Clinical trial NCT02221037
Conditions: Lung Injury, Acute and Respiratory Distress Syndrome, Adult
Keywords: PaO2/FiO2 Peri-operative lung injury EVLWI ARDS PVPI SOFA scores GSK2862277 Oesophagectomy
Sponsor: GlaxoSmithKline
Start date: 2015-04-28; Completion date: 2017-06-28
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Lung injury in patients undergoing oesophagectomy may occur during surgery (peri-operatively) as a result of One Lung Ventilation (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 are most elevated immediately after completion of surgery, and the development of clinical Acute Respiratory Distress Syndrome (ARDS)occurs immediately post-operatively (within 72 hours of surgery), with the majority of cases reported 24-48 hours after completion of surgery. This study is 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 in order to achieve optimal exposure at the site of injury following OLV and lung deflation. This study is a randomized 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. The primary endpoint for this study is the change in pulmonary vascular permeability index (PVPI) from pre-surgical levels to the end of surgery. GSK2862277 will be administered as an orally inhaled aerosol (single nebulized dose) over approximately 3 to 5 minutes (min) 1-3 hours prior to surgery. Subject will be monitored daily until discharge and followed up till day 28.

Detailed description:

Arms: arm 1: GSK2862277 will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will undergo either ventilated or collapsed lung BAL procedure. Regular assessments will be conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28 arm 2: Placebo will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will be undergo either ventilated or collapsed lung BAL procedure. Regular assessments will conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28
Interventions: intervention 1: GSK2862277 intervention 2: Placebo
Intervention descriptions: intervention 1: It is available as 26 milligrams (mg) white to off-white, uniform lyophilized cake that will be reconstituted (using reconstitution fluid formulated with polysorbate 80 in Water for Injection) to 40 mg/vial of Lyophile for reconstitution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device. intervention 2: It is a clear, colorless to pale yellow liquid, will be administered in volume to match active dose as solution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device.

Protocol documents:
Prot_000.pdf: 
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.
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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


2014N197251_05
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6
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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8
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


2014N197251_05
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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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Michael R. Wilson, Michael E. Goddard, Kieran P. O’Dea, Sharmila Choudhury, and 
Masao Takata. Differential roles of p55 and p75 tumor necrosis factor receptors on 
stretch-induced pulmonary edema in mice. Am J Physiol Lung Cell Mol Physiol 293: 
L60–L68, 2007
Michelet P, D'Journo XB, Roch A, Doddoli C, Marin V, Papazian L, Decamps I, Bregeon 
F, Thomas P, Auffray JP. Protective ventilation influences systemic inflammation after 
esophagectomy: A randomized controlled study. Anesthesiology 2006;105:911-919.
Monnet X, Anguel N, Osman D, Hamzaoui O, Richard C, Teboul JL: Assessing 
pulmonary permeability by transpulmonary thermodilution allows differentiation of 
hydrostatic pulmonary oedema from ALI/ARDS. Intensive Care Med 2007, 33:448-453
Monnet X, Persichini R, Ktari M, Jozwiak M, Richard C, Teboul JL. Precision of the 
transpulmonary thermodilution measurements. Crit Care. 2011;16:R204
Mori R, Kondo T, Ohshima T, Ishida Y, Mukaida N (2002) Accelerated wound healing 
in tumor necrosis-factor receptor p55-deficient mice with reduced leukocyte infiltration. 
FASEB J 16: 963–974. Luo D, Luo Y, He Y, et al. Differential functions of tumor 
necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and 
angiogenesis. Am J Pathol. 2006; 169: 1886–1898
Panacek E.A, Marshall J.C., Albertson T.E., Johnson D.H.; Johnson S, et al. Efficacy and 
safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment 
afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care 
Med 2004 Vol. 32, No. 11
Parekh D, Dancer R, Thickett D. Acute Lung Injury. Clinical Medicine 2011, Vol 11, No 
6: 615–18.
Park DP, Welch CA, Harrison DA, Palser TR, Cromwell DA, Gao F, et al. Outcomes 
following oesophagectomy in patients with oesophageal cancer: A secondary analysis of 
the icnarc case, mix programme database. Crit Care. 2009;13(Suppl 2):S1
Patel, B. V., Wilson, M. R., Odea, K. P. & Takata, M. TNF-Induced Death Signaling 
Triggers Alveolar Epithelial Dysfunction in Acute Lung Injury. The Journal of 
Immunology, 2013, 190.
Paul DJ, Jamieson GG, Watson DI, Devitt PG, Game PA. Perioperative risk analysis for 
acute respiratory distress syndrome after elective oesophagectomy. ANZ J Surg. 2011 
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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
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Biopharm, 15, 657-680.
Slutsky, A. S. & Ranieri, M. Ventilaor-Induced Lung Injury. NEJM. 2013. 369(22) 
p2126.
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Warnell I and Baudouin SV. Peri-operative risk factors for acute lung injury after elective 
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Tsai, J.A., Lund, M., Lundell, L and Nisson-Ekdahl, K. One-lung ventilation during 
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Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to 
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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.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
TFR116341
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Placebo Controlled, 
Double-blind, Multi-centre, Single Dose, Parallel Group, 
Randomised Clinical Trial of GSK2862277 in Patients 
undergoing Oesophagectomy Surgery
Compound Number 
:
GSK2862277
Effective Date 
:
17-NOV-2015
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol TFR116341.

This RAP is intended to describe the planned efficacy, safety & tolerability, 
pharmacokinetics and pharmacodynamic analyses required for the study. 

This version includes amendments to the originally approved RAP.

This RAP will be provided to the study team members to convey the content of i) the 
interim analyses output (including sample size re-estimation) and ii) the Statistical 
Analysis Complete (SAC) deliverable.

Note: Analyses and outputs to support the exploratory translational sub-study will be 
covered in a separate stand-alone RAP and such outputs are not expected to form 
part of the SAC deliverable for the main study
Author’s Name and Functional Area: 
 
17-NOV-2015
Manager, Statistics (Clinical Statistics)
Statistician (Clinical Statistics)
Approved via e-mail by: 
17-NOV-2015
Director (Clinical Statistics)
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
1.1.
RAP Amendments ........................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................10
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................10
2.2.
Study Objective(s) and Endpoint(s).............................................................10
2.3.
Study Design ..............................................................................................12
2.4.
Statistical Hypotheses.................................................................................12
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Interim Analyses .........................................................................................13
3.1.1.
Interim analysis #1: Unblinded safety review after approx 
10 patients have completed Day 7 visit; roughly 5 per 
study drug arm.............................................................................13
3.1.2.
Interim analysis #2: Unblinded safety review, futility 
analysis and sample size re-estimation after approx 40 
patients have completed Day 7 visit; roughly 20 per study 
drug arm. .....................................................................................14
3.2.
Final Analyses ............................................................................................19
4.
ANALYSIS POPULATIONS ...................................................................................19
4.1.
Protocol Deviations.....................................................................................20
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................22
6.1.
Overview of Planned Analyses ...................................................................22
7.
PRIMARY STATISTICAL ANALYSES....................................................................23
7.1.
Efficacy Analyses........................................................................................23
7.1.1.
Overview of Planned Efficacy Analyses .......................................23
7.1.2.
Planned Efficacy Statistical Analyses...........................................25
8.
SECONDARY STATISTICAL ANALYSES .............................................................29
8.1.
Efficacy Analyses........................................................................................29
8.1.1.
Overview of Planned Efficacy Analyses .......................................29
8.1.2.
Planned Efficacy Statistical Analyses...........................................30
8.2.
Safety Analyses..........................................................................................35
8.2.1.
Overview of Planned Analyses ....................................................35
8.3.
Pharmacokinetic Analyses..........................................................................36
8.3.1.
Overview of Planned Pharmacokinetic Analyses .........................36
8.3.2.
Drug Concentration Measures .....................................................36
8.3.3.
Pharmacokinetic Parameters.......................................................36
8.3.3.1.
Deriving Pharmacokinetic Parameters........................36
8.3.3.2.
Statistical Analysis of Pharmacokinetic
Parameters.................................................................37
8.4.
Pharmacodynamic (Biomarker) Analyses ...................................................38


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8.4.1.
Overview of Planned Pharmacodynamic (Biomarker) 
Analyses......................................................................................38
8.4.2.
Planned Pharmacodynamic (Biomarker) Statistical 
Analyses......................................................................................39
9.
OTHER STATISTICAL ANALYSES .......................................................................42
9.1.
Exploratory Statistical Analyses ..................................................................42
10. REFERENCES.......................................................................................................43
11. APPENDICES........................................................................................................44
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................45
11.1.1.
Exclusions from Per Protocol Populations....................................45
11.2.
Appendix 2: Time & Events.........................................................................46
11.2.1.
Protocol Defined Time & Events ..................................................46
11.3.
Appendix 3: Treatment States and Phases.................................................50
11.3.1.
Treatment Phases .......................................................................50
11.3.2.
Treatment States .........................................................................50
11.3.2.1.
Treatment States for AE Data.....................................50
11.4.
Appendix 4: Data Display Standards & Handling Conventions....................51
11.4.1.
Study Treatment & Sub-group Display Descriptors......................51
11.4.2.
Baseline Definition & Derivations .................................................52
11.4.2.1.
Baseline Definitions....................................................52
11.4.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................52
11.4.3.
Reporting Process & Standards...................................................53
11.5.
Appendix 5: Derived and Transformed Data ...............................................56
11.5.1.
General........................................................................................56
11.5.2.
Study Population..........................................................................56
11.5.3.
Safety ..........................................................................................57
11.5.4.
Efficacy........................................................................................58
11.5.5.
Pharmacokinetic ..........................................................................60
11.5.6.
Pharmacodynamic (Biomarker)....................................................61
11.5.7.
Exploratory Endpoints..................................................................61
11.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data ...............62
11.6.1.
Premature Withdrawals................................................................62
11.6.2.
Handling of Missing Data.............................................................62
11.6.2.1.
Handling of Missing Dates..........................................63
11.6.2.2.
Handling of Partial Dates............................................64
11.6.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................64
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................65
11.7.1.
Laboratory Values........................................................................65
11.7.2.
ECG.............................................................................................66
11.7.3.
Vital Signs....................................................................................66
11.8.
Appendix 8: Biomarker Details....................................................................68
11.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............70
11.9.1.
Handling of Covariates, Subgroups & Other Strata......................70
11.10. Appendix 10: PVPI and EVLW – Supplementary Information......................72
11.10.1. Data derivations to be performed by GSK....................................72


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11.10.2. Theoretical Underpinning of Transpulmonary 
Thermodilution Measurements.....................................................72
11.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................77
11.11.1. Bayesian Analyses (SAS Proc MCMC)........................................77
11.11.1.1. Prior Distributions .......................................................77
11.11.1.2. Initial Values...............................................................79
11.11.1.3. Convergence Diagnostics...........................................79
11.11.1.4. Additional Model Checking (optional at the 
discretion of the study statistician)..............................80
11.11.1.5. Possible corrective actions for non-converging 
MCMC models............................................................81
11.11.2. Mixed modelling assumptions (SAS Proc MIXED) .......................81
11.12. Appendix 12: Details of Simulation exercise that produced 
operational characteristics used in the protocol...........................................83
11.12.1. Simulations supporting interim analysis 2 ....................................83
11.12.2. Simulations providing operating characteristics of the 
target sample size (40 per arm) ...................................................91
11.13. Appendix 13: Abbreviations & Trade Marks ..............................................106
11.13.1. Abbreviations.............................................................................106
11.13.2. Trademarks ...............................................................................107
11.14. Appendix 14: List of Data Displays............................................................108
11.14.1. Data Display Numbering............................................................108
11.14.2. Mock Example Shell Referencing ..............................................108
11.14.3. Deliverable [Priority]...................................................................108
11.14.4. Study Population Tables............................................................109
11.14.5. Efficacy Tables ..........................................................................112
11.14.6. Efficacy Figures .........................................................................117
11.14.7. Safety Tables.............................................................................120
11.14.8. Safety Figures ...........................................................................125
11.14.9. Pharmacokinetic Tables.............................................................126
11.14.10.Pharmacokinetic Figures ...........................................................128
11.14.11.Pharmacodynamic (Biomarker) Tables......................................130
11.14.12.Pharmacodynamic (Biomarker) Figures.....................................132
11.14.13.Pharmacogenetic Tables ...........................................................134
11.14.14.ICH Listings ...............................................................................135
11.14.15.Non-ICH Listings........................................................................139
11.15. Appendix 15: Example Mock Shells for Data Displays ..............................143


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP details all planned analyses and outputs required for the final Clinical 
Study Report (CSR) of study GSK2862277 TFR116341.
Protocol

This RAP is based on protocol amendment 4 (Dated: 16/FEB/2015) of study 
GSK2862277 (GSK Document No. : 2014N197251_04 and eCRF Version (1).
Primary 
Objective

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 (PVPI).
Primary 
Endpoint

Baseline adjusted change in PVPI on completion of surgery
Study 
Design

A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, 
Randomised Clinical Trial of GSK2862277 in Patients undergoing 
Oesophagectomy Surgery

No formal sample size calculations were performed, however, the number of 
patients is based on computer simulations of baseline adjusted change in PVPI 
and PaO2/FiO2 on completion of surgery outcomes.  Posterior probabilities of 
each outcome are assessed in combination against chosen threshold criteria to 
determine the likelihood of success/failure of the study to detect true treatment 
differences.  A sample size of 40 subjects p.a. has an equivalent of a Type I 
error rate of 4.65% and a probability of 80.64% of detecting plausible effect 
sizes. A sufficient number of subjects will be enrolled such that 80 subjects 
complete dosing and assessments.

Patients enrolled in the study will be scheduled to undergo planned/elective 
trans-thoracic surgery for oesophagectomy.  Prior to surgery patients will 
receive a single nebulised dose of GSK2862277 or placebo.

A factorial treatment structure is used in the randomisation (Treatment and the 
lung which BAL is sampled from, both two level factors). Summary tables of the 
raw/observed data will be produced with all possible groupings (See Section 
11.4.1). Although each statistical model will contain adequate terms to account 
for the full factorial treatment structure the majority of statistical analyses for 
non BAL related endpoints will implicitly assume that the Treatment by BAL 
interaction is negligible and present results as treatment comparisons averaged 
over the levels of the BAL factor; without formally testing for it (mainly due to the 
small sample size). Informal checking of this assumption may consist of 
examining the posterior distribution for the interaction term and visually 
assessing whether it is non zero. If this is deemed to have occurred the 
corresponding summary tables and analysis outputs will be modified. For BAL 
related endpoints the starting assumption for summary tables and statistical 
modelling will be the interaction term is present, but outputs may be modified if 
the interaction is subsequently deemed negligible.

Due to the nature of the endpoints in this study (e.g. the invasive medical 
procedures needed to obtain PVPI) it is often not practical/ethical to schedule 


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Overview
Key Elements of the RAP
true baseline samples (pre-randomisation / pre-dose). However, in mitigation, it 
should be noted that the surgical procedure is expected to be the principal 
factor driving changes in many of these study endpoints (e.g. PVPI and 
PaO2/FiO2) and the scheduled baseline is measured before the surgical 
intervention. Therefore, potential interpretational difficulties (e.g. attributing 
causality: chance result or real treatment effect acting over the dose to baseline 
time period) should large differences between baseline values on the treatment 
arms are acknowledged but accepted (this is an exploratory and not 
confirmatory study). If the observed difference between treatments at baseline 
is deemed to be large / clinically important appropriate sensitivity analyses may 
be performed (for example, but not limited to, omitting the baseline term from 
the corresponding statistical model).
Planned 
Analyses

Interim analyses are detailed within Section 3.1 where applicable.

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to Database Freeze of the study data.
Analysis 
Populations

The ‘Safety Population’ will be used to evaluate study population andsafety and 
‘PK’ population to evaluate pharmacokinetics.

Per protocol populations have been defined that exclude “open and shut” 
cases; and will be used as part of efficacy and PD/Biomarkers analyses.
Hypothesis

The study was designed to estimate the effect of a single nebulised 26 mg dose 
of GSK2862277 relative to placebo on primary and secondary efficacy 
endpoints.

No formal statistical hypothesis tests will be conducted; instead an estimation 
approach will be undertaken.
Primary 
Analyses

The protocol proposed an end of study decision pathway, consisting of the 
primary endpoint and PaO2/FiO2 on completion of surgery (adjusting for the 
baseline values of each endpoint)

Evaluation of this decision pathway via joint modelling of the 2x endpoints 
constitutes the primary analysis.

The primary analysis utilises a Bayesian framework with Monte Carlo Markov 
Chain (MCMC) sampling techniques. The decision pathway will be evaluated 
via posterior distributions of appropriate combinations of the model parameters.

The decision pathway is not binding upon GSK but provides an a priori
yardstick to measure the success of the trial against.
Note: The marginal distribution of baseline adjusted PVPI on completion of surgery 
is obtained as part of the steps to evaluate the decision grid (hence this primary 
analysis does cover the primary objective/endpoint stated in the protocol).
Secondary 
Analyses

Baseline adjusted change in PVPI on completion of surgery: Bayesian 
ANCOVA model(s) with baseline and centre as fixed effects with covariate 
exploration / model building activities (e.g. duration of surgery and duration of 
one lung ventilation as plausible continuous covariates). Acts as confirmation 


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Overview
Key Elements of the RAP
that the marginal distribution from the Primary analysis is appropriate.

Baseline adjusted change in extravascular lung water index (EVLWI) and 
baseline adjusted change in PaO2/FiO2, on completion of surgery will be 
analysed in a similar manner to the Secondary Analysis of PVPI (single time
point analysis), described above.

Bayesian repeated measures analysis of post-operative PVPI, EVLWI and 
PaO2/FiO2 (separate model for each endpoint; assuming a mixed effects model 
structure). Baseline adjusted medians and 95% credible intervals will be 
constructed for the differences/ratios between GSK2862277 26 mg and 
Placebo at each of the post-operative time points.

Safety data will be presented in tabular format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards. 

Incidence and titres of serum anti-GSK2862277 antibodies post dosing will be 
summarised by treatment and listed by subject

Individual GSK2862277 plasma concentration-time profiles and median/mean 
(±SD) profiles will be plotted and listed. Derived PK parameters will be
summarised and listed.  BAL fluid and plasma urea data, along with the derived 
Dilution Factor will be summarised and listed.  BAL fluid concentrations of 
GSK2862277, the volume of ELF in BAL fluid and pooled ELF concentration of 
GSK2862277 will be summarised and graphically presented. No formal 
statistical analyses will be conducted.

Biomarkers in BAL will be analysed in a Bayesian framework assuming a mixed 
effects model structure.  Summary statistics from derived posterior probability 
distributions (such as treatment medians and 95% credible intervals) will be 
constructed for the differences/ratios between GSK286227 26 mg and Placebo
at each time point (and possibly within each BAL sampling location too).
Exploratory 
Analyses

Daily SOFA scores will be analysed using Bayesian repeated measures 
analyses.  Adjusted medians and 95% credible intervals will be presented in 
tables and graphically for each treatment by day, together with estimated 
treatment differences GSK2862277 26 mg – Placebo and the corresponding 
95% credible intervals. Note: Strong assumptions will be made to predict a 
baseline SOFA score for each subject to evaluate change from baseline SOFA 
(exploratory)

Blood/Cellular Biomarkers will be analysed in a similar fashion to the BAL 
biomarkers.

Other clinical parameters would be summarised by treatment and listed by 
subject. Statistical modelling would be conditional on the observed data.


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1.1.
RAP Amendments
Revision chronology:
RAP Section(s)
Amendment details
Reporting and Analysis Plan Final [10-JUL-2015]
Reporting and Analysis Plan Final Amendment 1 [17-NOV-2015] – Pre unblinding for IA1
Cover Page
Indicated RAP contains amended text
1
Clarified Analysis Populations for Efficacy PD/Biomarkers will 
be Per protocol (i.e. will not include “Open and Shut” cases)
1.1
Added Revision Chronology Table
3.1.2
Clarified IA2 will use mixture of Safety and Per protocol 
populations
7.1.1 & 8.1.1
Clarified Per Protocol 2 population to be used instead of Safety
8.4.1
Clarified Per Protocol 2 population to be used instead of Safety, 
except for BAL related outputs where Per Protocol 1 popualtion 
is required
8.4.1 Table 8
Updated List of Planned Biomarkers to reflect current plans at 
time of RAP amendment 1
11.1.1
Clarified that an upcoming eCRF version will have a variable 
indicating if a subject was an “open and shut case” and manual 
programming may be required to implement the populations if 
this variable is not retrospectively populated for existing 
subjects.
11.6.2.1
Added section for missing date/times for surgical procedures 
and biomarker samples to account for known missing data for 
subject
(known at time RAP amendment #1 written).
PPD


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RAP Section(s)
Amendment details
Reporting and Analysis Plan Final [10-JUL-2015]
Reporting and Analysis Plan Final Amendment 1 [17-NOV-2015] – Pre unblinding for IA1
11.7.1
Based upon medical monitor advice:

Corrected Low Flag value for Hemoglobin (Males and 
Females) because it was specified in g/dL and not g/L

Changed PR interval Lower and Upper PCI values

Change from Baseline “Increase from Baseline QTc”: 
Moved the range from the Lower to the Upper column 
(leaving Lower column blank)

Re-drew the Vital Sign Parameter (Change from 
Baseline) tables to only have one entry for Decreases 
and Increases respectively
11.8
Updated List of Planned Biomarkers to reflect current plans at 
time of RAP amendment 1
11.14
Amended populations for efficacy/Biomarker related outputs 
and corrected typos in timing/priority (e.g. “IA [2]” corrected to 
“IA2 [1]”)


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the substance of the originally planned primary 
statistical analysis specified in the protocol / protocol amendment 4 (Dated: 
16/FEB/2015). Clarification of how the four level treatment structure is incorporated into 
the decision grid and a mechanism to adjust for other covariates such as centre have been 
included in this RAP.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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
Secondary Objectives
Secondary Endpoints

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.

To evaluate the safety and tolerability 
of GSK2862277 administered 
preoperatively

AEs

Clinical laboratory safety data.

ECG readings

Vital signs

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

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.

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

To describe plasma pharmacokinetics 
of a single inhaled dose of 
GSK2862277.

Plasma concentrations of GSK2862277 and derived 
pharmacokinetic parameters.

To quantify the concentration of 

BAL concentrations of GSK2862277 and derived 


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Objectives
Endpoints
GSK2862277 in BAL and to compare 
to plasma levels of GSK2862277
pharmacokinetic parameters

Ratio of BAL concentration to plasma concentration.

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
Exploratory Objectives
Exploratory Endpoints

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

To evaluate changes in TNFR related 
and disease biology biomarkers in the 
blood of patients who have been 
treated with GSK286227 compared to 
placebo, on completion of surgery and 
in the immediate post-operative 
period.

Difference from placebo in levels of plasma biomarkers 
(e.g. IL-6, sRAGE) on completion of surgery and through 
to Day 4


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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

Randomised placebo controlled, double-blind, multi-centre, 
single dose parallel group, design in patients undergoing 
Oesophagectomy surgery.

Dosing

Single nebulised dose 1-5 hours prior to surgery.
Treatment Assignment

N=80 subjects randomised across two groups, dosed and 
completed all assessments (40 patients per group).

GSK RandAll NG used to generate randomisation schedules. 

Patients are randomized to receive 26 mg GSK2862277 or 
Placebo and either ventilated or collapsed lung BAL 
procedure.
Interim Analysis

Unblinded safety review after approx 10 patients have 
completed Day 7 visit; roughly 5 per arm

Unblinded safety review and futility analysis after approx 40 
patients have completed Day 7 visit; roughly 20 per arm
(includes Sample size re-estimation)
2.4.
Statistical Hypotheses
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 


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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.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
There are two interim analyses planned for this study both of which will use unblinded data (an 
unblinded sample size re-estimation will be performed as part of interim analysis #2).  Further 
details are given in Section 3.1.1 and Section 3.1.2.  The interim analyses will be performed by the 
study statistician (or designate).  The appropriate internal GSK procedures will be followed to 
ensure that access to unblinded subject level data is restricted to the specific study team members 
who require access.
3.1.1.
Interim analysis #1: Unblinded safety review after approx 10 
patients have completed Day 7 visit; roughly 5 per study drug 
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 (IA1) is being performed. IA1 will use the “Safety” population applicable at 
the time of the data cut.
The following safety outputs will be provided:

Demographic information

AE/SAEs

Laboratory data

Vital signs

ECG data

Concomitant medications

Listing of surgical procedure information for each subject
For further details of the output see Appendix 14.
Note: An additional informal check of the available plasma PK values may be made to give 
confidence dosing is occurring as intended. Samples will be batched and sent for analysis at 
designated intervals during the study and the results made available (batches will be timed to 
coincide with the interim analyses). The check would be basic; namely confirming subjects on 
active doses of GSK2862277 with available plasma PK concentrations at the time of the interim 
had at least one quantifiable post dose value of GSK2862277. No outputs will be reported from this 
step and the timing of the interim analyses will not be delayed on account of this. Appropriate 


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remedial action(s) would be taken if this check revealed potential problems with the dosing (for 
example, but not limited to, re-training of selected sites on the use of the equipment, or processing 
all the collected PK samples with formal PK and/or PK/PD modelling with a view to a dose 
adjustment – details would be documented in any associated protocol amendment and/or the 
CSR).
3.1.2.
Interim analysis #2: Unblinded safety review, futility analysis and 
sample size re-estimation after approx 40 patients have 
completed Day 7 visit; roughly 20 per study drug arm.
A “soft lock” of the database for those subjects in scope for interim analysis #2 (IA2) is 
planned. This should ensure the IA2 eCRF data are as clean as possible and that data for 
the potential analyses in Figure 1 are available in a reasonable timeframe. IA2 will use a 
mixture of the “Safety” and “Per Protocol” populations applicable at the time of the data 
cut.
In addition a Sample size re-estimation will take place at IA2 to determine if the overall 
target sample size should remain at 80 subjects (~40 p.a.).
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
Figure 1 indicates the flow of additional data to be reviewed upon a “Pause and Review” 
outcome and possible actions; although it should be stressed that Figure 1 is non-binding. 
Emerging patterns in the data may suggest other analyses not described here that may 
influence the action taken.
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 baseline adjusted 
endpoints on completion of surgery:

PVPI Ratio: Mean Active/Mean Placebo, 

P to F Ratio Difference: Mean Active – Mean Placebo
and will utilise predictive inference, decision pathway and confidence thresholds.
The interim analysis will assume that there is no interaction between study drug (active 
and placebo) and the location of the BAL lung sampling (collapsed or ventilated). 
Therefore the 4 treatments will be combined to two treatments (based on study drug) and 


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15
references to treatment arms in this section assume usage of Alternative Treatment 
descriptors #1 (See Section 11.4.1). The algorithm suggested in Section 9.3.1 of the 
protocol has been modified to allow adjustments for other covariates.
The algorithm for the interim analysis is as follows:
1. Apply any transformations to the endpoint(s) (and baseline(s)) and center any 
continuous covariates.
2. Fit a model similar in form to that described in Section 7.1.2 to the observed IA2 
data. Note: Should use separate variance covariance matrices (one per treatment 
arm).
3. The equivalent of adjusted least square means will be constructed for each 
endpoint on each treatment arm. 
4. Once MCMC model convergence has been achieved the current iteration’s values 
for the variance covariance matrix and the adjusted least square mean vector 
define a multivariate normal distribution for a future subjects data (a separate 
distribution per treatment arm)
5. Use the newly defined multivariate normal distributions to simulate enough 
subjects to achieve an overall total of 40 per arm
6. Repeat steps 4 & 5 1000 times (i.e. 1,000 samples once the MCMC model has 
converged).
7. For each treatment arm, use the median values of the adjusted least square means 
and the median values of each element of the variance covariance matrix to derive 
the hyperparameters of the Normal-Inverse-Wishart distribution for each 
treatment (i.e. constructed using the model adjusted IA2 immediately post 
surgical values rather than being derived directly from the raw/observed data) –
see Table 14 for how to obtain these parameters.
8. Derive Multivariate sample statistics from each simulated dataset (see Section 
11.12.1 for the list of sample statistics to derive). The sample statistics will be 
used to update the parameters of the Normal-Inverse-Wishart distribution for each 
treatment (see Table 15).
9. Use the updated Normal-Inverse-Wishart distributions to estimate the end of 
study mean treatment effects (i.e. condition on the Expected value of the VCV) 
and then determine the parameters describing the distribution of the mean end of 
study treatment difference (See Section 11.12.1).
10. Determine whether the probability of observing ANY decrease in PaO2/FiO2
means and Any increase in PVPI means is greater than 0.1
11. If so then record that simulated study as being futile
12. Repeat steps 8 to 10 1000 times
13. Determine the proportion of the 1000 simulated studies which meet the futility 
threshold
14. If the proportion is larger than 0.3 then the recommendation is to “Pause and 
Review”, otherwise the recommendation is to “Continue”


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Interim 
Analysis #2
Details
Additional 
details on 
the Method

PVPI and PaO2/FiO2 on completion of surgery

Baseline: PVPI and PaO2/FiO2 immediately prior to surgery (day 1)

Any transformation of a response variable is also expected to be applied to the 
corresponding baseline variable. Final decisions on transformations will be 
based on the observed data and model diagnostics (PVPI is expected to 
require a Ln (natural logarithm) transformation)

Any observations with missing model covariates (e.g. baseline) would be 
excluded from the model fitting process (i.e. also excluding the record from any 
centering of covariates) 

The above endpoints and baselines will be the average of any replicates 
available at the planned time points

The model specifications described in Section 7.1.2 (primary analysis) will also 
apply to the model fitted to the observed set of IA2 data where applicable. 
Exceptions include only using the burn in and thinning parameters to achieve 
MCMC model convergence (the number of posterior draws will be limited to 
1,000 to match the required number of future simulated study outcomes). In 
addition the IA2 model does not require directly fitting 4 separate treatment 
parameters. Therefore the following is an example construction for the adjusted 
least square equivalent Ln{PVPI}








Centers
Center
centers
i
i
PVPI
Pbo
#
ˆ
#
1
,

Output

By subject time profiles of PVPI and PaO2/FiO2 grouped by treatment will be 
produced using the available IA2 data.

Scatterplots of the observed IA2 data from each subjects will be produced 
(grouped by treatment and IA2 timepoint)

Descriptive statistics for absolute and change from baseline PVPI and 
PaO2/FiO2 grouped by treatment will be tabulated.

A set of summary text describing the IA2 process and recommendation will be 
produced. Note: In addition the full output from SAS PROC MCMC will be 
produced for statisticians to assess the suitability of the model but this is not 
expected to be disseminated further due to its technical nature.
Pause and 
Review 

In the event of a “Pause and Review” recommendation the analyses described 
in Figure 1 may be attempted in the order described therein.

Analyses in Figure 1 are expected to be the same as their respective end of 
study analyses (e.g. analyses involving BAL will account for the BAL lung 
sampled in the statistical modelling and if necessary compare active to placebo 
within each of those strata).

No formal decision criteria for Figure 1 are specified here.  The results of the 
analyses described in Figure 1 will be used to inform the decision to “Continue”, 
“Modify” or “Stop” in discussions with the study team.  Additional analyses may 
be performed if appropriate and documented in the CPSR.
Sample Size 
Restimation

The adjusted sample size (total number of subjects) will be determined by the 
clinical study team after reviewing the outcome of the following exercise. It is 


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Interim 
Analysis #2
Details
expected to be the smallest value from either the current upper limit (80) or the 
re-estimated value (i.e. it is expected to remain capped at 80 subjects). There is 
no minimum limit, so it is therefore possible that the re-estimated sample size 
chosen by the clinical study team is the same value as the observed number of 
IA2 subjects, and hence the study will cease recruiting new subjects.

The re-estimation will use the median estimates of each of the elements in the 
VCV matrix obtained from the (adjusted) modelling of the observed IA2 data. It 
will use the similar methodology to the protocol (see Section 11.12.2 for details 
of the simulation process), except that total sample size will be varied until the 
resulting operating characteristics for the “Overall success outcome” using the 
“Null” and “Minimum desired profile” scenarios match the ones obtained for a 
total sample size of 80 (roughly 4.65% and 80.64% respectively). If the point 
estimates for the variances from the observed IA2 data are larger than the 
assumed values used in the protocol then the procedure will start at 80 subjects 
and increase by 2 subjects until the criteria are met, and conversely if the 
observed variances are smaller the process will start at 80 subjects and 
decrease by 2 subjects until the criteria are met. Note: Larger increments may 
also be used to arrive in the “ball park” more quickly (e.g. 6, 10 or 20 subject 
increments)


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Figure 1
Flow chart of additional data and questions in the event of IA2 Pause and Review outcome (non-exhaustive list)
IA2 “Pause and Review”
Plasma PK (in subjects 
receiving active)
BAL: TNFRI (free and bound 
complex)
BAL: Inflammatory markers 
IL-6, IL-8 and TNFa 
Other Transpulmonary 
Thermodilution endpoints (e.g. 
EVLWI)
Exploratory clinical outcome 
measures (SOFA, Incidence of 
ARDS, Resource usage)
Surgical outcome(s)
>1 quantifiable concentration 
in majority of subjects?
Free decreases as complex 
increases (on active arm)?
Reduction in inflammation c.f. 
Pbo?
Consistent with PVPI trends?
Improvements c.f. Pbo?
Improvements c.f. Pbo?
No:
Stop study and investigate why not
No:
Stop study (no target engagement in 
this patient population)
Yes:
Check Serum markers. Exposure 
response modelling and modify dose 
or route (e.g. IH to IV)
No:
Investigate whether sub-group of 
patients respond in different ways 
and modify inc./excl. criteria
Dependent on what is observed: Investigate 
sub-groups / biological review for 
plausibility that benefit is drug related and 
not a chance observation
Key Question
Possible action(s)


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3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screen Failures

Comprise all subjects who enrolled but are 
recorded as screen failures

Screen Failures
Safety

Comprise of all subjects who receive at least 
one complete dose of study treatment.

This population will be based on the 
treatment the subject actually received.

Study Population

Safety

Efficacy
Pharmacokinetic
(PK)

Subjects in the ‘Safety’ population for whom 
a pharmacokinetic sample (plasma and/or 
BAL) was obtained and analysed.

PK
Per Protocol 1 
(PP1)

Subjects in the ‘Safety’ population for whom 
the treatment actually received was the same 
one they were randomised to (both study 
drug and BAL sampling location)

Met the protocol defined inclusion/exclusion 
criteria (if criteria are changed during course 
of study apply the set applicable at the time 
of their enrolment)

Not an “open and shut” (inoperable) surgical
case

Efficacy
Per Protocol 2 
(PP2)

Subjects in the ‘Safety’ population for whom 
the study drug actually received was the 
same one they were randomised to (study 
drug)

Met the protocol defined inclusion/exclusion 
criteria (if criteria are changed during course 
of study apply the set applicable at the time 
of their enrolment)

Not an “open and shut” (inoperable) surgical 
case

Efficacy


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20
Population
Definition / Criteria
Analyses Evaluated
Per Protocol 3 
(PP3)

Subjects in the ‘Safety’ population for whom 
the BAL lung actually sampled was the same 
one they were randomised to

Met the protocol defined inclusion/exclusion 
criteria (if criteria are changed during course 
of study apply the set applicable at the time 
of their enrolment)

Not an “open and shut” (inoperable) surgical 
case

Efficacy
Interim Analysis 1 
(IA1)*

Subjects in the ‘Safety’ population at the time 
of the Interim Analysis 1 data cut

Outputs detailing 
population 
membership
Interim Analysis 2 
(IA2)*

Subjects in the ‘Safety’ population at the time 
of the Interim Analysis 2 data cut

Outputs detailing 
population 
membership
NOTES : 

Please refer to Appendix 1: List of Data Displays which details the population to be used for each displays being 
generated.

*= Population will only be produced to support the end of study reporting. Outputs required to support each of the 
interim analyses will use the applicable population at the time of the respective interim analysis data cut.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o
For subjects involved in the interim analyses every effort will be made to review 
the (uncleaned) data from those subjects prior to unblinding those individuals. 
However given the interim database(s) may not be frozen these in-stream 
decisions may be revised if new information becomes apparent. Any such 
revision, and justification if necessary, would be noted in the study file.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Treatment States and Phases
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
11.8
Appendix 8: Biomarker Details
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
11.10
Appendix 10: PVPI and EVLW – Supplementary Information
11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
11.12
Appendix 12: Details of Simulation exercise that produced operational characteristics 
used in the protocol
11.13
Appendix 13: Abbreviations & Trade Marks
11.14
Appendix 14: List of Data Displays
11.15
Appendix 15: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Randomisation
Randomisation
Y
Blind broken (excluding when part of interim analyses)
Y
Subject Accountability
Study Population membership
Y
Y
Subject Disposition
Disposition
Y
Reasons for Screening Failures
Y
Y
Reasons for Withdrawals
Y
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography
Demographic Characteristics
Y
Y
Race & Racial Combinations
Y
Y
European Medicines Agency: Summaries for the European 
Clinical Trials Database (EudraCT)
Y
Medical Condition & Concomitant Medications
Concomitant Medication
Y
Y
Medical Conditions (Current and Past)
Y1
Y
Exposure
Exposure
Y
NOTES :

Y = Yes display generated.

1 = Summarise Current and Past conditions in separate tables


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
Further details regarding Transpulmonary Thermodilution (TPTD) measurements are 
provided in Appendix 10: PVPI and EVLW – Supplementary Information.
The primary efficacy analyses will be based on the “Per Protocol 2” population, unless 
otherwise specified.
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 3
Overview of Planned Efficacy Analyses
Endpoint / 
Parameter/ Display 
Type
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Transpulmonary Thermodilution
PVPI
Y
Y
Y
Y1.
Y
Y1.
PaO2/FiO2
Y
Y
Y
Y1
Y
Y1.
Joint Modelling of 
PVPI and PaO2/FiO2
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Natural logarithms of the observed response will be performed if it is deemed appropriate prior to modelling. If 
Natural logarithms are used results will be back-transformed for display purposes.
1.     Listing should also flag any discrepancies between the eCRF supplied PVPI and any in-house GSK re-derivations.
Figure 2 shows the proposed End of Study Decision Pathway based on joint modelling of 
PVPI and PaO2/FiO2. 
In crude terms decreases in PVPI and increases in PaO2/FiO2 (relative to the changes 
seen on the placebo arm) are the desired outcomes for the study drug.


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Figure 2
End of Study Decision Pathway
Note: In Figure 2 statements such as “ 11.6% ” translate as “the decrease (active 
relative to placebo) is less than 11.6%; i.e. when the ratio of the treatment means 
(Act/Pbo) is greater than 0.884”. The implication being that there is a 75% chance or 
more that study drug hasn’t decreased PVPI enough and the outcome is “Potentially 
Unsuccessful”.
The posterior probability of each Figure 2 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”
Note: The primary analysis will only use the pre-op and immediate post op values of 
PVPI and PaO2/FiO2. Secondary analysis (a repeated measures version of the joint 
modelling) may also include the same set of timepoints and comparisons, but because the 
estimates across multiple timepoints may be correlated there may be minor differences in 
the results from the Primary and Secondary analysis models. In such a scenario the 
primary analysis model will take precedence. Only if the study statistician deems any 


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discrepancies to be large enough to be of concern will further discussion and/or comment 
be added to the CSR.
7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

PVPI and PaO2/FiO2 on completion of surgery

Baseline: PVPI and PaO2/FiO2 immediately prior to surgery (day 1)

Any transformation of a response variable is also expected to be applied to the corresponding 
baseline variable. Final decisions on transformations will be based on the observed data and 
model diagnostics (PVPI is expected to require a Ln (natural logarithm) transformation)

Any observations with missing model covariates (e.g. baseline) would be excluded from the 
model fitting process (i.e. also excluding the record from any centering of covariates) 

The above endpoints and baselines will be the average of any replicates available at the 
planned time points
Model Specification

The (transformed) endpoints will be assumed to follow a multivariate normal distribution.  
Linear predictors will be derived for each subject (i.e. obtain a vector of means for the MVN 
distribution). Each treatment arm will also have a separate variance covariance matrix.

The linear predictors will consist of mean vectors to capture the effect of treatment for each 
endpoint and a variety of other model terms (an example is given at the end of this text). 

Main Treatment Descriptors to be used (i.e. 4 levels of the treatment term)

No intercept terms should be fitted for either endpoint (due to fitting all 4 levels of treatment).  

Baseline vectors will be fitted as continuous covariates (baseline values should be centered 
prior to inclusion in the model, centering to occur after any transformation of the individual 
subjects responses). 

Categorical  fixed effect vectors should be added for Center by Endpoint  (if recruitment is such 
that center terms are poorly estimated then appropriate action will be taken, including but not 
limited to, pooling of centers or removal of the term from the model). 

Non-informative priors will be utilized for each model parameter assigned either as a normal 
distribution centered on 0 with large variance 1E6 or as appropriate to the parameters 
distribution.

The prior for the variance covariance matrices 
Pbo

and 
Act

will be an inverse Wishart 
distribution (separate VCVs are not required for the BAL factor levels).  

SAS PROC MCMC will be used to combine the non-informative priors with the data observed 
to obtain sufficient draws from the posterior distribution (after any thinning) such that the 
MCSE/SD values for parameters of interest are less than 0.01 (anticipated to be in the region 
of ~100,000 draws).  If model convergence is poor then alternative initial parameter values 
should be considered.

The randomization seed used in PROC MCMC should itself be generated with an element of 
randomness - but there is no need to formally document this process (e.g. using Excel function 
RANDBETWEEN [1,9999999] and copying the result into the SAS code)

Combinations of the fitted model parameters will be used to answer the clinically relevant 
questions.


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Primary Statistical Analyses

Median values of the baseline adjusted response for each endpoint and their associated 95% 
credible intervals (equi-tailed) will be produced from the posterior distributions obtained via 
appropriate combinations of the fitted model parameters; akin to lease square means (e.g. 
Adjusted Pbo PVPI averaging over BAL = 










Centers
Center
centers
i
i
PVPI
PV
PVPI
PC
#
2
ˆ
ˆ
#
1
,
,


). 

The joint (bivariate) posterior probability distribution of the endpoints (averaging over BAL) will 
be obtained for the comparison(s) implied in Figure 2 by appropriate combinations of the fitted 
model parameters. The marginal posterior distributions for the comparisons for each endpoint 
will also be obtained from this joint posterior sample and be used to construct medians and 
95% equi-tail credible intervals for individual endpoints.  

Flag variables (taking binary values of 1 or 0) will be created to evaluate the steps in the end of 
study decision pathway for each simulated draw from the joint posterior distribution (Figure 2). 
The mean of each flag variable over the MCMC iterations is the estimate of the desired 
probability, and should be used to assess which study outcome has been observed. These flag 
variables (and constrained variables) may cause SAS to issue warning or error messages to 
the log due to their binary nature, especially if the result is clear cut and their value rarely 
changes (such warnings/errors should be reviewed but may be safely discounted)

In addition posterior probabilities of the differences (or ratios) for other cut-points (which may
be determined upon inspection of the data, or from developing business requirements), may 
also be computed.

Where applicable estimates would be derived at the means of any model covariates, akin to 
least squares means in PROC MIXED, and back transformed if necessary. When covariates 
are centered before the model fitting their mean is zero so the covariate can be dropped from 
the derivation.
The following describes the anticipated linear predictor for an hypothetical subject from center 
3, on active treatment, with BAL sampled from the collapsed lung and centered baseline values 
of -4.1 and -0.5 for P/F and PVPI respectively (note: additional covariates may be explored and 
added based on the observed data).


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Primary Statistical Analyses




































































































2
ˆ
ˆ
2
ˆ
ˆ
factor 
BAL
over 
averaging
P/F
Mean 
in 
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.
ˆ
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e
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 the
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 where
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assume
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link to
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)
I(C
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)
I(C
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I(C
),
I(C
and
1
)
I(C
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I(Act,
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)
Ventilated
I(Act,
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I(Pbo,
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I(Pbo,
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an 
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 term(s)
ˆ
ˆ
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,
ˆ
ˆ
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,
ˆ
ˆ
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ˆ
ˆ
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,
Center
Center
ˆ
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ˆ
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/
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/
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/
,
/
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4
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/
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PV
F
P
PC
F
P
AV
F
P
AC
PVPI
AV
F
P
AV
PVPI
AC
F
P
AC
PVPI
PV
F
P
PV
PVPI
PC
F
P
PC
Act
Pbo
Act
PVPI
F
P
MVN
PVPI
F
P
PVPI
AV
F
P
AV
PVPI
AC
F
P
AC
PVPI
PV
F
P
PV
PVPI
PC
F
P
PC
PVPI
F
P
PVPI
F
P
PVPI
F
P
PVPI
F
P
PVPI
F
P
PVPI
F
P
PVPI
F
P
g
e
y
y
y
y
Center
Where
Ventilated
Act
I
Collapsed
Act
I
Ventilated
Pbo
I
Collapsed
Pbo
I
Center
Center
Center
Center
Center
Center
Center
Center
C
I
C
I
C
I
C
I
C
I
S
B
S
B
y
y




















Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Posterior distributions for the Interaction between Study Drug and BAL will be produced and 
examined as part of the model fitting process (separate distribution per endpoint). If any of the 
endpoints is deemed to have a non-zero interaction then the treatment comparisons (study 
drug) will be obtained within each level of BAL, for BOTH endpoints and the same decision 
pathway will be applied to each. An example of the combinations required to obtain the 
Interaction term for PVPI is















2
ˆ
ˆ
2
ˆ
ˆ
/
,
/
,
/
,
/
,
F
P
AC
F
P
PV
F
P
AV
F
P
PC





A SAS coding trick may be required to fit separate variance covariance matrices to work 
around a known bug in the SASv9.3 TS1M2 MCMC procedure. Separate response variables 


CONFIDENTIAL
TFR116341
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Primary Statistical Analyses
may be required for each treatment arm (with all values set to missing if the record was from a 
subject not on that treatment). Multiple MVN model statements would link these endpoints to a 
distinct VCV matrix. See MCMC training course notes “An intro. to Bayesian methods using 
SAS” by 
 GSK, February 2014” Slide 56+ for details.
Model Results Presentation

Posterior treatment effects (adjusted Active and Placebo means averaging over the levels of 
BAL) and differences (or ratios) to placebo (marginals from the joint posterior probability 
distribution of the comparisons) will be displayed graphically. In addition a bivariate contour plot 
of the joint posterior distribution for the comparisons in Figure 2 may be produced (with the 
decision criteria overlaid onto it and the marginal distributions displayed) – this may require 
bespoke programming.

Median and 95% (equi-tail) credible intervals for the LSmean equivalents and Median and 95% 
(equi-tail) credible intervals for differences (or ratios) to placebo will be summarized.

Posterior probabilities for the end of study decision pathway (and other cut points)
Sensitivity and Supportive Statistical Analyses

Other potential a priori covariates include “Endpoint by duration of surgical procedure” and 
“Endpoint by duration of one lung ventilation” interaction terms. Each duration term would enter 
the model as a centered continuous covariate. The study statistician may explore the 
appropriateness of these terms, and whether they should enter as linear or higher order terms 
via scatterplots of covariate vs each endpoint. Given the relatively small sample sizes and 
exploratory nature of the trial the final analysis model used to make inferences may be 
selected via a combination of expert judgment and formal statistical model selection techniques 
(e.g. Bayes factors).

Intermediate model building outputs would not need to be formally reported – only the final 
chosen model would have associated Tables, Figures and Listings.

Optional (at discretion of study statistician): For robustness, assuming non-informative priors 
are used, the equivalent PROC MIXED model may be fitted and the LSMeans and estimates of 
differences compared to the results obtained from the PROC MCMC analysis. Output from this 
analysis may be listed as a stand alone output or as part of the MCMC raw SAS listings 
(conditional on PROC MIXED being used) – with no corresponding Tables or Figures.     

The above analyses may be repeated using the Per Protocol 1 population if deemed necessary 
by the study statistician                                                                                                                    
PPD


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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the “Per Protocol 2” population, unless 
otherwise specified.
Table 4 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 14: List of Data Displays.
Table 4
Overview of Planned Efficacy Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Transpulmonary Thermodilution5
Joint Modelling of PVPI 
and PaO2/FiO2
Y
Y
Y
Y1
Pulmonary Vascular 
Permeability Index 
(PVPI)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Extravascular Lung 
Water Index (EVLWI)4
Y
Y
Y
Y
Y
Y
Y2
Y
Y3
Extravascular Lung 
Water (EVLW)
Y2
Arterial Line Used
Y7
Y
Cardiac Output (CO)
Y2
Cardiac Index (CI)4
Y
Y2
Y
Y3
Global End-Diastolic 
Volume (GEDV)
Y2
Global End-Diastolic 
Volume Index (GEDI)4
Y
Y2
Y
Y3
Mean Arterial Pressure 
(MAP)
Y
Y
Y
Y
Systemic Vascular 
Resistance (SVR)
Y
Systemic Vascular 
Resistance Index 
(SVRI)4
Y
Y
Y
Y
Stroke Volume 
Variation (SVV)
Y
Y
Y
Y
Global Ejection 
Fraction (GEF)
Y
Y
Y
Y
Heart Rate (HR)
Y
Y
Y
Y
Blood Pressure (AP): 
Systolic and Diastolic
Y
Y
Y
Y
Central Venous 
Y
Y
Y
Y


CONFIDENTIAL
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30
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pressure (CVP)
Predicted Body 
Weight4
Y
Y
Predicted Body 
Surface Area4
Y
Y
Body Surface Area4
Y
Y
Oxygenation
PaO2/FiO2    4
Y
Y
Y
Y
Y
Y
Y
Y
Y
SpO2/FiO2   4
Y
Y
Y
Y
Y
Y
Correlation between 
PaO2/FiO2 and 
SpO2/FiO2   4
Y1
Mean Airway Pressure 
(Paw)
Y
Y
Y
Y
Oxygenation Index
Y
Y
Y
Y
SOFA
SOFA scores6
Y
Y
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Represented as scatterplot matrix
2.
List replicate values and the derived mean
3.
Derive mean of the replicate values prior to computing the change from baseline
4.
Derived in house by GSK from data collected on eCRF.
5.
Site instructed to set up machine to display the Absolute values and not the corresponding indexed values. If 
the site omitted to do this (monitors examining the PDF hard copy of the PiCCO output is an example of how 
GSK  may be alerted) then GSK will derive corresponding absolute versions using the formulas in Section 
11.5.4.
6.
Add footnotes to change from baseline SOFA outputs explaining the strong assumptions required to obtain 
the Baseline (see Section 11.4.2.1)
7.
Summarise the Number of distinct individuals and % of big N for each Response category
8.1.2.
Planned Efficacy Statistical Analyses
Secondary Statistical Analyses (Repeated Measures Joint Modelling of PVPI and 
PaO2/FiO2)
Endpoint(s)

All Post Surgery PVPI and PaO2/FiO2

Baseline: PVPI and PaO2/FiO2 immediately prior to surgery (day 1)

Any transformation of a response variable is also expected to be applied to the corresponding 
baseline variable. Final decisions on transformations will be based on the observed data and 
model diagnostics (PVPI is expected to require a Ln (natural logarithm) transformation)

Any observations with missing model covariates (e.g. baseline) would be excluded from the 
model fitting process (i.e. also excluding the record from any centering of covariates) 

The above endpoints and baselines will be the average of any replicates available at the 


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31
Secondary Statistical Analyses (Repeated Measures Joint Modelling of PVPI and 
PaO2/FiO2)
planned time points
Model Specification

Repeated measures version of the primary analysis (Section 7.1.2). Only changes related to 
the repeated measures are described in detail. 

4x Post surgery Planned Timepoints: on completion of surgery day1, day 2 day 3 and day 4 
(where available)

Center by endpoint model parameters to be duplicated in the linear predictor  (one repeat for 
each planned timepoint)

Additional model parameters (continuous & centered) to capture the Baseline by planned 
timepoint interaction

Obtain Bivariate and associated marginal distributions for the active Vs placebo comparisons 
(averaging over levels of BAL sampling) for each planned timepoint

Care should be taken in how the data are sorted/arranged, since the ordering of variables will 
now contain information on both endpoint and timepoint. A simplified example linear predictor 
is shown below for baseline, immediately post op day1 and day 2 timepoints for a hypothetical 
subject from center 3, on active treatment, with BAL sampled from the collapsed lung with 
centered baseline values of -4.1 and -0.5 for P/F and PVPI respectively (note: additional 
covariates may be explored and added based on the observed data and the additional 
timepoints would be added in a similar style and alternative orderings of the data may be used 
if easier to implement in SAS) :


CONFIDENTIAL
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32
Secondary Statistical Analyses (Repeated Measures Joint Modelling of PVPI and 
PaO2/FiO2)
















































































































2
ˆ
ˆ
2
ˆ
ˆ
BAL
over 
averaging
P/F
Mean 
in 
Diff
2
Day 
for 
Distn 
Posterior 
from
Sample
.
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
,
ˆ
of
ns
combinatio
e
appropriat
 with 
enumerated
are
ons
distributi
Posterior 
arm
 treatment
active
for the
matrix 
Covariance
Variance
4x4
a
is
 where
,
ˆ
ˆ
ˆ
ˆ
~
:
assume
data
observed
link to
To
0]
)
I(C
&
)
I(C
),
I(C
),
I(C
and
1
)
I(C
1,
Coll)
I(Act,
0,
Vent)
I(Act,
Vent),
I(Pbo,
Coll),
I(Pbo,
[Here
otherwise
zero
and
met 
condition 
if
1
with value
function
Indicator 
an 
is
I
and
zero
be
 to
d
constraine
 term(s)
ˆ
ˆ
ˆ
ˆ
*
,
ˆ
ˆ
ˆ
ˆ
*
,
ˆ
ˆ
ˆ
ˆ
*
,
ˆ
ˆ
ˆ
ˆ
*
,
ˆ
ˆ
ˆ
ˆ
5.0
5.0
1.4
1.4
Center
Center
Center
Center
*
ˆ
ˆ
ˆ
ˆ
/
,
,2
/
,
,2
/
,
,2
/
,
,2
,
,2
,
,2
/
,
,2
/
,
,2
,
,2
,
,2
/
,
,2
/
,
,2
,
,1
,
,1
/
,
,1
/
,
,1
,
,1
,
,1
/
,
,1
/
,
,1
2
4
1
3
2
/
2
1
/
1
2
4
1
3
2
/
2
1
/
1
5
4
2
1
3
5
,
,2
,
,1
/
,
,2
/
,
,1
,
,2
,
,1
/
,
,2
/
,
,1
,
,2
,
,1
/
,
,2
/
,
,1
,
,2
,
,1
/
,
,2
/
,
,1
,2
,1
/
,2
/
,1
,5
,5
/
5
/
,5
,4
4
/
,4
/
4
,3
3
/
,3
/
,3
,2
,2
/
,2
/
,2
,1
,1
/
1
/
,1
5
4
3
2
1
2
4
1
3
2
/
2
1
/
1
F
P
PV
D
F
P
PC
D
F
P
AV
D
F
P
AC
D
PVPI
AV
D
PVPI
AC
D
F
P
AV
D
F
P
AC
D
PVPI
PV
D
PVPI
PC
D
F
P
PV
D
F
P
PC
D
PVPI
AV
D
PVPI
AC
D
F
P
AV
D
F
P
AC
D
PVPI
PV
D
PVPI
PC
D
F
P
PV
D
F
P
PC
D
Act
Act
D
PVPI
D
PVPI
D
F
P
D
F
P
MVN
D
PVPI
D
PVPI
D
F
P
D
F
P
PVPI
AV
D
PVPI
AV
D
F
P
AV
D
F
P
AV
D
PVPI
AC
D
PVPI
AC
D
F
P
AC
D
F
P
AC
D
PVPI
PV
D
PVPI
PV
D
F
P
PV
D
F
P
PV
D
PVPI
PC
D
PVPI
PC
D
F
P
PC
D
F
P
PC
D
PVPI
D
PVPI
D
F
P
D
F
P
D
PVPI
PVPI
F
P
F
P
PVPI
PVPI
F
P
F
P
PVPI
PVPI
F
P
F
P
PVPI
PVPI
F
P
F
P
PVPI
PVPI
F
P
F
P
D
PVPI
D
PVPI
D
F
P
D
F
P
g
e
y
y
y
y
y
y
y
y
Center
Where
Vent
Act
I
Coll
Act
I
Vent
Pbo
I
Coll
Pbo
I
S
B
S
B
S
B
S
B
Diag
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
Center
C
I
C
I
C
I
C
I
C
I
y
y
y
y




































Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Checks similar to those for the Primary analysis of the interaction terms for Study Drug and 
BAL within each timepoint will be produced and if any of them suggest an interaction then 
ONLY the treatment comparisons within THAT timepoint only will be modified to account for 
the location of the BAL sampling
Model Results Presentation

Sets of outputs analogous to the Primary analysis will be produced for each planned timepoint; 


CONFIDENTIAL
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Secondary Statistical Analyses (Repeated Measures Joint Modelling of PVPI and 
PaO2/FiO2)
although the end of study decision pathway would not be applied to the resulting probabilities.
Sensitivity and Supportive Statistical Analyses

A similar approach will be performed to the primary analysis. Refer to the  Sensitivity and 
Supportive Statistical Analyses within the Primary Analysis Section 7.1.2

The analysis may be repeated using the exploratory endpoint (Imputed PaO2/FiO2).
Secondary Statistical Analyses (Univariate analyses – post surgery timepoint only)
Endpoint(s)

PVPI on completion of surgery

EVLWI on completion of surgery

PaO2/FiO2 on completion of surgery
Model Specification

A similar Bayesian repeated measures modeling approach will be implemented (c.f. the Joint 
modeling approach in the Secondary Analysis of PVPI and PaO2/FiO2; but with only one 
endpoint).

If deemed necessary natural logarithms of the observed responses may be implemented on a 
per endpoint basis.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Checks similar to those for the Primary analysis of the interaction terms for Study Drug and 
BAL within each timepoint may be produced
Model Results Presentation

Posterior means and treatment ratios will be displayed graphically.

Median, mean and 95% credible intervals for treatment means and ratios of all time points, to 
immediately prior to surgery.

Posterior probabilities that the ratios at all time points are less than 1, and other specific values
Sensitivity and Supportive Statistical Analyses

A similar approach will be performed to the primary analysis. Refer to the  Sensitivity and 
Supportive Statistical Analyses within the Primary Analysis Section 7.1.2
Secondary Statistical Analyses (SOFA)
Endpoint(s)

SOFA scores on Day 2 through to Day 4.
Model Specification

A Bayesian repeated measures model will be fit to SOFA scores (observed and imputed) 
measured on Day 2, Day 3 and Day 4.  The following categorical terms will be fit in the model: 
Day, Treatment and Treatment * Day, where Day is the repeated measures factor and 
treatment uses the 4x main treatment levels. An assessment will be made by the study 
statistician regarding including Baseline SOFA as a continuous covariate. The model will 
assume non-informative priors for all parameters. The modeling will implicitly combine the BAL 
sampling levels by study drug arm. The adjusted means for each Study Drug by Day will be 
obtained and the posterior distributions of these quantities will be displayed graphically, and 
the median and 95% credible interval (equi-tailed) will be calculated.  Posterior distributions of 
(combined) Active - Placebo for each post surgery time point will be generated.  The posterior 


CONFIDENTIAL
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Secondary Statistical Analyses (Univariate analyses – post surgery timepoint only)
probabilities that these differences, representing the true effect size, at each time point are less 
than 0, less than -1, less than -2 and less than -3 will be produced, in addition to other values 
which will be determined upon inspection of the data.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Checks similar to those for the Primary analysis of the interaction terms for Study Drug and 
BAL within each timepoint may be produced
Model Results Presentation

Adjusted medians and 95% credible intervals will be presented for each study drug by day, 
together with the median estimated study drug differences (Active – Placebo) and the 
corresponding 95% credible intervals. 

Plots of medians and 95% credible intervals from the model will be generated for each study 
drug by time point. Additionally, plots of differences and 95% credible intervals for the 
comparison of interest will be generated

Bayesian posterior probabilities that the true differences for each of the active treatments and 
placebo are greater than various levels will be produced, assuming non informative priors
Sensitivity and Supportive Statistical Analyses

A similar approach will be performed to the primary analysis. Refer to the  Sensitivity and 
Supportive Statistical Analyses within the Primary Analysis Section 7.1.2


CONFIDENTIAL
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35
8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the “Safety” population, unless otherwise specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 5
Overview of Planned Safety Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events
All AE’s1.
Y
Y
All Drug-related AE’s
Y
Serious AE’s
Y
Y
Withdrawal AE’s
Y
European Medicines 
Agency: Summaries for 
the European Clinical 
Trials Database (EudraCT)
Y
Clinical Laboratory
Clinical Chemistry2
Y
Y
Hematology 2
Y
Y
Urinalysis 3
Y
ECG
ECG Findings
Y
Y
Y
ECG Values
Y
Y4
Vital Signs
Vitals Values
Y
Y
Immunogenicity
Immunogenicity results
Y
Y
Surgical Procedure
Subject level information 
related to the Surgical 
Procedure
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
1.
Listings will include subject’s numbers for individual AE’s & AE system organ classes, preferred terms and 
verbatim text.
2.
Listings of chemistry (and/or haematology) abnormalities of PCI and all values for subjects with chemistry (and/or 
haematology) abnormalities of PCI. CRP to be excluded from these summaries (but will be included in the 
Biomarker outputs)
3.
Urinalysis results may be mapped to common nomenclatures prior to summarising
4.
Listings of ECG values of PCI and all ECG values for subjects with any PCI


CONFIDENTIAL
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36
8.3.
Pharmacokinetic Analyses
8.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified.
Table 6 provides an overview of the planned analyses, with full details being presented in 
Appendix 14: List of Data Displays. 
Table 6
Overview of Planned Pharmacokinetic Analyses
Endpoint / Parameter/ 
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Blood
Plasma Drug 
Concentration
Y
Y
Y
Y
Y
Y
Derived PK 
Parameters
Y
Y
Y
BAL
BAL Drug 
Concentration
Y
Plasma Urea & BAL 
Urea
Y
Dilution Factor
Y
Volume of ELF fluid1.
Y
Y
Volume of BAL fluid
Y
Total Drug in BAL fluid
Y
Derived ELF Drug 
Concentration1.
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
1.     Corrected for Dilution Factor.
8.3.2.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Process & Standards).
8.3.3.
Pharmacokinetic Parameters
8.3.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 4: Data Display Standards & Handling Conventions 
(Section 11.4.3 Reporting Process & Standards).


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
The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using WinNonLin Phoenix.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 7 will be determined from the plasma
concentration-time data, as data permits.
Table 7
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant estimated by linear regression analysis of the loge transformed 
concentration-time data
Section 11.5.5 details the BAL PK parameters to be derived, as data permits. These too 
will be summarised and listed.
8.3.3.2.
Statistical Analysis of Pharmacokinetic Parameters
There will be no formal statistical analyses of the pharmacokinetic parameter data.  PK 
parameters will be calculated based on the available data and listed.


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8.4.
Pharmacodynamic (Biomarker) Analyses
8.4.1.
Overview of Planned Pharmacodynamic (Biomarker) Analyses
The pharmacodynamic analyses will be based on the “Per Protocol 2” population, unless 
otherwise specified (e.g. for BAL related analyses which use “Per Protocol 1”). Further 
details of the biomarkers can be found in Appendix 8.
Table 8 provides an overview of the planned pharmacodynamic (Biomarker) analyses,
with full details of data displays being presented in Appendix 14: List of Data Displays.
Additional biomarkers may be added (or removed), and will follow a similar analysis 
strategy and any additional outputs would take the next available number. 
Table 8
Overview of Planned Pharmacodynamic (Biomarker) Analyses
Endpoint / Parameter/ 
Display Type
Untransformed/Transformed as appropriate
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
BAL
Free sTNFR1
Y
Y
Y
Y
Y
Y
Total sTNFR1
Y
Y
Y
Y
Y
Y
Complex sTNFR1
Y
Y
Y
Y
Y
Y
TNFa
Y
Y
Y
Y
Y
Y
IL-6
Y
Y
Y
Y
Y
Y
IL-8
Y
Y
Y
Y
Y
Y
IL-1b
Y
Y
Y
Y
Y
Y
MCP-1
Y
Y
Y
Y
Y
Y
CRP
Y
Y
Y
Y
Y
Y
IL-1ra
Y
Y
Y
Y
Y
Y
IL-10
Y
Y
Y
Y
Y
Y
Total protein
Y
Y
Y
Y
Y
Y
Total protein ratio
Y
Y
Y
Y
Y
Y
Surfactant Protein D
(SP-D)
Y
Y
Y
Y
Y
Y
RAGE
Y
Y
Y
Y
Y
Y
CC16
Y
Y
Y
Y
Y
Y
vWF
Y
Y
Y
Y
Y
Y
sICAM
Y
Y
Y
Y
Y
Y
MPO
Y
Y
Y
Y
Y
Y
Serum (Plasma when suffixed by [Plasma])
Free sTNFR1
Y
Y
Y
Y
Y
Y
Y
Y
Y
Total sTNFR1
Y
Y
Y
Y
Y
Y
Y
Y
Y
Complex sTNFR1
Y
Y
Y
Y
Y
Y
Y
Y
Y
IL-6
Y
Y
Y
Y
Y
Y
Y
Y
Y
IL-8
Y
Y
Y
Y
Y
Y
Y
Y
Y
CRP
Y
Y
Y
Y
Y
Y
Y
Y
Y
Total Protein [Plasma]
Y
Y
Y
Y
Y
Y
Y
Y
Y
Surfactant Protein D
(SP-D)
Y
Y
Y
Y
Y
Y
Y
Y
Y


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Endpoint / Parameter/ 
Display Type
Untransformed/Transformed as appropriate
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
RAGE
Y
Y
Y
Y
Y
Y
Y
Y
Y
CC16
Y
Y
Y
Y
Y
Y
Y
Y
Y
vWF
Y
Y
Y
Y
Y
Y
Y
Y
Y
sICAM
Y
Y
Y
Y
Y
Y
Y
Y
Y
MPO
Y
Y
Y
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

=Run as part of Clinical Chemistry Labs – and therefore may have different timepoints and require subsequent 
adjustments to the model / displays. For BAL there is only a single timepoint
8.4.2.
Planned Pharmacodynamic (Biomarker) Statistical Analyses
Planned Statistical Analyses (BAL Biomarkers)
Endpoint(s)

Absolute value of BAL biomarker (separate analysis per biomarker)

Any observations with missing model covariates would be excluded from the model fitting 
process (i.e. also excluding the record from any centering of covariates) 
Model Specification

For each biomarker, the values will be inspected to determine whether a data transformation is 
required.  

Main Treatment Descriptors to be used (i.e. 4 levels of the treatment term)

No intercept terms should be fitted for either endpoint (due to fitting all 4 levels of treatment).  

Categorical  fixed effect should be added for Center (if recruitment is such that center terms 
are poorly estimated then appropriate action will be taken, including but not limited to, pooling 
of centers or removal of the term from the model). 

Non-informative priors will be utilized for each model parameter assigned either as a normal 
distribution centered on 0 with large variance 1E6 or as appropriate to the parameters 
distribution.

Separate Variance parameters for each treatment arm.

SAS PROC MCMC will be used to combine the non-informative priors with the data observed 
to obtain sufficient draws from the posterior distribution (after any thinning) such that the 
MCSE/SD values for parameters of interest are less than 0.01 (anticipated to be in the region 
of ~100,000 draws).  If model convergence is poor then alternative initial parameter values 
should be considered.

The randomization seed used in PROC MCMC should itself be generated with an element of 
randomness - but there is no need to formally document this process (e.g. using Excel function 
RANDBETWEEN [1,9999999] and copying the result into the SAS code)

Combinations of the fitted model parameters will be used to answer the clinically relevant 
questions.

Median values of the adjusted response for each level of the main treatment descriptors and 
their associated 95% credible intervals (equi-tailed) will be produced from the posterior 


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Planned Statistical Analyses (BAL Biomarkers)
distributions obtained via appropriate combinations of the fitted model parameters; akin to 
lease square means

Posterior distributions will be obtained for the Active vs Placebo comparison within each level 
of the BAL sampling. These distributions will be used to determine the probability of any
reduction and any increase c.f. placebo. In addition posterior probabilities of the differences (or 
ratios) for other cut-points (which may be determined upon inspection of the data, or from 
developing business requirements), may also be computed.

Where applicable estimates would be derived at the means of any model covariates, akin to 
least squares means in PROC MIXED, and back transformed if necessary. When covariates 
are centered before the model fitting their mean is zero so the covariate can be dropped from 
the derivation.
Model Checking

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Potential covariates may also be explored (e.g. duration of surgery, age, gender). Only outputs 
from the final model will be reported
Model Results Presentation

By subject time profiles of biomarkers will be produced.

Scatterplot matricies of the correlation structures between BAL biomarkers may be produced.

Median and 95% (equi-tail) credible intervals for the LSmean equivalents and Median and 95% 
(equi-tail) credible intervals for differences (or ratios) to placebo will be summarized.

Posterior probabilities for the cut points
Planned Statistical Analyses (Serum Biomarkers)
Endpoint(s)

Absolute value of serum biomarker response (separate analysis per biomarker)

Timepoints: Day 1 (on completion of surgery), day 2, day 3, day 4 and day 8

Baseline: day 1 (Pre-dose)

Any transformation of a response variable is also expected to be applied to the corresponding 
baseline variable. Final decisions on transformations will be based on the observed data and 
model diagnostics (all biomarkers are expected to require a Ln (natural logarithm) 
transformation)

Any observations with missing model covariates (e.g. baseline) would be excluded from the 
model fitting process (i.e. also excluding the record from any centering of covariates)
Model Specification

The (transformed) endpoints will be assumed to follow a multivariate normal distribution.  
Linear predictors will be derived for each subject (i.e. obtain a vector of means for the MVN 
distribution). Each treatment arm will also have a separate variance covariance matrix. 

The linear predictors will consist of mean vectors to capture the effect of treatment for each 
time point and a variety of other model terms (an example is given at the end of this text). 

Main Treatment Descriptors to be used (i.e. 4 levels of the treatment term)

No intercept terms should be fitted for either endpoint (due to fitting all 4 levels of treatment).  

Baseline vectors will be fitted as continuous covariates (baseline values should be centered 
prior to inclusion in the model, centering to occur after any transformation of the individual 
subjects responses).


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Planned Statistical Analyses (Serum Biomarkers)

Categorical  fixed effect vectors should be added for Center (if recruitment is such that center 
terms are poorly estimated then appropriate action will be taken, including but not limited to, 
pooling of centers or removal of the term from the model). 

Non-informative priors will be utilized for each model parameter assigned either as a normal 
distribution centered on 0 with large variance 1E6 or as appropriate to the parameters 
distribution.

Each of the 4x variance covariance matrices will use an inverse Wishart distribution as its prior.

SAS PROC MCMC will be used to combine the non-informative priors with the data observed 
to obtain sufficient draws from the posterior distribution (after any thinning) such that the 
MCSE/SD values for parameters of interest are less than 0.01 (anticipated to be in the region 
of ~100,000 draws).  If model convergence is poor then alternative initial parameter values 
should be considered.

The randomization seed used in PROC MCMC should itself be generated with an element of 
randomness - but there is no need to formally document this process (e.g. using Excel function 
RANDBETWEEN [1,9999999] and copying the result into the SAS code)

Combinations of the fitted model parameters will be used to answer the clinically relevant 
questions.

Median values of the baseline adjusted response for each treatment by timepoint combination 
and their associated 95% credible intervals (equi-tailed) will be produced from the posterior 
distributions obtained via appropriate combinations of the fitted model parameters; akin to 
lease square means

Posterior distributions will be obtained for the Active vs Placebo comparison within each level 
of the BAL sampling for each time point. These distributions will be used to determine the 
probability of any reduction and any increase c.f. placebo. In addition posterior probabilities of 
the differences (or ratios) for other cut-points (which may be determined upon inspection of the 
data, or from developing business requirements), may also be computed.

Where applicable estimates would be derived at the means of any model covariates, akin to 
least squares means in PROC MIXED, and back transformed if necessary. When covariates 
are centered before the model fitting their mean is zero so the covariate can be dropped from 
the derivation.
Model Checking

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.

Potential covariates may also be explored (e.g. duration of surgery, age, gender). Only outputs 
from the final model will be reported
Model Results Presentation

By subject time profiles of biomarkers will be produced.

Scatterplot matricies of the correlation structures between BAL biomarkers may be produced 
(one page per timepoint – including baseline).

Median and 95% (equi-tail) credible intervals for the LSmean equivalents and Median and 95% 
(equi-tail) credible intervals for differences (or ratios) to placebo will be summarized.

Posterior probabilities for the cut points


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9.
OTHER STATISTICAL ANALYSES
9.1.
Exploratory Statistical Analyses
The strategy for each exploratory endpoint is to list and summarise by Study Medication 
(i.e. Assume BAL sampling location is irrelevant). Subsequent statistical analysis may be 
conditional on the observed data (at the discretion of the study statistician) and methods 
would be documented in the CSR.
Table 9 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 9
Overview of Planned Exploratory Statistical Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Clinical Outcomes
Diagnosis of ARDS out to 
day 28
Y
Y
28 day survival
Y
Y
Y
Organ failure free days out 
to day 28 
Y
Y
Resource Utilisation
Ventilator Free Days
Y
Y
ICU Length of Stay
Y
Y
Hospital Length of Stay
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     


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10.
REFERENCES
GlaxoSmithKline Document Number 2014N197251_04 Study ID TFR116341. APlacebo 
Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, Randomised 
Clinical Trial of GSK2862277 in Patients undergoing Oesophagectomy Surgery. Report 
Date 16-FEB-2015. 
Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, 
Ware LB, Bernard GR, Ely EW. Derivation and validation of Spo2/Fio2 ratio to impute 
for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure 
Assessment score. Crit Care Med. 2009 Apr;37(4):1317-21. doi: 
10.1097/CCM.0b013e31819cefa9.
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
Rice T.W. et al, 2007: Comparison of the SpO2/FIO2 Ratio and the PaO2/FIO2 Ratio in 
Patients With Acute Lung Injury or ARDS. CHEST (Critical Care Med.) 2007; 132:410–
417
Vincent JL, 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.


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11.
APPENDICES
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Treatment States and Phases
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
11.8
Appendix 8: Biomarker Details
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
11.10
Appendix 10: PVPI and EVLW – Supplementary Information
11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
11.12
Appendix 12: Details of Simulation exercise that produced operational characteristics 
used in the protocol
11.13
Appendix 13: Abbreviations & Trade Marks
11.14
Appendix 14: List of Data Displays
11.15
Appendix 15: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from Per Protocol Populations
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Per 
Protocol 
Population
ID
Number
Exclusion Description
1
01
Subject did not satisfy all of the inclusion and exclusion criteria (from whichever 
version of the protocol was active at the time of their enrolment)
02
Subject did not receive either i) the study drug they were randomised to, or ii) 
the actual BAL lung sampled was not the one they were randomised to have 
sampled
03
Subject was classified as inoperable upon commencement of surgical 
procedures (an “open and shut” case)
2
01
Subject did not satisfy all of the inclusion and exclusion criteria (from whichever 
version of the protocol was active at the time of their enrolment)
02
Subject did not receive the study drug they were randomised to
03
Subject was classified as inoperable upon commencement of surgical 
procedures (an “open and shut” case)
3
01
Subject did not satisfy all of the inclusion and exclusion criteria (from whichever 
version of the protocol was active at the time of their enrolment)
02
Actual BAL lung sampled for the subject was not the one they were randomised 
to have sampled
03
Subject was classified as inoperable upon commencement of surgical 
procedures (an “open and shut” case)
NOTES:

The above definitions may be modified during the in-stream protocol deviation reviews
(for example, subjects who were deemed to be in-operable upon commencement of their surgical 
procedure may be added to each of the per protocol populations – this may require anecdotal evidence 
followed up by bespoke communications between GSK and the sites as it is not possible to guarantee 
such scenarios could be accurately defined using  rules based on duration of surgery alone)
A planned eCRF update should add a variable indicating if an individual was an “open and shut case”. 
Prior to this update manual coding may be required to correctly compute the above populations (and 
also if the new variable is not retrospectively populated for existing subjects, e.g. those in IA1)


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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Table 10
Time and Events Table (Screening)
Procedures
Screening (7 to 28 days 
inclusive prior to surgery)
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.
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) sample3
X
IVRS
X


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Table 11
Time and Events Table Day 1
Procedures
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.
3.Only applicable at designated sites
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 12
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 
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 
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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11.3.
Appendix 3: Treatment States and Phases
11.3.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
Study Treatment Start date & time. Since this is a single dose study and the time spent on 
the nebuliser (On-treatment) is expected to be 3-5 minutes a separate “On-treatment” 
phase is not required for this study.
Treatment Phase
Definition
Pre-Treatment 
Date & Time ≤ Study Treatment Start Date & Time
Post-Treatment
Date & Time> Study Treatment Start Date & Time
11.3.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start date & time of the study treatment.
11.3.2.1.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date & Time ≤Study Treatment Start Date & Time
Post-Treatment
AE Start Date & Time > Study Treatment Start Date & Time
During Surgery
If Start of Surgery Date & Time ≤ AE Start Date & Time < End of Surgery Date & Time
Onset Time  
Since 1st Dose 
(Days Hours 
Minutes)
AE Onset Date & Time - Treatment Start Date & Time converted to D H M format by 
tu_times
Duration (Days 
Hours Minutes) 
AE Resolution Date & Time – AE Onset Date &Time converted to D H M format by 
tu_times
If resolution time not available then
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform OR value is missing


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11.4.
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1.
Study Treatment & Sub-group Display Descriptors
Main Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Placebo (BAL Collapsed lung)
Placebo (BAL Collapsed lung)
1
B
Placebo (BAL Ventilated lung)
Placebo (BAL Ventilated lung)
2
C
GSK2862277 (BAL Collapsed lung)
GSK2862277 26mg IH (BAL 
Collapsed lung)
3
D
GSK2862277 (BAL Ventilated lung)
GSK2862277 26mg IH (BAL 
Ventilated lung)
4
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
In addition two alternative sets of treatment descriptors are required. Unless otherwise 
stated the outputs should use the main treatment group descriptions
Alternative Treatment Group Descriptions #1
RandAll NG 
Alternative Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Placebo (BAL Collapsed lung)
Placebo
1
B
Placebo (BAL Ventilated lung)
C
GSK2862277 (BAL Collapsed lung)
GSK2862277 26mg IH
2
D
GSK2862277 (BAL Ventilated lung)
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Alternative Treatment Group Descriptions #2
RandAll NG 
Alternative Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Placebo (BAL Collapsed lung)
BAL Collapsed lung
1
C
GSK2862277 (BAL Collapsed lung)
B
Placebo (BAL Ventilated lung)
BAL Ventilated lung
2
D
GSK2862277 (BAL Ventilated lung)
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.


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11.4.2.
Baseline Definition & Derivations
11.4.2.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Day 1 
(Pre-Dose)
Day 1 ( 
Immediately 
prior to start of 
surgery)
Day 2
Primary
PVPI
X
Day 1 (Immediately 
prior to start of 
surgery)
Secondary
Transpulmonary 
Thermodilution 
output
X
Day 1 (Immediately 
prior to start of 
surgery)
PaO2/FiO2 Ratio
X
Day 1 (Immediately 
prior to start of 
surgery)
SOFA1
X
Derived Day 1 (Pre-
dose)
Biomarkers
Biomarker (Blood / 
Serum)
X
Day 1 (Pre-dose)
Immunogenicity
X
Day 1 (Pre-dose)
NOTES :

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

1 = See Section 11.5.4 for assumptions required to derive a Baseline SOFA score
11.4.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.4.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.


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11.4.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area (Final reporting effort at end of study)
HARP Server
: uk1salx00175
HARP Area
: gsk2862277/tfr116341/final
QC Spreadsheet
: gsk2862277/tfr116341/final/documents
Reporting Area (Interim analysis 1)
HARP Server
: uk1salx00175
HARP Area
: gsk2862277/tfr116341/ia1
QC Spreadsheet
: gsk2862277/tfr116341/ia1/documents
Reporting Area (Interim analysis 2)
HARP Server
: uk1salx00175
HARP Area
: gsk2862277/tfr116341/ia2
QC Spreadsheet
: gsk2862277/tfr116341/ia2/documents
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards AND/OR  
the set of CDISC standards implemented at GSK at time of database freeze (SDTM IG Version 
X.X & AdaM IG Version X.X.

Any interim analysis is expected to be performed using Legacy GSK A&R dataset standards
but the final reporting is expected to be performed in CDISC. However, if recruitment rates are 
high and/or the study is stopped after an interim analysis then the final reporting may also use 
the Legacy GSK A&R dataset standards.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for the final reporting effort (but will not be generated for the ia1 and 
ia2 reporting efforts).
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 


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Reporting Standards
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings. They may also be omitted from figures, summaries and statistical 
analyses if the time deviation was deemed to be clinically impactful.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.   

Unscheduled visits / data points may be included in figures if it is relevant. Relevant outputs 
would typically be those focused on safety, and unscheduled visits / data points may be 
included in derivations of some endpoints (e.g. maximum post dose change from baseline
body temperature). Less relevant outputs are those which aid activities that would not 
inherently utilise unscheduled visits / data points such as statistical modelling. For example, an 
individual subject time profile of body temperature should include any unscheduled 
temperature values; but a figure summarising body temperatures by treatment prior to 
statistical modelling should not display the unscheduled visit / data points.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and between geometric coefficient of variation CVb (%) will 
be reported.
[1] CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
Parameters Not 
Being Log 
Tmax


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Reporting Standards
Transformed
Listings
Additionally, include the first point, last point and number of points used in 
the determination of lambda_z for listings.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

The currently supported versions of the SAS SGxxx graphics procedures should be default 
choice for graphical displays (except for graphics produced by CPMS who may use their 
preferred software). If SGxxx cannot produce a required graphic then alternative software may 
be used. The default graphics options in SGxxx procedures may supersede IDSL Statistical 
Principals 7.01 to 7.13 (e.g. font choices and styles); since the SGxxx procedures post date the
authoring of the principles.

Whenever possible a treatment attribute map dataset should be used to keep symbols and 
colour schemes consistent across outputs, and where possible across individual subjects. This 
should be stored in the refdata area of HARP


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11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from Study Treatment Start Date:

If the reference has both Dates and Times then the Study Day should be computed using the 
Datepart only

Ref Date = Missing                     → Study Day = Missing 

Ref Date < Treatment Start Date→ Study Day = Ref Date –Treatment Start Date    

Ref Date ≥ Treatment Start Date→ Study Day = Ref Date – (Treatment Start Date) + 1    
Change from Baseline

The change from baseline will be calculated by subtracting the baseline values from the 
individual post-randomisation values.
11.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Age will be computed relative to SCREENING visit (so outputs will match inclusion criteria 
definition of age at time subjects sign the informed consent form)
Body Mass Index (BMI)

Calculated as Weight (kg) / Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Since this is a single dose study duration of exposure outputs may not be displayed


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Extent of Exposure

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
11.5.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
Adverse Events
AE’S OF Special Interest

No AE’s of special interest have been defined for this study. 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    

Categorical lab results from Urinanalysis may be mapped to a common nomenclature for the 
purposes of producing summary tables (for example, but not limited to, “+” , “Pos” and “Positive” 
may all be summarised under “Positive”). The medical monitor will advise on the mappings 
based upon the observed categories within each test and a listing of the actual mappings 


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Laboratory Parameters
applied to each lab test will be produced.
11.5.4.
Efficacy
Transpulmonary Thermodilution
Predicted Body Weight

Males: 








cm
Height
kg
BW
Where
Height
BW
ed
ed
,
...
4.
152
*
91
.0
50
Pr
Pr




Females:








cm
Height
kg
BW
Where
Height
BW
ed
ed
,
...
4.
152
*
91
.0
5.
45
Pr
Pr



Body Surface Area (DuBois formulae)







cm
Height
kg
Weight
m
BSA
Where
Height
Weight
BSA
,
,
...
*
*
007184
.0
2
725
.0
425
.0

Predicted Body Surface Area







cm
Height
kg
BW
m
PBSA
Where
Height
BW
PBSA
ed
ed
,
,
...
*
*
007184
.0
Pr
2
725
.0
425
.0
Pr

“Indexing” of values using the (Absolute value) data entered into the eCRF







2
2
m
&
L/min
,
L/min/m
,
BSA
CO
CI
where
BSA
CO
CI 







2
Pr
2
Pr
m
&
mL
,
mL/m
,
ed
ed
BSA
GEDV
GEDI
where
BSA
GEDV
GEDI 







kg
&
mL
,
mL/kg
,
Pr
Pr
ed
ed
BW
EVLW
EVLWI
where
BW
EVLW
EVLWI 







2
-5
2
-5
m
&
cm
*
s
*
dyn
,
m
*
cm
*
s
*
dyn
,
*
BSA
SVR
SVRI
where
BSA
SVR
SVRI 
Note: These alternative derivations may be used as a rough and ready check of the internal 
consistency of the parameters but small differences may occur due to rounding so they will not 
appear in any listings/outputs/analyses: 




CO
CVP
MAP
SVR
CI
CVP
MAP
SVRI




*
80
and
80
*
. 
Recovering the Absolute value from the “Indexed” value







2
2
m
&
L/min
,
L/min/m
,
*
BSA
CO
CI
where
BSA
CI
CO 







2
Pr
2
Pr
m
&
mL
,
mL/m
,
*
ed
ed
BSA
GEDV
GEDI
where
BSA
GEDI
GEDV 







kg
&
mL
,
mL/kg
,
*
Pr
Pr
ed
ed
BW
EVLW
EVLWI
where
BW
EVLWI
EVLW 







2
5
-
2
5
-
m
&
cm
*
s
*
dyn
,
m
*
cm
*
s
*
dyn
,
BSA
SVR
SVRI
where
BSA
SVRI
SVR 


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Secondary Endpoints
Calculation of PaO2/FiO2 and SpO2/FiO2

The PaO2/FiO2 endpoint will be calculated when patients are intubated and have an arterial line 
present. Prior to computing the ratio the PaO2 will be converted from kPa units to mmHg using the 
conversion rate 1/0.133 and FiO2 will be expressed as a proportion and not a percentage.

SpO2/ FiO2 will be calculated as a ratio of percentages, where patients are no longer intubated and 
the arterial line has been removed.
SOFA (Sequential Organ Failure Assessment)
Table below (SOFA Score points allocation algorithm) details how points should be allocated to each 
SOFA component.  Prior to analysis the CONMEDS dataset will be reviewed by the medical monitor 
who will flag observations which are adrenergic agents and vasopressors.   Adrenergic agents that do 
not appear in Vincent (1996), and for which a highest dose has been recorded, will be assigned a 
SOFA score of 2.
Zero points are assigned if none of the points scoring criteria are met. If any of the information required 
to derive an individual SOFA component score is missing or cannot be obtained then that component 
score will be set to a missing value.
Derivation of Baseline SOFA value: Not all required SOFA components are being measured on Day 1. 
When component data are available they should be used (Day 1 Pre-dose: lab samples). Since each 
subject is about to undergo surgery they will be assumed to have been sufficiently fit to satisfy the 
following assumptions: Respiration, Central Nervous System and Cardiovascular component scores 
fixed at 0 and Renal score derived solely from Creatinine Pre-dose lab result. 
SOFA Score points allocation algorithm
SOFA Score / 
Variable (x)
0
1
2
3
4
Respiration:
PaO2/FiO2
(mmHG)
x 400
300 x 
< 400
200 x < 300
100 x < 200
x < 100
With Respiratory support
(Note: if PaO2/FiO2 in these categories but 
subject not on respiratory support then a 
score of 2 should be assigned)
Coagulation:
Platelets (10^3 
/ mm^3)
x 150
100 x 
< 150
50 x < 100
20 x < 50
x < 20
Liver:
Bilirubin 
(mol/L)
x < 20
20 x < 
33
33 x < 102
102 x < 204
x 204


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Secondary Endpoints
Calculation of PaO2/FiO2 and SpO2/FiO2
Cardiovascular:
Hypotension
(Adrenergic 
agents 
administered 
for at least one 
hour; doses are 
in g/kg/min)
Mean 
Arterial 
Pressure 
70 
mmHg
Mean 
Arterial 
Pressure 
< 70 
mmHg
Dopamine≤5.0
(µg/kg/min)
or any dose of:
Dobutamine
Or any dose of 
an adrenergic 
agent not 
listed here or 
in 
Vincent(1996)
Dopamine 5.1-15.0
(µg/kg/min)
or Epinephrine≤0.1
or 
Norepinephrine≤0.1
Dopamine > 15.0
(µg/kg/min)
or Epinephrine>0.1
or
Norepinephrine>0.1
Central 
Nervous 
System:
Glasgow Coma 
Score
x 15
13 x 
14
10 x 12
6 x 9
x < 6
Renal:
Creatinine 
(mol/L)
                          
x 110
110 < x 
170
170 < x 300
300 < x 440
[Or 
Urine output < 500 
mL/day]
x > 440 
[Or
Urine output < 200 
mL/day]
             
Calculation of Oxygenation Index
The oxygenation index will be calculated as:
Oxygenation Index (%) = 
2
*
2
PaO
Paw
FiO
where Mean Airway Pressure (Paw) and PaO2 are measured in mmHg and FiO2 is entered as a % and 
not a proportion.
Conversion of Paw units from cmH2O to mmHg will be performed using the ratio 1 cmH2O = 1/1.36
mmHg.
Conversion of PaO2 units from kPa to mmHg will be performed using the ratio 1 kPa = 1/ 0.133 mmHg.
11.5.5.
Pharmacokinetic
Drug Concentration in BAL
Derivation of BAL/ELF Drug Concentration Data

Urea concentration data will be used to calculate the dilution effect of the lavage which is used 
to extract the epithelial lining fluid (ELF) from the lung. A correction for dilution will be applied to 
BAL drug concentrations as follows:
Epithelial Lining Fluid (ELF) Drug Concentration (pg/mL) =
BAL Drug Concentration (pg/mL) x Dilution Factor


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Drug Concentration in BAL
where 
Dilution Factor= Plasma Urea / BAL Urea
Plasma urea is measured from the plasma samples planned to be taken at a similar time to the 
BAL sample time.

Additionally the Volume of ELF in BAL fluid and the Total Drug in BAL fluid will be calculated as 
follows:
Volume of ELF in BAL Fluid (mL) = BAL Fluid Volume (mL)/Dilution Factor
Total Drug in BAL (pg) = BAL Drug Concentration (pg/mL) x BAL Volume (mL)
11.5.6.
Pharmacodynamic (Biomarker)
Pharmacodynamic (Biomarker)
Biomarkers

In general, it is assumed that biomarker endpoints will require variance stabilising 
transformations, such as taking a loge transformation prior to analysis (and that summary 
statistics appropriate to loge normally distributed data will apply for all summaries).  However, 
this assumption will be considered for each endpoint individually prior to the generation of 
summary tables or statistical analysis, and if deemed more appropriate, a loge transformation 
will not be applied, or non-parametric methods may be employed.

If transformations are used then the results will be reported on the back-transformed scale 
unless otherwise stated.
11.5.7.
Exploratory Endpoints
Exploratory Endpoints
Predicting missing PaO2/FiO2 using SpO2/FiO2

Rice (2007) describe the following linear model to predict SpO2/FiO2 using available PaO2/FiO2
values. 
SpO2/FiO2 = 64 + (0.84 * PaO2/FiO2)

For exploratory purposes (i.e. taking the very strong steps of disregarding the uncertainty of the 
original linear regression parameter estimates and the inverse estimation aspect of the 
proposal) the formulae will be re-arranged and used to impute missing PaO2/FiO2 values when a 
corresponding SpO2/FiO2 value is available (e.g. when the arterial line has been removed):
PaO2/FiO2 (Imputed) = (SpO2/FiO2 – 64) / 0.84  when PaO2/FiO2 is missing & SpO2/FiO2 available
PaO2/FiO2 (Imputed) = PaO2/FiO2 when PaO2/FiO2 is non-missing
PaO2/FiO2 (Imputed) = Missing in all other cases


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11.6.
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
11.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one 
who has completed all phases of the study including the follow-up visit.

Withdrawn subjects may be replaced in the study, but any replacement would 
take the next available randomisation number and not be guaranteed to receive 
the same treatment as the withdrawn subject.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.

In the event that the study is prematurely discontinued, all available data will be 
listed and a review carried out by the study team to assess which statistical 
analyses are still considered appropriate.
Surgery

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.
11.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
PVPI and 
EVLWI

In the case that PVPI and EVLWI are missing and cannot be derived using the 
methods described in Section 11.5.4, they will remain missing.
PK

Urea data:  Below the Lower Limit of Quantification (LLQ) values will be imputed 
with the relevant (BAL fluid) LLQ divided by 2 for the purpose of deriving the 
Dilution Factor.

Plasma concentrations: Refer to Section 11.5.3 or for further guidance see the 
PK Guidance document, GUI_00000051487, and the DB/CPMS guidelines 


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Element
Reporting Detail
‘Standards for the Handling of NQ impacted PK Parameters’ for more 
information.
Biomarkers

Values below LLQ will be set as LLQ/2

Values above the upper limit of quantification (ULQ) will be set as ULQ

Imputed values will be used for the purposes of the computation of change from 
baseline and for summaries, plots and analysis, if deemed applicable. 

Number of data imputed will be highlighted in the summaries and listings will report the 
values as below LLQ or above ULQ. 

If multiple LLQ’s and ULQ’s are available per assay (i.e. multiple runs with different 
standard curves are utilised) then the LLQ and/or ULQ value used for the above 
purposes shall be the minimum of the available LLQs and/or the maximum of the BLQ’s.

If more than a third of observations are below LLQ or above ULQ then no imputation will 
be performed for that subject.
11.6.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
3: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
Surgical 
Procedures 
/ Biomarker 
samples 
(Serum and 
BAL)

If the date/time of an event occurring during the surgical procedures is unknown 
then it shall remain missing. Any associated data values may be listed using the 
timeslicing keys to determine the chronological ordering.

Since each surgical procedure is bespoke it is not possible to impute a 
date/time, although depending upon the analysis and endpoint the planned time 
(or the time of a proximal event) may be sufficiently accurate to be used. 
Otherwise the data point may be omitted from the analysis and/or form part of a 
sensitivity analysis (e.g. Subject 
 has unknown BAL sample date/time and 
the proposed PK modelling may be sensitive to any assumed/imputed value, so 
the observation may be dropped).
PPD


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11.6.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
11.6.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
SOFA

If any of the information required to derive an individual SOFA component score 
is missing or cannot be obtained then that component score will be set to a 
missing value.  

However, in the case of missing PaO2/FiO2 ratios; SpO2/FiO2 ratios and the 
following corresponding thresholds for SpO2/FiO2 may be used (Pandharipande, 
2009):
SOFA Respiratory 
Score
PaO2/FiO2
SpO2/ FiO2
1
< 400
< 512
2
< 300
< 357
3
< 200
< 214
4
< 100
< 89

If subjects have missing SOFA components data due to procedural / operational 
causes then those component scores may be populated with the average 
response at that time point on the corresponding treatment arm.  Alternatively if 
it is the Day 3 value which requires imputation linear interpolation using the Day 
2 and Day 4 data may be used.
                                                                                                                                        


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11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.3
0.54
Female
0.3
0.54
Hemoglobin 
g/L
Male
90
180
Female
90
180
Lymphocytes 
x109/ L
0.6
3.0
Neutrophil Count 
x109/ L
1.5
20
Platelet Count 
x109/ L
100
600
While Blood Cell Count (WBC)
x109/ L
3
20
Note: For the following lab tests the corresponding normal ranges should be used as the PCI range:
Reticulocyte Count, RBC Count, MCV, MCH, MCHC, Monocytes, Eosinophils and Basophils
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
25
60
Calcium
mmol/L
1.8
2.75
Creatinine
mmol/L
30
160
Glucose
mmol/L
3
9
Potassium
mmol/L
2.5
5.5
Sodium
mmol/L
120
160
Total CO2
mmol/L
16
35
BUN
mmol/L
3
15
Chloride
no PCI required for 
this study
no PCI required for 
this study


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Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
4x ULN
AST/SGOT 
U/L
High
4x ULN
AlkPhos 
U/L
High
4x ULN
T Bilirubin 
(Note: Direct Bilirubin PCI not 
required for this study)
µmol/L
High
2xULN
T. Bilirubin + ALT
µmol/L
High
2xULN T. Bilirubin
+
U/L
4x ULN ALT
11.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QT Interval
msec
≥ 300
≤ 500
Absolute QTc Interval
(QTcB or QTcF)
msec
≥ 300
≤ 450
Absolute PR Interval
msec
< 90 
> 200 
Absolute QRS Interval
msec
< 70 
> 120
Absolute RR Interval
msec
< 375
> 1700
Change from Baseline
Increase from Baseline QTc
msec
> 60
11.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110


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Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decreases of 
magnitude
Increases of 
magnitude
Systolic Blood Pressure
mmHg
>50
>50
Diastolic Blood Pressure
mmHg
>30
>30
Heart Rate
bpm
>50
>50


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11.8.
Appendix 8: Biomarker Details
Note: These are the planned biomarkers at time of RAP writing. Additional items may be 
added or existing ones removed. 
Parameters (BICATCD Code)
Sample
Unit
LLQ
ULQ
Target Engagement *
Free sTNFR1
Serum & BAL
Total sTNFR1
Serum & BAL
Complex TNFR1
Serum & BAL
Pro-Inflammatory Biomarkers *
TNFa
BAL
IL-6
Serum & BAL
IL-8
Serum & BAL
IL-1b
BAL
MCP-1
BAL
Anti-Inflammatory Biomarkers *
CRP (Reactive Protein C) 
Plasma & BAL
IL1-ra
BAL
IL-10
BAL
Protein Permeability Index *
Total Protein in BAL
BAL
Total Protein in Plasma
Plasma
Total Protein Ratio (Ratio is derived from BAL and 
Plasma values)
Plasma & BAL
Markers of Epithelial Cell Injury
Surfactant Protein D
Serum & BAL
RAGE (Receptor for Advanced Glycation End 
products)*
Serum & BAL
Club Cell 16 (also known as CC10 and CC16)
Serum & BAL
Markers of Endothelial Injury
vWF
Serum & BAL
sICAM-1*
Serum & BAL
Markers of Neutrophil Activation*
MPO
Serum & BAL


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NOTE : 

* Expect biomarker parameters to be increased in oesophagectomy patients.

Serum sampling times: Day 1 Prior to Surgery,.Day 1 On Completion of Surgery, Day 2, Day 3, Day 4 and Day 
8/Day of Discharge.

BAL sampling time: Day 1 On Completion of Surgery.

N/A = No ranges are normally provided for parameters.

Display biomarkers in the order presented in the Table, and use Functional Category labels provided to further 
group them.

= Measured in plasma as part of Clinical Chemistry Labs so may have different sampling scheme and require 
appropriate adjustments to displays and/or models 


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11.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
11.9.1.
Handling of Covariates, Subgroups & Other Strata

The randomisation is stratified by Centre (site). However, the number of subjects 
recruited at a site may be small (it is conceivable that a site may not recruit sufficient 
subjects to have an individual from each of the four treatment arms). Therefore the 
statistical models should include a fixed categorical effect for centre by intent, but 
this centre term may be dropped. Alternatively low recruiting centres may be pooled 
by NHS region, or another suitable characteristic (e.g. shared research fellow) if 
deemed appropriate.

The following is a list of covariates that may be used in descriptive summaries and
statistical analyses, some of which may also be used for subgroup analyses (such 
outputs would take the next available number).

Additional covariates of clinical interest may also be considered. 

If the percentage of subjects is small within a particular subgroup, then the subgroup
categories may be refined prior to unblinding the trial.  

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
Category
Potential Covariates and / or Subgroups
Randomisation strata

Centre (site)

Research fellow assisting with study procedures

NHS authority the site belongs to (a potential 
mechanism to cluster centres that may behave 
similarly within the UK)
Subject characteristics

Gender

Age

Race / Ethnicity

Height / Weight / BMI
Medical History

Prior Oesophageal Chemotherapy

Smoking history

Medical history
Surgical Procedure

Duration of Surgery

Duration of One Lung Ventilation

Duration of anaesthesia

Inotrope usage


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Category
Potential Covariates and / or Subgroups
Immunogenicity

Did subject develop serum anti-GSK2862277 
antibodies
Clinical Outcomes / Resource 
Utilisation

Did subject develop ARDS during study 

Vent free days

ICU length of stay

Hospital length of stay

Organ failure free days


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11.10.
Appendix 10: PVPI and EVLW – Supplementary Information
11.10.1.
Data derivations to be performed by GSK
When appropriate, “Indexed” versions of the parameters will be derived as per Section 
11.5.4.
In the event that the sites did not configure their PiCCO machine to display the Absolute 
parameter sets and the only information available is the Indexed version of a PiCCO 
parameter then the Absolute value will be recovered from the indexed version using the 
appropriate equation from Section 11.5.4. 
11.10.2.
Theoretical Underpinning of Transpulmonary Thermodilution 
Measurements
This section briefly describes the theory behind the PiCCO machine. Not all of the items 
described are provided / outputted by the machine (see Table 13 for the parameters 
databased via the eCRF).
The transpulmonary thermodilution provides the measurement of cardiac output (CO), 
the global end-diastolic volume (GEDV) and intra-thoracic blood volume (ITBV) by 
passing a thermal indicator (cold solution) through the right heart, lungs and left heart 
and measuring the temperature changes at a known distance downstream, typically in the 
femoral artery.   The ITBV (a measure of all the blood contained within the chest), is 
measured by the GEDV, which is the sum of the end-diastolic volumes of all heart 
chambers, and pulmonary blood volume (PBV). 
Figure 3
Transpulmonary Thermodilution Curve showing mean transit time 
and downslope decay time (DSt) of the slope. The time point (A) 
represents the time of injection. The product of cardiac output and 
MTt equals the intrathoracic thermal volume. Multiplication of the 
cardiac output and the DSt equals the pulmonary thermal volume 
(PTV).


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The product of the CO and the mean transit time (MTt) of the thermal indicator, is the 
intrathoracic thermal volume (ITTV = ITBV + EVLW), i.e., the distribution volume of 
the thermal indicator.  The product of the CO and exponential downslope time (DSt) is 
the pulmonary thermal volume (PTV).   The GEDV is calculated as the difference 
between the intrathoracic and pulmonary thermal volume (GEDV = ITTV – PTV).  (See 
Figure 4.)
Figure 4
Determination of GEDV by transpulmonary thermodilution. The ITTV 
describes the distribution volume of the thermal indicator, including 
the volumes in the right atrium (RA), right ventricle (RV), left atrium 
and left ventricle (LV).
Intrathoracic blood volume (ITBV) is calculated from the GEDV by assuming a 
relationship of a constant ratio of 1.25.  (ITBV = 1.25 x GEDV).  This ratio allows the 
calculation of ITBV and consequently the calculation of the EVLW (ITTV – ITBV).  
PVPI is the ratio between EVLW and the pulmonary blood volume (PBV), which is 
deduced from the difference between the PTV and EVLW (PBV = PTV – EVLW).


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Table 13
Endpoints and abbreviations used in Transpulmonary 
Thermodilution
Timeframe
Grouping
Abbreviation 
/ Item
Databased
Description
Continuous1
Continuous 
cardiac output
Heart Rate
Yes
Heart Rate
AP
Yes
Arterial Pressures [Systolic 
Blood Pressure / Diastolic Blood 
Pressure]
CVP
Yes
Central Venous Pressure 
[manually entered into PiCCO 
machine]
CPO
No
Cardiac Power Output
CPI
No
Cardiac Power Index
Calibrated 
Continuous 
cardiac output
PCCO
No
Pulse Contour Cardiac Output: 
Calculated beat by beat as 
Stroke Volume * Heart Rate
PCCI
No
Pulse Contour Cardiac Index
Stroke Volume
SV
No
Stroke Volume
SVI
No
Stroke Volume Index: Assumed
to be Stroke Volume indexed by 
predicted body surface area
Afterload
SVR
Yes
Systematic Vascular 
Resistance: Determinant of 
afterload. Computed as 
80
*
)
(CO
Flow
CVP
MAP 
where 
Flow(CO)=Pressure/Resistance. 
Vasoconstriction implied if 
Flow(CO) is decreasing and 
Vasodilation implied if Flow(CO) 
is increasing provided pressure 
is constant
SVRI
No
Systematic Vascular Resistance 
Index: SVR * BSA (Body 
Surface Area - DuBois)
MAP
Yes
Mean Arterial Pressure


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Timeframe
Grouping
Abbreviation 
/ Item
Databased
Description
Volume 
responsiveness
SVV
Yes
Stroke Volume Variation: 
Variation in Stroke Volume over 
the breathing cycle for a specific 
time frame (only available in 
mechanically ventilated patients 
in sinus rhythm)
PPV
No
Pulse Pressure Variation: 
Variation in Pulse Pressure over 
the breathing cycle for a specific 
time frame (only available in 
mechanically ventilated patients 
in sinus rhythm)
Contractility
dPmax
No
Left contractility paramater
Discontinuous
Thermodilution 
Cardiac Output
CO (also 
known as 
COTDa)
Yes 
(triplicates)
Cardiac Output (thermodilution): 
Volume of blood pumped by 
heart in one minute.
CI
No
Cardiac Index: Cardiac Output 
indexed by body surface area
(DuBois)
Volumetric 
Preload
GEDV
Yes 
(triplicates)
Global End Diastolic Volume: 
Filling volume of all four heart 
chambers
GEDI
No
Global End Diastolic Volume 
Index: GEDV indexed to 
predicted body surface area
Contractility
GEF
Yes
Global Ejection Fraction
CFI
No
Cardiac Function Index: 
Measure of contractility 
(performance of cardiac 
muscle). Ratio of flow and 
preload: CFI = CO / GEDV
Pulmonary 
Edema
EVLW (also 
known as 
ELW)
Yes 
(triplicates)
Extra Vascular Lung Water: 
Includes intra-cellular, interstitial 
and intra-alveolar water (not 
pleural effusion)
EVLWI (also 
known as 
ELWI)
No
Extra Vascular Lung Water 
Index: EVLW indexed to
predicted body weight


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Timeframe
Grouping
Abbreviation 
/ Item
Databased
Description
PVPI
Yes
Pulmonary Vascular 
Permeability Index: EVLW 
indexed to Pulmonary Blood 
Volume 
Used internally 
by the PiCCO 
machine
ITBV
No
Intra-thoracic Blood Volume
PBV
No
Pulmonary blood volume
PTV
No
Pulmonary thermal volume
MTt
No
Mean transit time
DSt
No
Downslope decay time
ITTV
No
Intrathoracic thermal volume
LAV / RAV
No
Left / Right atrium Volume
LVV  / RVV
No
Left / Right ventricle Volume
Constant
Information / 
Demographics
BSA
No
Body Surface Area (DuBois): 
Manually derived from observed 
weight and height
PBW
No
Predicted Body Weight 
PBSA
No
Predicted Body Surface Area: 
Derived using same approach 
as DuBois but uses Predicted 
body weight instead of observed 
weight
Arterial Line 
Used
Yes
Typically Femoral (Brachial is 
the other option)
1.
A snapshot of the values for the continuous measurements would be taken when the 3x 
Thermodilutions are performed


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11.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
11.11.1.
Bayesian Analyses (SAS Proc MCMC)

The following points are for guidance and illustration only and do not guarantee a 
successful model convergence. They cannot cover all eventualities and do not remove 
the requirement to do what is best for the specific set of observed data being 
modelled.

Unless otherwise stated, data collected at screening and at unscheduled time points 
will not be included in the statistical analyses, i.e., only planned/scheduled post-
screening data will be included.

All credible intervals reported will be equal tail, unless otherwise specified.

Convergence for the parameters in the model needs to be verified.

The randomization seed used in PROC MCMC should itself be generated with an 
element of randomness - but there is no need to formally document this process (e.g. 
using Excel function RANDBETWEEN [1,9999999] and copying the result into the 
SAS code)

Unless the parameter is a flag variable (e.g. taking binary values of 1 or 0) the 
medians of the posterior distribution should be used.

Warnings/Erros in the SAS log regarding flag variables may be safely discounted

All effects will be entered on the same PARMS statement initially.  If necessary to 
aid model convergence parameters may be split across several PARMS lines.

Centring of continuous covariates will take place at the input dataset stage, using only 
individuals who contribute usable data to the model fitting process.

Individuals with missing covariates would be dropped from the model fitting process 
(alternative imputation strategies may be explored if required, e.g. substituting the 
covariate mean for a missing value)

Bespoke conjugate samplers (functions that can be called from within PROC MCMC) 
may be used to improve the computational performance and reduce the computational 
overheads. If such an approach is used it may require different parameterisations / 
prior specification but it should be set up act commensurate to the approaches 
described.
11.11.1.1. Prior Distributions
Unless otherwise specified, the following will be the default approach to selecting prior 
distributions:

Non-informative priors of the form Normal(0, Var=1E6) will be assigned to each 
fixed-effect parameter in the proposed statistical model.

Non-informative inverse-gamma priors of the form IG(a=2.001,b=0.001) will be 
used for scale parameters (variances). If these parameters do not lead to 
convergence than choose “a” small and “b” smaller than the expected standard 


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deviation (the expected standard deviation can be obtained from empirical 
estimates or by fitting the model using likelihood approaches such as in PROC 
MIXED).   

For scale parameters (variances) that may take values close to zero a non-
informative prior of the form Uniform(0, XXX) may be assigned for the standard 
deviation (SD) in place of the inverse gamma, where XXX is a suitably chosen 
range that covers clinically plausible values for the SD.

For repeated measures models, non-informative Inverse-Wishart priors of the 
form IW(υ, Σ) will be assigned for the unstructured VCV. The parameter υ 
represents the dimension of VCV (number of rows or columns) and the matrix Σ 
is an identity matrix of the same dimension as VCV. 
o
If there are issues with these distribution parameters then the identity 
version of Σ may be replaced with a diagonal matrix that uses best guesses 
for the residual variance at each repeated measure timepoint (or empirical 
estimates or the residual estimate from fitting likelihood based models 
using PROC MIXED). This only needs to be of the correct order of 
magnitude.
o
Alternatively, a Spatial power (with planned times as the “distances”) for 
the VCV may be explored. The prior for the correlation parameter 
is 
Uniform[-1,1], whereas the variance parameter  
is assumed to follow 
the IG(a=2.001,b=0.001) prior distribution.
It is good practice to ensure that each prior distribution is visualized to ensure it appears 
sensible, i.e., that it allows parameter values that generate clinically plausible response 
values and that it is truly non-informative over the region of the likelihood function 
where the data lies.
Note: 

The Gamma(a, b) density function takes the form
The mean is a/b and the variance is a/b2.

The IG(a, b) density function takes the form
The mode is b/(a+1), the mean is b/(a-1), if a>1, and the variance is b2/[(a-1)2(a-
2)], if a>2.

There is no requirement to formally report the prior visualisation outputs.


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11.11.1.2. Initial Values
Unless otherwise specified, initial parameter values of zero will be used for the fixed-
effect parameters. For remaining model parameters initial values may be drawn at 
random from their respected prior distribution.  If convergence of the Markov chain 
Monte Carlo (MCMC) algorithm is problematic then alternative estimates may be used 
(for example, these could be based on maximum likelihood estimates, or by setting any 
“intercept” parameter to lie roughly in the region of the observed data values).
11.11.1.3. Convergence Diagnostics
To be able to perform Bayesian inference using MCMC simulations the samples for all 
the parameters in the model need to be obtained from the corresponding target posterior 
distribution. To ensure that this is the case the following is a list of convergence 
diagnostics that can be applied for each parameter:
Comparing MCSE vs posterior standard deviation:

The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation of the posterior distribution (SD) to ensure that only a fraction of the 
posterior variability is due to the simulation, i.e., the ratio MCSE/SD should be as 
small as possible, typically close to 0.01.  

Adequate values for the number of MCMC samples / thinning / number of burn-in 
samples should be chosen to ensure that the ratio MCSE/SD for the key 
parameters in the model is approximately 0.01 (key parameters are those 
associated with treatment, or pre-specified comparisons of interest). 

For other model parameters, try to get the MCSE/SD values as close to 0.01 as 
possible, but if there is significant autocorrelation then values below 0.05 would 
be considered acceptable.

In addition, if possible, the number of tuning units and maximum number of 
tuning iterations may be increased to find a better proposal distribution for the 
model parameters, which in turn may reduce the MCSE/SD ratio.

Where possible the code should be written to allow the SAS compiler to identify 
and make use of conjugacy, since this can greatly reduce the corresponding 
MCSE/SD ratio.

Models selected with MCSE/SD values > 0.01would need a brief 
remark/justification added to the CSR to clarify why it was not possible to reach 
the target and why it is believed the subsequent model still has utility from an 
inference perspective.


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Geweke diagnostics:

The Geweke diagnostic test checks whether the mean estimates have converged 
by comparing means from the early and latter part of the Markov chain using a z-
score t-test. 

Large absolute values of the z-score statistic indicate rejection of the null 
hypothesis of no difference between the mean estimates obtained from the early 
and latter parts of the chain.
Diagnostic plots and visual inspection:

Trace plots of samples versus the simulation index can used to assess some 
aspects of convergence. The centre of the chain should appear stable with very 
small fluctuations, i.e., the distribution of points should not change as the chain 
progresses and the posterior mean and variance are relatively constant.

Autocorrelation plots can be used to assess degree of autocorrelation (should 
decline rapidly and show no oscillation patterns).

The posterior density should look reasonable for each parameter (e.g. for posterior 
parameters expected to follow a normal distribution, the density plot should not 
appear bi-modal, but for parameters acting as binary flags, then bi-modal is 
acceptable).

Examination of correlation structures between relevant posterior parameters 
should be used to provide information about what potential issues may be and 
also what corrective action(s) may be worthwhile attempting (scatterplots of the 
samples from the posterior distributions of the parameters).
Convergence for all the parameters in the model needs to be verified.
11.11.1.4. Additional Model Checking (optional at the discretion of the study 
statistician)
Additional model checking can be performed using the posterior predictive distribution.

For each observation generate as many expected values from the posterior 
predictive distribution as the number of MCMC samples.

Residuals for each observation are obtained by subtracting the expected values 
from the observed values.

For each subject calculate an average residual and an average expected value.

Model fitting can be checked by looking for patterns when plotting the average 
residual versus the average predicted value as in a maximum likelihood 
estimation setting.


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When non-informative priors are used and there is only a small amount of missing data a 
faster/easier alternative to the posterior predictive distribution model checking would be 
to fit the equivalent model using a frequentist approach (e.g. in SAS PROC MIXED) and 
utilise the built in diagnostic tools.
11.11.1.5. Possible corrective actions for non-converging MCMC models
Possible corrective actions include but are not limited to

Moving parameters (or combinations of parameters) onto separate PARMS 
statements (to form blocks that are updated independently in the MCMC 
algorithms)

Increasing the number of MCMC draws from the posterior distributions

Increasing the length of the burn in period

Increasing the thinning parameter (to reduce the autocorrelation)

Centring covariates (to reduce correlations between the posterior parameters)

Re-parameterising the model (e.g. using log-normal prior distributions to stop 
values being sampled that are below zero)

Re-scaling the parameters (e.g. if one parameter takes values orders of 
magnitudes different to the other model parameters then dividing it by a suitable 
constant but back transforming the rescaled parameter prior to its use in any 
subsequent manipulations)

Visualising the likelihood function of the dataset to determine if there are more 
appropriate starting estimates (or profiled versions of the likelihood for subsets of 
model parameters where difficulties are being encountered if it is a high 
dimensionality problem)

Consulting with internal GSK experts to resolve the issues
11.11.2.
Mixed modelling assumptions (SAS Proc MIXED)
The following applies to statistical models fitted using SAS Proc MIXED:

Model assumptions will be applied, but appropriate adjustments maybe made based 
on the data.

The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying 
‘type=UN’ on the REPEATED line.


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o
In the event that this model fails to converge, alternative correlation structures
may be considered such as CSH or CS. 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.

Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the (studentised) residuals and a plot of the 
(studentisd) residuals versus the fitted values (i.e. checking the normality assumption 
and constant variance assumption of the model respectively) to gain confidence that 
the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models may be 
explored using appropriate transformed data.


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11.12.
Appendix 12: Details of Simulation exercise that produced 
operational characteristics used in the protocol
This section describes in detail how simulations were used to choose the cut-off points 
and probability thresholds included in the protocol decision rules and how simulations 
were used to assess the operating characteristics of the target sample size (40 per arm).
11.12.1.
Simulations supporting interim analysis 2
This section is divided into a broad overview of the strategy and additional sub-sections 
containing further detail on specific topics

Feasibility considerations limited maximum number of subjects to 80. 

Assumption of 2x endpoints per subject available at 2x time points (pre-surgery 
(baseline) and immediately post surgery). PVPI was assumed to require Ln (natural 
logarithm) transformation. No covariate adjustments were allowed in these 
simulations, but the actual IA2 analysis may incorporate covariate adjustments (e.g. 
for centre effects)

Goal of simulation strategy was to optimise the timing and frequency of interim 
analyses and the decision rules therein.

Various scenarios of possible GSK2862277 treatment effects; expressed as 
differences from the placebo means were evaluated in conjunction with different IA2 
recruitment targets (hypothetical placebo means assumed to be the same as the 
baseline adjusted values estimated from the BALTI dataset (Perkins, 2014)). Table 20
details the possible treatment effects evaluated. Table 16 details the potential IA2 
timings and thresholds evaluated.

For each scenario the simulation process is split into “Outer” and “Inner” loops. 
Differences over the outer loops explore the impact of the “information content” 
within data available at the time of IA2. Differences over the inner loops explore the 
impact of the decision criteria and rules for a given set of “observed” interim data. In 
practice there will only be one set of observed study data. The a priori expectation 
was that the later the timing of IA2 (with respect to the possible 80 subjects) the more 
consistent the information content would be across outer loops and, therefore, less 
variability between outer loop outcomes.

Logistics of implementing these complex simulations sometimes dictated the 
approaches taken (e.g. using conjugacy rather than MCMC simulations to enumerate 
distributions).

Outer loops: For efficiency 10,000 sets of individual subject level data for the 
maximum possible study size are generated for each scenario (i.e. 80 subjects per 
dataset). Repeatedly subsetting these 80 subjects and creating summary statistics from
each subsample allows multiple IA2 timings to be evaluated without constantly 


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having to re-simulate subject level data. Sufficient summary statistics were created 
using the first 12 subjects (6 per arm.), the first 14 subjects (7 p.a.), etc, through to 78 
subjects (39 p.a.) in increments of 2 subjects. Thus, each of the 10,000 sets has 34 
associated sets of summary statistics. Operating characteristics of potential IA2 
timings (e.g. after 15 subjects per arm) were evaluated by selecting the corresponding 
10,000 sets of associated summary statistics and putting each of them through the 
inner loop process. These are the summary statistics (and dimensions) produced 
which act as inputs to the inner loop process:
o
Placebo Mean Vector [2x1], Variance Covariance matrix [2x2] and 
Correlation matrix [2x2]
o
Number of subjects on Placebo [scalar]
o
Active Mean Vector [2x1]  Variance Covariance matrix [2x2] and Correlation 
matrix [2x2]
o
Number of subjects on Active [scalar]
Note: This step may be introducing some form of correlation between the simulation
runs because the same subject level data is being used repeatedly (e.g. the summary 
statistics for 6 and 7 subjects per arm will only differ due to the 1x additional 
subject). Unfortunately computational run time, the number of scenarios and the 
protocol development timeline prohibited completely independent subject simulations
to create the various summary statistics used as inputs to the inner loops. 

Inner loops: The starting assumption for each inner loop was that the “observed” data 
at the time of the interim have been used to derive multivariate sample summary 
statistics (computed separately per treatment arm). By using the VCV matrix from the 
Baseline adjusted BALTI dataset and the baseline adjusted Placebo means in the 
scenarios simulation of separate baseline data points was not necessary for the inner 
loops in this exercise.
Initially these summary statistics are combined with a set of non-informative priors to 
produce the hyperparameters of a multivariate normal distribution for predicting an 
individual subjects future response (described for the placebo treatment arm; 
analogous results for the active arm):


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Table 14
Mechanism for updating hyperparameters to simulate remaining 
subjects (Pbo arm)
Par’
Prior
Value
s
Data (Sample 
Summary statistics)
Posterior Parameters
Pbo
,0





0
0
means)
Sample
Pbo
of
Vector 
(2x1
x
Pbo
,1

= 




pbo
pbo
Pbo
n
k
n
k


0
,0
0
*
*
x

Pbo
k ,0
0
pbo
n
at IA2
Pbo
k ,1
=

pbo
n
k 
0
Pbo
,0

0
pbo
n
at IA2
Pbo
,1

=

pbo
n

0

Pbo
,0





0
0
0
0


matrix
covariance
variance
sample
is
VCV
matrix
2x2
a
is
*
1
C
C
VCV
npbo 

Pbo
,1

=



















Pbo
Pbo
pbo
pbo
Pbo
n
k
n
k
,0
,0
0
0
,0
*
*
*


x
x
C
The Posterior parameters (subscripted with a 1) from Table 14 are used to sample the 
parameters of the Multivariate normal distribution for a future subject and generate 
sufficient data to “complete the study recruitment for the arm”. Each of the following 
steps constitutes one “inner loop”:
o
Draw a sample VCV matrix 
Pbo

(Note: 
Pbo

relates to an individual subject, 
not a mean) from the inverse Wishart  distribution parameterized using the 
posteriors
Pbo
,1

and 
Pbo
,1

o
Conditional on the sampled 
Pbo

draw a single sample (denoted 
Pbo
Fut,
μ
)
from a MVN distribution with a mean vector parameterised using the 
posterior for 
Pbo
,1

and a VCV matrix parameterised using 
Pbo
Pbo
k ,1
Sampled 
o
Draw sufficient subjects to reach a total of 40 per arm from the (same within 
an inner loop) MVN distribution i.e. from 


Pbo
MVN

,
~
Pbo
Fut,
μ
. For example if 
the timing of the interim analysis was after 15 subjects then sample 25 future 
subjects from the MVN.
o
Repeat this inner looping a total of 1,000 times
Conceptually 1,000 hybrid datasets are formed by repeatedly joining the observed 
data at time of the interim onto the 1,000 simulated sets of future subjects from the 
inner loops. Each of these “end of study datasets” (Eos) could then be analysed 
separately to obtain the joint probability of seeing any decrease in mean PaO2/FiO2 
in conjunction with any increase in mean PVPI (relative to placebo). 


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However for computational speed the mechanism of updating the MVN 
hyperparameters was also used to obtain the end of study posterior distributions for 
the mean of each treatment arm. This is achieved by deriving the same set of sample 
summary statistics from each set of future simulated subjects (the “future data”) and 
using the previous posteriors as priors. This results in Table 15. A further assumption 
uses the expected value of the inverse-Wishart distribution as the “sampled” 
Eos

when obtaining the MVN distribution for the Mean treatment effect parameters for 
each arm. To further speed computations matrix algebra is used to obtain a MVN 
distribution for the end of study mean treatment difference parameters. 
Using this distribution of mean treatment differences at the end of the study the 
probability of seeing any decrease in PaO2/FiO2 in conjunction with any increase in 
PVPI can be determined (since this problem is bivariate the SAS function 
PROBBNRM may be used).
Table 15
Mechanism for updating hyperparameters for end of study treatment 
effects (Pbo arm)
Par’
Prior
Values
Data (Sample 
Summary statistics
for future subjects)
Posterior
Pbo
,2

Pbo
,1

(Table 14)
Pbo
Fut,
x
Pbo
,2

= 




rem
Pbo
Pbo
Fut
rem
Pbo
n
k
n
k


,1
,
,1
1
*
*
x

Pbo
k ,2
Pbo
k ,1
(Table 14)
pbo
rem
n
n

80
Pbo
k ,2
=

rem
Pbo
n
k

,1
Pbo
,2

Pbo
,1

(Table 14)
pbo
rem
n
n

80
Pbo
,2

=

rem
Pbo
n

,1

Pbo
,2

Pbo
,1

(Table 14)


Pbo
Fut
rem
Pbo
Fut
VCV
n
,
,
*
1


C
Pbo
,2

=




















T
Pbo
Pbo
Fut
Pbo
Pbo
Fut
rem
rem
Pbo
Fut
Pbo
n
k
n
k
,1
,
,1
,
1
1
,
,1
*
*
*


x
x
C










Pbo
Pbo
Eos
Pbo
MVN
Eos
k
E
,2
,
,2
,
~
effect
  
Pbo
Mean 
study 
of
End

Pbo
,
μ


CONFIDENTIAL
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87
Hence








































Act
Pbo
Act
Act
Pbo
Pbo
Pbo
Act
MVN
Diff
Eos
k
k
,2
,2
,2
,2
,2
,2
,2
,2
1
2
1
2
,
~
Diffs
Trt 
Mean 
EoS




,
μ
Each of the parameters of the EoS Mean Trt Diffs MVN distribution for that inner 
loop is saved. 
The output of the outer and inner loops for a given scenario is a dataset with 
approximately 10,000 * 34 * 1,000 sets of parameters that describe the end of study 
MVN distribution of mean treatment differences. In addition, each record also 
contains sufficient metadata to link it back to its generating circumstances.
Iterative discussions within the study team led to the critical boundaries for the endpoints 
that would be considered futile (i.e. any decrease in PaO2/FiO2 in conjunction with any 
increase in PVPI). Once set, the optimisation questions became “timing of IA2 and how 
much confidence was required to declare futility”.
These outer/inner loop datasets allow multiple probability trigger thresholds to be 
evaluated without need to re-simulate (see topics below). 
Generation of the individual subject data for the outer loop
Subject level PVPI and PaO2/FiO2 data from BALTI prevention trial (Perkins, 2014) 
were available for 56 subjects at pre-surgery and immediately post-surgery time points.
PC SAS (v9.3 TS1M2) PROC MCMC was used to fit the model in Equation 1 to the 
BALTI trial data and, once convergence achieved, simultaneously generate 10,000 sets of 
80 subjects (40 per placebo arm using the fitted BALTI means and 40 per active arm 
using the BALTI means offset by a pre-specified amount; see Table 20). Each endpoint
for each of the 80 subjects is represented as a distinct model parameter.


CONFIDENTIAL
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88
Equation 1
MVN Model fitted to BALTI dataset for the ith Subject































loops)
(outer 
iterations
MCMC
10,000
 the
of
each 
for 
drawn 
be
 will
new
a
but 
iteration 
MCMC
given 
a
 within 
subjects
2k 
 the
of
each 
for 
same
 the
is
sampled
 the
and
40
 to
1
,
602481
.0
6105
.
48
~
,
765
.0
27
.
42
~
arms
Active
and
Placebo
for the
subject 
future
a
simulate
 to
used
on 
Distributi
profile"
desired
minimum
"
the
for 
arms
Active
and
Placebo
for 
rs
mean vecto
supplied
of
Example
1
0
0
1
,2
~
5.0
20
 values
initial
;
6
1
0
0
6
1
,
0
0
~
ˆ
ˆ
4.0
0.36
 values
initial
;
6
1
0
0
6
1
,
0
0
~
ˆ
ˆ
:
are
ons
distributi
Prior 
ments
both treat
common to
matrix 
Covariance
Variance
2x2
a
is
 where
,
ˆ
ˆ
~
:
assume
data
observed
link to
To
(Centered)
Subject 
ith 
for 
PVPI
surgery)
-
(pre
Baseline
(Centered)
Subject 
ith 
for 
PaO2/FiO2
surgery)
-
(pre
Baseline
/
56
 to
1
i
ˆ
ˆ
ˆ
0
0
ˆ
)
ln(
/
ˆ
ˆ
,
/
,
,
/
,
,
/
,
/
2
/
1
2
/
1
,
/
,
/
2
/
1
%
15
%
15
85
.0
15
.1
&
16252
.0
3405
.6
&
602481
.0
6105
.
48
765
.0
27
.
42
:
/






























































































k
y
y
y
y
E
E
E
E
S
B
S
B
y
y
y
y
BSPVPI
F
BSP
Where
S
B
S
B
BSPVPI
F
BSP
y
y
i
MVN
k
PVPI
Act
F
P
Act
i
MVN
k
PVPI
Pbo
F
P
Pbo
iWish
i
MVN
PVPI
BALTI
F
P
BALTI
i
MVN
PVPI
F
P
i
PVPI
F
P
MVN
i
PVPI
F
P
i
i
PVPI
BALTI
F
P
BALTI
PVPI
F
P
i
i
i
PVPI
F
P
rat
dif
a
p
PVPI
LN
F
P







Generation of the summary statistics for the outer loops
SAS PROC IML was used to read in the PROC MCMC output (a dataset with one row 
per outer loop containing all subjects data for both treatment arms), and to process each 
row in turn as follows:
Manipulate/split the row contents into a matrix of dimension 2x40 (separate matrices of 
endpoints per treatment arm). 


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Subset each 2x40 matrix into possible interim analysis 2 timings by taking the first 5 
observations and then 6th, 7th, etc until reaching the 39th and repeat the following 
Centre each endpoint and derive the sample mean and sample variance covariance 
matrix (n-1 as the divisor) and also express the sample variance covariance matrix 
in terms of correlations and save the n per arm at the time of interim
Save each element of these matrices (to give one row per outer loop per possible 
interim analysis timing containing Pbo and Active summary statistics)
Choice of IA2 timing
Potential IA2 timings examined in this simulation exercise were at 15, 20 and 25 subjects 
per arm (plus a sanity check of 39 per arm).
Choice of IA2 futility threshold probability (applies within each inner loop)
A series of potential futility threshold probabilities for each inner loop were evaluated
(ranging from 0.05 to 0.95 by increments of 0.05 using SAS formats). If the posterior 
probability of observing any decrease in PaO2/FiO2 in conjunction with any increase in 
PVPI exceeded the proposed threshold that inner loop was marked as futile.
Choice of IA2 proportion of futile inner loop studies that will trigger the Pause and 
Review IA2 outcome (applies within each outer loop)
A series of threshold proportions were evaluated (ranging from 0.05 to 0.95 by 
increments of 0.05 using SAS formats). If the proportion of the (1,000) inner loops 
marked as futile exceeded the proposed threshold proportion that outer loop was said to 
have declared a “Pause and Review” outcome.
Selecting the timing and futility threshold
Each inner loop * outer loop * potential IA2 timing * dataset scenario (Table 20) 
provides a posterior probability of observing any decrease in PaO2/FiO2 in conjunction 
with any increase in PVPI (giving 1,000*10,000*4*5 = 20,000,000 values).
A series of SAS formats were created to dichotomise each of these 20,000,000 posterior 
probabilities into binary outcomes (1=Yes/event occurs, 0=No/event did not occur). For 
example to evaluate 0.1 and 0.65 futility thresholds the following SAS formats would be
created:
Low – 0.1 = 0
and 
Low – 0.65 = 0
0.1 – High = 1
0.65 – High = 1
In turn, the dataset of posterior probabilities had each SAS formatted applied and was put 
through PROC FREQ to determine the proportion of inner loops where the posterior 
probability for futility exceeded the threshold implied by the SAS format (producing a 
record for each combination of SAS format * outer loop * potential IA2 timing * dataset 
scenario).


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Another set of SAS formats were created and applied in turn to the above dataset. These
flagged when the proportion of the inner loops exceeded the proposed value implied by 
the associated SAS format, i.e. a Pause and Review outcome. Expressing this information 
as a proportion of Pause and Review outcomes gives a final dataset with one record per 
potential IA2 timing * dataset scenario combination. 
Table 16 details the combinations of dataset scenario, IA2 timing, futility proportions and 
proportion required to declare Pause and Review that were evaluated. A subset of the 
simulation results pertinent to the choices made for the protocol are summarised in Table
17. Other results are available on file. The highlighted column in Table 17 reflects the 
operating characteristics of the IA2 rules/criteria selected by the study team.
Table 16
Factors varied in evaluating IA2 operating characteristics
Every combination of the following factors were evaluated
Hypothetical
Treatment 
Profile
Interim Timings 
(number of 
observed 
subjects per 
arm)
Inner loop 
futility threshold
Proportion of 
inner loops 
needed to 
declare “Pause 
and Review”
Null
Active as BALTI 
Pre-op
Half Active as 
BALTI Pre-op
Quarter Active as 
BALTI Pre-op
Minimum desired 
profile
39, 25, 20, 15
0.95, 0.9, 0.85, 
0.8, 0.75, 0.7, 
0.65, 0.6, 0.55, 
0.5, 0.45, 0.4, 
0.35, 0.3, 0.25, 
0.2, 0.15, 0.1, 
0.05
0.95, 0.9, 0.85, 
0.8, 0.75, 0.7, 
0.65, 0.6, 0.55, 
0.5, 0.45, 0.4, 
0.35, 0.3, 0.25, 
0.2, 0.15, 0.1, 
0.05


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Table 17
Selected results from simulation exercise to evaluate IA2 operating 
characteristics
Hypothetical 
Treatment 
Profile
% of simulated outer loops with Pause and Review outcome
[Inner loop Futility threshold: 0.1
Proportion of inner loops to declare “Pause and Review”: 0.3]
IA2 @ 39 p.a.
IA2 @ 25 p.a.
IA2 @ 20 p.a.
IA2 @ 15 p.a.
Null
71.69%
76.15%
76.26%
75.98%
Active as 
BALTI Pre-op
0.02%
0.31%
1.06%
2.62%
Half Active as 
BALTI Pre-op
6.17%
15.69%
20.59%
25.82%
Quarter Active 
as BALTI Pre-
op
31.65%
44.41%
48.13%
51.46%
Minimum 
desired profile
2.24%
7.96%
11.41%
16.46%
Note: Highlighted column (20 per arm) reflects the IA2 choices selected for the study protocol
Note: Whilst writing this RAP a minor error in the SAS code was discovered and 
corrected (results presented in this RAP reflect the corrected data). The SAS code was 
not adding dummy records to the first PROC FREQ output dataset to re-include the 
opposite outcome whenever all inner loops had identical results (i.e. either all 1,000 inner 
loops were futile, or all 1,000 inner loops were not futile). Therefore the denominators 
used in subsequent PROC FREQ’s (number of input records) were not always as large as 
they should have been; but this situation was infrequent, so the impact is deemed 
minimal.
11.12.2.
Simulations providing operating characteristics of the target 
sample size (40 per arm)
The simulated data relating to all 80 subjects within each of the 10,000 outer loops for 
each dataset scenario were used to obtain sets of sample summary statistics and then to 
obtain the parameters of the MVN distribution for the End of Study mean treatment 
differences (see Section 11.12.1 and Table 20). For clarification, since there are no inner 
loops non-informative priors were used (Table 14) along with the expected value of the 
inverse-Wishart distribution when deriving the parameters of the MVN distribution for 
the mean treatment difference.
Discussions within the study team led to the clinically relevant differences that make up 
Figure 2. The SAS PROBBNRM function was used to obtain the posterior probability of 
the mean treatment effects being in each region defined by Figure 2, for each outer loop,
using the corresponding MVN distribution for the mean treatment difference. This 
probability only depends upon the location of the clinically relevant differences.  


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To get the process started an arbitrary probability threshold was assigned as a “trigger” 
for each region and if the posterior probability of being in the region exceeded the trigger 
it was deemed to have occurred. Since more than one region may be triggered the 
algorithm to combined triggered regions to obtain a single outcome was codified as 
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”
Based on the arbitrary trigger thresholds each of the 10,000 outer loops was evaluated to 
determine which regions (if any) met their probability triggers, and subsequently, which 
outcome occurred for that outer loop (Note: The language used in Section 9.2.1 of the 
protocol refers to these probability triggers as “confidence levels”). The operating 
characteristic of each outcome is the number of observed occurrences expressed as a 
proportion of the 10,000 outer loops. These were presented to the study team and an 
iterative process was started to vary these thresholds and observe the impact on operating 
characteristics.
The “null” and “minimum desired profile” have different desired operating characteristics 
and the trigger thresholds were varied until the team were comfortable with the operating 
characteristics of both. This led to the criteria in Figure 2 (probability triggers of 0.75 for 
Step 1, 0.25 for Step 2 and 0.35 for Step 3; denoted {0.75, 0.25, 0.35}) and the resulting 
operating characteristics in Table 18  that were presented in Table 5 of the study protocol 
(re-produced here using all scenarios from Table 20).
Table 18
Results from Simulation exercise assuming 40 p.a. complete
Hypothetical 
Treatment 
Profile
% of simulated studies with outcome
Overall Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
4.65%
92.81%
2.54%
0%
Active as 
BALTI Pre-op
92.72%
6.83%
0.45%
0%
Half Active as 
BALTI Pre-op
40.93%
49.98%
9.09%
0%
Quarter Active 
as BALTI Pre-
op
15.61%
77.13%
7.26%
0%
Minimum 
desired profile
80.64%
13.63%
5.73%
0%
A well performing end of study decision pathway should not be expected to conclude 
success for the “Null” profile whilst reliably concluding success for the “minimum 
desired profile”. In the language of frequentist hypothesis testing the “Overall success” 


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probabilities for the Null and Minimum desired profile are akin to the Type I error rate 
and power for the study design respectively. These were estimated to be 4.65% and 
80.64% respectively so the study design and end of study pathway was deemed 
acceptable (assuming 40 evaluable subjects per arm and residual variance covariance 
estimates in line with the BALTI trial (Perkins, 2014)). 
An additional step evaluated the operating characteristics of the final end of study 
decision pathway (Figure 2) using 25, 30 and 35 subjects per arm. Unsurprisingly, the 
operating characteristics were not as good, given the reduced information content (see 
Table 19). 
This exercise was also repeated using the following sets of probability triggers for the 
three steps of Figure 2: {0.75, 0.25, 0.50}, {0.70, 0.25, 0.50}, {0.95, 0.25, 0.50}, {0.95, 
0.25, 0.35} and {0.75, 0.25, 0.25}; results presented in Table 21, Table 22, Table 23, 
Table 24 and Table 25 respectively.
Note: Candidate combinations of probability thresholds were selected based upon review 
of the distributions formed from the 10,000 outer loop probabilities associated with the 
3x outcomes described in Figure 2 for each dataset in Table 20 and for 25, 30 , 35 and 40 
per arm total sample size. These are shown in Figure 5, Figure 6, Figure 7, Figure 8 and 
Figure 9. In these figures the boxid’s titled “Fail”, “Strong Success” and “Success” 
correspond to the Step 1, Step 2 and Step 3 probability thresholds respectively. A 
threshold would be a vertical slice placed on the x-axis and the proportion exceeding the 
slice would be the expected proportion triggering that rule (but the overall outcome 
requires the codifying rules described above). 


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Table 19
Results from Sensitivity analysis assuming 25, 30 and 35 p.a. 
complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
9.38%
86.03%
4.59%
0%
30
7.32%
88.52%
4.16%
0%
35
5.65%
90.91%
3.44%
0%
Active as 
BALTI Pre-
op
25
88.49%
9.98%
1.53%
0%
30
90.04%
8.97%
0.99%
0%
35
91.51%
7.86%
0.63%
0%
Half Active 
as BALTI 
Pre-op
25
44.57%
46.42%
9.01%
0%
30
42.84%
47.68%
9.48%
0%
35
42.08%
48.64%
9.28%
0%
Quarter 
Active as 
BALTI Pre-
op
25
21.96%
68.95%
9.09%
0%
30
19.50%
72.31%
8.19%
0%
35
17.49%
74.95%
7.56%
0%
Minimum 
desired 
profile
25
76.41%
17.06%
6.53%
0%
30
77.71%
15.91%
6.38%
0%
35
79.25%
14.9%
5.85%
0%


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Table 20
Hypothetical scenarios for generating datasets
DID
DID Desc’
Pbo Vector for Immediate 
Post-op mean response
Active Vector for Post-op mean response
MAX n 
p.a.
nmc
1
Null











765
.0
27
.
42
:
/
p
PVPI
LN
F
P

CHANGE
NO
rat
dif
a















1
1
&
0
0
765
.0
27
.
42
&


40
10000
2
Active as BALTI 
Pre-op











765
.0
27
.
42
:
/
p
PVPI
LN
F
P



















%
1.
17
%
7.
25
829
.0
257
.1
&
188
.0
87
.
10
577
.0
14
.
53
&rat
dif
a


40
10000
3
Half Active as 
BALTI Pre-op











765
.0
27
.
42
:
/
p
PVPI
LN
F
P



















%
0.9
%
9.
12
910
.0
129
.1
&
094
.0
435
.5
671
.0
705
.
47
&rat
dif
a


40
10000
4
Quarter Active as 
BALTI Pre-op











765
.0
27
.
42
:
/
p
PVPI
LN
F
P



















%
6.4
%
4.6
954
.0
064
.1
&
047
.0
715
.2
718
.0
985
.
44
&rat
dif
a


40
10000
5
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


40
10000
DID = Dataset ID, p.a. = per arm, nmc = Number of MCMC iterations (Outer loops)


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Table 21
Results from probability threshold set {0.75, 0.25, 0.50} and 
Sensitivity analysis assuming 25, 30, 35 and 40 p.a. complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
6.06%
86.03%
7.91%
0%
30
4.46%
88.52%
7.02%
0%
35
3.52%
90.91%
5.57%
0%
40
2.65%
92.81%
4.54%
0%
Active as 
BALTI Pre-
op
25
88.15%
9.98%
1.87%
0%
30
89.75%
8.97%
1.28%
0%
35
91.31%
7.86%
0.83%
0%
40
92.57%
6.83%
0.60%
0%
Half Active 
as BALTI 
Pre-op
25
40.40%
46.42%
13.18%
0%
30
39.04%
47.68%
13.28%
0%
35
37.90%
48.64%
13.46%
0%
40
37.12%
49.98%
12.90%
0%
Quarter 
Active as 
BALTI Pre-
op
25
17.42%
68.95%
13.63%
0%
30
15.24%
72.31%
12.45%
0%
35
13.32%
74.95%
11.73%
0%
40
11.38%
77.13%
11.49%
0%
Minimum 
desired 
profile
25
73.06%
17.06%
9.88%
0%
30
74.61%
15.91%
9.48%
0%
35
76.04%
14.90%
9.06%
0%
40
77.53%
13.63%
8.84%
0%


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Table 22
Results from probability threshold set {0.70, 0.25, 0.50} and 
Sensitivity analysis assuming 25, 30, 35 and 40 p.a. complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
6.06%
87.89%
6.05%
0%
30
4.45%
90.31%
5.23%
0.01%
35
3.50%
92.73%
3.75%
0.02%
40
2.65%
93.96%
3.39%
0%
Active as 
BALTI Pre-
op
25
86.71%
10.60%
1.25%
1.44%
30
88.46%
9.43%
0.82%
1.29%
35
89.92%
8.12%
0.57%
1.39%
40
91.40%
7.01%
0.42%
1.17%
Half Active 
as BALTI 
Pre-op
25
39.47%
49.87%
9.73%
0.93%
30
38.13%
51.15%
9.81%
0.91%
35
37.13%
51.98%
10.12%
0.77%
40
36.16%
53.19%
9.69%
0.96%
Quarter 
Active as 
BALTI Pre-
op
25
17.16%
72.28%
10.30%
0.26%
30
15.08%
75.27%
9.49%
0.16%
35
13.12%
78.02%
8.66%
0.20%
40
11.24%
79.99%
8.63%
0.14%
Minimum 
desired 
profile
25
72.40%
19.14%
7.80%
0.66%
30
73.85%
17.97%
7.42%
0.76%
35
75.39%
16.76%
7.20%
0.65%
40
76.92%
15.23%
7.24%
0.61%


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Table 23
Results from probability threshold set {0.95, 0.25, 0.50} and 
Sensitivity analysis assuming 25, 30, 35 and 40 p.a. complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
6.06%
65.60%
28.34%
0%
30
4.46%
71.10%
24.44%
0%
35
3.52%
75.65%
20.83%
0%
40
2.65%
79.01%
18.34%
0%
Active as 
BALTI Pre-
op
25
88.15%
2.44%
9.41%
0%
30
89.75%
2.30%
7.95%
0%
35
91.31%
1.67%
7.02%
0%
40
92.57%
1.55%
5.88%
0%
Half Active 
as BALTI 
Pre-op
25
40.40%
22.09%
37.51%
0%
30
39.04%
23.24%
37.72%
0%
35
37.90%
23.89%
38.21%
0%
40
37.12%
24.84%
38.04%
0%
Quarter 
Active as 
BALTI Pre-
op
25
17.42%
42.69%
39.89%
0%
30
15.24%
46.59%
38.17%
0%
35
13.32%
49.17%
37.51%
0%
40
11.38%
52.51%
36.11%
0%
Minimum 
desired 
profile
25
73.06%
5.06%
21.88%
0%
30
74.61%
4.64%
20.75%
0%
35
76.04%
4.24%
19.72%
0%
40
77.53%
3.94%
18.53%
0%


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Table 24
Results from probability threshold set {0.95, 0.25, 0.35} and 
Sensitivity analysis assuming 25, 30, 35 and 40 p.a. complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
9.38%
65.60%
25.02%
0%
30
7.32%
71.10%
21.58%
0%
35
5.65%
75.65%
18.70%
0%
40
4.65%
79.01%
16.34%
0%
Active as 
BALTI Pre-
op
25
88.49%
2.44%
9.07%
0%
30
90.04%
2.30%
7.66%
0%
35
91.51%
1.67%
6.82%
0%
40
92.72%
1.55%
5.73%
0%
Half Active 
as BALTI 
Pre-op
25
44.57%
22.09%
33.34%
0%
30
42.84%
23.24%
33.92%
0%
35
42.08%
23.89%
34.03%
0%
40
40.93%
24.84%
34.23%
0%
Quarter 
Active as 
BALTI Pre-
op
25
21.96%
42.69%
35.35%
0%
30
19.50%
46.59%
33.91%
0%
35
17.49%
49.17%
33.34%
0%
40
15.61%
52.51%
31.88%
0%
Minimum 
desired 
profile
25
76.41%
5.06%
18.53%
0%
30
77.71%
4.64%
17.65%
0%
35
79.25%
4.24%
16.51%
0%
40
80.64%
3.94%
15.42%
0%


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Table 25
Results from probability threshold set {0.75, 0.25, 0.25} and 
Sensitivity analysis assuming 25, 30, 35 and 40 p.a. complete
Hypothetical 
Treatment 
Profile
n (p.a.)
% of simulated studies with outcome
Overall 
Success
Potentially 
Unsuccessful
Inconclusive
Inconsistent
Null
25
12.70%
86.03%
1.27%
0%
30
10.36%
88.52%
1.12%
0%
35
8.21%
90.91%
0.88%
0%
40
6.62%
92.81%
0.57%
0%
Active as 
BALTI Pre-
op
25
88.89%
9.98%
1.13%
0%
30
90.26%
8.97%
0.77%
0%
35
91.61%
7.86%
0.53%
0%
40
92.80%
6.83%
0.37%
0%
Half Active 
as BALTI 
Pre-op
25
48.33%
46.42%
5.25%
0%
30
46.59%
47.68%
5.73%
0%
35
45.81%
48.64%
5.55%
0%
40
44.63%
49.98%
5.39%
0%
Quarter 
Active as 
BALTI Pre-
op
25
26.85%
68.95%
4.20%
0%
30
23.87%
72.31%
3.82%
0%
35
21.64%
74.95%
3.41%
0%
40
19.92%
77.13%
2.95%
0%
Minimum 
desired 
profile
25
79.08%
17.06%
3.86%
0%
30
80.15%
15.91%
3.94%
0%
35
81.54%
14.90%
3.56%
0%
40
83.04%
13.63%
3.33%
0%


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Figure 5
Hypothetical Treatment Profile used to generate data (subjects)=Null


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Figure 6
Hypothetical Treatment Profile used to generate data (subjects)= 
Active as BALTI Pre-op


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Figure 7
Hypothetical Treatment Profile used to generate data (subjects)= 
Half Active as BALTI Pre-op


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Figure 8
Hypothetical Treatment Profile used to generate data (subjects)= 
Quarter Active as BALTI Pre-op


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Figure 9
Hypothetical Treatment Profile used to generate data (subjects)= 
Minimum desired profile


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11.13.
Appendix 13: Abbreviations & Trade Marks
11.13.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ELF
Epithelial Lining Fluid
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GSK
GlaxoSmithKline
GUI
Guidance
LOC
Last Observation Carries Forward
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOFA
Sequential Organ Failure Assessment
SOP
Standard Operation Procedure


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Abbreviation
Description
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
Note: See Table 13 for abbreviations used in Transpulmonary Thermodilution
11.13.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
Picco
SAS
Spotfire
WinNonlin


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11.14.
Appendix 14: List of Data Displays
11.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Pharmacodynamic and / or Biomarker
5.1 to 5.n
5.1 to 5.n
Pharmacogenetics
6.1 to 7.n
6.1 to 7.n
Section
Listings
ICH Listings
1 to x
Other Listings
(x+1) to z
11.14.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 15 : Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacogenetics
PGX_Fn
PGX_Tn
PGX_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.14.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
DS [X]
During Study
DE [X]
Dose Escalation
IAn [X]
Interim Analysis<n> Statistical Analysis Complete
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


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11.14.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Accountability
1.1.
n/a
POP_T1
Summary of Subject Accountability (subjects constituting 
each Statistical Analysis Population)
Statistical analysis population by 
treatment. Create categories for the 
main treatment descriptors and for each 
of the alternative sets (grouping by 
study medication and BAL sampling 
location) 
IA1 [1], IA2 [2], 
SAC [1]
Subject Disposition
1.2.
Safety
ES1
Summary of Subject Disposition
SAC [1]
1.3.
Screen 
Failures
ES6
Summary of Reasons for Screening Failure
Facilitates CONSORT diagram in 
publications. Therefore also sub-total 
the inclusion/exclusion category by the 
applicable individual criteria (e.g. 
exclusion due to presence of pre-
existing ADA antibodies).
SAC [1]
1.4.
Safety
DV1b
Summary of Important Protocol Deviations
Create Separate “block” for each of the 
three per protocol populations in the 
style given in the shell.
SAC [1]
Demography
1.5.
Safety
DM1
Summary of Demographic Characteristics (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
1.6.
Safety
DM1
Summary of Demographic Characteristics (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
1.7.
Safety
DM1
Summary of Demographic Characteristics (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
Safety
DM5
Summary of Race and Racial Combinations
Details (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
1.9.
Safety
DM5
Summary of Race and Racial Combinations
Details (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
1.10.
Safety
DM5
Summary of Race and Racial Combinations
Details (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
1.11.
Safety
SAFE_T1
Number of Subjects per Country by Treatment Group
Macro: EMA_COUNTRY
SAC [1]
1.12.
Safety
SAFE_T2
Number of Subjects in each Age Group by Treatment Group
Macro: EMA_AGEGRP
All age categories (in years) will be 
produced if they exist in the data, and 
according to the EMA requirements. If 
age unit is other than year, then 
programming modifications will be 
required.
SAC [1]
Medical Condition & Concomitant Medications
1.13.
Safety
MH4
Summary of Current Medical Conditions (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
1.14.
Safety
MH4
Summary of Current Medical Conditions (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
1.15.
Safety
MH4
Summary of Current Medical Conditions (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
1.16.
Safety
MH4
Summary of Past Medical Conditions (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.17.
Safety
MH4
Summary of Past Medical Conditions (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
1.18.
Safety
MH4
Summary of Past Medical Conditions (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
1.19.
Safety
CP_CM1
Summary of Concomitant Medications by Generic Term (by 
Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
1.20.
Safety
CP_CM1
Summary of Concomitant Medications by Generic Term (by 
Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
1.21.
Safety
CP_CM1
Summary of Concomitant Medications by Generic Term (by BAL 
Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]


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11.14.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Analysis
2.1.
PP1
EFF_T1
Summary Statistics supporting Primary Analysis (Absolute and 
Change from Baseline): PVPI and PaO2/FiO2 (by Treatment 
arm)
Use Main Treatment Group Descriptors
Only include timepoints associated with 
the primary analysis (i.e. the two 
assessments on Day 1: prior to 
surgery/post surgery).
IA2 [1], SAC [1]
2.2.
PP2
EFF_T1
Summary Statistics supporting Primary Analysis (Absolute and 
Change from Baseline): PVPI and PaO2/FiO2  (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
Only include timepoints associated with 
the primary analysis (i.e. the two 
assessments on Day 1: prior to 
surgery/post surgery).
IA2 [1], SAC [1]
2.3.
PP1
EFF_T1
Summary Statistics supporting Primary Analysis (Absolute and 
Change from Baseline): PVPI and PaO2/FiO2  (by BAL 
Location)
Use Alternative Treatment Group 
Descriptors #2
Only include timepoints associated with 
the primary analysis (i.e. the two 
assessments on Day 1: prior to 
surgery/post surgery).
IA2 [1], SAC [1]
2.4.
PP2
EFF_T2
Summary of Primary Statistical Analysis: Joint Modelling of PVPI 
and PaO2/FiO2.
Example shell conditional on the 
Trt*BAL interaction term being non-
significant.  Use expert judgement to 
override the shell if an alternative layout 
is more informative / easier to review
Assign a statistical analysis ID number 
to each analysis and page by this 
variable (mechanism to allow sensitivity 
analyses to be presented if applicable)
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Secondary Analyses
Transpulmonary Thermodilution
2.5.
PP1
EFF_T1
Summary Statistics (Absolute and Change from 
Baseline):Transpulmonary Thermodilution  (by Treatment arm)
Use Main Treatment Group Descriptors
See Table 4 for endpoints (Arterial Line, 
Predicted body weight, predicted body 
surface area and body surface area 
only do need to be summarised at 
multiple timepoints).
SAC [1]
2.6.
PP2
EFF_T1
Summary Statistics (Absolute and Change from 
Baseline):Transpulmonary Thermodilution  (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
See above comments
SAC [1]
2.7.
PP1
EFF_T1
Summary Statistics (Absolute and Change from 
Baseline):Transpulmonary Thermodilution  (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
See above comments
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
PP2
EFF_T2
Summary of Statistical Analysis: Repeated Measures Joint 
Modelling of PVPI and PaO2/FiO2
Example shell conditional on the 
Trt*BAL*Time interaction terms being 
non-significant.  Use expert judgement 
to override the shell if an alternative 
layout is more informative / easier to 
review
It is not possible to display all elements 
of the VCV from the actual MCMC 
modelling using this layout (e.g. the off 
diagonal elements across planned 
time). Add footnote to alert user that 
this has occurred.
Assign a statistical analysis ID number 
to each analysis and page by this 
variable (mechanism to allow sensitivity 
analyses to be presented if applicable)
SAC [1]
2.9.
PP2
EFF_T5
Summary of Statistical Analysis: Modelling of PVPI on 
Completion of Surgery
Example shell conditional on the 
Trt*BAL interaction term being non-
significant.  Use expert judgement to 
override the shell if an alternative layout 
is more informative / easier to review
Assign a statistical analysis ID number 
to each analysis and page by this 
variable (mechanism to allow sensitivity 
analyses to be presented if applicable)
SAC [1]
2.10.
PP2
EFF_T5
Summary of Statistical Analysis: Modelling of EVLWI on 
Completion of Surgery
See above comments
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Oxygenation (especially PaO2/FiO2)
2.11.
PP1
EFF_T1
Summary Statistics (Absolute and Change from 
Baseline):Oxygenation (by Treatment arm)
Use Main Treatment Group Descriptors
See Table 4 for endpoints. Also include 
the imputed version of PaO2/FiO2
SAC [1]
2.12.
PP2
EFF_T1
Summary Statistics (Absolute and Change from Baseline): 
Oxygenation  (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
See above comments
SAC [1]
2.13.
PP1
EFF_T1
Summary Statistics (Absolute and Change from Baseline): 
Oxygenation (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
See above comments
SAC [1]
2.14.
PP2
EFF_T5
Summary of Statistical Analysis: Modelling of PaO2/FiO2 on 
Completion of Surgery
Example shell conditional on the 
Trt*BAL interaction term being non-
significant.  Use expert judgement to 
override the shell if an alternative layout 
is more informative / easier to review
Assign a statistical analysis ID number 
to each analysis and page by this 
variable (mechanism to allow sensitivity 
analyses to be presented if applicable)
SAC [1]
SOFA
2.15.
PP2
EFF_T1
Summary Statistics (Absolute and Change from Baseline): Daily 
SOFA scores by Treatment and Time
Display Total SOFAs (observed then 
imputed).
SAC [1]
2.16.
PP2
EFF_T5
Summary of Statistical Analysis of Repeated Measures 
Modelling of SOFA
Make appropriate modifications to 
account for the repeated measures
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Analyses
Clinical Outcomes
2.17.
PP2
Summary of Diagnosed ARDS out to day 28 (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
2.18.
PP2
Summary of 28 day survival status (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
2.19.
PP2
Summary of Organ Failure Free days out to day 28 (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
Resource Utilisation
2.20.
PP2
Summary of Ventilator Free Days (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
2.21.
PP2
Summary of ICU Length of Stay (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
2.22.
PP2
Summary of Hospital Length of Stay (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC [2]
Bespoke outputs to support the Interim Analyses
2.23.
PP2
EFF_T3
Summary of Futility Statistical Analysis at Interim Analysis 2
IA2 [1]
2.24.
PP2
EFF_T4
Summary of Sample Size re-estimation process at Interim 
Analysis 2
IA2 [1]


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11.14.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Analysis
2.1.
PP2
EFF_F5
Spaghetti plots of PVPI and PaO2/FiO2 Time Profiles (by 
Treatment arm)
Separate plot per endpoint. Identify 
subjects using the main treatment 
descriptors. Plot Ln(PVPI) by using Ln 
scale axis
Only use Pre-Op and imm.Post Op 
timepoints
IA2 [1], SAC [1]
2.2.
PP2
EFF_F6
Scatterplots of PVPI Vs PaO2/FiO2 by Study Medication and 
Timepoint
Identify subjects using the main 
treatment descriptors
Only use Pre-Op and imm.Post Op 
timepoints
IA2 [1], SAC [1]
2.3.
PP2
EFF_F7
Adjusted Medians and 95% Credible Intervals from the Marginal 
Posterior Distributions for each Study medication (PVPI and 
PaO2/FiO2)
IA2 [1], SAC [1]
2.4.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals from the Marginal 
Posterior Distributions for Study medications comparisons (PVPI 
and PaO2/FiO2)
IA2 [1], SAC[1]
2.5.
PP2
EFF_F4
Joint Posterior Distribution and associated Marginals used to 
evaluate End of Study Decision Pathway
IA2 [1], SAC[1]
Secondary Analyses
Transpulmonary Thermodilution
2.6.
PP2
EFF_F1
Individual Subject PVPI and EVLWI Time Profiles
Include all data for the subjects (inc 
unscheduled). Use actual times. Try to 
keep all endpoints on the same page 
per subject and panel by endpoint 
SAC[1]


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.7.
PP2
EFF_F5
Spaghetti plots of PVPI and EVLWI Time Profiles (by Treatment 
arm)
Separate plot/page per endpoint. 
SAC[1]
2.8.
PP2
EFF_F6
Scatterplots of PVPI Vs PaO2/FiO2 by Study Medication and 
Timepoint
SAC[1]
2.9.
PP2
EFF_F7
Adjusted Medians and 95% Credible Intervals from the Marginal 
Posterior Distributions for each Study medication (PVPI and 
PaO2/FiO2)
Use Planned Timepoint as the x-axis of 
the plot but offset/group by treatment to 
avoid overlapping
SAC[1]
2.10.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals from the Marginal 
Posterior Distributions for Study medications comparisons (PVPI 
and PaO2/FiO2)
Use Planned Timepoint as the x-axis of 
the plot
SAC[1]
2.11.
PP2
EFF_F7
Adjusted Medians and 95% Credible Intervals for each Study 
medication from the Modelling of PVPI on Completion of Surgery
SAC[1]
2.12.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals for Study 
medication comparisons from the Modelling of PVPI on 
Completion of Surgery
SAC[1]
2.13.
PP2
EFF_F7
Adjusted Medians and 95% Credible Intervals for each Study 
medication from the Modelling of EVLWI on Completion of 
Surgery
SAC[1]
2.14.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals for Study 
medication comparisons from the Modelling of EVLWI on 
Completion of Surgery
SAC[1]
Oxygenation (especially PaO2/FiO2)
2.15.
PP2
EFF_F3
Individual Subject Oxygenation Time Profiles
Include all data for the subjects (inc 
unscheduled). Use actual times. If 
possible put all endpoints on the same 
panel. Add the imputed PaO2/FiO2 
profile as well.
SAC [1]


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.16.
PP2
EFF_F5
Spaghetti plots of PaO2/FiO2 and SpO2/FiO2 Time Profiles (by 
Treatment arm)
Separate plot/page per endpoint. 
Also add the impuited PaO2/FiO2
SAC [1]
2.17.
PP2
EFF_F2
Scatterplot of Observed PaO2/FiO2 and the PaO2/FiO2 value 
imputed from the associated SpO2/FiO2
Only plot data where observed 
PaO2/FiO2 and SpO2/FiO2 data are 
present. Identify data points using the 
main treatment descriptor symbols and 
the b-splines using the associated line 
pattern.
SAC[1]
2.18.
PP2
EFF_F7
Adjusted Medians and 95% Credible Intervals for each Study 
medication from the Modelling of PaO2/FiO2 on Completion of 
Surgery
SAC[1]
2.19.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals for Study 
medication comparisons from the Modelling of PaO2/FiO2 on 
Completion of Surgery
SAC[1]
SOFA
2.20.
PP2
EFF_F1
Individual Subject SOFA Time Profiles
Include all data for the subjects (inc 
unscheduled). Use actual times.
SAC [1]
2.21.
PP2
EFF_F7 / 
EFF_F1
Adjusted Medians and 95% Credible Intervals for each Study 
medication from the Repeated Measures Modelling of SOFA
Use Planned Timepoint as the x-axis of 
the plot but offset/group by treatment to 
avoid overlapping
SAC[1]
2.22.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals for Study 
medication comparisons from the Repeated Measures Modelling 
of SOFA
Use Planned Timepoint as the x-axis of 
the plot
SAC[1]
Exploratory Analyses
Clinical Outcomes
2.23.
PP2
Kaplan Meier survival curves for Day 28 Survival status (and 
approx 95% CIs) (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
SAC[2]


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11.14.7.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
CP_AE1p
Summary of All Serious Adverse Events (by Treatment arm)
Sort by System Organ Class
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.2.
Safety
CP_AE1p
Summary of All Serious Adverse Events (by Study Medication)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.3.
Safety
CP_AE1p
Summary of All Serious Adverse Events (by BAL Location)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
3.4.
Safety
CP_AE1p
Summary of All Adverse Events (by Treatment arm)
Sort by System Organ Class
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.5.
Safety
CP_AE1p
Summary of All Adverse Events (by Study Medication)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.6.
Safety
CP_AE1p
Summary of All Adverse Events (by BAL Location)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
3.7.
Safety
CP_AE1p
Summary of Drug-Related Adverse Events (by Treatment arm)
Sort by System Organ Class
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.8.
Safety
CP_AE1p
Summary of Drug-Related Adverse Events (by Study 
Medication)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.9.
Safety
CP_AE1p
Summary of Drug-Related Adverse Events (by BAL Location)
Sort by System Organ Class
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
Safety
AE2
Relationship between System Organ Class and Verbatim Text
IA1 [1], IA2 [2], 
SAC [1]
3.11.
Safety
SAFE_T3
All Non-Serious Adverse Event Counts that Occur in at least 5% of Any 
Treatment Group
Macro: EMA_AE
SAC [2]
3.12.
Safety
SAFE_T4
All Serious Adverse Event Counts
Macro: EMA_AE
The ‘Number of Related Fatalities’ is
only required at the Preferred Term 
level for reporting and is intentionally 
left out of the ‘Any events’ group
SAC [2]
Laboratory Values
3.13.
Safety
LB1
Summary of Chemistry Laboratory Values (by Treatment arm)
Exclude Pa02 from this summary
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.14.
Safety
LB1
Summary of Chemistry Laboratory Values (by Study Medication)
Exclude Pa02 from this summary
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.15.
Safety
LB1
Summary of Chemistry Laboratory Values (by BAL Location)
Exclude Pa02 from this summary
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
3.16.
Safety
LB1
Summary of Hematology Laboratory Values (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.17.
Safety
LB1
Summary of Hematology Laboratory Values (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.18.
Safety
LB1
Summary of Hematology Laboratory Values (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.19.
Safety
UR3b
Summary of Urinalysis Dipstick Results (by Treatment arm)
Use Main Treatment Group Descriptors
Note: Consult with medical monitor to 
“map” results within each test to a 
common nomenclature prior to 
summarising
IA1 [1], IA2 [2], 
SAC [1]
3.20.
Safety
UR3b
Summary of Urinalysis Dipstick Results (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
Note: Consult with medical monitor to 
“map” results within each test to a 
common nomenclature prior to 
summarising
IA1 [1], IA2 [2], 
SAC [1]
3.21.
Safety
UR3b
Summary of Urinalysis Dipstick Results (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
Note: Consult with medical monitor to 
“map” results within each test to a 
common nomenclature prior to 
summarising
IA1 [1], IA2 [2], 
SAC [1]
ECG 
3.22.
Safety
EG1
Summary of ECG Findings (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.23.
Safety
EG1
Summary of ECG Findings (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.24.
Safety
EG1
Summary of ECG Findings (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
3.25.
Safety
EG2
Summary of ECG Values (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.26.
Safety
EG2
Summary of ECG Values (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.27.
Safety
EG2
Summary of ECG Values (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
3.28.
Safety
EG2
Summary of Change from Baseline in ECG Values (by 
Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.29.
Safety
EG2
Summary of Change from Baseline in ECG Values (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.30.
Safety
EG2
Summary of Change from Baseline in ECG Values (by BAL 
Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]
Vital Signs
3.31.
Safety
VS1
Summary of Vital Signs (by Treatment arm)
Use Main Treatment Group Descriptors
IA1 [1], IA2 [2], 
SAC [1]
3.32.
Safety
VS1
Summary of Vital Signs (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
IA1 [1], IA2 [2], 
SAC [1]
3.33.
Safety
VS1
Summary of Vital Signs (by BAL Location)
Use Alternative Treatment Group 
Descriptors #2
IA1 [1], IA2 [2], 
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunogenicity
3.34.
Safety
IMM1
Summary of Treatment emergent Positive Immunogenicity 
results (by Study Medication)
Use Alternative Treatment Group 
Descriptors #1
Note: The screening test 
results are not being 
databased (pre-requisite for 
Negative test was an 
inclusion criterion). Therefore 
this table should only contain 
treatment emergent positive 
samples
SAC [2]


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11.14.8.
Safety Figures
No Safety figures are currently planned. Spotfire is intended to be used in-stream to 
review safety data in an ongoing manner. If appropriate selected Spotfire visualisations 
may be reproduced within HARP.


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11.14.9.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma
4.1.
PK
PKCT1
Summary of Plasma GSK2862277 Pharmacokinetic 
Concentration – Time Data (by Treatment arm)
Use Main Treatment Group Descriptors 
Planned time points: Day1: 0h, 1h, On 
completion of surgery; Day 2: 24 h, Day 
3: 48 h
SAC [1]
4.2.
PK
PKCT1
Summary of Plasma GSK2862277 Pharmacokinetic 
Concentration – Time Data (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2 
Planned time points: Day1: 0h, 1h, On 
completion of surgery; Day 2: 24 h, Day 
3: 48 h
SAC [1]
4.3.
PK
PKPT1
Summary of Derived Plasma GSK2862277 Pharmacokinetic 
Parameters (by Treatment arm)
Use Main Treatment Group Descriptors
SAC [1]
4.4.
PK
PKPT1
Summary of Derived Plasma GSK2862277 Pharmacokinetic 
Parameters (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2
SAC [1]
4.5.
PK
PKPT3
Summary of Derived Plasma GSK2862277 Pharmacokinetic 
Parameters (log transformed) (by Treatment arm)
Use Main Treatment Group Descriptors
SAC [1]
4.6.
PK
PKPT3
Summary of Derived Plasma GSK2862277 Pharmacokinetic 
Parameters (log transformed) (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2
SAC [1]
BAL
4.7.
PK
Non-standard
PK_T1
Summary of Derived Lung ELF Drug Concentrations and 
Volume Data (by Treatment arm)
Use Main Treatment Group Descriptors
Exclude Placebo data.  Only expecting 
pooled wash and pooled volume in this 
study.  
SAC [1]


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Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.8.
PK
Non-standard
PK_T1
Summary of Derived Lung ELF Drug Concentrations and 
Volume Data (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2
Exclude Placebo data.  Only expecting 
pooled wash and pooled volume in this 
study.  
SAC [1]


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11.14.10. Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma
4.1.
PK
PKCF3
Median Plasma GSK2862277 Concentration-Time Plots (Linear 
and Semi-log) (by Treatment arm)
Use Main Treatment Group Descriptors
Planned time points: Day1: 0h, 1h, On 
completion of surgery; Day 2: 24 h, Day 
3: 48 h.  Add a horizontal line at y-axis 
at LLQ and add footnote LLQ = ... 
SAC [1]
4.2.
PK
PKCF3
Median Plasma GSK2862277 Concentration-Time Plots (Linear 
and Semi-log) (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2
Planned time points: Day1: 0h, 1h, On 
completion of surgery; Day 2: 24 h, Day 
3: 48 h.  Add a horizontal line at y-axis 
at LLQ and add footnote LLQ = ... 
SAC [1]
4.3.
PK
PKCF1
Individual Subject Plasma GSK2862277 Concentration – Time 
Plots (Linear and Semi-log) (by Treatment arm)
Use Main Treatment Group Descriptors
Plot Planned time points: Day1: 0h, 1h, 
On completion of surgery; Day 2: 24 h, 
Day 3: 48 h and actual time points.  
Paginate by time point type.
SAC [1]
4.4.
PK
PKCF1
Individual Subject Plasma GSK2862277 Concentration – Time 
Plots (Linear and Semi-log) (by Study Medication)
Use Alternative Treatment Group 
Descriptors #2
Plot Planned time points: Day1: 0h, 1h, 
On completion of surgery; Day 2: 24 h, 
Day 3: 48 h and actual time points.  
Paginate by time point type.
SAC [1]


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Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
BAL
4.5.
PK
Non-Standard
PK_F1
(Study 
PII11115117 
can provide 
examples)
Median Plasma and Individual Subject Derived Lung ELF 
GSK2862277 Concentrations Plot (Semi-Log) (by Treatment 
arm)
Use Main Treatment Group Descriptors
Exclude Placebo data. Legend to 
identify subjid.  Plasma based on 
planned rel. Time.  Elf on actual rel. 
Time of Pooled wash.  Elf data will be 
the pooled sample value.  Include 
footnotes.  Adjust x-axis to represent 
planned time points 0h, 1h, On 
completion of surgery; 24 h, 48 h.
Use common y-axis range over this plot 
and the sister plot by study medication
SAC [1]
4.6.
PK
Non-Standard
PK_F1
Median Plasma and Individual Subject Derived Lung ELF 
GSK2862277 Concentrations Plot (Semi-Log) (by Study 
Medication)
Use Alternative Treatment Group 
Descriptors #2
Exclude Placebo data. Legend to 
identify subjid.  Plasma based on 
planned rel. Time.  Elf on actual rel. 
Time of Pooled wash.  Elf data will be 
the pooled sample value.  Include 
footnotes.  Adjust x-axis to represent 
planned time points 0h, 1h, On 
completion of surgery; 24 h, 48 h.
SAC [1]


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11.14.11. Pharmacodynamic (Biomarker) Tables
Pharmacodynamic (Biomarker) : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
BAL Biomarkers
5.1.
PP1
EFF_T1
Summary Statistics of BAL Biomarkers On Completion of 
Surgery (by Treatment arm)
No change form Baseline
Add additional page by variable of the 
functional category of the biomarker
Use Main Treatment Group Descriptors
SAC [1]
5.2.
PP1
EFF_T1
Summary Statistics of BAL Biomarkers On Completion of 
Surgery (by Study Medication)
No change form Baseline
Add additional page by variable of the 
functional category of the biomarker
Use Alternative Treatment Group 
Descriptors #1
SAC [1]
5.3.
PP1
EFF_T1
Summary Statistics of BAL Biomarkers On Completion of 
Surgery (by BAL Location)
No change form Baseline
Add additional page by variable of the 
functional category of the biomarker
Use Alternative Treatment Group 
Descriptors #2
SAC [1]
5.4.
PP1
Summary of Statistical Analyses of BAL Biomarkers
Group by functional categories and 
Repeat table layouts for each BAL 
Biomarker
Present only the final model per 
biomarker
SAC [1]
Serum Biomarkers
5.5.
PP1
EFF_T1
Summary Statistics (Absolute and Change from Baseline): 
Serum Biomarkers by Time (by Treatment arm)
Add additional page by variable of the 
functional category of the biomarker
Use Main Treatment Group Descriptors
SAC [1]


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Pharmacodynamic (Biomarker) : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.6.
PP2
EFF_T1
Summary Statistics (Absolute and Change from Baseline): 
Serum Biomarkers by Time (by Study Medication)
Add additional page by variable of the 
functional category of the biomarker
Use Alternative Treatment Group 
Descriptors #1
SAC [1]
5.7.
PP1
EFF_T1
Summary Statistics (Absolute and Change from Baseline): 
Serum Biomarkers by Time (by BAL Location)
Add additional page by variable of the 
functional category of the biomarker 
Use Alternative Treatment Group 
Descriptors #2
SAC [1]
5.8.
PP2 
Summary of Statistical Analysis in Serum Biomarkers
Group by functional categories and 
Repeat table layouts for each BAL 
Biomarker
Present only the final model per 
biomarker
SAC [1]


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11.14.12. Pharmacodynamic (Biomarker) Figures
Pharmacodynamic (and or Biomarker) : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
BAL Biomarkers
5.1.
PP1
Box Plots of the BAL Biomarkers by Treatment Arm
Use imputed result.
For each biomarker also plot individual
data points alongside each box.  Plot 
treatment arms side by side.
Include LLQ and ULQ as reference 
lines where it makes sense to and 
footnote appropriately
SAC [1]
Serum Biomarkers
5.2.
PP2
Raw Time profiles of the Serum Biomarkers by Subject
Paginate by Treatment.  For each 
subject plot biomarkers within a 
functional class on a single graph when 
units permit.
Include LLQ and ULQ as reference 
lines where it makes sense to and 
footnote appropriately
SAC [1]
5.3.
PP2
Spaghetti plots of the Serum Biomarkers by Treatment arm
For each biomarker plot time profiles of 
individuals within a treatment on a 
single graph.  Use common axis ranges 
across pages/panels for each 
biomarker
Include LLQ and ULQ as reference 
lines where it makes sense to and 
footnote appropriately
SAC [1]


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Pharmacodynamic (and or Biomarker) : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.4.
PP2
Spaghetti plots of the Serum Biomarkers by Study 
Medication
For each biomarker plot time profiles of 
individuals within a study medication on 
a single graph.  Plot study medications 
side by side but identify the BAL 
location within each study medication. 
Use common axis ranges across 
pages/panels for each biomarker
Include LLQ and ULQ as reference 
lines where it makes sense to and 
footnote appropriately
SAC [1]
5.5.
PP2
Scatterplot matrix of Serum Biomarkers by Treatment Arm
Plot all patients on same scatterplot.  
Indicate treatment groups by using 
different colours. Paginate by planned 
sampling times
SAC [1]       
5.6.
PP2
Scatterplot matrix of Serum Biomarkers by Time
Plot all patients and time points on 
same scatterplot.  Indicate individual 
timepoints by using different colours. 
Paginate by Treatment Arm
SAC [1]
5.7.
PP2
EFF_F7 / 
EFF_F1
Adjusted Medians and 95% Credible Intervals for each Study 
medication from the Repeated Measures Modelling of Serum 
Biomarkers
Repeat for each biomarker
Use Planned Timepoint as the x-axis of 
the plot but offset/group by treatment to 
avoid overlapping
5.8.
PP2
EFF_F8
Adjusted Medians and 95% Credible Intervals for Study 
medication comparisons from the Repeated Measures Modelling 
of Serum Biomarkers
Repeat for each biomarker
Use Planned Timepoint as the x-axis of 
the plot


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11.14.13. Pharmacogenetic Tables
Pharmacogenetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacogenetics
6.1.
Safety
GN1
Summary of Genetics Subject Accountability
SAC [2]
6.2.
Safety
GN2
Summary of Genetic Consent Not Obtained / Withdrawn
SAC [2]


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11.14.14. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Accountability
1.
n/a
POP_L1
Listing of Subject Accountability (subjects constituting each 
Statistical Analysis Population)
Also list out the subject IDs who will 
participate in the Translational Sub-
Study
IA1 [1], IA2 [2], 
SAC [1]
Randomisation
2.
Safety
CP_TA1
Listing of Randomised and Actual Treatments
Omit cohort column
Include Site ID
Include Randomisation number and 
Randomisation Date/Time (if only date 
available then modify column labels)
Split Actual Treatment column into two 
separate columns (“Actual Study 
Medication” and “Actual BAL Sampled”)
Create corresponding Deviation 
columns for each actual treatment 
column
IA1 [1], IA2 [2], 
SAC [1]
3.
Safety
BL1
Listing of Subjects for whom Treatment Blind was Broken 
(excluding when broken to support the interim analyses)
SAC [2]
Subject Disposition
4.
Screen 
Failures
ES7
Listing of Reasons for Screening Failure
See notes for corresponding summary 
table
SAC [2]
5.
Safety
DV2
Listing of Important Protocol Deviations
Add additional columns to cover the 3x 
per protocol populations
IA1 [1], IA2 [2], 
SAC [1]
6.
Safety
IE3
Listing of subjects with Inclusion/Exclusion Criteria Deviations
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
7.
Safety
CP_ES10x
Listing of Subjects who Withdrew from Study
Modify the contents and re-label the 
cross over related column names as 
appropriate to a parallel group design. 
Keep the date of last contact.
SAC [2]
Demography
8.
Safety
DM2
Listing of Demographic Characteristics
IA1 [1], IA2 [2], 
SAC [1]
9.
Safety
DM9
Listing of Race
IA1 [1], IA2 [2], 
SAC [1]
Medical Condition & Concomitant Medications
10.
Safety
MH2
Listing of Current and Past Medical Conditions
Combine both current and past items 
into one listing
IA1 [1], IA2 [2], 
SAC [1]
11.
Safety
CP_CM3
Listing of Concomitant Medications by Generic Term
IA1 [1], IA2 [2], 
SAC [1]
Exposure
12.
Safety
EX3
Listing of Exposure Data
SAC [2]
Adverse Events
13.
Safety
CP_AE8a
Listing of All Serious Adverse Events
IA1 [1], IA2 [2], 
SAC [1]
14.
Safety
CP_AE8
Listing of All Adverse Events
IA1 [1], IA2 [2], 
SAC [1]
15.
Safety
CP_AE8
Listing of Adverse Events Leading to Withdrawal from Study
IA1 [1], IA2 [2], 
SAC [1]
16.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
IA1 [1], IA2 [2], 
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory Values
17.
Safety
CP_LB5
Listing of Clinical Chemistry Abnormalities of Potential Clinical 
Importance
IA1 [1], IA2 [2], 
SAC [1]
18.
Safety
CP_LB5
Listing of All Clinical Chemistry Laboratory Data for Subjects 
with PCI Abnormalities
IA1 [1], IA2 [2], 
SAC [1]
19.
Safety
CP_LB5
Listing of Hematology Abnormalities of Potential Clinical 
Importance
IA1 [1], IA2 [2], 
SAC [1]
20.
Safety
CP_LB5
Listing of All Hematology Laboratory Data for Subjects with PCI 
Abnormalities
IA1 [1], IA2 [2], 
SAC [1]
21.
n/a
LB13
Listing of Laboratory Tests and Associated Reference Ranges
Add centre/site column if necessary to 
distinguish different sets of normal 
ranges (and add corresponding date 
range(s) if normal ranges have 
changed within a site during conduct of 
study)
IA1 [1], IA2 [2], 
SAC [1]
22.
Safety
Base on AE2
Relationship between Urinalysis Summary Table Categories and 
Verbatim Text
Describes the mapping of test results to 
categories used in corresponding 
summary table. Base on AE2 shell 
(System Organ class becomes the Lab 
test name, Preferred term becomes the 
Category result was mapped onto)
IA1 [1], IA2 [2], 
SAC [1]
ECG
23.
Safety
CP_EG3
Listing of All ECG Values for Subjects with any Value of 
Potential Clinical Importance
IA1 [1], IA2 [2], 
SAC [1]
24.
Safety
CP_EG3
Listing of ECG Values of Potential Clinical Importance
IA1 [1], IA2 [2], 
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
25.
Safety
CP_EG5
Listing of Abnormal ECG Findings
IA1 [1], IA2 [2], 
SAC [1]
Vital Signs
26.
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical Importance
IA1 [1], IA2 [2], 
SAC [1]
27.
Safety
CP_VS4
Listing of All Vital Signs of for Subjects with any Value of 
Potential Clinical Importance
IA1 [1], IA2 [2], 
SAC [1]
Immunogenicity
28.
Safety
IMM2
Listing of Immunogenicity results
Omit drug concentration units column.
Omit titre column if not applicable to 
observed data.
SAC [2]


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11.14.15. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy Endpoints
29.
Safety
EFF_L2
Listing of Transpulmonary Thermodilution Data
IA2 [1] SAC [1]
30.
Safety
EFF_L3
Listing of Oxygenation Data
IA2 [1] SAC [1]
31.
Safety
EFF_L3
Listing of Change from Baseline Oxygenation Data
Keep Baseline record (actual values) 
but post baseline entries should contain 
the change values (Vent mode changes 
should be flagged)
IA2 [1] SAC [1]
32.
Safety
EFF_L4
Listing of SOFA Data
SAC [1]
33.
PP2
Non-standard
SAS Output from Primary Statistical Analysis: Joint Modelling of 
PVPI and PaO2/FiO2.
SAC [1]
34.
PP2
Non-standard
SAS Output from Statistical analysis: Modelling of PVPI on 
Completion of Surgery
SAC [1]
35.
PP2
Non-standard
SAS Output from Statistical analysis: Modelling of PaO2/FiO2 on 
Completion of Surgery
SAC [1]
36.
PP2
Non-standard
SAS Output from Statistical analysis: Modelling of EVLWI on 
Completion of Surgery
SAC [1]
37.
PP2
Non-standard
SAS Output from Statistical analysis: Repeated Measures 
Modelling of SOFA
SAC [1]
38.
PP2
Non-standard
SAS Output from PROC MCMC Futility analysis at Interim 
Analysis 2
Interim analysis #2 only.
IA2 [1]
39.
PP2
Non-standard 
SAS Output from Sample Size Re-estimation at Interim Analysis 
2
Interim analysis #2 only.
IA2 [1]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Surgical Procedure
40.
Safety
EFF_L1
Listing of Information relating to the surgical procedure by 
Subject 
New page per subject. Group and order
subjects by Treatment, Centre and ID
IA1 [1], IA2 [2], 
SAC [1]
PK (Plasma and BAL)
41.
PK
PKCL1p
Listing of GSK2862277 Plasma Pharmacokinetic Concentration 
- Time Data
Use Main Treatment Descriptors
SAC [1]
42.
PK
PKPL1p
Listing of Derived GSK2862277 Plasma Pharmacokinetic 
Parameters
Use Main Treatment Descriptors
SAC [1]
43.
PK
PKLU1p
Listing of Derived GSK2862277 Lung ELF concentrations
Use Main Treatment Descriptors
SAC [1]
44.
PK 
Non-standard
Listing of Data required to obtain Lung ELF concentrations
Use Main Treatment Descriptors
Create bespoke by-subject listing that 
includes the BAL Drug concentration, 
Plasma Urea and BAL Urea, dilution 
factor, Volume of ELF, Volume of BAL 
and Total drug in BAL fluid
SAC [1]
Pharmacodynamic (and or Biomarker)
BAL Biomarkers
45.
Safety
Listing of BAL Biomarker data
SAC [1]
46.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker Free 
sTNFR1
SAC [1]
47.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker Total 
sTNFR1
SAC [1]
48.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker 
Complex sTNFR1
SAC [1]
49.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker TNFa
SAC [1]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
50.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker IL-6
SAC [1]
51.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker IL-8
SAC [1]
52.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker IL-1b
SAC [1]
53.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker MCP-1
SAC [1]
54.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker CRP 
SAC [1]
55.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker IL1-ra
SAC [1]
56.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker IL-10
SAC [1]
57.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker Total 
Protein
SAC [1]
58.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker SP-D 
SAC [1]
59.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker RAGE 
SAC [1]
60.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker CC16
SAC [1]
61.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker vWF 
SAC [1]
62.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker sICAM-
1
SAC [1]
63.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker MPO
SAC [1]
64.
PP1
Non-standard
SAS Output from Statistical Modelling of BAL biomarker Total 
Protein Ratio
SAC [1]
Serum Biomarkers
65.
Safety
Listing of Serum Biomarker data
SAC [1]
66.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker Free 
sTNFR1
SAC [1]


CONFIDENTIAL
TFR116341
142
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
67.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker Total 
sTNFR1
SAC [1]
68.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker 
Complex sTNFR1
SAC [1]
69.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker IL-6
SAC [1]
70.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker IL-8
SAC [1]
71.
PP2
Non-standard
SAS Output from Statistical Modelling of Plasma biomarker CRP 
SAC [1]
72.
PP2
Non-standard
SAS Output from Statistical Modelling of Plasma biomarker Total 
Protein 
SAC [1]
73.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker SP-D 
SAC [1]
74.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker 
RAGE 
SAC [1]
75.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker CC16 
SAC [1]
76.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker vWF 
SAC [1]
77.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker 
sICAM-1
SAC [1]
78.
PP2
Non-standard
SAS Output from Statistical Modelling of Serum biomarker MPO
SAC [1]
Exploratory
79.
Safety
EFF_L7
Listing of Subjects Diagnosed with ARDS out to day 28
SAC [2]
80.
Safety
EFF_L5
Listing of day 28 survival status
SAC [2]
81.
Safety
EFF_L6
Listing of Organ Failure Free days
Keep Subject and metadata and 
replace Vent free days with Organ 
failure free days
SAC [2]
82.
Safety
EFF_L6
Listing of day 28 Resource Usage
SAC [2]


CONFIDENTIAL
TFR116341
143
11.15.
Appendix 15: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request


CONFIDENTIAL
TFR116341
1
Appendix 15: Example Mock Shells for Data Displays
Example 
: PK_T1
Page 1 of n
Protocol
: TFR116341
Population
: Pharmacokinetic
Table X.X
Summary of Derived Lung ELF Drug Concentrations and Volume Data
Treatment: 26.0 mcg 
                 Planned
                 Relative             Geometric               90% CI
                 Time          N        Mean              (Lower,Upper)           SD Logs        CVb (%)
---------------------------------------------------------------------------------------------------------
ELF Drug        Day 1(1)        10       110133.4     (52983.6,228927.1)              1.09        151.6
Conc (pg/mL)
                 Day 1(2)        10       63196.2      (40464.7,98697.4)               0.66         74.7
                 Day 1(3)        10       48241.2      (35806.4,64994.2)               0.44         46.8
Pooled ELF Drug Day 1           10       55374.3      (39768.3,77104.4)               0.49         52.6
Conc (pg/mL)    (Pooled Washes)
Volume of ELF   Day 1 (1)       10        0.0330        (0.0164,0.0662)               1.042       140.1
in BAL Fluid
(mL)
                 Day 1(2)        10        0.0996        (0.0526,0.1886)               0.953       121.6
                 Day 1(3)        10        0.1970        (0.1000,0.3882)               1.012       133.7


CONFIDENTIAL
TFR116341
2
Example 
: PK_F1
Page 1 of n
Protocol
:TFR116341
Population
: Pharmacokinetic
Table X.X
Median Plasma and Individual Subject Derived Lung ELF GSK2862277 Concentrations Plot (Semi-Log) Pooled Washes
PPD


CONFIDENTIAL
TFR116341
3
Example
: EFF_T1 
Protocol: TFR116343                                                                             Page 1 of 34
Population: Biomaker
                                                Table 12.1
             Summary of Raw Immune Function Biomarker data and change from Baseline
Endpoint (unit): PVPI (xxx)
                              Planned        n
                       Visit  Relative      imp  Mean                                          Min
Treatment  N  Item     [1]    Time       n  [2]   [3]   95% CI of Mean         SD    Median    [4]     Max
------------------------------------------------------------------------------------------------------------
0.002       6 Analyte  P1D1   PRE-DOSE   6    0 8.40    (6.65, 10.15)        1.664   8.60    5.6     10.5
mg/kg IV      numeric         (BL)
SD            result
                              2 HOUR     6    0 7.95    (6.17, 9.73)         1.697   7.55    5.8     10.8
                              6 HOUR     6    0 8.30    (5.88, 10.72)        2.308   7.40    6.2     11.9
                              24 HOUR    6    0 9.03    (6.46, 11.60)        2.449   8.80    6.3     12.1
                              48 HOUR    6    0 8.42   (5.99, 10.84)        2.309   7.90    5.7     11.8
              Change   P1D1   2 HOUR     6    0 -4.86   (-15.68, 5.97)       10.318  -1.37   -23.4   3.6
              from
              Baseline
                              6 HOUR     6    0 -0.79   (-20.78, 19.20)      19.046  0.20    -21.3   19.5
                              24 HOUR    6    0 7.47    (-11.68, 26.62)      18.245  7.09    -18.2   33.3
                              48 HOUR    6    0 -0.19   (-15.45, 15.07)      14.543  -2.64   -16.0   20.7
[1] P=Study Part, D=Study day relative to 1st dose
[2] Number of imputed observations (imputed using 1/2 of the LLQ)
[3] NA = Not Applicable (due to >= 75% of values being LLQ )
[4] NC = Non-Calculable (due to presence of LLQ values)
Programming Notes: Paginate by endpoint. Indicate the baseline timepoint (e.g. suffix with “(BL)”). If no imputations for the endpoints 
then drop the nimp column and any associated footnotes. Modify as appropriate to the endpoint(s) being summarised.
PPD


CONFIDENTIAL
TFR116341
4
Example
: EFF_T1 (contd)
Protocol: TFR116343                                                                             Page 2 of 34
Population: Biomaker
                                                 Table 12.1
             Summary of Raw Immune Function Biomarker data and percentage change from Baseline
Endpoint (unit): PVPI (xxx)
                                        Planned        n
                                 Visit  Relative      imp  Geo.    95% CI of Geo.     SD
          Treatment  N  Item     [1]    Time       n  [2]  Mean         Mean         Logs  CV (%)
          ---------------------------------------------------------------------------------------
          0.002       6 Analyte  P1D1   PRE-DOSE   6    0 8.25   (6.57, 10.35)      0.216  21.9
          mg/kg IV      numeric         (BL)
          SD            result
                                        2 HOUR     6    0 7.81   (6.27, 9.72)       0.209  21.1
                                        6 HOUR     6    0 8.05   (6.11, 10.62)      0.263  26.8
                                        24 HOUR    6    0 8.76   (6.56, 11.69)      0.275  28.0
                                        48 HOUR    6    0 8.16   (6.14, 10.85)      0.272  27.7
                        Change   P1D1   2 HOUR     6    0 NA     NA                 NA     NA
                        from
                       Baseline
                                        6 HOUR     6    0 NA     NA                 NA     NA
                                        24 HOUR    6    0 NA     NA                 NA     NA
                                        48 HOUR    6    0 NA     NA                 NA     NA
[1] P=Study Part, D=Study day relative to 1st dose
[2] Number of imputed observations (imputed using 1/2 of the LLQ)
[3] NA = Not Applicable (due to >= 75% of values being LLQ )
[4] NC = Non-Calculable (due to presence of LLQ values)
PPD


CONFIDENTIAL
TFR116341
5
Example 
: EFF_T2 
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Primary Statistical Analysis: Joint Modelling of PVPI and PaO2/FiO2. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                   Planned.                    Sample   Sample
                                   Relative                    Mean     Variance Covariance Sample
Treatment                     N   Time          Endpoint   n  Vector   Matrix              Correlation
---------------------------------------------------------------------------------------------------------
Placebo (BAL Collapsed lung)  20  Pre-Op (BL)   Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
                                                 PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX 
                                   Imm. Post Op. Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
                                                 PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX
Placebo (BAL Ventilated lung) 20  Pre-Op (BL)   Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
                                                 PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX 
                                   Imm. Post Op. Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
                                                 PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX
GSK2862277 26mg IH            20  Pre-Op (BL)   Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
(BAL Collapsed lung)                            PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX 
                                   Imm. Post Op. Ln{PVPI}  XX  XX.X     XX.XXX   XX.XXX     X.XX
                                                 PaO2/FiO2 XX  XX.X     XX.XXX   XX.XXX
PPD


CONFIDENTIAL
TFR116341
6
Example 
: EFF_T2 (Contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Primary Statistical Analysis: Joint Modelling of PVPI and PaO2/FiO2. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                   Planned.                     Median   Median
                                   Relative                     Mean     Variance Covariance Median
Item                              Time          Endpoint       Vector   Matrix              Correlation
---------------------------------------------------------------------------------------------------------
Adjusted Placebo (averaging       Imm. Post Op. Ln{PVPI}       XX.X     XX.XXX   XX.XXX     X.XX
over BAL)                                       PaO2/FiO2      XX.X     XX.XXX   XX.XXX 
Adjusted Active  (averaging       Imm. Post Op. Ln{PVPI}       XX.X     XX.XXX   XX.XXX     X.XX
over BAL)                                       PaO2/FiO2      XX.X     XX.XXX   XX.XXX 
Adjusted Active Vs Placebo        Imm. Post Op. PVPI Ratio     XX.X     XX.XXX   XX.XXX     X.XX
Joint Distribution                              PaO2/FiO2 Diff XX.X     XX.XXX   XX.XXX 
(averaging over BAL)                            
PPD


CONFIDENTIAL
TFR116341
7
Example 
: EFF_T2 (Contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Primary Statistical Analysis: Joint Modelling of PVPI and PaO2/FiO2. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                     Planned.  
Item                                Relative                             95% Credible
(units)                             Time                    Median       Interval                MCSE/SD
---------------------------------------------------------------------------------------------------------
Adjusted Pbo PVPI averaging over    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
BAL (xxx)    
Adjusted Pbo PaO2/FiO2 averaging    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
over BAL (kPa)   
Adjusted Act PVPI averaging over    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
BAL (xxx)   
Adjusted Act PaO2/FiO2 averaging    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
over BAL (kPa)   
Note: Values used for continuous covariates in model adjustment: Baseline PVPI = xxx (unit), Baseline 
PaO2/FiO2 = xxx (unit), Age = 36 Years, Height = xx cm, etc
PPD


CONFIDENTIAL
TFR116341
8
Example 
: EFF_T2 (contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Primary Statistical Analysis: Joint Modelling of PVPI and PaO2/FiO2. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                            Planned.   
Item                                       Relative                      95% Credible
(units)                                    Time             Median       Interval                MCSE/SD
---------------------------------------------------------------------------------------------------------
Ratio of Act/Pbo PVPI averaging over BAL   Imm. Post Op.    XX.XX        (X.XXX, XX.XXX)         X.XXX
Difference Act-Pbo P/F  averaging over BAL Imm. Post Op.    XX.XX        (X.XXX, XX.XXX)         X.XXX
(kPa)
Note: Values used for continuous covariates in model adjustment: Baseline PVPI = xxx (unit), Baseline 
PaO2/FiO2 = xxx (unit), Age = 36 Years, Height = xx cm, etc
PPD


CONFIDENTIAL
TFR116341
9
Example 
: EFF_T2 (contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Primary Statistical Analysis: Joint Modelling of PVPI and PaO2/FiO2. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                               
                                                                       Threshold     Observed
End of Study Decision Pathway  Criteria                               Probability   Probability   Met
---------------------------------------------------------------------------------------------------------
Outcome 1: Robust Success      Pr(PVPI ratio (A/P) < 0.884                  
                                           AND
                                   PaO2/FiO2 Diff (A-P) >= 5.3 kPa)           0.25        0.0328     N
Outcome 2: Success             Pr(PVPI ratio (A/P) < 0.884)                  0.35        0.0856     N
Outcome 3: Potentially         Pr(PVPI ratio (A/P) >= 0.884)                 0.75        0.9144     Y
            Unsuccessful
OVERALL END OF STUDY OUTCOME   Potentially Unsuccessful
Programming note: Use more appropriate descriptors for the labels (e.g. update when timeslicing keys are set). Add any other posterior 
probability statements in a similar manner to those in GSK2586881 ACE114622 (e.g. PD Table 12.207), for example....
Item   
(units)       Comparison                                Posterior Probability Statement          Value
------------------------------------------------------------------------------------------------------------
XXXXX         (Act / Pbo) Imm. Post Op.                 < 0.10 i.e. More than 90% reduction       0.0740
PPD


CONFIDENTIAL
TFR116341
10
Example 
: EFF_T3 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Table X.XX
The SAS System
TFR116341 Interim Analysis 2 (IA2) Statistical Analysis Outcome
"PAUSE and REVIEW" 
Number of Observed Placebo Subjects at IA2 = 22 
Number of Observed Active Subjects at IA2 = 18 
Number of Placebo Subjects required (per simulated dataset) to reach end of study target of 40 = 18 
Number of Active Subjects required (per simulated dataset) to reach end of study target of 40 = 22 
Number of simulated datasets = 1000 
Futility criteria for each simulated dataset: If the joint probability of {Any Decrease in P/F AND Any Increase in PVPI} is > 0.1 then simulated 
study is futile 
If the proportion of future simulated datasets meeting futility criteria is > 0.3 then statistcial analysis recommendation is to "Pause and Review", 
otherwise recommendation is to "Continue" 
Note: As per protocol, this statistcial analysis recommendation is not binding and may be over-ruled by expert judgement of GSK Study Team if 
deemed appropriate 
Proportion of future datasets meeting futility criteria = 0.932, therefore... 
Statistical analysis recommendation is to "PAUSE and REVIEW" 


CONFIDENTIAL
TFR116341
11
Example 
: EFF_T4 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Table X.XX
<<<
Precise specification up to the expert judgement of the statistician/programmer. Should contain...
Selected SAS output from sample size re-estimation procedure: Assumed VCV matrix used in protocol, the estimated VCV matrix from 
the IA2 data, and the recommended number of subjects and the operating characteristics under the re-estimated number assuming a Null 
and Minimum desired profile for the remaining (unobserved) subjects
>>>


CONFIDENTIAL
TFR116341
12
Example 
: EFF_T5 
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Statistical Analysis: Modelling of PVPI on Completion of Surgery. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                    Planned.  
Item                                Relative                             95% Credible
(units)                             Time                    Median       Interval                MCSE/SD
---------------------------------------------------------------------------------------------------------
Adjusted Pbo PVPI averaging over    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
BAL (xxx)    
Adjusted Act PVPI averaging over    Imm. Post Op.           XX.XX        (X.XXX, XX.XXX)         X.XXX
BAL (xxx)   
Note: Values used for continuous covariates in model adjustment: Baseline PVPI = xxx (unit), Baseline 
PaO2/FiO2 = xxx (unit), Age = 36 Years, Height = xx cm, etc
PPD


CONFIDENTIAL
TFR116341
13
Example 
: EFF_T5 (contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Statistical Analysis: Modelling of PVPI on Completion of Surgery. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
                                            Planned.   
Item                                       Relative                      95% Credible
(units)                                    Time             Median       Interval                MCSE/SD
---------------------------------------------------------------------------------------------------------
Ratio of Act/Pbo PVPI averaging over BAL   Imm. Post Op.    XX.XX        (X.XXX, XX.XXX)         X.XXX
Note: Values used for continuous covariates in model adjustment: Baseline PVPI = xxx (unit), Baseline 
PaO2/FiO2 = xxx (unit), Age = 36 Years, Height = xx cm, etc
PPD


CONFIDENTIAL
TFR116341
14
Example 
: EFF_T5 (contd)
Protocol: TFR116341                                                                             Page 2 of 30
Population: Safety
                                                Table 12.207
                 Summary of Statistical Analysis: Modelling of PVPI on Completion of Surgery. 
------------------------------------------ Statistical Analysis ID=1 ----------------------------------
Item   
(units)                 Comparison                         Posterior Probability Statement           Value
------------------------------------------------------------------------------------------------------------
Ratio of Act/Pbo        (Act / Pbo) Imm. Post Op.          < 1.00 i.e. Any reduction                 0.6740
PVPI averaging over BAL                                    < 0.10 i.e. More than 90% reduction       0.0740
Programming note: Use more appropriate descriptors for the labels (e.g. update when timeslicing keys are set). Add any other posterior 
probability statements in a similar manner to those above
PPD


CONFIDENTIAL
TFR116341
15
Example 
: EFF_F1 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
16
Example 
: EFF_F2 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
17
Example 
: EFF_F3 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX
PPD
PPD


CONFIDENTIAL
TFR116341
18
Example 
: EFF_F4 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
19
Example 
: EFF_F5 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
20
Example 
: EFF_F6 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
21
Example 
: EFF_F7 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
22
Example 
: EFF_F8 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Figure X.XX


CONFIDENTIAL
TFR116341
23
Example 
: EFF_L1 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Listing X.XX
Actual Treatment: Placebo BAL Collapsed Lung, Subject ID xxx, (Inv ID: xxx)
Subject Demographics
Derived Age
Sex
Race
Subject Background
Prior Oesophageal Chemotherapy  : [No] or [Yes and end date of treatment]
Smoking History: [Never Smoked] or [Current Smoker] or [Former Smoker and date last smoked]
Medical History: {Exclude the GSK cardiovascular risk factor items, Group by Past and Current}
Study treatment
Actual Study Drug received: [Name and date/time of Start of nebulisation]
Oesophagectomy procedure
Type of Surgery: [Trans Thoracic Oesophagectomy] or [Free text box from eCRF]
Start (rel to Dosing): [Start date and time of procedure] ([Start of procedure relative to dosing (hh:mm)])
Stop (rel to Dosing): [Stop date and time of procedure] ([End of procedure relative to dosing (hh:mm)])
Duration of Oesophagectomy procedure: [Duration of procedure (hh:mm)]
Did subject receive blood transfusion (amount and units): [Yes: amount and units] or [No]
Ventilation: Two Lung Ventilation


CONFIDENTIAL
TFR116341
24
Example 
: EFF_L1 (Contd) 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Listing X.XX
Actual Treatment: Placebo BAL Collapsed Lung, Subject ID xxx, (Inv ID: xxx)
All information from “Two-lung ventilation (At start of ventilation)” item of eCRF: [Mode of Ventilation, Tidal Volume, PEEP, Peal 
Pressure and Plateau Pressure]
Did ventilation continue post surgery: [No] or [Yes and Mode of ventilation]
Ventilation: One Lung Ventilation (OLV)
Start of OLV (rel to Dosing and Surgery): [Start date and time of OLV] ([Start of OLV relative to dosing (hh:mm)],[Start rel’ to surgery 
(hh:mm)])
End of OLV: [End date/time of OLV] ([End of OLV relative to dosing (hh:mm)],[End rel’ to surgery (hh:mm)])
Duration of One Lung Ventilation: [Duration of One Lung ventilation (hh:mm)]
All information from “One-lung ventilation (baseline)” item of eCRF: [Mode of Ventilation, Tidal Volume, PEEP, Peal Pressure and Plateau 
Pressure]
Anaesthetic
Start of anaesthia (rel to Dosing and Surgery): [Start date and time of anaesthia] ([Start of anaesthia relative to dosing (hh:mm)],[Start 
rel’ to surgery (hh:mm)])
End of anaesthia (rel to Dosing and Surgery): [End of anaesthia],[End of anaesthia relative to dosing (hh:mm)],[End rel’ to surgery 
(hh:mm)] 
Duration of anaesthia: [Duration of anaesthia (hh:mm)]
Anaesthetic and operative agents: [Epidural Anasthesia] or [free text box from eCRF]
Method of maintenance: [Volatile anaesthetic] or [TIVA]
Was Inotrope used intra-op?: [No] or [Drug Used and For how long (hh:mm)]
Was Inotrope used post-op?: [No] or [Drug Used and For how long (hh:mm)]


CONFIDENTIAL
TFR116341
25
Example 
: EFF_ L1 (Contd) 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Listing X.XX
Actual Treatment: Placebo BAL Collapsed Lung, Subject ID xxx, (Inv ID: xxx)
BAL Procedure
Start of BAL (rel to Dosing and Surgery): [Start date and time of BAL] ([Start of BAL relative to dosing (hh:mm)],[Start rel’ to surgery 
(hh:mm)])
Lung BAL performed on: [Left] or [Right]
Actual Lung BAL performed on: [Deflated (Collapsed)] or [Inflated (Ventilated)]
Fluid balance in 24hr period from start of surgery
Fluid intake start date/time: [Fluid intake start date/time]
Fluid intake stop date/time: [Fluid intake stop date/time]
Total Input (ml): [Total input]
Total Output (ml): [Total output]
Net total: [Derived as Total Input – Total Output]
Urine Output (ml): [Urine output]
Other Output (ml): [Other output]
Post operative complications
Did the subject receive antibiotics for a suspected respiratory tract infection?: [Yes] or [No]
Did the subject develop a significant pleural effusion?: [Yes] or [No]
Did the subject develop an Empyema?: [Yes] or [No]
Did the patient suffer from aspiration pneumonitis?: [Yes] or [No]


CONFIDENTIAL
TFR116341
26
Example 
: EFF_L2 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Listing X.XX
Listing of Transpulmonary Thermodilution Data
Treatment/
Inv ID/
Subject
Weight 
(kg)/ 
Pred. 
Weight 
(kg)/
Pred. 
BSA 
(m**2)
Visit / 
Planned 
Relative 
Time
Actual Date/Time
Time since 
start of 
Surgery
Item (units)
Result
Change from 
Baseline (BL)
Placebo (BAL 
Collapsed 
lung)/
89/
100/
233
Day 1 / 
Imm. Prior 
to Surgery
(BL)
DDMMMYYY / 
HH:MM
+/- XXh 
XXm
Arterial Line used
Femoral
n/a
Cardiac output rep1 (xxx)
XX
n/a
Cardiac output rep2 (xxx)
XX
n/a
Cardiac output rep3 (xxx)
XX
n/a
Cardiac output Mean (xxx)
XX
n/a
Mean Arterial Pressure (xxx)
XX
n/a
etc
Day 1 / 
Imm. Post 
Surgery
DDMMMYYY / 
HH:MM
+/- XXh 
XXm
Arterial Line used
Femoral
Cardiac output rep1 (xxx)
XX
n/a
Cardiac output rep2 (xxx)
XX
n/a
Cardiac output rep3 (xxx)
XX
n/a
Cardiac output Mean (xxx)
XX
XX
Mean Arterial Pressure (xxx)
XX
XX
PPD


CONFIDENTIAL
TFR116341
27
Example 
: EFF_L3 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
Listing X.XX
Listing of Oxygenation Data
Treatment: Placebo (BAL Collapsed lung) Inv.ID:
 Subject:
Visit/
Planned
Relative
Time/Time                                                                    Peak  Plateau
Since                                                                        Vent. Vent.   Mean     
Dose                                 Oxy.             PaO2/             Peep Pr.   Pr.     Airway     Tidal
Planned          Pa02   Fi02   Pa02/ Ind.  Sa02 SaO2/ FiO2  Vent        (cm  (cm   (cm     Pressure   Volume
  Actual   Vent  (mmHg) (%)     Fi02 (%)   (%)  FiO2  (Imp) Mode        H20) H20)  H20)    (cm H2O)   (mL)
------------------------------------------------------------------------------------------------------------
SCREENING/  Y 4  XX     XX        XX XX.X  XX     XX    XX  Pressure    XX   XX    XX      XX.X       XXX.XX
SCREENING/                                                  controlled
-0.38
PART B/     Y 4  XX     XX        XX XX.X  XX     XX    XX  Pressure    XX   XX    XX      XX.X       XXX.XX
0.5 H/                                                      controlled
0.02
PPD
PPD


CONFIDENTIAL
TFR116341
28
Example 
: EFF_L4 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
                                                Listing 227
         Listing of SOFA and Change from Baseline SOFA Scores (Sequential Organ Failure Assessment)
Treatment: Placebo BID
                                               __SOFA Component {1}__         Observed  Observed
                                                              Central           SOFA      Chg.
           Inv.ID               Study  Respi-  Coagu-         Nervous          Score    Baseline
           /Subj    Visit        Day   ration  lation  Liver  System   Renal  (Total)     SOFA [2]
           -------------------------------------------------------------------------------------
           XXXXXX/  Baseline        1       4       0      1        4      0        12         0
           XXXXX
                    Day 4           4
                    Follow-up       7
                    Day 7
           XXXXXX/  Baseline        1       1       0      2        4      0        11         0
           XXXXX
                    Day 4           4       2       2      2        1      2        11         0
                    Follow-up       7               3      2        2      2
                    Day 7
[1]: Individual organ function scored on a 0-4 point scale (0: Normal, 4: Most Abnormal)
[2]: String Assumptions made to obtain a baseline SOFA value
PPD


CONFIDENTIAL
TFR116341
29
Example 
: EFF_L5 
Page 1 of n
Protocol
: TFR116341
Population
: Safety
                                     Listing of Day 28 Survival Status
Treatment: Placebo BID
                                   Randomization Date/                                  28 Day
              Inv./       Age/     Event or Censoring   Endpoint Description for      Survival
              Subj.       Sex      Date                 28 Day Survival                 (days)
              --------------------------------------------------------------------------------
             
     XX/      XXOCT201X/           Event: Died                          6
              XXXXX       Male     XXOCT201X
             
     XX/      XXAPR201X/           Censor: Last adequate asmt          28
              XXXXX       Male     XXMAY201X 
PPD
PPD
PPD


CONFIDENTIAL
TFR116341
30
Example 
: EFF_L6
Page 1 of n
Protocol
: TFR116341
Population
: Safety
                                                Listing 225
                                      Listing of Day 28 Resource usage
Treatment: Placebo BID
                                             Hospital-
                  Inv. ID/Sex/Age/           isation Start/  ICU Start/      Vent.  Days      Days
                  Race/Death Date            End Date/       End Date/       free   Alive in  Alive in
      Subject     (blank if alive)           Discharged      Discharged      days   Hospital  ICU
      ------------------------------------------------------------------------------------------------
           XXXXX  XXXXXX/M/XX/White -        XXOCT201X/      XXOCT201X/        0      6         6
                  White/Caucasian/European   XXOCT201X/      XXOCT201X/
                  Heritage/XXOCT201X         Y               Y
           XXXXX  XXXXXX/M/XX/White -        XXAPR201X/      XXAPR201X/        8     28         4
                  White/Caucasian/European    /              XXAPR201X/
                  Heritage/                  N               Y
Note: Evaluation Interval: Day of first dose to Day of first dose +27 days
Note: Partial days rounded up during computations
PPD


CONFIDENTIAL
TFR116341
31
Example 
: EFF_L7
Page 1 of n
Protocol
: TFR116341
Population
: Safety
                                                Listing 229
                    Listing of Date and Time of Individual Subjects Surgical Procedures
                                                   
                                   Invid./         Did the subject develop ARDS
              Treatment            Subj.           while in hospital?              
-----------------------------------------------------------------------------------------------
              Placebo BID          XXXXXX/         Y
                                   XXXXXX


CONFIDENTIAL
TFR116341
32
Example 
: POP_T1 
Page 1 of n
Protocol
: TFR116341
Population
: n/a
Summary X.XX
Summary of Subject Accountability (subjects constituting each Statistical Analysis Population)
Treatment 
Descriptors
Treatment
Number of individuals in population
Screen 
Failures
Safety
PK
PP1
PP2
PP3
IA1
IA2
Screening failures
n/a
23
0
0
0
0
0
0
0
Main Treatment 
Group 
Descriptions
Placebo (BAL 
Collapsed lung)
0
15
x
x
x
x
x
x
Placebo (BAL 
Ventilated lung)
0
25
x
x
x
x
x
x
GSK2862277 26mg 
IH (BAL Collapsed 
lung)
0
18
x
x
x
x
x
x
GSK2862277 26mg 
IH (BAL Ventilated 
lung)
0
22
x
x
x
x
x
x
Alternative 
Treatment Group 
Descriptions #1
Placebo
0
40
x
x
x
x
x
x
GSK2862277 26mg 
IH
0
40
x
x
x
x
x
x
Alternative 
Treatment Group 
Descriptions #2
BAL Collapsed lung
0
33
x
x
x
x
x
x
BAL Ventilated lung
0
47
x
x
x
x
x
x
Note: n/a = not applicable, PP = Per Protocol


CONFIDENTIAL
TFR116341
33
Example 
: POP_L1 
Page 1 of n
Protocol
: TFR116341
Population
: n/a
Listing X.XX
Listing of Subject Accountability (subjects constituting each Statistical Analysis Population)
Inv ID
Screening 
ID or 
Subject ID
Actual 
treatment
Screen 
Failures
Safety
PK
PP1
PP2
PP3
IA1
IA2
Translational 
Sub-Study
n/a
Y
.
.
.
.
.
.
.
.
n/a
Y
.
.
.
.
.
.
.
.
n/a
Y
.
.
.
.
.
.
.
.
Placebo 
BAL 
Collapsed
.
Y
Y
Y
Y
Y
Y
Y
.
Placebo 
BAL 
Collapsed
.
Y
Y
.
.
Y
.
.
Y
Note: n/a = not applicable, PP = Per Protocol, Y = Included in population, “.” = Excluded from population
Programming note: Label Center ID as Inv Id. If a subject was not a screen failure use their Subject ID. Break on Centres. Add additional 
columns if required
PPD