response and available PD data, before switching to patients with plaque psoriasis dosing 
a cohort of healthy volunteers with pre-existing ADA, at the same dose, without 
DTH.
Section 3.2 Study Design Detail. PART B Psoriasis patients, 1st paragraph 1st and 2nd
sentences
REVISED TEXT
At the beginning of each cohort sentinel dosing in subjects without pre-existing ADA 
will occur, such that one subject will receive active and one subject will receive placebo. 
After review of the safety data at 48 hours post-dose an additional 5 active (3 without 
and 2 with pre-existing ADA) and 12 placebo subjects (1 with and 1 without pre-

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existing ADA) will be dosed (no more than 2 subjects per day with dosing separated by 
at least 1 hour). 
Section 4.1 Number of Subjects, 1st paragraph
REVISED TEXT
Approximately 6467 subjects will be enrolled to complete dosing and critical 
assessments.  The subject numbers will be split to approximately 3240 healthy volunteers 
and 3227 patients with psoriasis.
Section 4.2.2 Exclusion Criteria #8
ADDED TEXT
8.
Part A (only cohorts, 1-4 without DTH challenge, and DTH cohort 5) 
only:Subjects who test positive for pre-existing ADA to GSK2831781 at screening.
Section 5.3 Treatment Assignment, 2nd paragraph 3rd sentence
ADDED TEXT
In Part B, the sentinel subjects will be required to be ADA negative and subsequent 
subjects will be stratified by ADA status (ADA negative or ADA positive).

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Section 5.3 Treatment Assignment, Table
REVISED TEXT
Regimen
Description
Ratio (Active:Placebo)
E
0.15mg/kg GSK2831781 IV single dose
1:1 for HV DTH (ADA-)
3:1 for Psoriasis patients
HV No DTH (ADA +)
F
0.5mg/kg GSK2831781 IV single dose
4:2 for psoriasis (ADA-)
2:1 for psoriasis (ADA+)
3:1
G
1.5mg/kg GSK2831781 IV single dose
4:2 for psoriasis (ADA-)
2:1 for psoriasis (ADA+)
3:1
H
5mg/kg GSK2831781 IV single dose
4:2 for psoriasis (ADA-)
2:1 for psoriasis (ADA+)
3:1
Section 6.7.1 Blood Sample Collection, 2nd paragraph
REVISED TEXT
In Parts A cohorts 1-5 and B, only subjects with a negative pre-existing ADA status at 
screening will be included.
Section 9.1 Hypothesis and Treatment Comparisons, 4th paragraph
ADDED TEXT
Exploratory comparisons will be conducted to investigate the effect of ADA status at 
baseline on the pharmacokinetics of GSK2831781.
Section 9.2.1 Sample Size Assumptions, 2nd paragraph
REVISED TEXT
It is anticipated that sufficient number of healthy volunteers and patients will be enrolled 
in the study so that data are obtained from approximately 3240 healthy subjects (2026 on 

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active, 12 14 on placebo) and approximately 3227 psoriasis patients (2418 on active, 89
on placebo).
Section 9.3.1 Interim Analysis, 1st paragraph 1st sentence, 2nd paragraph 1st sentence
ADDED TEXT
Dependant on the dose cohorts reached in the escalation, formal interim analyses may be 
performed after the last subject in the Healthy Volunteer DTH group cohort has 
completed their 4 week post dose assessment visit, and also after the last subject in the 
Psoriasis group has completed the final PK assessment visit, to inform internal 
development decisions.
For Parts A and B of the study, review of safety, tolerability, available pharmacokinetic 
and DTH induration for healthy volunteers or PASI and PLSS for psoriasis patients at the 
end of each cohort will be performed by DEC to aid decisions to proceed to higher dose 
strengths or, between cohorts 5 and 6 to subjects with pre-existing ADA.
Section 9.3.2.2 Pharmacokinetic Analysis, Derived Plasma Pharmacokinetic 
Parameters, 15th paragraph
ADDED TEXT
Descriptive statistics (n, arithmetic mean, standard deviation, 95%CI, minimum, median 
and maximum,) will be calculated for all pharmacokinetic parameters by treatment and 
pre-existing ADA status, where applicable.  
CHANGE 4
Change to indicate removal of  psoriasis cohort which is the same as the top dose level 
for healthy volunteers
Section 3.2.1 Study Design Detail, 1st paragraph 4th sentence
ADDED TEXT
If a dose switch then occurs later, psoriasis cohorts would start one dose higher than at 
the last dose used in healthy volunteers.
Section 3.3.1 Design Rationale, 8th paragraph 1st sentence
REVISED TEXT
Dose escalation in psoriasis patients will be started at the same dose as one dose higher 
than the maximum dose investigated in healthy volunteers following a DTH challenge.

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Section 5.4 Planned Dose Adjustments, 5th paragraph 3rd bullet
ADDED TEXT

Replacement of the highest dose level in psoriasis cohorts with a lower dose 
than the scheduled starting dose for psoriasis cohorts
CHANGE 5
Change in risk mitigation activities to support inclusion of subjects with pre-existing 
ADA
Section 3.4 Risk Management, Table 5, IP risk
ADDED TEXT
Potential risk
Summary of data
Impact eligibility 
criteria
Strategy-monitoring criteria
IP risk
Infusion-
reaction/hypersensitivity
The first study in humans 
will be conducted by IV 
administration.
Subjects will be 
excluded if history of 
severe allergic 
reaction. (Exclusion 
#4)
Initial cohorts (1-5) 
will exclude 
subjects with pre-
existing ADA 
(Exclusion criteria 
#8)
Subjects will be in a phase 1 unit 
and closely monitored for 72 hours 
post dosing. 
IV doses will be administered for 2 
hours.  However, dosing duration 
may be modified based on safety 
data with the approval of the PI and 
sponsor.
Guidelines for monitoring relevant 
adverse events encompassing 
hypersensitivity, angioedema and 
anaphylaxis 
and for management of acute 
anaphylactic shock and minor 
allergic episodes will be in place at 
investigational sites. 
Study sites will include facilities and 
expertise for emergency 
care/resuscitation, including access 
to hospital and Intensive Care Unit 
(ICU).
Pre-medications are permitted at 
investigator’s discretion (Section 
6.3.4).

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Potential risk
Summary of data
Impact eligibility 
criteria
Strategy-monitoring criteria
Cytokine release
Hyper-immune activation 
leading to activation of the 
innate immune system is 
only a theoretical safety 
concern, as there is no in 
vitro and in vivo evidence 
of cytokine release 
associated with LAG-3+ 
and T cell depletion 
mechanism, in the 
presence or absence of 
pre-existing ADA.
Initial cohorts (1-5) 
will exclude 
subjects with pre-
existing ADA 
(Exclusion criteria 
#8)
Study sites will include facilities and 
expertise for emergency 
care/resuscitation, including access 
to hospital and ICU.
Monitoring for clinical symptoms 
associated with cytokine release 
such as fever, nausea, chills, 
hypotension, tachycardia, asthenia, 
headache, rash, tongue and throat 
swelling, and dyspnea. 
Standard safety haematology and 
clinical chemistry assessments to 
include CRP will be performed.
In addition limited cytokine analysis 
will be performed within 24 hours if 
any clinical signs suggest cytokine 
release syndrome (See Section 
6.3.7)
Type III 
Hypersensitivity 
(Immune complex 
deposition in kidney, 
liver, skin)
Reactions due to 
immune complexes 
formed from pre-
existing ADA and 
GSK2831781 are a 
theoretical risk. Risk is 
assessed as low as pre-
existing ADAs are 
predominantly of low 
titre.
Initial cohorts (1-5) 
will exclude 
subjects with pre-
existing ADA 
(Exclusion criteria 
#8)
Targeted clinical monitoring will 
include physical examination,  
urinalysis to detect haematuria 
and proteinuria, and clnical 
chemistry to monitor renal and 
liver function. 
Section 6.3.4 Infusion-related Reactions and Hypersensitivity Reactions, 1st
paragraph 1st sentence
ADDED TEXT
Subjects with a history of allergies or urticaria, allergic responses to foods, drugs, or 
insects may receive diphenhydramine and paracetamol (acetaminophen) prior to dosing at 
the discretion of the Principal Investigator or as a result of emerging data.  
CHANGE 6
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Section 4.2.1 Inclusion Criteria #2
REVISED TEXT
2.
A body weight ≤120 kg and BMI within the range 19 – 32 kg/m2 (inclusive). For 
healthy volunteer subjects participating in Germany the BMI must be within the 
range of 19 – 30 kg/m2 (inclusive). 
CHANGE 7 
Change to allow assessments for clinical response in psoriasis subjects  beyond Day121 if 
a response is still present
Section 6.1 Time and Events Table, Table 6 Screening and Follow-up
REVISED/ADDED TEXT
Protocol Activity
Screeningi
Follow Up
Up to 35 Days prior to Day 1
Week Xa
Window
Psoriatic Body Surface Area
Xf
Xk
Psoriatic Lesion Severity Score
Xf
Xk
Psoriasis Area Severity Index
Xk
k
Subjects with psoriasis may be assessed for BSA, PASI and for index lesion PLSS, if reduction from baseline is 
maintained at Day 121 (See Section 6.3.5.3)
Section 6.3.5 Immunosuppression, Infections and Malignancies
ADDED TEXT
6.5.3
Follow-up of subjects with psoriasis who exhibit clinical effect
Subjects who maintain a clinical response in BSA, PASI and or PLSS (of index lesion) at 
Day 121 compared to baseline may be assessed for clinical response at follow-up and if 
still maintained, at the final surveillance visit.
CHANGE 8
Change to allow flexibility of assays used for exploratory assessment of ex vivo 
stimulation.
Section 6.1 Time and Events Table , Table 6, Table 7, Table 8, Table 9,
REVISED TEXT
Replace Ex Vivo Antigen Stimulation Test 
WITH

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Ex Vivo Antigen/Cytokine Stimulation Test
Section 6.8.6 Ex vivo Antigen Stimulation 
REVISED TEXT
6.8.6 Ex vivo Antigen/Cytokine Stimulation
Studies may be initiated, dependent on feasibility, to assess antigen specific or 
polyclonally or cytokine activated T cell response in ex vivo blood. Amongst other 
assays to measure antigen specific T cell responses, an IFNγ T cell ELISpot may be used 
to monitor antigen-specific immune responses to the challenge antigens, as well to 
Tetanus toxoid or other antigens as an internal/safety control.
CHANGE 9
To clarify extent of additional duration of screening for vaccinated subjects
Section 6.1 Time and Events Table, Table 6 Screening and Follow-up, footnote i
ADDED TEXT
i. Screening can be longer, up to a maximum of 42 days if vaccinations are required prior to dosing.
CHANGE 10
To clarify measurement of Body Surface Area
Section 6.4.1 Body Surface Area (BSA), 2nd paragraph
REVISED TEXT
The BSA will be estimated by the number of patients’ palm areas affected (the patients 
palm and thumb  together), assuming that one “handprint” reflects approoximately 1% of 
’palm’ method whereby the palm to the proximal interphalangeal (PIP) joints, 
including the thumb, of the patient represents 1% of the total BSA)
(RamseyChristensen et al, 19912006).
Section 11 References
ADDED TEXT
Christensen TE, Callis KP, Papenfuss J, et al. Observations of Psoriasis in the Absence of 
Therapeutic Intervention Identifies Two Unappreciated Morphologic Variants, Thin-
Plaque and Thick-Plaque Psoriasis, and their Associated Phenotypes. J Invest Derm, 
2006;126:2397-2401.

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DELETED TEXT
Ramsay B, Lawrence CM. Measurement of involved surface area in patien ts with 
psoriasis. Br J Dermatol. 1991 Jun;124(6): 565-70.
CHANGE 11
To add flexibility to clinical specimen potentially used for transcriptomics
Section 6.8.1 LAG-3+ cells in DTH challenge site skin biopsies (Part A), 4th
paragraph 2nd sentence
ADDED TEXT
These sections may also be analysed for histology including but not limited to the number 
of perivascular infiltrates and mRNA transcriptome analysis for novel biomarkers 
(see Section 6.8.9 and SPM).

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AMENDMENT 6
Summary of Amendment Changes with Rationale
This amendment has been introduced to meet country specific regulatory and ethics 
requirements. 
This includes update of the exclusion criteria to include aspartate aminotransferase and/or 
gamma glutamyltransferase outside of normal range at screening and/or at baseline and 
amendment of text for malignancy history. Specific sections of the protocol have also 
been updated to provide greater clarity regarding the composition of the Dose Escalation 
Committee and to provide a clearer explanation of the decision making by the DEC.
List of Specific Changes
CHANGE 1
Change to provide clearer explanation of dose escalation activities by the DEC.
Section 3.2 Study Design Detail, 4th paragraph 
REVISED TEXT
Based on DEC review the criteria which are defined in Section 5.4, ‘Planned Dose 
Adjustments’, Section 5.7 ‘Dose Adjustment/Stopping Pharmacokinetic Criteria’ 
and the DEC Charter, the DEC may recommend that, doses and intervals between 
doses levels may be are changed within these limits based on any of the following 
emergent data: safety and tolerability, PK, clinical measures and PD (See Section 5.4).
CHANGE 2
Reference to protocol Section 3.2 added to text.
Section 3.4 Risk Management, 2nd paragraph, 5th line
REVISED TEXT
After the GSK medical monitor and investigator have reviewed the safety data up to 48 
hours, the remaining subjects (where appropriate) from that cohort will be dosed (see 
Section 3.2).  
CHANGE 3
LLQ stated in Figure 1 was based on original planned technology but assay subsequently 
required different technology which was more sensitive (100ng/ml rather than 10 ng/ml). 
Figure 1 has been updated with correct LLQ.

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Section 3.3.2.1 Human PK Prediction, Figure 1
REVISED SCHEMATIC

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CHANGE 4
Updated Hepatotoxicity Section of the Risk Table to reflect changes made to Exclusion 
Criteria 10.
Section 3.4, Table 5 
REVISED TEXT
Hepatotoxicity
Minimal to mild Kupffer 
cell activation at doses 
>30mg/kg in primates.
Only subjects with  
liver chemistry 
results within the 
limits specified in the 
inclusion and 
exclusion criteria 
will be included 
(Inclusion #10; 
Exclusion #10)
Standard GSK liver stopping applied 
for dosing new subjects,  and 
monitoring guidance (See Section 
5.5 and Section 5.6.1)
CHANGE 5
Modification of exclusion criteria to remove exception for subjects with malignancy and 
to include aspartate aminotransferase and gamma glutamyltransferase outside of normal 
range at screening and/or baseline.
Section 4.2.2 Exclusion Criteria
REVISED TEXT
9. History of malignancy, except for basal cell or squamous cell carcinoma, or in situ
cervical carcinoma that has been fully treated and shows no evidence of recurrence.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). Subjects with an 
aspartate aminotransferase and/or gamma glutamyltransferase level above the 
upper limit of normal at screening and/or baseline will be excluded.
CHANGE 6
Modification of text to give further detail on the membership of the Dose Escalation 
Committee and to provide more explicit information on the decision making of the DEC.
Section 5.4 Planned Dose Adjustments, 2ndparagraph 1st sentence
REVISED TEXT
Safety/tolerability data monitoring and the decision to proceed to the next dose level of 
GSK2831781 will be made by the DEC, consisting of the Principal Investigators (or 
appropriate designees), GSK Medical Monitor, GSK Study Team Leader (either Clinical 
Investigator Lead [CIL] and/or Operations and Science Lead [OSL]), GSK CPMS

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representative, a GSK GCSP representative, and GSK Statistician and an independent 
GSK expert on FTIH studies.  The DEC may also call on ad hoc internal/external 
members with specific expertise.
Section 5.4 Planned Dose Adjustments, 3rd paragraph 3rd sentence and 4th
paragraph 3rd sentence
REVISED TEXT
Outcomes of DEC review could include escalation to the next dose, stopping the
escalation, 
Section 5.4 Planned Dose Adjustments, after 4th paragraph 
ADDED TEXT
Apart from stopping of the dose escalation, alterations to the planned dose levels 
and intervals between dose levels will be limited to the following.  Other changes will 
require a substantial amendment:

Reduction in the dose increment to the next dose level (based on higher 
exposure than predicted and/or safety data of clinical significance).

Introduction of an additional dose level cohort between the current and 
next planned dose level (based on higher exposure than predicted and/or 
safety data of clinical significance).
CHANGE 7
Reference to protocol Section 5.4 added to text.
Section 9.3.1 Interim Analysis, 4th paragraph, 5th line
REVISED TEXT
PK data will provide supporting evidence for each dose modification decision. 
Importantly, if the emerging PK data is significantly different from the predicted values, 
adjustment may have to be made to the planned doses (see Section 5.4).
CHANGE 8
Reference to current IB updated in Section 1.2.1 GSK2831781, Section 4.2 Eligibility 
Criteria and References.
REVISED TEXT
2013N175515_00 2013N175515_01

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AMENDMENT 5
Summary of Amendment Changes with Rationale
This amendment is to replace 2 Healthy Volunteer cohorts undergoing DTH challenge 
with those without DTH challenge, in order to reduce complexity of study and improve 
operational feasibility.
The opportunity has been taken to make some other changes to correct text that was not 
logistically possible, or required clarification, add flexibility to timing of vaccination, and 
remove limitation in PK assessment due to an improved assay. Additional text has also 
been added to the eligibility criteria in order to meet country specific ethics requirements.
List of Specific Changes
CHANGE 1
Change to indicate change in study design - that the 2 initial DTH cohorts have been 
replaced by no DTH cohorts, including resulting change in subject numbers. 
Synopsis, 2nd paragraph, 2nd and 3rd sentences 
REVISED TEXT
Part A of the study will be a single dose escalation in healthy volunteers. The first 24
cohorts will be given an intravenous (IV) dose of GSK2831781 or placebo over 
approximately 2 hours on Day 1. The latter last healthy volunteer cohorts will receive a 
skin challenge of 2 Tuberculin Unit (TU) or 10TU Purified Protein Derivative (PPD) on 
Day 1.
Section 1.1 Study Rationale, 1st paragraph, 1st ,2nd 4th, 5th sentences
REVISED TEXT
This study is the first administration of GSK2831781 in humans and will evaluate in two 
parts the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and 
immunogenicity of single intravenous (IV) doses of GSK2831781 administered to 
healthy volunteers (Part A ), including  a cohort of those previously vaccinated with 
Bacillus Calmette Guérin (BCG) (Part A delayed type hypersensitivity [DTH] cohorts) 
and patients with plaque psoriasis (Part B). Single dose escalation will allow for the 
identification of any immediate dose-limiting toxicities. Investigation of pharmacology 
in healthy subjects in the Part A DTH cohort will confirm whether the selected dose is
aim to select doses likely to result in pharmacodynamic effects in immune-inflammatory 
diseases associated with the target Lymphocyte Activation Gene 3+ (LAG-3+) T cells, 
which are then tested in Part B. As there are very low levels of LAG-3+ T cells in blood 
it is necessary to monitor LAG-3+ cells at the site of antigen challenge or the disease site. 
The use of a DTH in healthy subjects in Part A allows investigations into the impact of 
GSK2831781 on immunological endpoints after a controlled challenge.  The switch to 
patients with psoriasis in Part B, once a pharmacological effect has been seen, or at a 

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dose by which effects would be expected, then allows investigations of higher doses in a 
chronic disease setting. Measuring the pharmacology of GSK2831781 using the 
depletion of LAG-3+ T cells in skin biopsies from Tuberculin Purified Protein Derivative 
(PPD) skin challenge and lesional skin biopsies from patients with psoriasis, is an 
important component of the study and for the latter may enable an understanding of the 
dose response relationship, which will be important for decision making and the design of 
future studies in immuno-inflammatory diseases, including psoriasis.
CHANGE 2
Changes made to reflect the updated study design and increased screening period from 30 
to 35 days.

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Section 3.1 Study Schematic
REVISED GRAPHIC

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CHANGE 3
Change to indicate change in study design - that the 2 initial DTH cohorts have been 
replaced by no DTH cohorts, including resulting change in subject numbers. 
Section 3.1.2 Study Design Summary, Table 1
REVISED TEXT
Planned 
Doses
Number of 
subjects 
(active:placebo)
Safety Follow-up 
period to progress 
to next 
subjects/cohorts
PPD DTH 
Challenge if 
Healthy 
volunteer/ Biopsy 
if patient
Follow-up and end of 
exclusion of systemic 
immunosuppressives
0.0075mg/kg
6:32
1:1 wait 48 hours 
post-dose
5:21 wait 28 days 
post-dose
No DTH
Day 11385 ± 2 days
(84 days post-dosing)
0.04mg/kg
Day 175147 ± 3 days
(146 days post-dosing)
0.15mg/kg
6:6
1:1 wait 48 hours 
post-dose
5:25 wait 28 days 
post-dose
DTH
Day 219 ± 7 days
(190 days post-dosing)
Note: Cohorts with a DTH starts dosing on Day 29
Maximum dose for healthy volunteers may change based on emerging exposure or earlier reduction in DTH 
response(See Section 3.2.1)
CHANGE 4
Change to indicate change in study design - that the 2 initial DTH cohorts have been 
replaced by no DTH cohorts. 
Section 3.2 Study Design Detail, 3rd paragraph, 2nd sentence
REVISED TEXT
Healthy volunteers will be dosed up to a maximum dose of 0.15mg/kg (unless criteria in 
Section 3.2.1 are met) or until a reduction in DTH response occurs (whichever is sooner).
CHANGE 5
Change made to reflect the increased screening period from 30 to 35 days.
Section 3.2 Study Design Detail, PART A, Healthy volunteers without DTH, Healthy 
volunteers with DTH and PART B, Psoriasis patients, 3rd paragraph

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REVISED TEXT
Subjects will attend screening up to 30 35 days before dosing
CHANGE 6
Change to indicate change in study design - that the 2 initial DTH cohorts have been 
replaced by no DTH cohorts, including resulting change in subject numbers. 
Section 3.2 Study Design Detail, PART A, Healthy volunteers without DTH
REVISED TEXT
In cohorts 1 and 2, one active and one placebo subject will be recruited in each 
cohort.
For cohorts 3 and 4, one active and one placebo subject will be recruited initially. 
After the GSK medical monitor and Investigator have reviewed the safety data up 
to 48 hours post dose, an additional 5 active and 1 placebo subjects will be dosed (no 
more than 2 subjects per day with dosing separated by at least 1 hour).
After the DEC have reviewed the safety data up to 28 days on all subjects within the 
cohort along with the available PK data, a dose escalation may occur to the next planned 
dose. If safety findings are noted in the active subjects in cohorts with 2 subjects, the 
cohort may be expanded to a maximum cohort size of 6:3 (active:placebo) or the 
escalation stopped (See Section 5.5).
CHANGE 7 
Change to indicate change in study design - that the 2 initial DTH cohorts have been 
replaced by no DTH cohorts, including resulting change in subject numbers. 
Section 3.2 Study Design Detail, PART A, Healthy volunteers with DTH, 1st
paragraph
REVISED TEXT
One active and one placebo subject will be recruited initially in each cohort. After the 
GSK medical monitor and investigator have reviewed the safety data up to 48 hours post 
dose, an additional 5 active and 25 placebo subjects will be dosed (no more than 2 
subjects per day with dosing separated by at least 1 hour). Once data up to 28 days post 
dose has been collected for all subjects within the cohort, the DEC will review the safety 
data along with the available PK data, the DTH clinical response data and available PD 
data, before proceeding to the next dose level or switching to patients with plaque 
psoriasis.
CHANGE 8
Change to indicate change in study design

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Section 3.2 Study Design Detail, PART A, Healthy volunteers with DTH, 8th
paragraph, 1st sentence
DELETED TEXT
All subjects in the 0.0075 and the 0.04mg/kg cohorts will attend a surveillance visit at 6 
months and 12 months. 
CHANGE 9
Change to indicate change in study design.
Section 3.2.1 Healthy Volunteer to Patient Switching, 1st,  2nd paragraph 1st and 2nd
sentences
DELETED TEXT/REVISED TEXT
The switch from healthy volunteers to patients with psoriasis will occur when clear 
reduction of DTH response is found on review by the DEC.  Reduction of DTH response 
leading to a decision to switch dosing to psoriasis patients will be defined as at least 3 out 
of 6 subjects on active treatment within a cohort showing an induration response on post 
dosing PPD re-challenge less than or equal to their baseline induration response.   
Switching to psoriasis patients may also occur if a strong trend in inhibition is seen, as 
will be documented in the DEC Guidance/Charter document.  If there is no reduction 
detectable by 0.15mg/kg the switch will occur at this dose.  This will ensure that healthy 
volunteers do not require more than approximately 6 months lifestyle restrictions that is 
required until GSK2831781 plasma concentrations become on average below the in vitro 
EC50 for LAG-3+ T cells depletion (See Section 3.3.2).
If a dose switch occurs earlier than 0.15mg/kg, extra cohorts would be added at the lower 
doses for psoriasis patients so that the starting dose is the same as the last dose used in 
healthy volunteers.  When the decision to switch to psoriasis patients is made, no further 
dosing of healthy volunteers will occur.
CHANGE 10
Change to indicate change in study design.
Section 3.3.1 Design Rationale, 1st paragraph
REVISED TEXT
This study has been designed to be a 2-part study. Firstly, in Part A, a single ascending 
dose escalation will enrol healthy volunteers previously vaccinated with BCG (Part A 
DTH cohorts only) and then Part B will initiate and enrol patients with psoriasis.  
Section 3.3.1 Design Rationale, 2nd paragraph 2nd sentence
The assessment of GSK2831781 pharmacology in healthy subjects is challenging due to 
the low numbers of LAG-3+ T cells in the blood of healthy volunteers which makes the 

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monitoring of the depletion of this cell population technically difficult.  To circumvent 
this issue, the last cohort of Part A of the study will employ a DTH model of a PPD 
intradermal injection, in healthy volunteers previously vaccinated with BCG to induce a 
DTH skin reaction and an increase of LAG-3+ T cells in the skin. 
Section 3.3.1 Design Rationale, 5th paragraph 1st sentence
Proof of pharmacology and mechanism will be tested in healthy subjects up to a dose 
demonstrating reduction of DTH response, or up to 0.15mg/kg (to limit duration of 
exposure above the in vitro EC50 ADCC killing activity) before switching to psoriasis 
patients for further evaluation of pharmacology and mechanism (see Section 3.3.2.3 for 
dose rationale).  
CHANGE 11
Increase in sensitivity of PK assay has made sentence redundant.
Section 3.3.2.1 Human PK Prediction, 1st paragraph, 7th sentence 
DELETED TEXT
Of note, with the current expected limit of quantification of the bioanalytical assay of 100 
ng/mL, plasma concentrations are not anticipated to be measurable at the 3 first doses 
proposed (0.0003, 0.0015 and 0.0075 mg/kg).]
CHANGE 12
Text revised to reflect updated study design.
Section 3.3.2.3 Assessment of GSK2831781 pharmacology in healthy volunteers, 2nd
paragraph
REVISED TEXT
To assess the pharmacology of GSK2831781 in healthy volunteers and confirm the 
findings in the baboon study conducted with the parent molecule IMP731 where a 
depletion of peripheral LAG-3 expressing T cells was associated with an inhibition of a 
DTH response (Poirier et al, 2011), a DTH challenge will be conducted at the 0.0075, 
0.04 and 0.15 mg/kg proposed doses or until a pharmacological effect has been seen (see 
Section 5.4 Planned Dose Adjustments). 
Section 3.3.2.3 Assessment of GSK2831781 pharmacology in healthy volunteers, 5th
paragraph 1st and 2nd sentences
However, reduction of the DTH response could occur at a lower or higher dose. 
Therefore, the decisions to switch to psoriasis patients will be based on demonstration of 
reduction of the DTH response but with  There will be a maximum dose for healthy 
subjects of 0.15mg/kg (dose could be altered dependent on emerging PK data and/or PD 
data), to limit the duration of exposure above the in vitro EC50 ADCC killing activity 

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(where there are lifestyle and medication restrictions), to no more than approximately 6 
months (See Section 3.2.1 and Section 5.4 Planned Dose Adjustments)
CHANGE 13
Vaccine changed to M-M-RVAXPRO as Priorix SPC has the 6 week requirement 
between MMR and PPD.
Section 3.4 Risk Management, Table 5 Summary of Key Issues, Their Impact and 
Strategy to Mitigate Risk – Vaccination section
REVISED TEXT
As per Boostrix-IPV and/or M-M-RVAXPRO Priorix or equivalent SPC.
CHANGE 14
Subject numbers updated to reflect updated study design.
Section 4.1 Number of Subjects, 1st paragraph
REVISED TEXT
Approximately 63 64 subjects will be enrolled to complete dosing and critical 
assessments.  The subject numbers will be split to approximately 31 32 healthy 
volunteers and 32 patients with psoriasis.
CHANGE 15
Text updated to reflect updated study design and addition of anti-Hepatitis B core 
antibody testing to hepatitis B exclusion criteria to support new sponsor guidance for first 
time in human studies of immunosuppressive drugs. Text also added to meet country 
specific ethics requirements.
Section 4.2.1 Inclusion Criteria and Section 4.2.2 Exclusion Criteria
Amend all instances of ‘Part A DTH cohorts’ to ‘Part A DTH cohort’ and ‘Part A (only 
cohorts with DTH challenge)’ to ‘Part A (only cohort with DTH challenge)
ADDED TEXT 
4.2.1 Inclusion Criteria
2. A body weight ≤120 kg and BMI within the range 19 – 32 kg/m2 (inclusive). For 
subjects participating in Germany the BMI must be within the range of 19 – 30 
kg/m2 (inclusive).

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12. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form, and has provided written 
informed consent.
4.2.2
Exclusion Criteria
13. A positive pre-study Hepatitis B surface antigen or Hepatitis B core antibody, or 
positive Hepatitis C antibody result within 3 months of screening.
31. Vulnerable subjects (e.g. person kept in detention).
32. Subjects who are not able to understand and communicate in the native 
language of the country where the study is conducted.
33. Subjects who work for the Sponsor or CRO.
CHANGE 16
Table and text updated to reflect updated study design.
Section 5.3 Treatment Assignment, Regimen table rows 4-6
REVISED TEXT
Regimen
Description
Ratio (Active:Placebo)
C
0.0075mg/kg GSK2831781 IV single dose
23:1
D
0.04mg/kg GSK2831781 IV single dose
23:1
E
0.15mg/kg GSK2831781 IV single dose
21:1 for HV
3:1 for Psoriasis 
patients
CHANGE 17
Text modified to reflect updated study design.
Section 5.4 Planned Dose Adjustments, 3rd paragraph, 1st sentence
REVISED TEXT
For healthy volunteer cohorts, once safety data up to 28 days post-dose has been 
collected in all subjects for that cohort, the DEC will review the safety/tolerability data 
(including trends in neutrophil counts), the available PK data and for the DTH cohorts, 
the clinical DTH response (induration diameter), before proceeding to the next dose level 
(See Section 3.2.1).  

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CHANGE 18
Text added to determine cause of clinical symptoms if required so as not to assume 
clinical symptoms are due to viral reactivation.
Section 5.6.5 Febrile Monitoring Criteria, 2nd sentence
REVISED TEXT
If the subject demonstrates any clinical symptoms consistent with viral reactivation e.g. 
fever, a blood sample will be taken and analysed for viral reactivation and/or other 
appropriate medical investigations as suggested by the clinical context.
CHANGE 19
Text modified to reflect updated study design.
Section 5.10.1 PPD 2TU and 10TU Dose, 1st paragraph, 3rd paragraph 1st sentence
REVISED TEXT
In Part A Healthy volunteers DTH cohorts only
In the Part A DTH cohorts, on Day 1, 0.1ml of PPD 2 TU (0.04 µg/0.1ml) will be 
injected intradermally into the volar aspect of the left forearm and the volar aspect of the 
right forearm.
CHANGE 20
Text added to provide additional clarity regarding immunisations.
Section 5.14 Concomitant Medications and Non-Drug Therapies, 2nd sentence
REVISED TEXT
In those who are likely to require immunisation in the period up to the follow-up visit for 
non-study reasons, such as subjects requiring vaccinations or boosters for their 
professional activity, the administration of any required vaccination/booster should be 
given at least 4 weeks prior to Day 1.
CHANGE 21
Time and Events tables and footnotes revised  to reflect updated study design.
All Time and Events Tables, ECG Footnote
Triplicate. Only required if screening ECG not within 305 days of Day 1.

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Section 6.1 Time and Events Table 7 (Day 8-121) and Footnotes
Out Patient Visits
Day 8
168 hour post-
infusion start
Day 11
Day 15
Day 18
Day 22
Day 25a Day 29k
Day 43
Day 57 l
Day 85 Day 121
-/+1d
-/+1d
-/+1d
-/+1d
-/+1d
-/+1d
-/+1d
-/+2d
-/+2d
-/+2d
-/+3d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
j.
Triplicate.  Only required if screening ECG not within 305 days of Day 1.
k.
Cohort 0.0015mg/kg last out patient visit will be on Day 29.
l.
Cohort 0.0075mg/kg last out patient visit will be on Day 57.
Section 6.1 Time and Events Table 8 Footnotes 
a.
Cohort 0.0075mg/kg last out patient visit will be on Day 85 Triplicate. Only required if screening ECG not 
within 35 days of Day 1.
o.
Triplicate. Only required if screening ECG not within 35 days of Day 1.
Section 6.1 Time and Events Table 10 Footnotes 
a.
When PK is taken in the healthy volunteer DTH cohorts all PK times are relative to the start of the infusion on Day 
29. 

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CHANGE 22
Text added to determine cause of clinical symptoms if required so as not to assume 
clinical symptoms are due to viral reactivation.
Section 6.3.5 Immunosupression, Infection and Malignancies, final sentence
REVISED TEXT
If the subject demonstrates any clinical symptoms consistent with viral reactivation e.g. 
fever, then another sample would be taken and this and the baseline sample sent for 
analysis and/or other appropriate medical investigations as suggested by the clinical 
context.
CHANGE 23
Addition of anti-Hepatitis B core antibody testing to hepatitis B exclusion criteria to 
support new sponsor guidance for first time in human studies of immunosuppressive 
drugs.
Section 6.3.7 Clinical Laboratory Assessments, Other screening Tests, 2nd row
REVISED TEXT
Hepatitis B (HBsAg, HBcAb)
CHANGE 24
Add flexibility to allow timing of vaccination by extending default maximum screening 
period and specifying M-M-RVAXPRO vaccine for MMR.
Section 6.3.8 Vaccination
REVISED TEXT
Subjects who have no history of vaccination for diphtheria, pertussis, and tetanus may 
consent to receive a booster of an appropriate licensed combined vaccine. at least 2 
weeks prior to dosing (If a suitable serology test is available to confirm vaccination 
status then this may be used prior to vaccinating.).
Subjects who have no history of vaccination for measles, mumps and rubella may have a 
serology sample taken to assess levels of antibodies and if necessary may consent to 
receive a booster of an appropriate licensed combined vaccine. consent  to receive a 
booster of an appropriate licensed combined vaccine (M-M-RVAXPRO or similar) at 
least 4 weeks prior to dosing which will be given after serology results are available 
to assess levels of antibodies.  

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It has been reported that live attenuated measles, mumps, and rubella virus vaccines 
given individually may result in a temporary depression of tuberculin skin 
sensitivity (PPD challenge). Therefore, for this study, vaccination using M-M-
RVAXPRO (or similar) should be administered a minimum of 28 days (4 weeks) 
before the first PPD challenge (based on advice in SPC). When a serology sample to 
assess MMR vaccination status is taken, results must be obtained and interpreted 
prior to administering MMR vaccination. If required, MMR vaccination will be 
administered at a separate visit during the screening period.
CHANGE 25
Subject numbers revised to reflect updated study design.
Section 9.2.1 Sample Size Assumptions, 2nd paragraph
REVISED TEXT
It is anticipated that sufficient number of healthy volunteers and patients will be enrolled 
in the study so that data are obtained from approximately 31 32 healthy subjects (20 on 
active, 11 12 on placebo) and approximately 32 psoriasis patients (24 on active, 8 on 
placebo). 
CHANGE 26
Add additional interim analysis after healthy volunteer DTH cohort.
Section 9.3.1 Interim Analysis
REVISED TEXT
Dependant on the dose cohorts reached in the escalation, a formal interim analyses may 
be performed after the last subject in the Healthy Volunteer group has completed their 
4 week post dose assessment visit, and also after the last subject in the Psoriasis 
group has completed the final PK assessment visit, to inform internal development 
decisions. If required, an additional interim analysis for internal development 
decisions may also be performed after the last subject in the Psoriasis group has 
completed their 6 week post dose assessment visit.
CHANGE 27
To confirm final analysis of Part A will be reported when after all subjects in Part A have 
completed their follow-up visit.
Section 9.3.2 Final Analyses
ADDED TEXT
Final analysis of Part A will be reported when after all subjects in Part A have 
completed their follow-up visit. Final analysis for all endpoints will be reported 
when all subjects in all groups have completed their 12 month surveillance visit.

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CHANGE 28
Text revised to meet country specific ethics requirements.
Section 10.2 Regulatory and Ethical Considerations, Including the Informed 
Consent Process, 3rd paragraph
REVISED TEXT
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 1996 
(Germany) and 2008 (UK) Declaration of Helsinki.

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AMENDMENT 4
Summary of Amendment Changes with Rationale
To reinstate eligibility criteria regarding vaccinations at MHRA request, and to enable 
this, to add potential to vaccinate during screening and potential to use serology.
List of Specific Changes
CHANGE 1
Re-instated text due to inclusion #8 being re-instated.
Section 3.4 Risk Management, Table 5, 3rd row
ADDED TEXT
Impact eligibility criteria column
Subjects will need to be vaccinated against infectious agents (Inclusion #8).
CHANGE 2
Potential risk information added relating to vaccinations.
Section 3.4 Risk Management, Table 5
ADDED TEXT
Vaccination 
As per Boostrix-IPV 
and/or Priorix or 
equivalent SPC.
Subjects who are 
ineligible due to 
lack of history of 
vaccinations for 
diphtheria, tetanus, 
pertussis, measles, 
mumps or rubella, 
who consent to 
vaccination may 
only be vaccinated 
in accordance with 
the restrictions for 
these vaccines in 
the SPC. If such 
subjects are unable 
to be vaccinated, 
they will be 
ineligible for the 
study.
As per Boostrix-IPV and/or Priorix 
or equivalent SPC.

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CHANGE 3
Re-instated criteria as per MHRA request with slight amendment to wording for clarity.
Section 4.2.1 Inclusion criteria
8.
Subjects with a history of vaccination for Tetanus, diphtheria, measles, 
pertussis, mumps and rubella.
CHANGE 4
Addition of serology testing and vaccinations if required to support inclusion criteria #8.
Section 6.1 Time and Events Table, Table 6
Protocol Activity
Screeningh
Follow Up
Surveillance Visit
Up to 30 Days prior to 
Day 1
Week Xa
6 monthsb
12 months
Window
-/+14d
-/+14d
Serology to 
confirm 
vaccination 
status (if 
required)
Xi
Vaccination for MMR 
and/or DPT (only if 
required)
Xi
h.
Screening can be longer if vaccinations are required prior to dosing.
i.
See Section 6.3.8 for more details.

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CHANGE 5
Addition of ECG at Day -1 or Day 1 to reconfirm eligibility if screening was greater than 30 days prior to Day 1.  Also extended 
concomitant medications review to include Day -1 for the same reason in Table 7 and Table 9.
Section 6.1 Time and Events Table, Table 7 
Protocol Activity
Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 hour 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25a
Day 
29
Window
-/+1d
-/+1d -/+1d -/+1d -/+1d -/+1d -/+1d
12 - Lead ECG
Xj
X
◄--------------►b
X
X
Concomitant 
Medications
◄-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
j.
Triplicate.  Only required if screening ECG not within 30 days of Day 1.

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Section 6.1 Time and Events Table, Table 8
Protocol Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 3 Day 
28
Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 
hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29 
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 
85 
(Day 
57 
post-
dose)a
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
-/+3d
-/+1d -/+1d -/+1d -/+1d -/+1d -/+1d -/+1d -/+2d -/+2d -/+2d -/+3d
12 - Lead 
ECG
Xo
X
◄-----------►b
X
X
o.
Triplicate.  Only required if screening ECG not within 30 days of Day 1.
Section 6.1 Time and Events Table, Table 9
Protocol Activity Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1 Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
43
Day 
57
Day 
85
Day 
121
Window
-/+1d
-/+1d -/+1d -/+1d -/+1d -/+1d -/+1d -/+2d -/+2d -/+2d -/+3d
12 - Lead 
ECG
Xk
X
◄------------►a
X
X
Concomitant 
Medications
◄-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------►
k.
Triplicate.  Only required if screening ECG not within 30 days of Day 1.

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CHANGE 6
Addition of serology testing if required to support inclusion criteria #8
Section 6.3.7 Clinical Laboratory assessments
ADDED TEXT
Other screening tests
Serology to confirm vaccination status (if required)
CHANGE 7
Addition of details regarding serology testing andvaccinations to support inclusion 
criteria #8.
Section 6.3.8 Vaccination
Subjects who have no history of vaccination for diphtheria, pertussis, and tetanus 
may consent to receive a booster of an appropriate licensed combined vaccine.  (If a 
suitable serology test is available to confirm vaccination status then this may be used 
prior to vaccinating.)
Subjects who have no history of vaccination for measles, mumps and rubella may 
have a serology sample taken to assess levels of antibodies and if necessary may 
consent to receive a booster of an appropriate licensed combined vaccine.  
For further details refer to the SPM.  
CHANGE 8
Replaced template guidance text with investigational product ID.
Section 12.2 Pharmacogenetic research
Replaced [insert the name of the study treatment] with GSK2831781 throughout section.

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AMENDMENT 3
Summary of Amendment Changes with Rationale
This amendment is to remove the inclusion criteria for history of vaccination for tetanus, 
diphtheria, measles, pertussis, mumps and rubella, following a comprehensive assessment 
of the relevance of this criterion based on the mode of action, the risk assessment, 
existing clinical precedence and feasibility. In addition, it is to remove the exclusion of 
subjects from high risk areas for tuberculosis, as the use of the Quantiferon test for latent 
and active TB makes this redundant.
The opportunity has been taken to make some other changes to correct text that was not 
logistically possible, or required clarification.
List of Specific Changes
CHANGE 1
Change made for operational reasons to enable samples to arrive at lab for testing 
following occurrence of clinical signs.
Section 3.4 Risk Management, Table 5, 2nd row
REVISED TEXT
Strategy-monitoring criteria column, 4th paragraph
In addition limited cytokine analysis will be performed within 24 hours of dosing if any clinical signs suggest cytokine 
release syndrome (See Section 6.3.7).
Section 6.3.7 Clinical Laboratory Assessments 4th paragraph
REVISED TEXT
Cytokines for safety assessment may include but are not limited to IL-6, TNFα, IL-8, IL-
1b.  Analysis will be performed within 24 hours of dosing if any clinical signs suggest 
cytokine release syndrome. 
CHANGE 2
Change made following review of risks. Review of other T cell agents targeting specific 
T cells subsets, as well as pre-clinical experiments did not support the need for these 
specific vaccinations as an inclusion criteria to mitigate risk of infections. Additional 
guidance for subjects who may need vaccinations for other reasons, to be reviewed and 
vaccinated prior to study.

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Section 3.4 Risk Management, Table 5, 3rd row
DELETED TEXT
Impact eligibility criteria column, 4th paragraph
Subjects will need to be vaccinated against standard infectious agents (Inclusion #8).
Section 4.2.1 Inclusion Criteria, #8
DELETED TEXT
9.
Subjects with a history of current vaccination for Tetanus, diphtheria, measles, 
pertussis, mumps and rubella.
Section 5.14 Concomitant Medications and Non-Drug Therapies
ADDED TEXT
It is recommended that a subject’s vaccination record and the need for immunisation 
prior to Day 1 should be carefully investigated in all subjects prior to entering the study. 
In those who are likely to require immunisation in the period up to the follow up visit, 
such as subjects requiring vaccinations or boosters for their professional activity, the 
administration of any required vaccination/booster should be given at least 4 weeks prior 
to Day 1.
CHANGE 3
As Quantiferon testing is part of the criteria and can be used for both latent and active 
detection of tuberculosis, exclusion text based on prior location is redundant.
Section 4.2.2 Exclusion Criteria, #2
REVISED TEXT
10. Subjects from a high risk area of the world for tuberculosis or who have history of 
tuberculosis or have close family members with confirmed MTB infection or who 
are positive at screening by Quantiferon testing.
CHANGE 4
Correction to status of pharmacist, to ensure consistency.
Section 5.10 Preparation/Handling/Storage/Accountability, 2nd paragraph
Study treatment must be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study may receive study treatment.  Only authorized 
site staff may supply or administer study treatment.  An un-blinded pharmacist will 
perform the dilutions and preparation of the IV bags for active and placebo subjects.  The 
un-blinded pharmacist must ensure that the blind is maintained.  

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CHANGE 5
Change made to ensure consistent terminology for timing of live vaccine restrictions 
through protocol.
Section 5.14.2.2 Part A and B
REVISED TEXT
Live, attenuated or recombinant vaccine(s) within one month 4 weeks of Day 1 and until 
completion of the follow up visit.
CHANGE 6
Clarification of type of ECG used during infusion, compared to at other times, and 
addition of action on finding of abnormalities.
Section 6.1 Time and Events Table, Table 7 (footnote b), Table 8 (footnote b), 
Table 9 (footnote a)
REVISED TEXT
Continuous 2-lead ECG during infusion. Only significant abnormalities during this time will be databased.
Section 6.3.3 Electrocardiogram (ECG), 3rd bullet
REVISED TEXT

2-lead ECG will be measured continuously during the IV infusion (0-2 hours).  Only 
abnormalities during this time will be databased.  If abnormalities are detected a 
12-lead ECG will be obtained.

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AMENDMENT 2
Summary of Amendment Changes with Rationale
This amendment is to include a test at screening to only allow pre-existing ADA-
subjects to be included in Parts A and B of the study.  This will minimise the potential for 
diluting/confounding a signal of pharmacological or clinical response.  
The opportunity has been taken to make some other changes to correct inconsistencies 
and clarifications for exploratory assays.
List of Specific Changes
CHANGE 1
Repetitive paragraph removed and remaining paragraph reworded to combine healthy 
volunteer and psoriasis patient measures.
Synopsis, 2nd paragraph, last sentence
DELETED TEXT
Safety, delayed type hypersensitivity (DTH) measures, pharmacokinetic (PK) and 
pharmacodynamic (PD) data will be reviewed, after each cohort, by the dose escalation 
committee (DEC) before dose escalation occurs.
Synopsis, 4th paragraph
REVISED TEXT
Safety, delayed type hypersensitivity (DTH) clinical response measures, 
pharmacokinetic (PK) and pharmacodynamic (PD) data will be reviewed, after each 
cohort, by the dose escalation committee (DEC) before dose escalation occurs.
ADDED TEXT
All dosing will be carried out in healthy volunteers and patients with psoriasis who do not 
have pre-existing antibodies to GSK2831781.
CHANGE 2
Paragraph added to provide background on pre-existing ADA findings in pre-clinical 
investigations. 

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Section 1.2.1 Brief Background, GSK2831781
ADDED TEXT
Pre-existing anti-drug antibodies (ADA) that bind GSK2831781 have been noted in 
approximately 10 - 32% and 6 - 45% of sera from healthy and psoriatic human 
subjects respectively.  The relevance of pre-existing ADAs for biotherapeutics in 
general is poorly understood, but they may have an effect on pharmacological and 
clinical parameters (Xue et al, 2013).
CHANGE 3
Addition of exploratory endpoint relating to the functional activity of GSK2831781 to 
bind LAG-3+.
Section 2 Objectives and Endpoints
ADDED TEXT
To evaluate the effect of a single IV dose 
of GSK2831781 in healthy volunteers and 
psoriasis patients on pharmacodynamic 
biomarkers.

Proof of pharmacology biomarker 
endpoints may include, but not limited 
to, the following as data permit:

LAG-3 expression on different 
blood immune cell populations 
including T cells

Transcriptomic profiling to assess 
mRNA levels in peripheral blood

Quantification of LAG-3 mRNA 
in whole blood

Functional activity of 
GSK2831781 to bind to LAG-3+ 
cells and induce Fc3a receptor 
signalling

Antigen specific T cell response

Inflammatory cytokine levels

Free and GSK2831781 bound 
sLAG-3 concentrations

NK cell CD16 receptor occupancy 
in whole blood

NK cell activation marker 
expression in whole blood
CHANGE 4

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Additional text added to clarify that only subjects that do not have pre-existing ADAs 
will be included in the study.  Also, added time window between the first DTH challenge 
and the second DTH challenge to allow flexibility for the site.
Section 3.2 Study Design Detail, 1st paragraph, 2nd sentence
ADDED TEXT
In Parts A and B of the study subjects will be screened for pre-existing ADA status 
and  only subjects who do not have pre-existing ADAs will be randomised.
REVISED TEXT
Healthy Volunteers with DTH
Day 28 to Day 32 - After a period of at least 28 days (-/+ 3 days) from the first 
challenge, subjects will return to the unit and will remain resident in the unit from Day 28 
(-/+ 3 days) until at least 72 hours after dosing.
CHANGE 5
Rationale added regarding the inclusion of ADA- subjects only.
Section 3.3.1 Design Rationale, 9th paragraph
ADDED TEXT
Due to the presence of pre-existing ADA in a variable percentage in sera from both 
healthy and psoriatic human subjects, the initial investigation of GSK2831781 will 
be carried out in ADA negative subjects in Part A and Part B of the study to 
minimise the potential for diluting/confounding a signal of pharmacological or 
clinical response.
CHANGE 6
Change made to rectify an inconsistency in the protocol regarding the time when a 
vaccine may be given prior to the study start.
Section 3.4 Risk Management, Table 5, 3rd row
REVISED TEXT
Strategy-monitoring criteria column, 4th paragraph
Close monitoring of subjects for infections to follow-up visit with targeted surveillance to 
12 months.
Subjects will not be allowed to receive live (attenuated) vaccine within the 4 weeks prior 
to dosing Day 1 or during the study until the end of follow-up.

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CHANGE 7
Change made to rectify an inconsistency in the protocol regarding the time when a 
vaccine may be given prior to the study start.  Addition of exclusion criteria for ADA+ 
subjects.  Also, clarified that #20 and #21 are only required for subjects receiving the 
DTH challenge.
Section 4.2.2 Exclusion Criteria, #1
REVISED TEXT
11. Received live, attenuated or recombinant vaccine(s) within 4 weeks of screening 
(Part A) and within 4 weeks of dosing (Part B) Day 1 or plan to receive a vaccination 
during the study until follow-up.
Section 4.2.2 Exclusion Criteria, #8
ADDED TEXT
j.
Subjects who test positive for pre-existing ADA to GSK2831781 at screening.
Section 4.2.2 Exclusion Criteria, #20 and 21
REVISED TEXT
20. Part A (only cohorts with DTH challenge) only: Use of nicotine patches on the 
arm at screening that would interfere with the injection sites.
21. Part A (only cohorts with DTH challenge) only: Subjects participating, within 
seven days of screening, in recreational sun-bathing, or the use of a sun-bed, on the 
area of the skin from the wrist to the shoulder (inclusive).
CHANGE 8
Amended text to allow screen failure data to be collected to meet the CONSORT 
requirements.
Section 4.4 Screen and Baseline Failures
DELETED TEXT
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to GSK.
ADDED TEXT
Screen failures are defined as subjects who consent to participate in the clinical trial 
but are never subsequently randomized. In order to ensure transparent reporting 
of screen failure subjects, meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required including, but 

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not limited to, Demography, Screen Failure details, Eligibility Criteria, and any 
Serious Adverse Events.
CHANGE 9
Change made to rectify an inconsistency in the protocol regarding the time when a 
vaccine may be given prior to the study start.  
Section 5.14.2.2 Prohibited Medications and Non-Drug Therapies, Part A and B
REVISED TEXT
Live, attenuated or recombinant vaccine(s) within one month of screening Day 1 and 
until completion of the follow up visit.
CHANGE 10
Blood volume increased to allow for extra blood tests due to pre-existing ADA screening 
and any repeated tests required.  As the study takes place over a long duration this is not 
perceived to be a safety risk. 
Section 6 Study Assessments and Procedures
REVISED TEXT
No more than 500 600 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

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CHANGE 11
Inclusion of a sample for pre-existing ADA testing.
Section 6.1 Time and Events Table, Table 6
REVISED TEXT
Protocol Activity
Screening
Follow Up
Surveillance Visit
Up to 30 Days prior to 
Day 1
Week Xa
6 monthsb
12 months
Immunogenicity 
Sample
X
X
CHANGE 12
Inclusion of in vitro LAG-3+ activity blood test.  Also added footnote to confirm when 
weight should be measured to calculate dose required.
Section 6.1 Time and Events Table, Table 7
ADDED TEXT
Protoco
l 
Activity
Base
-line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -
1
Pre-
dos
e
0 
hou
r
2 hour 
post-
infusio
n start
4 hour 
post-
infusio
n start
6 hour 
post-
infusio
n start
12 hour 
post-
infusio
n start
24 hour 
post-
infusio
n start
48 hour 
post-
infusio
n start
72 hour 
post-
infusio
n start
168 
hour 
post-
infusio
n start
Da
y 
11
Da
y 
15
Da
y 
18
Da
y 
22
Da
y 
25a
Da
y 
29
In vitro 
LAG-3+ 
activity
X
X
X
ADDED TEXT
i.
To calculate the correct dose, weight must be measured on Day -1 or Day 1 pre-
dose.
CHANGE 13
Inclusion of in vitro LAG-3+ activity blood test and time window on Day 28.  Also added 
footnote to confirm when weight should be measured to calculate dose required.

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Section 6.1 Time and Events Table, Table 8
ADDED TEXT
Protocol 
Activity
1st 
Challenge
In Clinic Period
Out Patient Visits
Day 
28
Day 29 (Day 1)
Day 30 
(Day 2 
post-
dose)
Day 31 
(Day 3 
post-
dose)
Day 32 
(Day 4 
post-
dose)
Day 
1
Day 
3
Day 
28
Pre-
dose
0
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hours 
post-
infusion 
start
72 hour 
post-
infusion 
start
Day 
36 
(Day 
8 
post-
dose)
Day 
39 
(Day 
11 
post-
dose)
Day 
43 
(Day 
15 
post-
dose)
Day 
46 
(Day 
18 
post-
dose)
Day 
50 
(Day 
22 
post-
dose)
Day 
53 
(Day 
25 
post-
dose)
Day 
57 
(Day 
29 
post-
dose)
Day 
71 
(Day 
43 
post-
dose)
Day 85 
(Day 
57 
post-
dose)a
Day 
113 
(Day 
85 
post-
dose)
Day 
149 
(Day 
121 
post-
dose)
Window
-
/+3d
-/+1d -/+1d -/+1d -/+1d -/+1d -/+1d -/+1d -/+2d -/+2d -/+2d -/+3d
In vitro 
LAG-3+ 
activity
X
X
X
ADDED TEXT
n.
To calculate the correct dose, weight must be measured on Day 28 or Day 29 pre-dose.
CHANGE 14
Inclusion of in vitro LAG-3+ activity blood test.  Also added footnote to confirm when weight should be measured to calculate dose 
required.

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Section 6.1 Time and Events Table, Table 9
ADDED TEXT
Protocol Activity Base-
line
In Clinic Period
Out Patient Visits
Day 1
Day 2
Day 3
Day 4
Day 8
Day -1 Pre-
dose
0 
hour
2 hour 
post-
infusion 
start
4 hour 
post-
infusion 
start
6 hour 
post-
infusion 
start
12 hour 
post-
infusion 
start
24 hour 
post-
infusion 
start
48 hour 
post-
infusion 
start
72 hour 
post-
infusion 
start
168 
post-
infusion 
start
Day 
11
Day 
15
Day 
18
Day 
22
Day 
25
Day 
29
Day 
43
Day 
57
Day 
85
Day 
121
In vitro LAG-3+ 
activity 
X
X
X
ADDED TEXT
j.
To calculate the correct dose, weight must be measured on Day -1 or Day 1 pre-dose.

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CHANGE 15
Included a blood test for serum tryptase if a suspected acute hypersensitivity reaction 
occurs.
Section 6.3.4 Infusion-related Reactions and Hypersensitivity Reactions, 2nd
paragraph
ADDED TEXT
In the event of a suspected acute hypersensitivity reaction a blood sample should be 
taken between 30minutes – 3 hours of the event for serum tryptase analysis.
CHANGE 16
Added further information regarding the ADA testing.
Section 6.7.1 Immunogenicity, Blood Sample Collection
ADDED TEXT
In Parts A and B, only subjects with a negative pre-existing ADA status at screening 
will be included.
Section 6.7.1 Immunogenicity, Sample Analysis
REVISED TEXT
Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a 
validated immunoelectrochemiluminescent (ECL) assays. The assay involves screening, 
confirmation and titration steps (tiered-testing approach). Immunogenicity assays will 
be performed by Clinical Immunology, GSK.  ADAs to GSK2831781 will be 
detected using a validated bridging electrochemiluminescent (ECL) immunoassay. 
This assay will be used both to prospectively define subjects’ pre-existing ADA 
status and to evaluate post-dose ADA responses.  The bioanalytical cut points of 
screening and confirmation for a positive antibody response will be determined 
statistically during ADA assay validation from drug-naive human serum samples.  
Samples will be directly tested in confirmatory ADA assay to define subjects’ pre-
existing ADA status for subject screening if required. An ADA assay involving 
screening, confirmation and titration steps (tiered-testing approach) will be adopted 
for study samples. Confirmed positive samples will be titrated to obtain the titre of the 
anti-GSK2831781 antibodies.  Further antibody characterization may be performed, if 
needed.  Results will be reported at the end of the study.  Samples testing positive for 
anti-GSK2831781 antibodies may be further characterized for the presence of 
GSK2831781 neutralising activity (NAb) using a validated ADCC reporter gene 
assay, if needed.  Details on sample preparation, storage and analysis will be given in the 
SPM.

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CHANGE 17
Added section relating to the in vitro LAG-3+ activity assay.
Section 6.8.7 In Vitro LAG-3+ activity
ADDED TEXT
The functional activity of GSK2831781 to bind to LAG-3+ cells and induce Fc gamma 
receptor 3A signalling may be assessed using the Fc gamma 3A reporter cell assay
CHANGE 18
Changed volume of blood required for PGx due to change in guidelines.
Section 12.2 Pharmacogenetic Research, Study Assessments and Procedures, 2nd
paragraph
REVISED TEXT
In addition to any blood samples taken for the clinical study, a whole blood sample 
(~106ml) will be collected for the PGx research using a tube containing EDTA.

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AMENDMENT 1
Summary of Amendment Changes with Rationale
This amendment is to address the queries raised by the MHRA.
The opportunity has been taken to make some minor administrative changes.
List of Specific Changes
CHANGE 1
Incorrect doses removed from Follow-up box.
Section 3.1 Study Schematic, Healthy Volunteers (DTH) schematic
REVISED TEXT
CHANGE 2
Change made to address comment from MHRA.

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Table 1 Dose escalation/Cohort Structure and Safety review periods, 8th row.
REVISED TEXT
Planned 
Doses
Number of 
subjects 
(active:placebo)
Safety Follow-up 
period to progress 
to next 
subjects/cohorts
PPD DTH 
Challenge if 
Healthy 
volunteer/ Biopsy 
if patient
Follow-up and end of 
exclusion of systemic 
immunosuppressives
Healthy Volunteers
0.0003mg/kg
1:1
1:1 wait 28 days post-
dose
No DTH
Day 29 ± 1 day
(28 days post-dosing)
0.0015mg/kg
Day 43 ± 1 day
(42 days post-dosing)
0.0075mg/kg
6:3
1:1 wait 48 hours 
post-dose
5:2 wait 28 days post-
dose
DTH
Day 113 ± 2 days
(84 days post-dosing)
0.04mg/kg
Day 175 ± 3 days
(146 days post-dosing)
0.15mg/kg
Day 219 ± 7 days
(190 days post-dosing)
Note: Cohorts with a DTH start dosing on Day 29
Maximum dose for healthy volunteers may change based on emerging exposure or earlier reduction in DTH 
response (See Section 3.2.1)
CHANGE 3
Allowance of a phone call to replace the 12 month visit has been removed as per MHRA 
request.  Clarification of why additional 6 month surveillance visit for 0.15mg/kg cohort 
is not required, as per MHRA request.  Removal of incorrect doses from text in ‘Healthy 
volunteers with DTH’ paragraph.

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Section 3.2 Study Design Detail
REVISED TEXT
Healthy volunteers without DTH
All subjects will attend a surveillance visit at 6 and 12 months (a telephone call is 
permitted for the 12 month visit if required).
REVISED TEXT
Healthy volunteers with DTH
All subjects in the 0.003, 0.0015, 0.0075 and the 0.04mg/kg cohorts will attend a 
surveillance visit at 6 months and 12 months (a telephone call is permitted for the 12 
month visit if required). As the follow-up visit is at approximately 6 months (190 days 
post-dose, as per Table 1), subjects in the 0.15mg/kg cohort do not require an 
additional post-dose surveillance visit at 6 months and will only attend a surveillance 
visit at 12 months (a telephone call is permitted for the 12 month visit if required).
CHANGE 4
Change made to address comment from MHRA.
Section 3.2.1 Healthy Volunteer to Patient Switching, 2nd paragraph
REVISED TEXT
If a dose switch occurs earlier than 0.15mg/kg, extra cohorts would be added at the lower 
doses for psoriasis patients so that the starting dose is the same as the last dose used in 
healthy volunteers.  When the decision to switch to psoriasis patients is made, no 
further dosing of healthy volunteers will occur.  If the understanding of EC50 for 
LAG-3+ T cells depletion change and/or emerging PK profiles differs markedly from 
prediction, the maximum dose for healthy volunteers may also change.  If GSK2831781 
exposure is substantially less than predicted the maximum dose into healthy 
subjects would be increased to a dose predicted by the emerging pharmacokinetic 
data to provide a similar exposure as currently predicted at 0.15mg/kg (i.e. a target 
AUC of ~1800µg*h/mL (See Table 2).  If a dose switch then occurs later, psoriasis 
cohorts would start at the last dose used in healthy volunteers.  Details of dose adjustment 
can be found in Section 5.4.
CHANGE 5
Change made for clarity as per MHRA request.

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Section 3.3.1 Design Rationale, 5th paragraph, 2nd sentence
REVISED TEXT
This dose of 0.15 mg/kg might be altered if emerging PK profiles differ markedly from 
predictions (See Section 3.2.1).  
CHANGE 6
Change made for clarity as per MHRA request.
Section 3.3.2.3 Assessment of GSK2831781 pharmacology in healthy volunteers, 5th
paragraph
REVISED TEXT
However, reduction of the DTH response could occur at a lower or higher dose. 
Therefore, the decisions to switch to psoriasis patients will be based on demonstration of 
reduction of the DTH response but with a maximum dose for healthy subjects of 
0.15mg/kg (dose could be altered dependent on emerging PK data and/or PD data), to 
limit the duration of exposure above the in vitro EC50 ADCC killing activity (where 
there are lifestyle and medication restrictions), to no more than approximately 6 months 
(See Section 3.2.1 and Section 5.4 Planned Dose Adjustments).
CHANGE 7
Change made for clarity as per MHRA request.
Section 5.4 Planned Dose Adjustments, 3rd paragraph, last sentence
REVISED TEXT
If emerging PK data departs from prediction, outcomes may also include continuing dose 
escalation in healthy volunteers beyond the maximum of 0.15mg/kg up to a maximum 
duration of exposure above EC50 of approximately 6 months, if there are no other 
safety/tolerability findings or reduction of DTH response (See Section 3.2.1).  
CHANGE 8
Change made to address comment from MHRA.
Section 5.5 Dose Adjustment/Stopping/Monitoring Criteria, 1st and 2nd paragraphs
REVISED TEXT
If one or more subject experiences an Serious Adverse Event (SAE) that can be 
reasonably attributed to GSK2831781, the dose escalation will be temporarily halted and 
no further subject will be dosed until a full safety review of the data has taken place. 
Relevant reporting and discussion with the DEC, (which must include the GSK medical 
monitor), relevant GSK personnel, and with the Ethics Committee and Regulatory 

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Agency will then take place prior to any resumption of dosing.  If following the safety 
review a decision is made to restart dose escalation, this may be allowed after 
approval of a substantial amendment.
If two or more subjects experience a severe or significant non-serious AE that can be 
reasonably attributed to GSK2831781, the dose escalation will be temporarily halted and 
no further subject will be dosed until a full safety review of the study has taken place. 
Relevant reporting and discussion with the DEC (which must include the GSK medical 
monitor), relevant GSK personnel, and with the Ethics Committee and Regulatory 
Agency will then take place prior to any resumption of dosing.  If following the safety 
review a decision is made to restart dose escalation, this may be allowed after 
approval of a substantial amendment.
CHANGE 9
Change made to address comment from MHRA.
Section 5.5 Dose Adjustment/Stopping/Monitoring Criteria
REVISED TEXT
22. Neutropenia (the following must be confirmed by repeat samples): 

If one subject experiences neutrophil count < 1.5 x 109/L for >7 days for the 
first 28 days for the first 2 healthy volunteer cohorts.

If one or more subjects experiences neutrophil count <0.5 x 109/L for >7 days
CHANGE 10
Allowance of a phone call to replace the 12 month visit has been removed as per MHRA 
request.
Section 6.1 Time and Events Table, Table 6 Footnote c.
DELETED TEXT
c.
A telephone call is permitted for healthy volunteers only, if required.

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CHANGE 11
Correction to demographic parameters being collected.
Section 6.2 Demographic/Medical History Assessments, 1st paragraph
REVISED TEXT
The following demographic parameters will be captured: date year of birth, gender, race 
and ethnicity.
CHANGE 12
Removal of viral testing parameters from screening list for consistency with Time and 
Events table.  These tests are taken at baseline and are reflected in the baseline tests list.
Section 6.3.7 Clinical Laboratory Assessments, Other screening tests, 6th row
REVISED TEXT
Other screening tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
FSH and estradiol (as needed in women of non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).
CMV, EBV, HSV, VZV 
Thyroid Function Test
Quantiferon test