A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, Randomised Clinical Trial of GSK2862277 in Patients Undergoing Oesophagectomy Surgery
Phase: PHASE2
Conditions: Lung Injury, Acute and Respiratory Distress Syndrome, Adult
Sponsor: GlaxoSmithKline

2014N197251_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
TFR116341
1
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Placebo Controlled, Double-blind, Multi-centre, Single Dose, 
Parallel Group, Randomised Clinical Trial of GSK2862277 in 
Patients undergoing Oesophagectomy Surgery
Compound Number:
GSK2862277
Development Phase:
IIA
Effective Date:
23-AUG-2016
Protocol Amendment Number:05
SYNOPSIS: GSK2862277 is a fully-human domain antibody (dAb) that potently and 
selectively binds to TNF Receptor 1 (TNFR1) and inhibits signalling. The aims of this 
placebo-controlled study are to evaluate the, safety, tolerability, pharmacokinetics and 
pharmacodynamics of GSK2862277 in patients scheduled to undergo surgical resection 
of oesophageal cancer. There will be two treatment groups comprising one active and one 
placebo arm with approximately 40 patients per arm.
The primary objective of the study will be to evaluate the effect of GSK2862277 on the 
pulmonary vascular permeability in oesophagectomy patients following surgery. A 
number of key secondary endpoints are also included in the study to evaluate the effect of 
GSK2862277 on tissue dysfunction in the lung that may also occur after surgery. A 
single nebulised dose will be used in order to achieve optimal exposure in the lung, the 
initial site of injury.
Subject: Infection, autoantibodies, TNFR1; dAb; Oesophagectomy; Acute Respiratory 
Distress Syndrome; Acute Lung Injury.
Author (s):
 (Fibrosis DPU); 
 (VEO); 
 (Clin 
Immunology); 
 (CPSSO); 
 (Discovery Medicine); 
 
 (Clin Development) 
 (Clinical Statistics); 
 (BPS); 
 (CPMS); 
 (Biopharm Research)
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
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The GlaxoSmithKline group of companies
TFR116341
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N197251_00
2014-MAY-23
Original
2014N197251_01
2014-JUN-02
Amendment No. 1
The amendment was made to correct an error in the study title and to revise the limits on 
exclusion criteria for alcohol consumption.
2014N197251_02
2014-JUL-23
Amendment No. 2
The amendment was made to reduce the upper threshold for AST & ALT liver enzyme 
values for inclusion in the study, as per instruction from the UK competent authority 
(Medicines and Healthcare Regulatory Authority [MHRA]). A change to the QTc 
inclusion criteria was also made to correct an error not previously identified.
2014N197251_03
2014-NOV-16
Amendment No. 3
The amendment was made to account for the possibility of inoperable cases during the 
initial stages of oesophagectomy surgery, where subjects would have to be withdrawn; 
additional time window for dosing; amending randomisation window to up-to 72 hours 
prior to day of surgery. Blood sample aliquots for a translational sub-study clarified, 
materials and methods of dose preparation added as an appendix. Additional 
minor/typographical updates and typographical changes have also been made.
2014N197251_04
2015-FEB-16
Amendment No. 4
The amendment was made to remove the mandatory 1 hour post-dose ECG due to 
concerns over logistics prior to surgery (on the condition that alternative cardiac 
monitoring is in place).  Also, a 24 hour window has been added for the pre-dose 
assessments and a typographical error in exclusion criteria #6 has been amended.  A PK 
sample has also been included if a liver event occurs as this had been omitted in error.  
The opportunity has also been taken to make some other minor amendments.
2014N197251_05
2016-AUG-23
Amendment No. 5
The amendment was made to detail the inclusion of an external expert to the safety 
review team.  The opportunity has also been taken to make some other minor 
amendments.

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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-
hours 
Phone/Cel
l/
Pager 
Number
email
GSK Address
Primary 
Medical 
Monitor
Resp CEDD, GSK Gunnels 
Wood Road, Stevenage, 
Hertfordshire SG1 2NY
Secondary 
Medical 
Monitor
709 Swedeland Road
King of Prussia, PA 19406 
USA
Tertiary 
Medical 
Monitor
Resp CEDD, GSK Gunnels 
Wood Road, Stevenage, 
Hertfordshire SG1 2NY
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): 2014-000643-33
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number TFR116341
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.............................................................................................9
1.
INTRODUCTION....................................................................................................12
1.1.
Study Rationale ..........................................................................................13
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
3.
STUDY DESIGN ....................................................................................................18
3.1.
Study Schematic.........................................................................................18
3.2.
Peri-operative schematic ............................................................................19
3.3.
Discussion of Study Design ........................................................................19
3.3.1.
Design Rationale .........................................................................20
3.3.2.
Dose Rationale ............................................................................20
3.4.
Risk Management.......................................................................................22
4.
STUDY POPULATION...........................................................................................23
4.1.
Number of Subjects ....................................................................................23
4.2.
Eligibility Criteria .........................................................................................23
4.2.1.
Inclusion Criteria..........................................................................23
4.2.2.
Exclusion Criteria.........................................................................24
4.2.2.1.
Criteria Based Upon Medical Histories .......................24
4.2.2.2.
Criteria Based Upon Diagnostic Assessments............25
4.2.2.3.
Other Criteria..............................................................25
4.3.
Screen and Baseline Failures .....................................................................25
4.4.
Withdrawal Criteria and Procedures............................................................26
4.5.
Subject Completion.....................................................................................26
5.
STUDY TREATMENT ............................................................................................27
5.1.
Investigational Product and Other Study Treatment....................................27
5.2.
Treatment Assignment................................................................................27
5.3.
Study Stopping Criteria...............................................................................28
5.4.
Blinding.......................................................................................................28
5.5.
Packaging and Labelling.............................................................................29
5.6.
Preparation/Handling/Storage/Accountability..............................................29
5.7.
Assessment of Compliance ........................................................................30
5.8.
Treatment of Study Treatment Overdose....................................................30
5.9.
Concomitant Medications and Non-Drug Therapies....................................30
5.9.1.
Permitted Medications .................................................................30
5.9.2.
Prohibited Medications and Non-Drug Therapies.........................30
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................31
6.1.
Time and Events Table...............................................................................32
6.2.
Demographic/Medical History Assessments ...............................................36
6.3.
Safety .........................................................................................................36
6.3.1.
Physical Exams ...........................................................................36
6.3.2.
Vital Signs....................................................................................36
6.3.3.
Electrocardiogram (ECG).............................................................37
6.3.4.
GSK2862277 Antibodies (Immunogenicity)..................................37

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6.3.5.
Clinical Laboratory Assessments .................................................37
6.4.
Pharmacokinetics .......................................................................................38
6.4.1.
Blood Sample Collection..............................................................38
6.4.2.
BAL Sample Collection ................................................................38
6.4.3.
Sample Analysis ..........................................................................39
6.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................39
6.5.1.
BAL collection..............................................................................39
6.5.2.
Pharmacodynamic Markers in Serum and BAL............................39
6.5.3.
Disease Biomarkers.....................................................................39
6.6.
Pharmacogenetics......................................................................................40
6.7.
Efficacy.......................................................................................................40
6.7.1.
Transpulmonary Thermodilution ..................................................40
6.7.2.
PaO2 / FiO2 Ratio.........................................................................41
6.7.3.
Pulse Oximetry ............................................................................41
6.7.4.
Oxygenation Index.......................................................................41
6.7.5.
Sequential Organ Failure Assessment (SOFA) score ..................41
6.8.
Clinical assessments of disease progression..............................................42
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, PREGNANCY AND 
MEDICAL DEVICE INCIDENTS.............................................................................42
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................42
7.1.1.
Time period for collecting AE and SAE information......................42
7.1.2.
Method of Detecting AEs and SAEs.............................................43
7.1.3.
Definition of Adverse Events........................................................43
7.1.4.
Definition of Serious Adverse Events...........................................44
7.1.5.
Death Events...............................................................................45
7.1.6.
Prompt Reporting of SAEs to GSK...............................................45
7.1.7.
Regulatory Reporting Requirements For SAEs............................45
8.
DATA MANAGEMENT ...........................................................................................46
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................46
9.1.
Hypotheses and Treatment Comparisons...................................................46
9.2.
Sample Size Considerations.......................................................................47
9.2.1.
Sample Size Assumptions ...........................................................47
9.2.2.
Sample Size Sensitivity................................................................48
9.2.3.
Sample Size Re-estimation..........................................................49
9.3.
Data Analysis Considerations .....................................................................50
9.3.1.
Interim Analysis ...........................................................................50
9.4.
Final Analyses ............................................................................................51
9.4.1.
Safety Analyses...........................................................................51
9.4.2.
Pharmacokinetic Analyses...........................................................51
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................52
9.4.4.
Pharmacodynamic/Biomarker Analyses.......................................52
10. STUDY GOVERNANCE CONSIDERATIONS........................................................52
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............52
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................52
10.2.1.
Urgent Safety Measures ..............................................................53
10.3.
Quality Control (Study Monitoring) ..............................................................53
10.4.
Quality Assurance.......................................................................................53

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10.5.
Study and Site Closure ...............................................................................54
10.6.
Records Retention......................................................................................54
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................55
11. REFERENCES.......................................................................................................56
12. APPENDICES........................................................................................................60
12.1.
Appendix 1: Liver Safety Process ...............................................................60
12.2.
Appendix 2: Pharmacogenetic research .....................................................62
12.3.
Appendix 3: SOFA Score Table..................................................................67
12.4.
Appendix 4: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of Adverse Events and Medical Device Incidents .......................68
12.5.
Appendix 5: Protocol Amendment Changes................................................71
12.6.
Appendix 6 Preparation of Active and Placebo Drug for Dosing..................89
12.6.1.
Dose Preparation for 26mg GSK2862277....................................89
12.6.1.1.
Preparation of placebo dose.......................................90
12.6.2.
Instructions for Transportation .....................................................90

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LIST OF ABBREVIATIONS
µg
Microgram
AE
Adverse Event
ALI
Acute Lung Injury
ALT
Alanine aminotransferase (SGPT)
Anti-HA
Anti-hemagglutinin
ARDS
Acute respiratory distress syndrome
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
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
BAL
Broncho-alveolar lavage
BP
Blood pressure
BUN
Blood urea nitrogen
CI
Confidence Interval
Cmax
Maximum observed concentration 
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacokinetics Modelling & Simulation
CPSSO
Clinical Pharmacology Science and Study Operations
CRF
Case Report Form
CRS
Cytokine Release Syndrome
CV
Coefficient of variance
dAb
Domain antibody
DNA
Deoxyribonucleic acid
DPU
Discovery Performance Unit
DRE
Disease-related event
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ELF
Epithelial Lining Fluid
EVLW
Extra Vascular Lung Water
EVLWI
Extra Vascular Lung Water Index
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FiO2
Oxygen Requirement
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GCS
Glasgow Coma Score
GCSP
Global Clinical Safety and Pharmacovigilence
GEDV
Global end-diastolic volume
GGT
Gamma glutamyltransferase
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen

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HIV
Human Immunodeficiency Virus
HR
Heart rate
HRT
Hormone replacement therapy
IA
Interim analysis
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICU
Intensive Care Unit
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IH
Inhalation
IL
Interleukin
IM
Intramuscular
IRB
Institutional Review Board
ITU
Intensive therapy unit
IV
Intravenous
IVRS
Interactive voice response system
Kg
Kilogram
L
Litre
LPS
Lipopolysaccharide
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
Msec
Milliseconds
NF-κB
Nuclear factor κB
OI
Oxygenation Index
OLV
One Lung Ventilation
PaO2
Partial Pressure of Oxygen in arterial blood
Paw
Mean airway pressure
PD
Pharmacodynamic
PEEP
Positive and expiratory pressure
PGx
Pharmacogenetics
PiCCO
Pulse Contour Cardiac Output
PK
Pharmacokinetic
POD
Post operative day
PTS-DMPK
Platform Technologies and Science - Drug Metabolism and 
Pharmacokinetics
PVPI
Pulmonary vascular permeability index
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)

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SD
Standard deviation
SDS
Safety Data Sheet
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOFA
Sequential Organ Failure Assessment
SRT
Safety review team
SPM
Study Procedures Manual
sRAGE
Soluble receptor for advanced glycation end-products
SVR
Systemic vascular resistance 
SVV
Stroke volume variation
TA
Technical Agreement
TB
Tuberculosis
tmax
Time of occurrence of Cmax
TNF
Tumor necrosis factor
TNFR1
Tumor necrosis factor receptor 1
TNFR2
Tumor necrosis factor receptor 2
Tregs
Regulatory T cells
UK
United Kingdom
US
United States
VILI
Ventilator Induced Lung Injury
vWF
Von Willebrand Factor
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
WinNonlin

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1.
INTRODUCTION
GSK2862277 is a fully-human domain antibody (dAb) that potently and selectively binds 
to TNF Receptor 1 (TNFR1) and inhibits signalling. GSK2862277 is being investigated 
for potential utility in prevention and treatment of Acute Respiratory Distress Syndrome 
(ARDS) and other acute inflammatory conditions by either inhalation (IH) or intravenous 
(IV) routes.
Current experience with selective TNFR1-targetting therapies in humans is limited to 
GSK-sponsored Phase I trials in healthy subjects with GSK2862277 and a predecessor 
molecule known as GSK1995057.  Therapeutic antibodies that bind to TNF-are well 
established in the clinical management of certain chronic inflammatory conditions and 
have also been evaluated in patients with sepsis.  Since sepsis is a common risk factor for 
development of ARDS, experience from these trials is informative to the development of 
TNFR1 antagonists in ARDS patients.  The results of TNF-antibody trials have been 
highly variable with many failing to demonstrate a significant survival benefit [Abraham, 
1997; Abraham, 1998; Cohen, 1996; Bernard, 2014]. In one study (with Etanercept) a 
dose related increase in mortality was observed [Fisher, 1996], whereas others have 
demonstrated a reduction in 28-day all-cause mortality and organ dysfunction [Panacek, 
2004].  Recently, a meta-analysis of fifteen trials evaluating anti-TNF-antibodies in 
sepsis patients [Qiu, 2013] concluded that as a class, anti-TNF-agents produce a 
significant survival benefit in patients with sepsis. We anticipate that by selectively 
antagonising TNFR1, GSK2862277 will mitigate the detrimental effects of TNF-whilst 
sparing or potentiating the beneficial effects of TNF-signalling through the other 
cognate receptor, TNFR2.  Therefore, in contrast to existing pan-TNF signalling 
inhibitors, selective TNFR1 inhibition with GSK2862277 may deliver improved safety 
and efficacy in acute inflammatory conditions such as ARDS.
Multiple experimental approaches have revealed that TNFR1 mediates most of the well 
characterised biological activities of TNF-α. The binding of TNF-α to TNFR1 triggers 
the activation of important transcription factors, NF-κB and AP-1 and caspase proteins 
that mediate inflammation and cellular apoptosis, respectively [Mori, 2006].  
Signalling of TNF-α through TNFR2 is less well characterised and conflicting 
observations in different tissues hamper a clear understanding of this pathway.  More 
recently it is has been suggested that TNFR2 signalling is important in regulating the 
apoptotic activity of TNF-α and in the propagation of survival/proliferation signals in 
neuronal cells [Marchetti, 2004], epithelial cells [Al-Lamki, 2005], and other 
mesenchymal cells [Bluml, 2010]. TNFR2 may also be important in the control of 
inflammation since TNFR2 is expressed on a highly suppressive subset of regulatory T-
cells (Tregs) [Chen, 2008] and adoptive transfer of TNFR2-deficient CD4+ T-cells 
results in more severe inflammation and tissue destruction in the CD4+ T-cell transfer 
model of colitis in mice [Dayer, 2009].
TNFR1 deficient mice are protected against  ventilator-induced lung injury (VILI) and 
acid-induced lung injury due to the absence of TNFR1-mediated death signals that trigger 
alveolar epithelial dysfunction [Patel, 2013], and inflammatory signals that lead to 

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endothelial injury and neutrophil migration [Bertok, 2011]. Interestingly, mice 
genetically deficient in TNFR2 succumb to VILI-induced ARDS and death more quickly 
than wild-type mice, or mice deficient in both receptors 
When administered directly to the lungs of mice challenged with acid instillation or 
ventilation with large tidal volumes, mouse TNFR1-targeting dAbs attenuate the 
subsequent development of pulmonary oedema, arterial hypoxemia, and inflammation 
[Bertok, 2012; Wakabayashi, 2013].  Human TNFR1-targetting dAbs attenuate activation 
of human endothelial cells and inhibit migration and priming of human neutrophils in 
vitro. When administered directly to the lungs of Cynomolgus monkeys and healthy 
human patients via nebulisation, TNFR1-targetting dAbs attenuate the in vivo pulmonary 
inflammation, epithelial injury, and endothelial injury associated with pulmonary 
endotoxin (LPS) challenge [Investigator Brochure GlaxoSmithKline Document Number
2012N147005_02 ; Proudfoot, 2014].
ARDS is a serious condition associated with significant morbidity, mortality and 
healthcare utilisation, for which no effective pharmacologic treatment is available. 
Selectively antagonising TNFR1 with GSK2862277 and sparing or potentiating TNFR2 
signalling may attenuate the inflammation and tissue injury associated with ARDS and 
encourage repair and resolution. If acute treatment with GSK2862277 is well tolerated 
and improves pulmonary physiology, it may lead to improved outcomes and survival in 
ARDS patients.
An initial Phase I study in healthy volunteers has been completed (TFR116343). 
GSK2862277 was administered as single intravenous doses from 0.002 mg/kg to 2.0 
mg/kg or single inhaled doses of 26.0 mg to healthy subjects.  In addition, repeat dosing 
with 2.0 mg/kg IV and 26.0 mg IH in healthy subjects was also performed in this study. 
One subject, who was later shown to have high levels of pre-existing anti-drug 
antibodies, developed symptoms consistent with cytokine release syndrome (CRS), 
which was self-limiting and mild in severity. No SAEs or deaths were reported during the 
study and there were no clinically significant changes in ECGs or vital signs. The 
terminal half-life was approximately 5 hours in serum and 9 hours following IV dosing; 
as expected for a domain antibody. Engagement of pharmacology in humans was 
demonstrated using an ex vivo whole blood TNF-α stimulation assay that measured the 
inhibition of induced IL-8 release. GSK2862277 was shown to be potent in this assay 
with an IC90 of 38,000 pg/mL. Further details can be found in the Investigator Brochure
(GlaxoSmithKline Document Number 2012N147005_02 ).
Overall GSK2862277 was considered to be well-tolerated, with an acceptable PK/PD 
profile to merit further investigation in patients.
1.1.
Study Rationale
Respiratory complications remain a relatively frequent and significant complication 
following oesophagectomy surgery and are associated with a significant risk of mortality. 
The reported incidence of ARDS after oesophagectomy varies substantially by region 
with a range of 13-33% in studies that used the consensus definition for ARDS 
[Schilling, 1998; Schilling, 2001; Tandon, 2001; Paul, 2011]. Analysis of large case 

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series and recent trials in patients undergoing oesophagectomy in the UK indicate that 
between 20-25% of patients develop ARDS post-operatively [Park, 2009; Perkins, 2014]. 
The aetiological heterogeneity and physiological flux often encountered in cohorts of 
ARDS patients makes the conduct of small experimental medicine studies challenging. In 
contrast, patients undergoing oesophagectomy represent a single aetiology where injury 
is more controlled with respect to timing and severity. Numerous physiological and 
biochemical assessments of lung injury can be made during the immediate post operative 
period, some of which are associated with clinical outcome in this cohort [Park, 2009].
The most common surgical approach in patients undergoing resection of oesophageal 
cancer is to perform a transthoracic oesophagectomy. Access to the oesophagus is 
achieved through the deflation of one of the lungs, whilst gas exchange is maintained in 
the contralateral lung using one-lung ventilation (OLV).  Lung deflation may illicit 
ischemic injury and/or reperfusion injury upon re-inflation, whilst the high-inspired 
oxygen concentrations and inflation pressures associated with OLV risk the development 
of VILI [Michelet, 2006].  Lung injury associated with mechanical ventilation is an 
established concept involving direct injury to the alveolar epithelium and pulmonary 
vascular endothelium leading to inflammation, permeability dysfunction and pulmonary 
oedema [Slutsky, 2013]. As a result of these insults, systemic inflammation, increased 
pulmonary vascular permeability, and hypoxaemia can develop in the period immediately 
following OLV [Tsai, 2009; D’Journo, 2010; Perkins, 2014]. High levels of systemic 
inflammation and severe hypoxaemia immediately post-operatively predict progression to 
severe respiratory complications [D’Journo, 2010; Park, 2009] following 
oesophagectomy.
This study will be the first investigation of GSK2862277 in patients and is primarily 
designed to investigate the impact of pre-operative administration of GSK2862277 on 
biological and physiological markers of lung injury in patients undergoing surgical 
resection of oesophageal cancer. A single nebulised dose of GSK2862277 will be 
administered prior to surgery in order to achieve optimal exposure at the site of injury 
following OLV and lung deflation.  This study will test the hypothesis that inhibition of 
TNFR1 signalling during surgery will reduce tissue damage and inflammation in the 
lungs and reduce the severity of both systemic inflammation and post-operative 
complications. It is anticipated that selective blockade of TNFR1 using GSK2862277 will 
attenuate the inflammation and alveolar epithelial and endothelial tissue injury observed 
post-surgery in these patients, whilst encouraging normal resolution and repair processes.
This study will also investigate the safety and tolerability of inhaled GSK2862277 in this 
patient population, and provides for exploration of pharmacokinetics, pharmacodynamics 
and immunogenicity.  The primary endpoint for this study is the change in pulmonary 
vascular permeability index (PVPI) from pre-surgical levels to the end of surgery. This 
physiological endpoint will be measured by single indicator transpulmonary 
thermodilution, using the PiCCO haemodynamic analyser. This technique allows an 
indirect determination of extra vascular lung water (EVLW; mL/kg) that can either be 
indexed to predicted body weight (EVLW Index (EVLWI)), or, for a more specific 
measure of vascular permeability, to pulmonary blood volume (via PVPI).

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Determination of EVLW by single indicator thermodilution correlates closely to actual 
lung water levels in humans and large animal models, is an independent predictor of 
mortality in ARDS and sepsis patients, and has previously been used to assess pulmonary 
oedema in oesophagectomy and other thoracic surgery patients [Brown, 2009; Perkins, 
2014].  Recent clinical investigations into the diagnostic utility of both EVLWI and PVPI 
in patients with ARDS-related pulmonary oedema and cardiogenic pulmonary oedema 
suggests PVPI may be a useful means with which to discriminate between permeability
oedema (due to lung injury) and hydrostatic oedema caused by left-sided heart failure 
[Monnet, 2007]. This is reinforced by clinical trials that show that EVLWI and PVPI 
measures are strongly correlated in ARDS patients and weakly correlated in patients with 
cardiogenic pulmonary oedema [Kushimoto, 2012].
A reduction in PVPI of 15% or more is considered to be meaningful based on the known 
precision of the PiCCO instrument [Monnet, 2011].
A key secondary objective of the trial will be to evaluate the effect of GSK2862277 on 
post-operative hypoxaemia using the ratio of partial pressure of arterial oxygen and 
fraction of inspired oxygen (PaO2/FiO2) at the end of surgery. PaO2/FiO2 is a measure of 
the arterial hypoxaemia that may occur in oesophagectomy patients post-surgery as a 
result of lung injury following OLV and/or lung deflation.  
Previous clinical trials suggest that both PaO2/FiO2 and EVLW measures are sufficiently 
sensitive to reflect changes in underlying pulmonary pathophysiology in response to 
pharmacological interventions.  For example, nitric oxide transiently corrects arterial 
hypoxaemia when delivered directly to the lungs of ARDS patients, which is reflected in 
an approximately 3 kPa increase (20mmHg) in PaO2/FiO2 [Afshari, 2011]. Similarly, a 
single inhaled dose of salbutamol was shown to decrease post-operative EVLW by 
2.3 mL/kg and PVPI by 0.5 units in a thoracic surgery population [Licker, 2008]. 
The expression profiles of biomarkers of inflammation and tissue injury in the ventilated 
versus the collapsed lung could be different at the end of surgery, therefore, subjects will 
be randomised to have broncho-alveolar lavage (BAL) samples taken from either the 
ventilated or collapsed lung to explore the effect of GSK2862277 on biomarkers 
measured in BAL from both ventilated and collapsed lungs.
Finally, patients will be followed up during the rest of their hospital stay to explore 
whether GSK2862277 treatment impacts the development of respiratory and non-
respiratory complications.

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2.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
1.1
Primary: To evaluate whether a single 
nebulised dose of GSK2862277 prevents 
peri-operative lung injury compared to placebo, 
as assessed by measurement of pulmonary 
vascular permeability.

Baseline adjusted change in PVPI 
on completion of surgery
2.1
Secondary: To evaluate whether a single 
nebulised dose of GSK2862277 prevents peri-
operative lung injury compared to placebo, as 
assessed by measurement of pulmonary 
oedema.

Baseline adjusted change in 
EVLWI on completion of surgery 
2.2
Secondary: To evaluate the safety and
tolerability of GSK2862277 administered pre-
operatively.

AEs

Clinical laboratory safety data.

ECG readings

Vital signs
2.3
Secondary: To evaluate whether a single 
nebulised dose of GSK2862277 prevents peri-
operative lung injury compared to placebo, as 
assessed by degree of hypoxaemia

Baseline adjusted change in 
PaO2/FiO2 on completion of 
surgery
2.4
Secondary: To evaluate differences in 
expression profile of BAL biomarkers from both 
ventilated and collapsed lungs immediately after 
surgery 

Levels of BAL biomarkers (e.g. IL-
6, sRAGE, protein levels) on 
completion of surgery.
2.5
Secondary: To evaluate the effect of a single IH 
dose of GSK2862277 compared to placebo, on 
attenuating lung and distal organ injury over the 
post-operative period

Change over time in PaO2/FiO2
post-operatively on Day 2 through 
to Day 4 (as available; SpO2/FiO2
when arterial line removed)

Change over time in PVPI and 
EVLWI post-operatively on Day 2 
through to Day 4

Daily SOFA scores on Day 2 
through to Day 4
2.6
Secondary: To describe plasma 
pharmacokinetics of a single inhaled dose of 
GSK2862277.

Plasma concentrations of 
GSK2862277 and derived 
pharmacokinetic parameters.
2.7
Secondary: To quantify the concentration of 
GSK2862277 in BAL and to compare to plasma 
levels of GSK2862277.

BAL concentrations of 
GSK2862277 and derived 
pharmacokinetic parameters

Ratio of BAL concentration to 
plasma concentration.
2.8
Secondary: To evaluate the levels and 
specificity of any anti-drug antibodies formed 
following dosing with GSK2862277.

Incidence and  titers of serum 
anti-GSK2862277 antibodies post 
dosing

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Objectives
Endpoints
3.1
Exploratory: To evaluate the effect of 
GSK2862277 compared to placebo on clinical 
and patient outcomes.
Further exploratory evaluation of 
effectiveness may be conducted 
where data permit. Endpoints may 
include, but are not limited to:

Diagnosis of ARDS out to day 28; 

28 day survival; 

Ventilator Free Days; ICU & 
hospital length of stay; 

Organ Failure Free Days; 

Haemodynamic assessments 
(e.g. Cardiac Index, Global End 
Diastolic Volume, etc)

Oxygenation Index
3.2
Exploratory: To evaluate changes in TNFR-
related and disease biology biomarkers in the 
blood of patients who have been treated with 
GSK2862277 compared to placebo, on 
completion of surgery and in the immediate 
post-operative period.

Difference from placebo in levels 
of blood and cellular, biomarkers 
(e.g. IL-6  sRAGE) on completion 
of surgery and through to Day 4.

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3.
STUDY DESIGN
3.1.
Study Schematic

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3.2.
Peri-operative schematic
To aid understanding of the flow of events around the time of surgery for each patient, a 
schematic representing an example timeline with key study events is included below:
Timing of events indicated above and location of patients relative to surgery start/finish, 
and dosing events are subject to reasonable deviation as clinically indicated, and may 
differ slightly across participating study centres. See the Time and Events Tables 
Section 6.1 for detailed planned procedure and assessment time points.
3.3.
Discussion of Study Design
The proposed study will be a randomised placebo controlled, double-blind, multi-centre, 
single dose parallel group, design. There will be two treatment groups comprising one 
active and one placebo arm with approximately 40 patients per group. Patients enrolled in 
the study will be scheduled to undergo planned/elective trans-thoracic surgery for 
oesophagectomy. In the previous GSK2862277 FTIH study, one subject who was 
subsequently shown to have high levels of pre-existing anti-HAVH antibodies developed 
a mild infusion reaction following intravenous dosing of GSK2862277.  To further 
mitigate the risk to patients in this trial, all subjects will be pre-screened prior to dosing to 
ensure the absence of any pre-existing antibodies capable of binding to GSK2862277. 
The production of anti-drug antibodies post-dosing will be assessed during the study but 
is not expected to occur after a single inhaled dose of GSK2862277.
The primary objective of the study will be to evaluate the effect of GSK2862277 on the 
development of pulmonary vascular permeability in oesophagectomy patients following 
surgery. A number of key secondary endpoints are also included in the study to evaluate 
the effect of GSK2862277 on tissue dysfunction in the lung that may also occur after 
surgery. A range of biomarkers will be measured to demonstrate GSK2862277 
pharmacology in this patient population in addition to measuring biological responses to 

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injury. Patients will be followed up to explore the effect of GSK2862277 treatment on the 
occurrence of post-operative complications and healthcare utilisation.
3.3.1.
Design Rationale
Delivery of GSK2862277 directly to the lungs of oesophagectomy patients prior to 
surgery may prevent the alveolar epithelial dysfunction brought about by intraoperative
VILI. It is considered that this method of delivery will ensure optimal drug exposure in 
the lung to ensure a robust test of whether local inhibition of TNFR1 is able to attenuate 
the early pathological changes which lead to progression of lung injury.
Patients will be randomized via a central allocation system to receive either GSK2862277 
or placebo as an inhaled (via nebulisation) dose. A single inhaled dose of GSK2862277 
or placebo to match will be administered approximately 1-5 hours prior to the subject’s 
start of (knife to skin) surgery, before the initiation of pre-operative procedures. 
Regular assessments will be conducted until the time of patient discharge. Patients will be 
followed up as outpatients at Day 28 if they have been discharged from hospital before 
that time.
3.3.2.
Dose Rationale
Data from prior clinical pharmacology studies in healthy human patients conducted with 
GSK2862277 and the closely related and pharmacologically comparable molecule 
GSK1995057, establish dose: exposure relationships following inhaled dosing, and 
development of a robust human PK/PD model to support dose selection in patients.
Lung injury in patients undergoing oesophagectomy may occur during surgery (peri-
operatively) as a result of OLV and/or during the immediate post-operative period when 
patients receive intensive care. This is reinforced by the observation that physiological 
markers of lung injury (e.g. PVPI and PaO2/FiO2) are most elevated immediately after 
completion of surgery, and the development of clinical ARDS occurs immediately post-
operatively (within 72 hours of surgery), with the majority of cases reported 24-48 hours 
after completion of surgery. Increases in systemic inflammation also peak immediately 
after completion of surgery, with a suggestion that TNFR1 signalling (as reflected by IL-
6 and IL-8 levels) begin to wane after this time point [Perkins, 2014].   It is anticipated 
that attenuation of TNFR1 signalling in the lungs of patients peri-operatively will prevent 
damage to the lung during OLV and reduce subsequent systemic inflammation in the post 
operative phase. 
Given the potential for VILI and alveolar epithelial dysfunction peri-operatively, 
achieving sufficient exposure at the alveolar epithelial lining of the lung during this 
period (first 24 hours) is considered crucial to protecting against peri-operative lung 
injury. Delivering GSK2862277 directly to the lungs is also preferred in this patient 
population given the potential for blood loss, haemodilution, and volume expansion 
during surgery. Experience with healthy subjects suggests that GSK2862277 can be 
efficiently delivered to human lungs by nebulising an aerosol optimised for delivery to 
peripheral airways.

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In summary, this study will investigate the effect of a single nebulised dose on peri-
operative lung injury, and the development of systemic inflammation and other 
complications in the post-operative period.  GSK2862277 will be administered as an 
orally inhaled aerosol over approximately 3 to 5 minutes. 
The proposed dose for this study is 26 mg via nebulisation. The resulting exposure within 
the lung compartment is expected to be maintained at greater than that required to inhibit 
90% of TNFR1 signalling (IC90 based on IL-8 inhibition in various human cell systems).  
In a previous study in healthy volunteers who also received nebulised endotoxin (LPS), 
lung levels (derived from lavage) 7 hours post dose were approximately 40 µg/mL in the 
epithelial lining fluid (ELF). Therefore with elimination half-life estimated to be in the 
region of 5-9 hours it is predicted that concentrations above IC90 will be maintained for at 
least 24 hours. Although peak exposures will be significantly above that predicted to be 
required for efficacy (>IC90), consideration also needs to be given to the significant 
variability between individual exposures (40% CV on AUC between patients at 26 mg), 
increased levels of TNF-that may alter the potency of GSK2862277, and also the 
potential for dilution due to fluid in the lungs (oedema). This single inhaled dose is 
expected to achieve and maintain sufficient inhibition to enable exploration of the effects 
of TNFR1 inhibition within the lungs taking all these pharmacological and practical 
considerations into account.

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3.4.
Risk Management
Table 1
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk
Summary of data
Impact- eligibility 
criteria
Strategy-
monitoring/stopping 
criteria
Pre-existing anti-
framework antibodies 
present in humans 
may interact with 
GSK2862277 
causing TNFR1 
activation and 
cytokine release in 
vivo.
One subject enrolled in 
the FTIH trial 
experienced mild, self-
limiting symptoms 
consistent with cytokine 
release syndrome after 
receiving 2mg/kg IV 
dosing GSK2862277 
for 5 days.  The subject 
was found to have high 
titres of pre-existing 
anti-framework 
antibodies.
Exclusion of patients 
with pre-existing 
antibodies to 
GSK2862277.
Screening for pre-
existing antibodies. 
Based on known 
pharmacological 
class effects, 
potential for impact 
on host immunity.
No infections attributed 
to treatment with 
GSK2862277 noted in 
clinical trials to date.
Exclusion of patients 
with a positive 
QuantiFERON-TB 
Gold test at screening 
for mycobacterium 
tuberculosis. 
Exclusion of patients 
who screen positive 
for Hepatitis B or 
Hepatitis C.
Exclusion of patients 
who are known to be 
HIV positive.
Patients will be 
monitored for signs of 
infection during dosing 
and throughout follow-
up within the hospital.
Risk of impact to 
vaccine efficacy and 
safety of live or 
attenuated vaccines.
No data available.
Patients having 
received any type of 
vaccination within 3 
weeks of scheduled 
surgery or are 
expected to be 
vaccinated before the 
end of the study (Day 
28).
Ensure no actual or 
planned vaccine 
administration as part 
of routine study visit
assessments.

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4.
STUDY POPULATION
4.1.
Number of Subjects
Sufficient patients will be enrolled such that approximately 80 patients complete dosing 
and critical assessments.
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 Investigator Brochure 
(GlaxoSmithKline Document Number 2012N147005_02 ).
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.
4.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1.
Subject has a planned elective transthoracic oesophagectomy
2.
Male or female between 18 and 80 years of age inclusive, at the time of signing the 
informed consent.
3.
Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form.
4.
A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented 
tubal ligation or hysterectomy; 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 will be required to use one of the 
contraception methods listed in the appendix of this concept protocol 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 enrollment.  For most 
forms of HRT, at least 2-4 weeks should 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 without use of a contraceptive method.

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5.
Liver parameters according to the thresholds below: AST and ALT < 3xULN; 
alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
6.
QTcB or QTcF 450 msec at screening
o
Either QTcB or QTcF, machine or manual over-read can be used. This applies to 
both males and females. The QT correction formula used to determine inclusion 
and discontinuation for an individual subject should be the same throughout the 
study.

Based on average QTc value of triplicate ECGs obtained over a brief recording 
period.
It is recognised that in some subjects the QTc may be variable over time (e.g. intermittent 
use of a pacemaker; junctional rhythm). Inclusion of these subjects should be discussed 
with the medical monitor prior to enrolment.
4.2.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Positive screening test for pre-existing antibodies that bind GSK2862277.
2.
Current evidence or history of pneumonia within 14 days before dosing.
3.
Diagnosis of chronic respiratory disease with a forced expiratory volume in one 
second (FEV1) less than 50% predicted or resting oxygen saturations of less 92%.
4.
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.
5.
The subject has received an investigational product within the following time period 
prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the 
duration of the biological effect of the investigational product (whichever is longer). 
6.
Use of corticosteroids (IV, oral or IM) at a dose of > 10 mg/day prednisolone (or 
equivalent) within 14 days prior to dosing, or anti-Tumor Necrosis Factor (anti-
TNF) or anti-Interleukin-1 (anti-IL1) within 60 days prior to dosing.
4.2.2.1.
Criteria Based Upon Medical Histories
7.
History or current evidence of clinically significant renal disease, diabetes 
mellitus/metabolic syndrome, hypertension, peripheral vascular disease or any other 
clinically significant respiratory, cardiovascular, neurological, endocrine, or 
hematological abnormalities that are uncontrolled on permitted therapy. Significant 
is defined as any disease that, in the opinion of the Investigator, would put the safety 
of the patients at risk through study participation, or which would affect the safety 
analysis or other analysis if the disease/condition exacerbated during the study. 

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8.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
9.
History of regular alcohol consumption within 6 months of the study, defined as:

an average weekly intake of >28 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits.
4.2.2.2.
Criteria Based Upon Diagnostic Assessments
10. Screens positive for Hepatitis B surface antigen, Hepatitis C antibody 
11. Known Human Immunodeficiency Virus (HIV) positive; testing will be conducted in 
accordance with local procedures
12. Tests positive for Mycobacterium tuberculosis using QuantiFERON Gold Test.
4.2.2.3.
Other Criteria
13. Subject has received a live attenuated vaccine(s) within 3 weeks of randomisation or 
will require vaccination with a live attenuated vaccine prior to the end of the study 
(Day 28).
14. Unwillingness or inability to follow the procedures outlined in the protocol.
15. Subject is mentally or legally incapacitated.
4.3.
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation and will 
be transmitted to GSK.
A screen failure is defined as any subject who has been assigned a subject identifier, but 
does not continue in the study beyond Visit 1 (screening) or any subject who completes 
Visit 1 but is subsequently found to be ineligible for the study based on findings from 
laboratory or any other screening test conducted at Visit 1.
Additionally, if a subject completes written informed consent and experiences a serious 
adverse event (SAE) in the time period between completing written informed consent and 
the planned Visit 1 date, the subject will be assigned a subject identifier and classified as 
a screen failure.
The interactive voice response system (IVRS) used to track study enrolment will be 
notified and at a minimum the following information will be collected in the eCRF for 
screen failures:

Date of screening visit

Subject identifier

Demographic information, including race, age and gender

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
Inclusion/exclusion criteria

Reason subject failed screening Serious Adverse Events information, if applicable, 
for any SAE that occurred in the time period between completing written informed 
consent and planned Visit 1 date.
4.4.
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.
In some cases, a subject may be randomised to the study and surgery initiated, but 
subsequently halted due to a decision being made that the case is in fact inoperable. In the 
event of an open and shut case subjects will be withdrawn from the study by the 
investigator. As the subjects will have received a dose of study dose prior to surgery, 
every effort should be made to complete as many safety and PK procedures as possible 
prior to hospital discharge and the Day 28 assessments.
Should a subject fail to attend the clinic for their final Day 28 visit, the site should 
attempt to contact the subject and re-schedule the missed visit as soon as possible. In 
cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject (3 telephone calls and if necessary a certified letter to the subject’s last known 
mailing address) so that they can appropriately be withdrawn from the study. 
These contact attempts should be documented in the subject’s medical record. Should the 
subject continue to be unreachable, then and only then will he/she be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other 
patients withdrawing from the study, an alternative reason for discontinuation should be 
recorded in the eCRF.
4.5.
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.
Once subjects have completed the study they will return to normal standard of care 
treatment for a patient with oesophageal cancer.

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5.
STUDY TREATMENT
5.1.
Investigational Product and Other Study Treatment
Study Treatment
Product name:
GSK2862277
Placebo/Diluent to Match 
IH GSK2862277
Reconstitution Fluid for IH 
GSK2862277
Formulation 
description:
The GSK2862277 
drug product is 
formulated with 
sucrose, glycine, 
sodium dihydrogen 
phosphate, and 
polysorbate 801
Placebo/Diluent to Match 
IH GSK2862277is 
formulated with sucrose, 
glycine, sodium 
dihydrogen phosphate, 
and polysorbate 80 in 
Water for Injection1
Reconstitution Fluid for IH 
GSK2862277is 
formulated with 
polysorbate 80 in Water 
for Injection
Dosage form:
Lyophile for 
reconstitution for 
inhalation
Solution for inhalation
Not applicable
Unit dose 
strength(s)/ 
Dosage level(s):
40 mg/vial.
26 mg.
Volume to match active 
dose.
Not applicable
Route/
Administration 
Duration:
Inhalation
Nebulised solution.
Duration of 
nebulisation will be 
approximately 3-5 min.
To match active
Not applicable
Dosing 
instructions:
Patients single dosed.
To match active
Not applicable
Physical 
description:
White to off-white, 
uniform lyophilized 
cake.
A clear, colorless to pale 
yellow liquid.
A clear, colorless to pale 
yellow liquid.
Device:
Pari eFlow with s30 
mesh (article number 
678G2003)
Pari eFlow with s30 mesh 
(article number 
678G2003)
Not applicable
Manufacturer/
source of 
procurement:
Drug product – GSK, 
Parma
Device – Pari Pharma
Placebo/Diluent to Match 
IH GSK2862277 – GSK, 
Parma
Device – Pari Pharma
GSK, Parma
1In addition to the excipients listed, sodium hydroxide is added to adjust the pH
5.2.
Treatment Assignment
Patients will be assigned to receive either ventilated or collapsed lung BAL procedure 
and either active drug or placebo via nebulisation in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.

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As data emerge during the interim analyses, flexibility to change remaining subject 
randomisation of the BAL procedure to only either the collapsed or ventilated lung will 
be retained.
5.3.
Study Stopping Criteria
If any trends or unexpected increases in safety signals are observed, which in the 
Investigator’s opinion, are of greater intensity, frequency, or duration than expected for 
the patient group under investigation, the GSK Medical Monitor should be notified as 
soon as possible. If the Investigator and GSK Medical Monitor consider that there is a 
reasonable possibility that the event was related to treatment with the investigational 
product, the study may be put on-hold until all available safety data from the study has 
been reviewed.
Two interim reviews are planned during the course of the study at which emerging safety 
data will be formally reviewed:
Interim analysis #1: Unblinded safety review after approx 10 patients have 
completed Day 7 visit; roughly 5 per arm.
The principal objective will be to determine whether there are any clear safety signals 
that would preclude continuation of the study.
Unless there are safety concerns recruitment into the study may continue whilst interim 
analysis 1 is being performed.
Interim analysis #2: Unblinded safety review and futility analysis after approx (40 
patients have completed Day 7 visit; roughly 20 per arm.)
Although interim analysis #2 is scheduled to occur after approximately 20 patients per 
arm have been recruited and completed the Day 7 study visit, it is possible that 
recruitment rates may be lower than anticipated in which case the interim analysis may 
occur after a fixed time with whatever data are available. 
The same set of safety outputs as interim analysis #1 will also be reviewed.
Unless there are safety concerns, recruitment may continue whilst interim analysis #2 
data are collected and the analysis performed. At completion of interim #2 the study may 
be stopped for futility if there is no evidence for a positive effect of GSK2862277 across 
study endpoints. . The RAP will contain further details and operating characteristics of 
the futility component of Interim analysis #2.
5.4.
Blinding
This will be a double-blind (sponsor unblind) study. The investigator and subject will be 
blinded. GSK staff (the sponsor) will not be blinded. At least one site pharmacist (at each 
site) will not be blinded to study treatment in order to enable preparation of each patient’s 
dose. See Section 5.6 for further details.

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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, but without revealing the treatment assignment of the 
unblinded subject, unless that information is important for the safety of patients currently 
in the study. The date and reason for the unblinding must be fully documented in the 
appropriate data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may 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.
5.5.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
5.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2862277 and 
reconstitution will be detailed in Section 12.6 and the Study Procedures Manual (SPM).
Unblinded pharmacists at each clinical site are a necessary requirement to enable 
preparation of study treatment, but other site staff including the investigator and study 
patients will remain blinded to study treatment.
Study treatment must be dispensed or administered according to procedures described in 
the TA.  Only patients enrolled in the study may receive study treatment.  Only 
authorized site staff may supply or administer study treatment.  All study treatment must 
be stored in a secure area with access limited to the investigator and authorized site staff.  
Storage instructions for all study treatments supplied by GSK (including active drug 
product as well as prepared solutions) are provided in the TA. 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 and returned to GSK, or 
destroyed locally, as appropriate and the amount administered to patients. The required 

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accountability unit for this study will be per individual 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 unintentional occupational exposure. In the event of unintentional occupational 
exposure notify the monitor, medical monitor and/or study manager.  A Safety Data 
Sheet (SDS)/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.
5.7.
Assessment of Compliance
When patients 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.
5.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2862277 over and above the initial 26 mg IH dose 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.
5.9.
Concomitant Medications and Non-Drug Therapies
5.9.1.
Permitted Medications
All medications that are required by the patient will be allowed.  All concomitant 
medications should be recorded in the CRF.
5.9.2.
Prohibited Medications and Non-Drug Therapies
No medications will be prohibited.

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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, Serum/plasma biomarkers, immunogenicity assessments 
may be altered during the course of the study based on newly available data to ensure 
appropriate monitoring. The change in timing or addition of time points for any planned 
study assessments must be 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 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 500 mL of blood will be collected over the 
duration of the study, including any extra assessments that may be required.
It is recognised that assessments and procedures not specifically listed as part of this 
protocol may be performed as part of standard of care according to local practices.

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6.1.
Time and Events Table
Table 2
Time and Events Table (Screening)
Procedures
Screening (7 to 28 days inclusive prior to 
surgery)4
1.
Rest the subject in a supine or semi-recumbent position for at least 5 
min and then take three measurements 5 minutes apart. 
2.
HIV testing dependent on local practice
3.
If repeat screening is required previous results from ADA screening 
and Quantiferon-GOLD testing can be used for up to 60 days.
4.
In case of repeat screening, screening can occur less than 7 days prior 
to dosing if ADA and Quantiferon results are available.
5.
Can occur any time during the study after eligibility is confirmed and
consent provided
Informed Consent
X
Demography
X
Medical History
X
Smoking Status & History
X
Quantiferon-GOLD for TB3
X
HepB, HepC, HIV testing2
X
Inclusion/Exclusion Criteria
X
Concomitant Medication
X
Physical Examination
X
Vital Signs
X
12-lead ECG1
X
Serious Adverse Events
X
Clinical Labs including Haematology and Chemistry
X
Pre-existing ADA screening3
X
Pharmacogenetics (PGx) sample5
X
IVRS
X

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Table 3
Time and Events Table Day 1
Pre-dose4
0 h1
1 h
Immediately 
prior or at 
start of 
surgery
On 
completion 
of surgery
1.Dosing may occur 1-5 hours prior to surgery
2.Randomisation & associated IVRS activities may be 
conducted up-to 72 hours prior to administration of study 
treatment (can be longer on agreement with the sponsor for 
extenuating circumstances e.g. bank holiday weekends).
3.Only applicable at designated sites. Can be taken at screening 
if required.
4.Can be taken up to 24 hours prior to dosing
5.If 12 lead ECG is not available, monitoring by 3 lead 
ECG/telemetry (or similar) is acceptable
NB: Time points (except pre-dose) refer to post-start of drug 
administration on Day 1.
Pre-dose is defined as the time from admission to hospital up to 
the administration of study treatment.
Randomisation
X2
Brief Physical Examination
X
Concomitant Medication
X
IVRS
X2
Vital Signs
X
X
12-lead ECG
X
X5
Adverse Events
X
Serious Adverse Events
X
Clinical Labs including Haematology and 
Chemistry
X
Blood sample for immunogenicity
X
Blood sample for PK
X
X
X
Blood sample for urea and total protein
X
Blood samples for translational sub-study3
X
X
Sample for Urinalysis
X
Blood sample for serum biomarkers
X
X
Nebulised (IH) Study Treatment
X
Transpulmonary thermodilution
X
X
P/F Ratio:

Arterial blood sample

Record FiO2
X
X
Measure SpO2 using pulse oximetry
X
X
BAL Sampling
X

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Table 4
Time and Events Table (Days 2 to 28)
Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
1.
If discharged before Day 8 take blood and 
urine samples on day of discharge
2.
PVPI will be measured via single-indicator 
transpulmonary thermodilution as long as 
the subject remains in the ICU with a patent 
indwelling PiCCO catheter, up to Day
3.
Sequential Organ Failure Assessment 
(SOFA) Score will only be calculated up to 
Day 4.
4.
If no arterial blood sample calculate MAP 
using equation: 2X diastolic blood pressure 
+ systolic blood pressure. Then divide by 3.
5.
Only applicable at designated sites
6.
Sample to be taken 24 to 26 hours post-
dose of study treatment.
7.
Sample to be taken 46 to 50 hours post-
dose of study treatment.
Day 
2
Day 
3
Day 
4
Day 
81
Concomitant Medication
X
X
X
X
X
X
IVRS
X
X
Transpulmonary thermodilution2
X
X
X
P/F Ratio 

Arterial blood sample (as available)

Record FiO2
X
X
X
Measure SpO2 using pulse oximetry
X
X
X
Additional SOFA Components3

Glasgow Coma Score (GCS)

Record Mean Arterial Pressure4 or 
administration of vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
X
X
X
Vital Signs
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
Clinical Labs including Haematology and Chemistry
X
X
X
X
Blood sample for serum biomarkers
X
X
X
X
Blood samples for translational sub-study5
X
Blood sample for Immunogenicity
X
X
Blood sample for PK
X6
X7
Sample for Urinalysis
X

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Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
8.
Organ Failure Free Days needs to be 
recorded every day until Day 28 (See SPM).
Day 
2
Day 
3
Day 
4
Day 
81
Organ Failure Free Days
X8
ARDS diagnosis status
X
Ventilator Free Days
X
ICU & Hospital Length of Stay
X
Survival
X

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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 (pack-years), medical conditions will also be 
assessed at baseline. More information will be provided in the SPM.
6.3.
Safety
Planned time points 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.
Information regarding surgery and blood product administration will also be captured if 
applicable. More information will be provided in the SPM.
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner.   The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety.  
The SRT for this project will review data from this study in collaboration with an 
independent external (to GSK) expert reviewer.
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).
6.3.2.
Vital Signs
Vital sign measurements to be measured in a semi-recumbent or supine position (after 5 
minutes rest if time point is an outpatient visit) will include systolic and diastolic blood 
pressure, pulse rate, temperature and respiratory rate.

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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, RR and QTc intervals.
At the 1 hour post-dose time point monitoring by 3 lead ECG/telemetry (or similar) is 
acceptable if 12 lead ECG is not available.
6.3.4.
GSK2862277 Antibodies (Immunogenicity)
Blood samples for testing antibodies against GSK2862277 will be collected at the time 
points indicated in the Time and Events Tables. The actual date and time of each blood 
sample collection will be recorded.
6.3.5.
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 
Quest. 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 clinically 
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 Section 12.4.
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
Haemoglobin
Eosinophils
Haematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose
Total CO2
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase

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Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other screening tests
HIV (tested in accordance with local practise)
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C 
antibody Chiron RIBA immunoblot assay (or other third generation immunoassay) should be 
reflexively performed on the same sample to confirm the result) 
FSH and estradiol (as needed in women of non-child bearing potential only)
Quantiferon GOLD for assessment of TB
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 72 hours after the last dose of study treatment 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.
6.4.
Pharmacokinetics
6.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK2862277 will be collected at the time 
points indicated in Section 6.1, Time and Events Tables.  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 Study Procedures 
Manual (SPM).
6.4.2.
BAL Sample Collection
BAL samples for PK analysis of GSK2862277 will be collected at the time points listed 
in the Time and Events Table. Details of BAL sample collection, processing, storage and 
shipping procedures are provided in the SPM.
GSK2862277 concentration in BAL will need to be corrected for dilution using urea 
concentration as a correction factor to estimate the volume of ELF removed via the 
lavage. A plasma sample taken at the same time as the BAL, or as soon as practically 
possible, will be used to determine the plasma urea concentration which will then be used 
with the BAL urea concentration to determine the dilution factor.
Where: Dilution factor = urea(plasma)/urea(BAL).

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6.4.3.
Sample Analysis
Sample analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the Study Procedures Manual.
Concentrations of GSK2862277 will be determined in samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site 
(detailed in the SPM).
Once the sample has been analyzed for GSK2862277 any remaining sample volume may 
be analyzed for other compound-related metabolites and the results reported under a 
separate PTS-DMPK, GlaxoSmithKline protocol.
6.5.
Biomarker(s)/Pharmacodynamic Markers
6.5.1.
BAL collection
Bronchoscopy and brochoalveolar lavage (BAL) will be performed in accordance with 
the site standard procedures at times outlined in Section 6.1, Time and Events Tables. 
These standard procedures will reflect current standards of practice in hospital care and 
will include (but are not limited to) the following items:

Bronchoscopy will only be performed by an appropriately qualified member of staff.

The Bronchoscopist will be assisted by suitably qualified staff.

Oxygen supplementation will be given to all subjects. Further details on these 
procedures are in the SPM. 

Low volumes of fluid will be used compared to a standard lavage (See SPM for 
details).
6.5.2.
Pharmacodynamic Markers in Serum and BAL
Samples will be collected to determine concentrations of biomarkers in serum and BAL 
(these may include but are not limited to sTNFR1 and IL-6) using an appropriately 
validated assay. Samples will be collected at times outlined in Section 6.1, Time and 
Events Tables.  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. Details on sample preparation, storage and analysis will 
be given in the SPM.
6.5.3.
Disease Biomarkers
Blood and BAL sample(s) will be collected during this study and may be used for the 
purposes of measuring biomarkers to identify factors that may influence the development 
of ARDS in patients undergoing surgery for oesophageal cancer, and/or medically related 
conditions, as well as the biological and clinical responses to GSK2862277.  If relevant, 
this approach will be extended to include the identification of biomarkers associated with 
adverse events.

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Samples will be collected at the time points indicated in Section 6.1, Time and Events 
Tables. The timing of the collections may be adjusted on the basis of emerging PK or PD 
data from this study or other new information in order to ensure optimal evaluation of the 
biomarker endpoints.
Candidate biomarkers and subsequently discovered biomarkers of the biological response 
associated with the development of ARDS or medically related conditions and/or the 
action of GSK2862277 may be identified by application of:

Detection of protein endpoints in serum and BAL by immunoassay and/or equivalent 
alternative technologies (these may include but are not limited to vWF and sRAGE).

Total protein determination in plasma for protein permeability analysis 

Cellular assays and RNA analysis
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
6.6.
Pharmacogenetics
With the subject’s consent, blood samples will be obtained for pharmacogenetics (PGx) 
analysis. Information regarding PGx research is included in Section 12.2. The 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 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.
6.7.
Efficacy
6.7.1.
Transpulmonary Thermodilution
Measurement of PVPI and EVLWI
Extravascular lung water (EVLW) refers to the fluid within the lung but outside the 
vascular compartment. It includes extravasated plasma, intracellular water, lymphatic 
fluid, and surfactant.
EVLW will be measured by trans-pulmonary thermodilution via a PiCCO haemodynamic 
monitor.
PVPI is a derived value from EVLW, and is considered to be less variable than EVLWI 
alone. Further details can be found in the SPM.
Other supportive parameters from the PiCCO monitor that are calculated at the same time 
as EVLW and PVPI, may also be databased e.g. GEDV, SVV, SVR, HR etc.

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6.7.2.
PaO2 / FiO2 Ratio
Oxygenation and function of gas exchange will be assessed by the comparison of partial 
pressure of oxygen arterially (PaO2) divided by the fraction of oxygen that is being 
inspired (FiO2), sometimes referred to simply as the ‘P to F ratio’. The P to F ratio will be 
assessed at time points during the period of intubation and mechanical ventilation.
An arterial blood sample is required for determination of the partial pressure of oxygen 
and the percentage of O2 which is being inspired should be recorded at the corresponding 
time point. Further details can be found in the SPM.
6.7.3.
Pulse Oximetry
SpO2 will be collected using pulse oximetry.  This will be used to calculate SOFA score 
when a patient no longer has an arterial line to calculate PaO2.
6.7.4.
Oxygenation Index
Oxygenation index (OI) (sometimes termed oxygenation factor) is another measure of 
gas exchange and pulmonary efficiency which factors in the mean airway pressure (Paw) 
term in the calculation step [El-Khatib, 2004]. 
It is calculated using the equation: 
Oxygenation Index = (FiO2 * Mean Airway Pressure) / PaO2
Further details can be found in the SPM.
6.7.5.
Sequential Organ Failure Assessment (SOFA) score
The SOFA score is a way of grading organ dysfunction. Scores range from 0 to 4 and 
represent the extent of dysfunction or failure [Vincent, 1996].
The SOFA score is made up of the following components:

PaO2/FiO2 (mmHg) or SpO2/FiO2 (mm/Hg)

Glasgow Coma Score (GCS)

Mean Arterial Pressure or administration of vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
Please refer to Section 12.3 for further details. SOFA scores will be generated at the time 
points stipulated in Section 6.1, Time and Events Tables.

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6.8.
Clinical assessments of disease progression
The following data will be collected:

Diagnosis of ARDS

ARDS in the post-operative period (including date & time of diagnosis)

SOFA score post operatively

28 day survival 

Ventilator Free Days; ICU & hospital length of stay

Organ Failure Free Days
Other post-operative complications; e.g. anastamotic leak e.t.c.
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, 
PREGNANCY AND MEDICAL DEVICE INCIDENTS
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator or site staff are 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.  
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 Section 12.4.
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 
Section 12.4.

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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:

“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 (hematology, 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.

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
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

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 

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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 
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 that in the judgement of 
the investigator and medical monitor causes prolongation of hospitalization out of 
what would be expected for normal clinical course:

ALT 5xULN and bilirubin 2xULN (>35% direct)
NOTES:
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).
Refer to Section 12.1 for the required liver chemistry follow-up instructions.
7.1.5.
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 
noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
7.1.6.
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.
7.1.7.
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 patients 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 

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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 Investigator Brochure (GlaxoSmithKline Document 
Number 2012N147005_02 ) 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
Precision Estimation
No formal statistical hypotheses will be tested in this study. Safety related objectives will 
be assessed via summary tables, listings and figures.
In addition to summary tables, listings and figures, study objectives relating to efficacy 
(for example, lung physiology and biomarkers) may be evaluated using posterior 
distribution(s) for the effect of GSK2862277 relative to Placebo. Point estimates and 
corresponding 95% credible intervals will be constructed for the difference between the 
mean of the test treatment and the mean of the reference treatment, (test) - (reference) 
No adjustment for multiplicity will be performed due to the Bayesian analysis 
framework.
Note: If data require log transformation prior to analysis then point estimates and 
corresponding 95% credible intervals will be constructed for the ratio of test treatment to 
placebo treatment (test) / (reference) in place of those for differences in means.

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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The number of patients described in Section 4.1 is based upon:

Operating characteristics from computer simulations.

A balance of feasibility considerations (e.g. anticipated duration of study under 
predicted recruitment rates)
The two endpoints selected for the computer simulations were chosen because they 
reflect two key physiological parameters that are anticipated will be impacted by 
administration of GSK2862277. The endpoints are 

Baseline adjusted change in PVPI on completion of surgery 

Baseline adjusted change in PaO2/FiO2 on completion of surgery. 
However, many other factors and study endpoints also influence the final progression 
decision, so the simulation work is for guidance only and the criteria listed in Figure 1 are 
non-binding but are intended to provide a point of reference for a successful outcome. 
The success thresholds in Figure 1 should be achievable using this study design when the 
true drug effects are larger than the minimum desired profile (this statement is based 
upon estimates of minimum detectable differences derived from access to data from the 
BALTI prevention trial (Perkins, 2014). 
Various confidence levels were examined in the simulation exercise but only the final 
choices that gave acceptable operating characteristics are presented (Figure 1). 
The posterior probability of each outcome will be derived and, if it exceeds its respective
confidence level, that outcome will be deemed to have occurred. Combinations of 
occurring outcomes imply the following four end-of-study states:
Overall success
1 of the “Success” outcomes
AND
0 “Failures”
Potentially Unsuccessful
0 “Success” outcomes 
AND
1 “Failure”
Inconclusive
0 “Success” outcomes
AND
0 “Failures”
Inconsistent
1 of the “Success” outcomes
AND
1 “Failure”
Full details of the computer simulation exercise and its results will be described in the 
RAP. 

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Figure 1
Proposed end of study decision pathway
9.2.2.
Sample Size Sensitivity
Table 5
Selected results from Sensitivity analysis
Hypothetical Treatment 
Profile
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
4.65%
92.81%
2.54%
0%
Minimum desired profile
80.64%
13.63%
5.73%
0%
Table 5 shows a sample size of 40 p.a. would have an equivalent of a Type I error rate of 
4.65% using the decision pathway (Figure 1) and has a high probability (80.64%) of 
detecting plausible effect sizes. This is deemed acceptable given the exploratory early 
phase status of this study. 
The data in Table 5 were obtained from computer simulations utilising subject level 
historical information from the BALTI prevention trial [Perkins, 2014]. These data were 
used to estimate change from baseline response post surgery and the variances and 
correlations between the two endpoints (see Table 6). 

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The BALTI prevention trial means were assumed to represent future placebo data and 
several hypothetical GSK2862277 effect profiles were evaluated (although only 2x 
profiles are presented in Table 6).
Ten thousand sets of studies (40 patients per arm) were simulated using the multivariate 
normal distributions implied by Table 6. Each of the 10,000 simulated studies was put 
through the process shown in Figure 1 and the end of study status recorded (Table 5).
Table 6
Example sets of Scenarios to evaluate operating characteristics
Hypothetical 
Treatment 
Profile
Placebo Vector of 
mean responses
Active Vector of mean responses
and
Implied treatment effect relative to Placebo
Null











765
.0
27
.
42
:
)
(
/
p
PVPI
LN
kPa
F
P

CHANGE
NO
rat
dif
a















1
1
&
0
0
&
765
.0
27
.
42


Minimum 
desired 
profile











765
.0
27
.
42
:
/
p
PVPI
LN
F
P



















%
15
%
15
85
.0
15
.1
&
16252
.0
3405
.6
&
602481
.0
6105
.
48
rat
dif
a


Note: Variance covariance matrix for an individual’s Change from Baseline on 
completion of  surgery endpoints (derived from data Perkins, 2014)):





0785513
.0
467621
.0
143.17249
, 
Correlation





1
14313
.0
1
9.2.3.
Sample Size Re-estimation
No sample size re-estimation is currently planned for this study. However, if during the 
course of the study, new information becomes available about clinically meaningful 
differences or variability estimates, sample size re-estimation may be considered. Full 
details of the procedure used would be specified in the RAP, and any subsequent change 
to the target sample size would be documented. 
An example scenario might be if Interim analysis #2 data suggest a robust treatment 
effect can be demonstrated using a smaller sample size than stated in Section 3.1 then an 
appropriate reduction in the recruitment target would be justified.

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9.3.
Data Analysis Considerations
9.3.1.
Interim Analysis
Interim analysis #1: Unblinded safety review after approx 10 patients have 
completed Day 7 visit; roughly 5 per arm.
The principal objective will be to determine whether there are any emerging safety trends 
/ signals which might require modifications to be made and/or suspension of recruitment 
pending further data review. 
Unless there are safety concerns recruitment into the study may continue whilst interim 
analysis 1 is being performed.
Further details of the contents of the safety outputs will be provided in the RAP.
Interim analysis #2: Unblinded safety review and futility analysis after approx 40 
patients have completed Day 7 visit; roughly 20 per arm.
The outcome of interim analysis #2 will be communicated by GSK to the sites as either 
“Continue”, or “Pause and Review”. 
Upon a “Pause and Review” communication the available data will be reviewed by the 
study team (un-blinded) and additional data may be requested from the sites to determine 
whether to:

Stop the study early for futility 

Modify aspects of its design 

Resume and continue unaltered 
Although interim analysis #2 is scheduled to occur after approximately 20 patients p.a. 
have available data up to Day 7, it is possible that recruitment rates may be lower than 
anticipated in which case the interim analysis may occur after a fixed time with whatever 
data are available. 
The futility analysis component of Interim analysis #2 will use the same endpoints as 
Figure 1 but will utilise predictive inference and a different decision pathway and 
confidence thresholds; as follows:

For each treatment arm the available data will be used to obtain the hyper-
parameters of a multivariate normal distribution (i.e. obtain a Normal-Inverse-
Wishart distribution for each treatment)

Sample a variance covariance matrix and a mean vector (conditional on the 
sampled variance covariance matrix) from each Normal-Inverse-Wishart 
distribution

Use this newly defined multivariate normal distribution to simulate enough 
subjects to achieve an overall total of 40 per arm

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
Use this hybrid dataset (observed and simulated subjects) to determine whether 
the probability of observing Any decrease in P/F AND Any increase in PVPI is 
greater than 0.1. 
IF so THEN record that simulated study as being futile

Repeat the previous 3x steps 1000 times.

Determine the proportion of the 1000 simulated studies which met the futility 
threshold. 
IF this proportion is larger than 0.3 then the recommendation is to “Pause and 
Review”, otherwise the recommendation is to “Continue”
Note: Expert judgement may be used by the GSK study team if deemed appropriate to 
override the recommendation from the above statistical analysis (for example, to account 
for other clinically relevant factors).
The same set of safety outputs as interim analysis #1 will also be reviewed.
Unless there are safety concerns recruitment may continue whilst interim analysis #2 data 
are collected and the analysis performed.
The RAP will contain further details and operating characteristics of the futility 
component of Interim analysis #2.
9.4.
Final Analyses
9.4.1.
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.
9.4.2.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline.  Plasma GSK2862277 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin 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: maximum observed 
plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-
time curve [AUC(0-t)]. Since the proposed sampling regimen is sparse, definitive 
pharmacokinetics will not be derived from this data and instead data will be compared 
against previously collected definitive data from healthy volunteers for informal 
comparability. AUC’s or Cmax values will be calculated as appropriate for each dosing 
day and possibly over the PK sampling window (0-72 hours) if appropriate. 

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Pharmacokinetic data will be listed and may be presented in graphical 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.
Derived pharmacokinetic parameters will be listed and summarised descriptively by 
treatment. Descriptive statistics (n, arithmetic mean, standard deviation, 90%CI, 
minimum, median and maximum,) will be calculated for all pharmacokinetic parameters 
by treatment.
In addition, for loge-transformed variables geometric mean, 90% confidence interval and 
%CVb (100 * √ (exp(SD2) -1)) will be provided, where the SD is the standard deviation 
of log-transformed data.
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses
No formal PK/PD analysis will be conducted. 
9.4.4.
Pharmacodynamic/Biomarker Analyses
Full details of the endpoints and statistical analysis models not described here 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 enrollment of patients begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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 2008 
Declaration of Helsinki.  This includes, but is not limited to, the following:

IEC review and favorable 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

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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IEC)
Information regarding pharmacogenetic research is included in Section 12.2.  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 
Section 12.2), 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.
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 patients, the sponsor 
and the investigator will take appropriate urgent safety measures to protect patients 
against any immediate hazard.
The sponsor will work with the investigator to ensure the IEC/IRB is notified.
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 patients 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 

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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 
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 

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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 
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 patients, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.

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11.
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Perkins G.D., Gates S, Park D., Gao F., Knox C, Holloway B, McAuley D.F, Ryan J., 
Marzouk J, Cooke M.W., Lamb S.E. , Thickett D.R. . The Beta Agonist Lung Injury Trial 
(BALTI) Prevention: A Randomized Controlled Trial. AJRCCM. In press Jan 2014
Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial 
(BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med. 
2006 Feb 1;173(3):281-7. Epub 2005 Oct 27.
Proudfoot A, et al: A novel TNFR1-targeting domain antibody attenuates pulmonary 
inflammation in a human model of lung injury, via actions on the lung micro-vascular 
endothelium. Abs. ID/Title: #57200. American Thoracic Society 2014 international 
conference.
Qiu P, Cui X, Sun J, Welsh J, Natanson C, Eichacker PQ. Antitumor necrosis factor 
therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit 
Care Med. 2013 Oct;41(10):2419-29.
Schilling M, Gassmann N, Sigurdsson G, Regli B, Stoupis C, Furrer M, Signer C, 
Redaelli C, Büchler M: Role of thromboxane and leukotriene B4 in patients with acute 
respiratory distress syndrome after oesophagectomy. Br J Anaesth 1998, 80:36-40.
Schilling MK, Eichenberger M, Maurer CA, Sigurdsson G, Buchler MW. Ketoconazole 
and pulmonary failure after esophagectomy: a prospective clinical trial. Diseases of the 
Esophagus 2001;14(1):37-40
Schuirmann DJ. 1987. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet and 
Biopharm, 15, 657-680.
Slutsky, A. S. & Ranieri, M. Ventilaor-Induced Lung Injury. NEJM. 2013. 369(22) 
p2126.
Tandon S, Batchelor A, Bullock R, Gascoigne A, Griffin M, Hayes N, Hing J, Shaw I, 
Warnell I and Baudouin SV. Peri-operative risk factors for acute lung injury after elective 
oesophagectomy. Br. J. Anaesth. (2001) 86 (5): 633-638.
Tsai, J.A., Lund, M., Lundell, L and Nisson-Ekdahl, K. One-lung ventilation during 
thoracoabdominal esophagectomy elicits complement activation. J Surgical Res 2009, 
152 (2) 331-337.
Vincent JL1, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, 
Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to 
describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related 
Problems of the European Society of Intensive Care Medicine.  Intensive Care Med. 
1996; 22:707-10.
Wakabayashi K, Wilson MR, Patel BV, Morley PJ, Bayliffe A, Takata M. Inhibition Of 
Tnf Receptor P55 By A Domain Antibody Attenuates Acid-Induced Lung Injury In Mice. 
Am J Respir Crit Care Med 187;2013:A5964

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12.
APPENDICES
12.1.
Appendix 1: Liver Safety Process
The procedures listed below are to be followed if a subject has ALT, bilirubin and/or INR 
elevations that meet the definition of an SAE (as defined in Section 7.1.4):

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
confirm follow-up.

Complete the liver event case report forms. 

Upon completion of the safety follow-up withdraw the subject from the study unless 
further safety follow up is required.

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.

Obtain viral hepatitis serology including:

Hepatitis A IgM antibody.

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 

Hepatitis C RNA. 

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours from last 
dose. 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 in the time 
period indicated above, 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).

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.

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
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.

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week (James, 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, 
2002; Mallal, 
2002; 
Mallal, 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.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia Chung, 
2010; Ferrell, 
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, 2004; 
Liu, 2008; 
Schulz, 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 GSK2862277. 
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 
GSK2862277.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK2862277, 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 
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.
If taking blood samples: 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 randomized 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 
GSK2862277 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 
GSK2862277.
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.  
Patients 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 GSK2862277.  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
Patients 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 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.
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: SOFA Score Table
[Vincent, 1996]

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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 
of 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.
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.
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 

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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 GlaxoSmithKline Document Number 2012N147005_02 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.  
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. 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 

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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.
Medical Devices
Documenting Medical Device Incidents
Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form. In addition, for incidents fulfilling the definition of an 
AE or an SAE, the appropriate AE/SAE data collection tool will be completed as 
previously described.
The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.  It is very important that the investigator provides his/her 
assessment of causality to the medical device provided by GSK at the time of the 
initial report, and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.  A remedial action is any action other than routine 
maintenance or servicing of a device where such action is necessary to prevent recurrence 
of an incident.  This includes any amendment to the design to prevent recurrence.
Follow-up of Medical Device Incidents
All medical device incidents involving an AE, will be followed until resolution of the 
event, until the condition stabilizes, until the condition is otherwise explained, or until the 
subject is lost to follow-up. This applies to all patients, including those withdrawn 
prematurely. The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as may be indicated to elucidate as completely as practical 
the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.

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12.5.
Appendix 5: Protocol Amendment Changes
Amendment 5
Summary of Amendment Changes with Rationale
This amendment was produced to include information regarding inclusion of an external 
expert to the SRT.  The opportunity has also been taken to include minor changes that 
had previously been documented in File Notes.  
List of Specific Changes
CHANGE 1
This text has been updated to clearly reflect the intentions for open/shut cases.
Section 4.4 Withdrawal Criteria and Procedures
REVISED TEXT
In some cases, a subject may be randomised to the study and surgery initiated, but 
subsequently halted due to a decision being made that the case is in fact inoperable. In the 
event of an open and shut case subjects will be withdrawn from the study by the 
investigator. As the subjects will have received a dose of study dose prior to surgery, 
every effort should be made to complete as many safety and PK procedures of the Day 
28 follow-up assessments and procedures as possible prior to hospital discharge and the 
Day 28 assessments.
CHANGE 2
Footnote #3 added to clarify screening window for patients that have repeat screening.
Footnote #4 was removed in error in a previous amendment.
Corresponding footnotes have been added to the table.
Section 6.1 Time and Events Table, Table 2
ADDED TEXT
3.
In case of repeat screening, screening can occur less than 7 days prior to dosing if ADA and 
Quantiferon results are available.
4.
Can occur any time during the study after eligibility is confirmed and consent provided
CHANGE 3
Footnote #2 revised to allow flexibility in extenuating circumstances

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Footnote #3 revised to allow flexibility for translational samples
Section 6.1 Time and Events Table, Table 3
REVISED TEXT
2.
Randomisation & associated IVRS activities may be conducted up-to 72 hours prior to administration of study 
treatment (can be longer on agreement with the sponsor for extenuating circumstances e.g. bank 
holiday weekends).
3.
Only applicable at designated sites. Can be taken at screening if required.
CHANGE 4
Added text to provide more detail regarding the safety review team that was already in 
place and to detail that an external expert has been added to that team.
Section 6.3 Safety
ADDED TEXT
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all 
available safety data related to the project, including in-stream data from this study, 
in an ongoing manner.   The SRT is an internal GSK requirement put in place to 
ensure holistic evaluation of the safety profile of an investigational product with 
systematic, periodic and documented reviews of available safety data, with the 
appropriate communication and escalation of new findings that have the potential to 
impact patient safety.  
The SRT for this project will review data from this study in collaboration with an 
independent external (to GSK) expert reviewer.
CHANGE 5
Section has been removed as all SAEs are being recorded for this study and therefore this 
section is not required.
Section 7.1.6 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
DELETED TEXT
Certain events are typically associated with the disease under study and are recognised, 
and common, post-operative problems with Oesphagectomy. These need not be reported 
according to the standard process for expedited reporting of SAEs to GSK (even though 
the event may meet the definition of a serious adverse event).  These events will be 
recorded on the DRE page in the subject’s CRF within 5 working days.  These DREs will 
be monitored by the Safety Review Team (SRT) on routine basis.   

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NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the Investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The Investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
CHANGE 6
Section removed as it is not relevant to this study.
Appendix 4: Procedures for Detection, Evaluation, Follow-Up and Reporting of 
Adverse Events and Medical Device Incidents
DELETED TEXT
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.
Amendment 4
Summary of Amendment Changes with Rationale
The amendment was produced after discussions concerning logistical set-up of the study.  
Changes include: removal of mandatory 1 hour post-dose ECG (on the condition that 
alternative cardiac monitoring is in place); 24 hour window has been added for the pre-
dose assessments.  A typographical error in exclusion criteria #6 has been amended.  A 
PK sample has also been included if a liver event occurs as this had been omitted in error.  
The opportunity has also been taken to make some other minor amendments.
List of Specific Changes
CHANGE 1
Correction of a typographical error. 
Section 4.2.2 Exclusion Criteria #6
PREVIOUS TEXT
Use of corticosteroids (IV, oral or IM) at a dose of ≥10 mg/day prednisolone (or 
equivalent) within 14 days prior to dosing, or anti-Tumor Necrosis Factor (anti-TNF) or 
anti-Interleukin-1 (anti-IL1) within 60 days prior to dosing.

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REVISED TEXT
Use of corticosteroids (IV, oral or IM) at a dose of ≥> 10 mg/day prednisolone (or 
equivalent) within 14 days prior to dosing, or anti-Tumor Necrosis Factor (anti-TNF) or 
anti-Interleukin-1 (anti-IL1) within 60 days prior to dosing.
CHANGE 2
This change is to allow ADA screening and TB testing results to be re-used if repeat 
screening is required.  Also to remove an unclear footnote.  Corresponding footnote 
numbering has been updated.
Section 6.1 Time and Events Table; Table 2
DELETED TEXT
3.
Can occur any time during the study after eligibility is confirmed and consent provided.
ADDED TEXT
3.
If repeat screening is required previous results from ADA screening and Quantiferon-GOLD testing can be 
used for up to 60 days.

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CHANGE 3
Removal of mandatory 1 hour post-dose 12-lead ECG to help with the logistical requirements prior to surgery.  Cardiac monitoring will 
be ongoing during this time as standard of care.  OI has been removed as it is a derived value and replaced with SpO2.
Section 6.1 Time and Events Table; Table 3
PREVIOUS TEXT
Pre-dose
01 h
1 h
Immediately 
prior or at 
start of 
surgery
On 
completion 
of surgery
1.Dosing may occur  1-5 hours prior to surgery
2.Randomisation & associated IVRS activities may be 
conducted up-to 72 hours prior to administration of study 
treatment.
3.Only applicable at designated sites
NB: Time points (except pre-dose) refer to post-start of drug 
administration on Day 1.
Pre-dose is defined as the time from admission to hospital up to 
the administration of study treatment.
12-lead ECG
X
X
Oxygenation Index
X
X
REVISED TEXT
Pre-dose4
01 h
1 h
Immediately 
prior or at 
start of 
surgery
On 
completion 
of surgery
1.
Dosing may occur  1-5 hours prior to surgery
2.
Randomisation & associated IVRS activities may be 
conducted up-to 72 hours prior to administration of study 
treatment.
3.
Only applicable at designated sites
4.
Can be taken up to 24 hours prior to dosing 
5.
If 12 lead ECG not available, monitoring by 3 lead 
ECG/telemetry (or similar) is acceptable
NB: Time points (except pre-dose) refer to post-start of drug 
administration on Day 1.
Pre-dose is defined as the time from admission to hospital up to 
the administration of study treatment.
12-lead ECG
X
X5
Oxygenation Index Measure SpO2 using 
pulse oximetry
X
X

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CHANGE 4
Changes have been made to add clarity and to correct errors.
PREVIOUS TEXT
Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
1. If discharged before Day 8 take blood and urine 
samples on day of discharge
2. PVPI will be measured via single-indicator 
transpulmonary thermodilution as long as the 
subject remains in the ICU with a patent indwelling 
PiCCO catheter, up to Day 4.
3. Sequential Organ Failure Assessment (SOFA) 
Score will only be calculated up to Day 4.
4. Sample to be taken 24 to 26 hours post-dose of 
study treatment.
5. Sample to be taken 46 to 50 hours post-dose of 
study treatment.
6. Only applicable at designated sites
Day 
2
Day 
3
Day 
4
Day 
81
P/F Ratio (as available)

Arterial blood sample

Record FiO2
X
X
X
SOFA Components3

PaO2/FiO2 (mmHg) (as available)

Glasgow Coma Score (GCS)

Mean Arterial Pressure or administration of 
vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
X
X
X
SpO2/FiO2 ratio:

Pulse Oximetry

Record FiO2
X
X
X
Blood samples for translational sub-study6
X
Organ Failure Free Days
X

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REVISED TEXT
Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
1. If discharged before Day 8 take blood and urine 
samples on day of discharge
2. PVPI will be measured via single-indicator 
transpulmonary thermodilution as long as the 
subject remains in the ICU with a patent indwelling 
PiCCO catheter, up to Day 4.
3. Sequential Organ Failure Assessment (SOFA) 
Score will only be calculated up to Day 4.
4. If no arterial blood sample calculate MAP 
using equation: 2X diastolic blood pressure + 
systolic blood pressure. Then divide by 3.
5. Only applicable at designated sites
6. Sample to be taken 24 to 26 hours post-dose of 
study treatment.
7. Sample to be taken 46 to 50 hours post-dose of 
study treatment.
8. Organ Failure Free Days needs to be 
recorded every day until Day 28 (See SPM).
Day 
2
Day 
3
Day 
4
Day 
81
P/F Ratio (as available)

Arterial blood sample (as available)

Record FiO2
X
X
X
Measure SpO2 using pulse oximetry
X
X
X
Additional SOFA Components3

PaO2/FiO2 (mmHg) (as available)

Glasgow Coma Score (GCS)

Record Mean Arterial Pressure4 or 
administration of vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
X
X
X
SpO2/FiO2 ratio:

Pulse Oximetry

Record FiO2
X
X
X
Blood samples for translational sub-study5
X
X
Organ Failure Free Days
X8

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CHANGE 5
Change made to correct inaccuracy and to add clarity regarding requirements for cardiac 
monitoring at 1 hour post-dose.
Section 6.3.3 Electrocardiogram (ECG)
PREVIOUS TEXT
Single 12-lead ECGs will be obtained at each time point during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, RR and 
QTc intervals.
REVISED TEXT
Triplicate 12-lead ECGs will be obtained at screening and single 12-lead ECGs will 
be obtained at each time point thereafter during the study, using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, RR and QTc 
intervals.
At the 1 hour post-dose time point monitoring by 3 lead ECG/telemetry (or similar) 
is acceptable if 12 lead ECG is not available.
CHANGE 6
Changes made for clarity.
Section 6.7 Efficacy
ADDED TEXT
6.7.1 Transpulmonary Thermodilution
Measurement of PVPI and EVLWI
Other supportive parameters from the PiCCO monitor that are calculated at the 
same time as EVLW and PVPI, may also be databased e.g. GEDV, SVV, SVR, HR 
etc.
ADDED TEXT
6.7.3 Pulse Oximetry
SpO2 will be collected using pulse oximetry.  This will be used to calculate SOFA 
score when a patient no longer has an arterial line to calculate PaO2.

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PREVIOUS TEXT
6.7.4 Oxygenation Index
Oxygenation index (OI) (sometimes termed oxygenation factor) is another measure of 
gas exchange and pulmonary efficiency which is also reflective of changes in 
intrapulmonary shunt. OI calculation takes into account the P to F assessment but 
crucially also takes into account important variables governing mechanical ventilation 
such as inspiratory time, Positive End Expiratory Pressure (PEEP) and tidal volume via 
the addition of the  mean airway pressure (Paw) term in the calculation step [El-Khatib, 
2004]. 
Further details can be found in the SPM.
REVISED TEXT
6.7.4 Oxygenation Index
Oxygenation index (OI) (sometimes termed oxygenation factor) is another measure of 
gas exchange and pulmonary efficiency which is also reflective of changes in 
intrapulmonary shunt. OI calculation takes into account the P to F assessment but 
crucially also takes into account important variables governing mechanical ventilation 
such as inspiratory time, Positive End Expiratory Pressure (PEEP) and tidal volume via 
the addition of the factors in the mean airway pressure (Paw) term in the calculation step 
[El-Khatib, 2004]. 
It is calculated using the equation: 
Oxygenation Index = (FiO2 * Mean Airway Pressure) / PaO2
Further details can be found in the SPM.
PREVIOUS TEXT
6.7.5 The Sequential Organ Failure Assessment (SOFA) score
The SOFA score is made up of the following components:

PaO2/FiO2 (mmHg)
REVISED TEXT
6.7.5 The Sequential Organ Failure Assessment (SOFA) score
The SOFA score is made up of the following components:

PaO2/FiO2 (mmHg) or SpO2/FiO2 (mm/Hg)

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CHANGE 7
Added wording to collect a PK blood sample if there is a liver event.  This had been 
omitted in error.
Appendix 1: Liver Safety Process
ADDED TEXT

Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours from 
last dose. 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 in the time period indicated above, do not obtain 
a PK sample.  Instructions for sample handling and shipping are included in the 
SPM.
CHANGE 8
Update of suppliers.
Section 12.6 Appendix 6 Preparation of Active and Placebo Drug for Dosing
PREVIOUS TEXT

Pari eFlow Filter Valve Set (041G0500) (supplied by Fisher Scientific)

Pari disposable filters (for use with Filter Valve Set) (041B0522/3) (supplied by 
Fisher Scientific)
REVISED TEXT

Pari eFlow Filter Valve Set (041G0500) (supplied by Fisher Scientific Ancillare)

Pari disposable filters (for use with Filter Valve Set) (041B0522/3) (supplied by 
Fisher Scientific Ancillare)

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Amendment 3
Amendment 3 was produced after discussions concerning logistical set-up of the study. 
Changes include: widening the window for dosing study treatment; incorporating a 
process for instances of inoperable cases (so called ‘open-and-shut’ cases); and allowing 
randomisation to be conducted up-to 72 hours prior to day of surgery. 
Section 3.3.1
Previous Text:
Patients will be randomized via a central allocation system to receive either GSK2862277 
or placebo as an inhaled (via nebulisation) dose. A single inhaled dose of GSK2862277 
or placebo to match will be administered approximately 1-3 hours prior to the subjects 
scheduled surgery, before the initiation of pre-operative procedures.
Revised Text:
Patients will be randomized via a central allocation system to receive either GSK2862277 
or placebo as an inhaled (via nebulisation) dose. A single inhaled dose of GSK2862277 
or placebo to match will be administered approximately 1-5 hours prior to the subjects 
start of (knife to skin) surgery, before the initiation of pre-operative procedures.
Section 4.3
Additional text:
A screen failure is defined as any subject who has been assigned a subject identifier, but 
does not continue in the study beyond Visit 1 (screening) or any subject who completes 
Visit 1 but is subsequently found to be ineligible for the study based on findings from 
laboratory or any other screening test conducted at Visit 1.
Additionally, if a subject completes written informed consent and experiences a serious 
adverse event (SAE) in the time period between completing written informed consent and 
the planned Visit 1 date, the subject will be assigned a subject identifier and classified as
a screen failure.
The interactive voice response system (IVRS) used to track study enrolment will be 
notified and at a minimum the following information will be collected in the eCRF for 
screen failures:

Date of screening visit

Subject identifier

Demographic information, including race, age and gender

Inclusion/exclusion criteria

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
Reason subject failed screening
Serious Adverse Events information, if applicable, for any SAE that occurred in the time 
period between completing written informed consent and planned Visit 1 date
Section 4.4
Additional Text:
In some cases, a subject may be randomised to the study and surgery initiated, but 
subsequently halted due to a decision being made that the case is in fact inoperable. In the 
event of an open and shut case subjects will be withdrawn from the study by the 
investigator. As the subjects will have received a dose of study dose prior to surgery, 
every effort should be made to complete as many of the Day 28 follow-up assessments 
and procedures as possible, prior to hospital discharge.
Section 5.6
Additional Text:
A description of the methods and materials required for preparation of GSK2862277 and 
reconstitution will be detailed in Section 12.6 and the Study Procedures Manual (SPM).
Additional Text:
Blood sample for PK/Urea/Total Protein.

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Section 6.1 Additional rows in Time & Events Tables
Pre-dose
01 h
1 h
Immediately 
prior or at 
start of 
surgery
On 
completion 
of surgery
1.Dosing may occur  1-5 hours prior to surgery
2.Randomisation & associated IVRS activities may be
conducted up-to 72 hours prior to administration of study 
treatment.
3.Only applicable at designated sites
NB: Time points (except pre-dose) refer to post-start of drug 
administration on Day 1.
Pre-dose is defined as the time from admission to hospital up to 
the administration of study treatment.
Randomisation
X2
Brief Physical Examination
X
Concomitant Medication
X
IVRS
X2
Vital Signs
X
X
12-lead ECG
X
X
Adverse Events
X
Serious Adverse Events
X
Clinical Labs including Haematology and 
Chemistry
X
Blood sample for immunogenicity
X
Blood sample for PK
X
X
X
Blood sample for urea and total protein
X
Blood samples for translational sub-study3
X
X
Sample for Urinalysis
X
Blood sample for serum biomarkers
X
X
Nebulised (IH) Study Treatment
X
Transpulmonary thermodilution
X
X
P/F Ratio:

Arterial blood sample

Record FiO2
X
X
Oxygenation Index
X
X
BAL Sampling
X

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Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
1. If discharged before Day 8 take blood and urine 
samples on day of discharge
2. PVPI will be measured via single-indicator 
transpulmonary thermodilution as long as the 
subject remains in the ICU with a patent indwelling 
PiCCO catheter, up to Day 4.
3. Sequential Organ Failure Assessment (SOFA) 
Score will only be calculated up to Day 4.
4. Sample to be taken 24 to 26 hours post-dose of 
study treatment.
5. Sample to be taken 46 to 50 hours post-dose of 
study treatment.
6. Only applicable at designated sites
Day 
2
Day 
3
Day 
4
Day 
81
Concomitant Medication
X
X
X
X
X
X
IVRS
X
X
Transpulmonary thermodilution2
X
X
X
P/F Ratio (as available)

Arterial blood sample

Record FiO2
X
X
X
SOFA Components3

PaO2/FiO2 (mmHg) (as available)

Glasgow Coma Score (GCS)

Mean Arterial Pressure or administration of 
vasopressors required

Bilirubin

Platelets

Creatinine (or urine output)
X
X
X
SpO2/FiO2 ratio:

Pulse Oximetry

Record FiO2
X
X
X
Vital Signs
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
Clinical Labs including Haematology and Chemistry
X
X
X
X
Blood sample for serum biomarkers
X
X
X
X
Blood samples for translational sub-study6
X
Blood sample for Immunogenicity
X
X
Blood sample for PK
X4
X5
Sample for Urinalysis
X
Organ Failure Free Days
X
ARDS diagnosis status
X
Ventilator Free Days
X

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Procedures
Daily until 
discharge
Day of 
discharge
Day 28
(FU) ±3 
days
Day 
2
Day 
3
Day 
4
Day 
81
ICU & Hospital Length of Stay
X
Survival
X

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Section 6.3.5. Clinical Laboratory Assessments 
Clinical Chemistry Table: Total Protein Removed
Section 6.5.3
Previous Text
Blood (serum and plasma) and BAL sample(s)...
Revised Text
Blood (serum and plasma) and BAL sample(s)...
Previous Text
Candidate biomarkers and subsequently discovered biomarkers of the biological response 
associated with the development of ARDS or medically related conditions and/or the 
action of GSK2862277 may be identified by application of:

Detection of protein endpoints in serum and BAL by immunoassay and/or equivalent 
alternative technologies (these may include but are not limited to vWF and sRAGE).

Total protein determination in plasma for protein permeability analysis 
Revised Text
Candidate biomarkers and subsequently discovered biomarkers of the biological response 
associated with the development of ARDS or medically related conditions and/or the 
action of GSK2862277 may be identified by application of:

Detection of protein endpoints in serum and BAL by immunoassay and/or equivalent 
alternative technologies (these may include but are not limited to vWF and sRAGE).

Total protein determination in plasma for protein permeability analysis 

Cellular assays and RNA analysis

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Amendment 2
Amendment 2 was made to reduce the upper threshold for AST & ALT liver enzyme 
values for inclusion in the study, as per instruction from the UK competent authority 
(Medicines and Healthcare Regulatory Authority [MHRA]). A change to the QTc 
inclusion criteria was also made to correct an error not previously identified.
Previous text:
5.
Liver parameters according to the thresholds below: AST and ALT < 5xULN; 
alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin > 1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
6.
QTcB or QTcF 480 msec at screening
Either QTcB or QTcF, machine or manual over-read can be used. This applies to both 
males and females. The QT correction formula used to determine inclusion and 
discontinuation for an individual subject should be the same throughout the study.
Revised text:
5.
Liver parameters according to the thresholds below: AST and ALT < 3xULN; 
alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin > 1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
6.
QTcB or QTcF 450 msec at screening
Either QTcB or QTcF, machine or manual over-read can be used. This applies to both 
males and females. The QT correction formula used to determine inclusion and 
discontinuation for an individual subject should be the same throughout the study.

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Amendment 1
Amendment 1 was made to correct an error in the protocol title:
Previous text:
A Placebo Controlled, Double-blind, Multi-centre, Repeat Dose, Parallel Group, 
Randomised Clinical Trial of GSK2862277 in Patients undergoing Oesophagectomy 
Surgery
Revised text:
A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, 
Randomised Clinical Trial of GSK2862277 in Patients undergoing Oesophagectomy 
Surgery
A revision to the exclusion criteria around alcohol consumption was also made:
Previous text:
7.
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 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits.
Revised text:
3.
History of regular alcohol consumption within 6 months of the study, defined as:

an average weekly intake of >28 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits.

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12.6.
Appendix 6 Preparation of Active and Placebo Drug for 
Dosing
Subjects will be administered either a single 26mg dose of GSK2862277 or placebo via 
IH.
For IH administration, compatibility has been established with the following components:
Material Use
Component Composition
Syringes
Polypropylene
Needles
18G to 23G Stainless Steel
The following materials will be required (if catalogue numbers change then you will be 
notified):

GSK2862277, 40mg vials (supplied by GSK)

Placebo/Diluent to Match IH GSK2862277 (supplied by GSK)

Reconstitution Fluid for IH GSK2862277 (supplied by GSK)

Nebuliser System (Controller + Handset) (PARI eFlow nebuliser with 4 mL cup and 
size 30 mesh, article number 678G2003) (supplied by GSK)

Additional Nebuliser Handsets (PARI eFlow nebuliser with 4 mL cup and size 30 
mesh, article number 678G8203) (supplied by GSK).

Pari eFlow Filter Valve Set (041G0500) (supplied by Ancillare)

Pari disposable filters (for use with Filter Valve Set) (041B0522/3) (supplied 
byAncillare)
12.6.1.
Dose Preparation for 26mg GSK2862277
1. For each subject, remove 1 vial of GSK2862277, 40mg/vial from 2°C to 8°C 
storage.
2. Reconstitute GSK2862277, 40mg/vial lyophilized DP to 20mg/mL solution of 
GSK2862277 by injecting 2.3mL Reconstitution Fluid for IH GSK2862277 directly 
into the vial using a fresh 3mL syringe and needle assembly (Use a fresh syringe 
and needle assembly to reconstitute each lyophilized DP vial).  Following addition 
of Reconstitution Fluid for IH GSK2862277, gently swirl the vial to dissolve the 
lyophilized cake. Avoid vigorous shaking or agitation of the reconstituted 20mg/mL 
solution of GSK2862277.
3. Prior to withdrawal into syringe, invert the vial 5 times to ensure complete mixing.  
Then, using a fresh needle and a 3mL PP syringe, slowly withdraw 1.3mL 
reconstituted 20mg/mL solution of GSK2862277 and add to nebuliser cup.

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This reconstituted solution in the syringe must be transferred to the nebulizer cup as 
soon as possible. The reconstituted 20mg/mL solution of GSK2862277 is stable for 12 
hours at 25°C and for 24 hours when stored at 5°C in the original vial.
Dosing must occur within 24hrs of reconstitution of the GSK2862277 lyophilised DP.
12.6.1.1.
Preparation of placebo dose
1. Use 1 vial of GSK2862277 Placebo/Diluent to Match IH GSK2862277 for each 
subject.
2. Using a fresh needle and a 3mL PP syringe, slowly withdraw 1.3mL and add to 
nebuliser cup.
This solution can be stored for 12 hours at 25°C and for 24 hours at 5°C prior to use.
12.6.2.
Instructions for Transportation
If the reconstituted 20mg/mL solution of GSK2862277 needs to be transported from a 
pharmacy to a clinical site, the solution must be stored at 2°C to 8°C in the glass vial 
(primary container) prior to transportation. The transportation must take no more than 4 
hours at 2°C to 8°C while the reconstituted solution is in the glass vial. 
Dosing must occur within 24hrs of reconstitution of the GSK2862277 lyophilised DP 
while stored at 2°C to 8°C.