A Randomised, Placebo-controlled, Double-blind (Sponsor Open), Segmental LPS Challenge Study to Investigate the Pharmacodynamics of GSK2798745 in Healthy Participants
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of 
GSK2798745 in healthy participants
Protocol Number: 207464 / Amendment 02
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model
Compound Number:
GSK2798745
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):  2017-002388-16
Approval Date: 21-May-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 2 (2016N304618_02)
21-MAY-2018
Protocol Amendment 1 (2016N304618_01)
02-FEB-2018
Original Protocol (2016N304618_00)
24-OCT-2017
The original protocol (24-Oct-2017) was published internally only, it was not reviewed
by the competent authority or the research ethics committee.
Protocol Amendment 1 (02-Feb-2018) was submitted to both the competent authority and 
the research ethics committee. The Summary of Changes table for Amendment 1 is in 
Appendix 7
Protocol Amendment 2 21-May-2018
Overall Rationale for the Amendment: The protocol was amended in response to
comments from the competent authority. 
(Note: ‘Additions’ are underlined and ‘deletions’ are striked off)
Section # and 
Name
Description of Change
Brief Rationale
Section 1. 
Synopsis and 
Section 4 
Objectives and 
Endpoints
Endpoint: PK parameters of 
GSK2798745 in plasma (AUC [0-
2624] and Cmax).
Error corrected from previous version
Section 6.2
Exclusion Criteria
Deleted:
Abnormal blood pressure as 
determined by the investigator.
Added: 
Values outside of the following 
ranges; 90-140 mmHg for systolic 
blood pressure, 50-90 mmHg for 
diastolic blood pressure and 50-90 
beats/minute for heart rate.
Added:
An AV block greater than Grade 1
Requested by the competent authority
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.4
Blinding
All study staff involved in clinical 
assessments (which includes the 
investigator, sub-investigators, 
other site staff) and the participant 
will be blinded to the treatment 
allocated to individual participants 
and to post challenge PD total 
protein in BAL sample results.
Error corrected from previous version
Section 8.3
Study Stopping 
Criteria
Added: 
Participants who have been dosed 
at the time of the study halt will 
continue in the study, as planned. 
Further participants may be dosed 
only if, after review, the sponsor 
and investigator consider it safe to 
do so and only after ethics and 
regulatory approval of a
substantial amendment.
Requested by the competent authority
Section 9.5
Adverse events
Added: 
Adverse event/serious adverse 
event reporting will meet the 
requirements set out in Section 
12.2.4 of the ICH E3 Guidelines.
Requested by the competent authority
Section 9.5.3
Follow-up of AEs 
and SAEs
All AE/SAEs, will be followed until 
the event is resolved, stabilized, 
otherwise explained, or the 
participant is lost to follow-up
Requested by the competent authority
Throughout
Updated the abbreviation table
and minor formatting at few 
places.
Minor, therefore have not been 
summarized
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
Screening ...................................................................................................12
2.2.
Treatment period ........................................................................................13
2.3.
Follow-up/Early Withdrawal ........................................................................15
3.
INTRODUCTION....................................................................................................16
3.1.
Study Rationale ..........................................................................................16
3.2.
Background ................................................................................................17
3.3.
Benefit/Risk Assessment ............................................................................18
3.3.1.
Risk Assessment .........................................................................18
3.3.2.
Benefit Assessment.....................................................................25
3.3.3.
Overall Benefit:Risk Conclusion...................................................25
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................29
5.3.
Participant and Study Completion...............................................................29
5.4.
Scientific Rationale for Study Design ..........................................................29
5.5.
Dose Justification........................................................................................30
5.5.1.
Dose Rationale ............................................................................30
5.5.2.
Treatment Effect Rationale ..........................................................32
6.
STUDY POPULATION...........................................................................................34
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................37
6.3.1.
Meals and Dietary Restrictions ....................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................37
6.3.3.
Activity .........................................................................................37
6.4.
Screen Failures...........................................................................................37
7.
TREATMENTS.......................................................................................................38
7.1.
Treatments Administered............................................................................38
7.1.1.
Dose Modification ........................................................................39
7.2.
Challenge Agents .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................40
7.4.
Blinding.......................................................................................................40
7.5.
Preparation/Handling/Storage/Accountability..............................................41
7.6.
Treatment Compliance................................................................................41
7.7.
Concomitant Therapy..................................................................................42
7.7.1.
Permitted Medications .................................................................42
7.7.2.
Prohibited Medications.................................................................42
7.8.
Treatment after the End of the Study ..........................................................42
 
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8.
DISCONTINUATION CRITERIA.............................................................................43
8.1.
Individual Stopping Criteria .........................................................................43
8.1.1.
Liver Chemistry Stopping Criteria ................................................43
8.1.2.
QTc Stopping Criteria ..................................................................43
8.1.3.
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria........................................43
8.1.3.1.
Asymptomatic Participant ...........................................43
8.1.3.2.
Symptomatic Participant.............................................43
8.1.4.
Bronchoscopy Stopping Criteria...................................................44
8.2.
Withdrawal from the Study..........................................................................44
8.3.
Study Stopping Criteria...............................................................................44
8.4.
Lost to Follow Up........................................................................................44
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
9.1.
Bronchoscopy.............................................................................................46
9.2.
Segmental lung challenge...........................................................................47
9.3.
Pharmacodynamic Assessments ................................................................47
9.4.
Pharmacokinetics .......................................................................................47
9.5.
Adverse Events...........................................................................................47
9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................48
9.5.2.
Method of Detecting AEs and SAEs.............................................48
9.5.3.
Follow-up of AEs and SAEs.........................................................48
9.5.4.
Regulatory Reporting Requirements for SAEs .............................48
9.6.
Treatment of Overdose...............................................................................49
9.7.
Safety Assessments ...................................................................................49
9.7.1.
Physical Examinations.................................................................50
9.7.2.
Vital Signs....................................................................................50
9.7.3.
Pulse Oximetry ............................................................................50
9.7.4.
Electrocardiograms......................................................................50
9.7.5.
Spirometry ...................................................................................50
9.7.6.
Clinical Safety Laboratory Assessments ......................................51
9.7.7.
Faecal Occult Blood Test (FOBT) ................................................51
9.7.8.
Columbia Suicide Severity Rating Scale (C-SSRS) .....................51
9.8.
Exploratory biomarkers...............................................................................52
9.9.
Genetics .....................................................................................................52
10. STATISTICAL CONSIDERATIONS........................................................................53
10.1.
Sample Size Determination ........................................................................53
10.2.
Populations for Analyses ............................................................................55
10.3.
Statistical Analyses.....................................................................................56
10.3.1.
Efficacy Analyses.........................................................................56
10.3.2.
Safety Analyses...........................................................................56
10.3.3.
Other Analyses ............................................................................56
10.3.4.
Interim Analyses ..........................................................................56
11. REFERENCES.......................................................................................................60
12. APPENDICES........................................................................................................63
12.1.
Appendix 1: Abbreviations and Trademarks................................................63
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................66
12.3.
Appendix 3: Study Governance Considerations..........................................68
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................72
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................77
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................80
12.7.
Appendix 7: Protocol Amendment History...................................................82
 
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1.
SYNOPSIS
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of GSK2798745 in 
healthy participants
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model
Rationale:  
The influx of protein-rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function, is a fundamental underlying 
defect in Acute Respiratory Distress Syndrome (ARDS).  In this Phase 1,
proof-of-mechanism study, a segmental lipopolysaccharide (LPS) challenge will be used 
as a surrogate injury model to investigate the effects of Transient receptor potential 
vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man.  
The LPS model has been widely used for the evaluation of anti-inflammatory agents, and 
will aid in the characterization of TRPV4 blockade on lung permeability and 
inflammation. It is hypothesised that TRPV4 inhibitors modulate the LPS response by 
reducing LPS induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4)
mediated activation of endothelial cells] or indirectly [e.g. autocrine cytokine 
activation]).  The assessment of TRPV4 mediated effects on LPS induced lung barrier 
damage in healthy volunteers is considered a viable strategy before conducting studies in 
an ARDS patient population.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To investigate the effect of 
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers.

Baseline adjusted total protein 
concentration in 
bronchoalveolar lavage (BAL) 
samples at 24 h after segmental LPS 
challenge.
Secondary

To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs.

Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge.
 
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Objectives
Endpoints

To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers.

Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry
(forced expiratory volume in 
1 second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood
test (FOBT).

To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers 

PK parameters of GSK2798745 in 
plasma (AUC [0-26] and Cmax).
Overall Design:
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.  
Participants will be randomised 1:1 to take 2 single doses (3 tablets total):  either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later. The first dose will be administered on Day 1 at 2 h before 
baseline BAL sampling from a segment in the left lower lobe.  4 ng/kg LPS will 
subsequently be instilled into the right middle segment and saline control into the lingula 
segment of the contralateral side.  The second dose of study treatment will be 
administered 10 hours after LPS challenge followed by post-dose BAL sampling on 
Day 2.  A schematic of the study is provided in Figure 1.
Figure 1
Study schematic
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic.
 
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Number of Participants:
Sufficient participants will be screened to ensure that a maximum of 60 evaluable 
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted, to assess the difference, if any, between treatments in 
the primary endpoint. Recruitment can continue whilst interim analyses are conducted.
Depending on the results of the interim analyses, recruitment may be stopped.  
Treatment Groups and Duration:
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2). Participants will receive a 
follow up phone call 2 days after discharge, and return to the study site on Day 8 
(1 day) for a follow-up visit.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamics and exploratory biomarker assessments 
may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The IRB/IEC will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the informed consent form (ICF).
 
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2.1.
Screening
Screening 
(Days –28 to –2)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination 
X
Height and weight
X
Medical history 
X
Past and current medical conditions  
X
HIV, Hepatitis B and C screening
X
FSH and oestradiol1
X
Drug, alcohol and cotinine screen
X
C-SSRS
X
Laboratory assessments2
X
12-lead ECG3
X
Vital signs4
X
Spirometry5
X
FOBT6
X
C-SSRS:  Columbia Suicide Severity Rating Scale; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; HIV:  human immunodeficiency virus.
1.
Postmenopausal females whose postmenopausal status is in doubt only.
2.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile. 
3.
In triplicate.
4.
Blood pressure and heart rate in triplicate.  Single temperature measurement.
5.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form.
6.
May be measured during the screening window or on Day –1.  FOBT cards will be provided at screening and must be returned to the laboratory and analysed before dosing.
 
 
 
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2.2.
Treatment period
Day –12
Day 11
Day 21
Pre-
dose
0 h
1 h
2 h
3 h
6 h
8 h
12 h
14 h
25.5 h
26 h
30 h
Day 4
Inpatient stay2
===============================================================
Telephone call3
X
Drug, alcohol and cotinine screen
X
Laboratory assessments4
X
X
12-lead ECG5
X
X
X
Blood pressure and heart rate5
X
X
X
X
X
X
X
Temperature6
X
X
X
X
X
X
X
X
X
Spirometry7
X
X
X
X
X
C-SSRS
X
Randomisation
X
Study treatment
X
X
Pulse oximetry8
X
X
Bronchoscopy, baseline BAL and
challenge9
X
Bronchoscopy and post-challenge 
BAL10
X
Blood sample for exploratory 
biomarkers11
X11
X
X
X11
Blood sample for PK
See footnote 12
AE review
========================================================================
SAE review
=================================================================================
Concomitant medication review
=================================================================================
 
 
 
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AE:  adverse event; BAL:  bronchoalveolar lavage; ECG:  electrocardiogram; PK:  pharmacokinetic; SAE:  serious adverse event, C-SSRS:  Columbia Suicide Severity Rating Scale.
1.
Time points relative to the first dose on Day 1.
2.
Admission on Day –1, at a time to allow all Day –1 procedures to be done; discharge on Day 2, at least 4 h after the bronchoscopy.
3.
To check for any AEs.
4.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile. 
5.
Triplicate on Day-1 and pre-dose. Single measurements at time points after dosing. 
6.
Immediately before BAL sampling/LPS challenge at the 2-h time point.
7.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurements at each time point, the highest of which should be recorded in the case 
report form.
8.
Pulse oximetry to be measured during bronchoscopy procedures. Only AEs to be recorded. 
9.
BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers. Baseline BAL sample from a segment in the left lower lobe, followed by segmental 
challenge of the lungs:  LPS in right middle segment; saline control in the lingula segment of the contralateral side.  Challenges to be done as close as possible to 2 h post-dose.   
10. BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers.  Baseline and post-dose measurements to be done by the same person, where 
possible.
11. Blood samples for exploratory biomarkers. The 2- and 26-h blood samples should be taken immediately before BAL sampling.
12. PK samples will be taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 h after the first dose.  The 2- and 26-h blood sample should be taken 
immediately before BAL sampling
 
 
 
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2.3.
Follow-up/Early Withdrawal
Follow-up/Early Withdrawal
(Day 8 [1 day])
Outpatient visit
X
Full physical examination 
X
Weight
X
Laboratory assessments1
X
12-lead ECG2
X
Vital signs3
X
Spirometry4
X
FOBT5
X
AE review
X
SAE review
X
Concomitant medication review
X
AE:  adverse event; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; SAE: serious adverse event.
1.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins and urinalysis.
2.
Single measurement.
3.
Blood pressure, heart rate, temperature.  Single measurement.
4.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form.
5.
FOBT cards will be provided upon discharge from the unit and should be returned by the follow-up/early withdrawal visit. 
 
 
 
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3.
INTRODUCTION
GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) 
channel blocker being investigated for the treatment of acute respiratory distress 
syndrome (ARDS). TRPV4 blockade is expected to ameliorate the injury inflicted to the 
alveolar capillary barrier in ARDS patients and reduce the leakage of protein and fluid 
into the alveolar space. Studies investigating administration of GSK2798745 have been 
conducted in healthy volunteers and in patients with chronic heart failure.
GSK2798745 has been administered orally to healthy participants as single doses ranging 
from 0.25 to 12.5 mg. A dosage of 5 mg once daily has been administered for up to 
14 days in healthy participants.  Further, GSK2798745 at a dose of 2.4 mg has been 
evaluated as a single dose and subsequently as repeated doses for 7 days in participants 
with heart failure.
No clinically significant safety concerns were observed with single or repeat 
administration of GSK2798745 in either healthy volunteers or participants with heart 
failure. 
3.1.
Study Rationale
The influx of protein rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function is a fundamental underlying 
defect in ARDS. In this Phase 1 proof of mechanism study, a segmental 
lipopolysaccharide (LPS) challenge will be used as a surrogate injury model to 
investigate the effects of TRPV4 channel blockade on alveolar-septal barrier permeability 
in man. The LPS model has been widely used for the evaluation of anti-inflammatory 
agents [Zielen, 2015], and will aid in the characterization of TRPV4 blockade on lung 
permeability and inflammation. 
Segmental LPS challenge, in which a small quantity of the endotoxin, LPS, is 
administered directly to one segment of the lung, is a model of focal and self-limiting 
lung inflammation.  LPS induces pulmonary endothelial cell permeability [Fu, 2009] via 
calcium dependent cytoskeleton rearrangement [Bannerman, 1998; Gandhirajan, 2013]. 
LPS may also directly act on endothelial cells to cause permeability by degrading 
intercellular junctions [Bannerman, 1998].  The upregulation of a pro-inflammatory 
signalling cascade via NF-kB leading to endothelial activation and pro-inflammatory 
mediator release [Bosmann, 2012] may be regulated by the influx of calcium
[Kandasamy, 2013], and may also induce further calcium influx and endothelial 
permeability [Lush, 2000; Tiruppathi, 2006].  
Under normal conditions, concentrations of total protein in alveolar fluid are low. LPS 
induced endothelial damage leads to accumulation of protein rich fluid into the lung due 
to the migration of large molecules, such as albumin, from blood to the alveolar space. 
Preclinical and clinical studies have shown a positive correlation between amount of 
protein the bronchoalveolar lavage and extent of lung damage [Holter, 1986; Moazed, 
2016; Yu, 2015]. In the lung, TRPV4, a Ca2+-permeable non-selective cation channel, is 
widely expressed in cells involved in ARDS, namely microvascular endothelium, 
 
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alveolar epithelium, alveolar macrophages, and circulating neutrophils and monocytes,
and is a known regulator of endothelial permeability [Narita, 2015; Suresh, 2015; 
Huh, 2012] and pulmonary oedema [Balakrishna, 2014; Hamanaka, 2007]. Therefore,
TRPV4 may play an important role in LPS-induced alveolar permeability. The relevance 
of the TRPV4 channel to LPS induced injury has been confirmed in a mouse sepsis 
model. In this severe injury model, administration of a TRPV4 inhibitor 1 h prior to LPS 
injection (i.p.) increased survival by 70%.  Although this study was not specifically 
designed to evaluate bronchoalveolar lavage (BAL) protein levels, total protein 
concentrations in BAL fluid of mice pre-treated with a TRPV4 inhibitor were reduced by 
approximately 20% after the LPS challenge in TRPV4 treated mice compared with 
controls [Dalsgaard, 2016].  
It is hypothesised that TRPV4 inhibitors modulate the LPS response by reducing LPS 
induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4) mediated 
activation of endothelial cells] or indirectly [e.g. autocrine cytokine activation]).
Given the link to ARDS of endothelial damage and fluid leak, assessment of TRPV4 
mediated effects on LPS induced lung barrier damage in healthy volunteers is important 
to establish whether beneficial effects may be observed in an ARDS patient population.  
3.2.
Background
ARDS is an acute inflammatory lung injury, associated with increased pulmonary 
vascular permeability, increased lung weight, and loss of aerated lung tissue [Bellani,
2016]. Treatment options remain limited to supportive care including mechanical 
ventilation and ARDS represents a significant unmet need accounting for over 10% of 
intensive care unit (ICU) admissions and a mortality rate of up to 40% [Bellani, 2016; 
Matthay, 2012].  The syndrome is characterised by acute hypoxemic respiratory failure 
and non-cardiogenic pulmonary oedema and may be precipitated by direct (e.g. 
pneumonia and aspiration) and indirect insults (e.g. sepsis and transfusion related acute 
lung injury ([TRALI]) to the lung. Dysregulated inflammation, inappropriate 
accumulation and activity of leukocytes and platelets, uncontrolled activation of 
coagulation pathways, and altered permeability of alveolar endothelial and epithelial 
barriers are central to the pathophysiology of ARDS [Matthay, 2012]. Damage to the 
alveolar-capillary membrane leads to increased vascular permeability, and the 
development of interstitial and alveolar protein rich oedema, leading to reduced gas 
exchange, ventilation perfusion mismatching and arterial hypoxaemia. 
TRPV4 has been implicated as a key regulator of lung endothelial barrier integrity, and 
specifically, the integrity of the lung alveolar-capillary endothelium, which is most 
relevant to alveolar flooding associated with acute lung injury. TRPV4 activation by 
hydrostatic stretch in lung microvessels leads to increased endothelial Ca2+ concentration 
and a diverse set of vascular responses, including an increase in endothelial permeability 
[Morty, 2014]. The importance of TRPV4 in maintaining pulmonary barrier function has 
been demonstrated in the settings of elevated pulmonary venous [Thorneloe, 2012] or 
airway pressure [Hamanaka, 2007], and following treatment with chemical and biological 
toxins such as Hydrochloric acid (HCl) and platelet activating factor [Balakrishna, 2014; 
Morty, 2014; Yin, 2016] . In these studies, TRPV4 blockade limited lung damage by 
 
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reducing plasma fluid leak into the alveolar space (thus increasing arterial oxygenation), 
and by modulating neutrophil and macrophage recruitment and activity and reducing 
overall mortality in response to LPS [Balakrishna, 2014; Morty, 2014; Yin, 2016; 
Dalsgaard, 2016].  This evidence suggests TRPV4 channel blockade may benefit patients 
with ARDS where alveolar capillary leak is a primary driver of injury, by reducing fluid 
leak, reducing ventilation perfusion mismatching, improving oxygenation and reducing
the need for mechanical ventilation with potential reductions in mortality.
3.3.
Benefit/Risk Assessment
3.3.1.
Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2798745 may be found in the Investigator’s 
Brochure.
All potential risks of GSK2798745 are based on pre-clinical data. No risks have been 
identified in the clinical studies of GSK2798745 conducted before the effective date of 
this protocol.
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2798745]
Vascular lesions
Dogs (4-week study): at 30 mg/kg/day, 2 males had arterial 
lesions
One male: Heart – Coronary artery inflammation; Thymus 
– Arteriole inflammation with fibroplasia 
One male: Epididymides – Artery degeneration/necrosis 
with inflammation
Dogs (13-week study): At 10 mg/kg/day, 1 male and 1 female 
had arterial lesions
One male: Epididymides – Arteriole degeneration/necrosis 
with lymphocytic inflammation
One female: Bladder – Arteriole degeneration/necrosis 
with lymphocytic inflammation
Participant Monitoring: The arterial lesions noted in heart, 
thymus, epididymides, and urinary bladder cannot be 
monitored directly. There is currently no human translation 
biomarker or understanding of the underlying mechanism.
Participant Exposure: Since these effects cannot be 
monitored directly in clinical studies, coverage of ≥30 fold will 
be maintained from the no-effect dose (3 mg/kg/day); 
exposure will not intentionally exceed the average daily area 
under concentration-time curve (AUC) of 0.513 hr*µg/mL 
and/or maximum observed plasma concentration (Cmax) of 
0.050 µg/mL on an individual basis.
Myocardial toxicity
Dogs (4-week study): at 30 mg/kg/day, myofibre
degeneration/necrosis and inflammation (2 animals)
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment,
including relevant history of acute coronary syndromes 
(including unstable angina), coronary angioplasty, or stenting,
will be excluded.
Participant Monitoring: Cardiac troponin levels will be 
monitored and ECGs will be done during the study.
Participant Exposure: Exposure levels will be maintained 
below the threshold detailed in the Dose Justification Section 
(see Section 5.5).
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Mortality/moribund 
condition; poor viability
Dogs (4-week study): at 30 mg/kg/day, one male terminated 
early (Day 6) due to poor clinical condition. Another male had 
transient whole body shaking on Days 8 and 9.
Dogs (13-week study): at 10 mg/kg/day one male was 
terminated early (Day 74) due to welfare reasons.
Rats (micronucleus and comet study): mortality occurred 
following 1 to 3 doses at ≥600mg/kg/day
Participant Monitoring: Weight and adverse events reported 
by participants will be monitored.
Gastrointestinal (GI) 
and/or hepatic toxicity
GI toxicity: ≥3 mg/kg/day in dogs and at 30 and 300 
mg/kg/day in rats, consisting of mucosal erosion/ulceration in 
the stomach and/or duodenum.
Hepatic Toxicity: Biliary epithelial hypertrophy/hyperplasia 
and periductal mixed inflammatory cell infiltrate into the liver 
was observed at 300 mg/kg/day in rat (7-day study) and focal 
hepatocellular degeneration in 1 male dog at 30 mg/kg/day 
(4-week study)
Participant Selection: Participants with active ulcer disease or 
GI bleeding or those who are taking concomitant medications, 
including nonsteroidal anti-inflammatory drugs (NSAIDs) and 
steroids, will be excluded. Assessment of faecal occult blood 
will be performed before and after dosing.
Participant Monitoring: Participants will be monitored for GI 
intolerance (e.g by adverse events such as abdominal 
discomfort) and sequential clinical chemistry analysis, 
including liver enzymes. Follow-up faecal occult blood test
(FOBT) will be conducted.
Testicular toxicity
Inconsistent finding in rats (4-week study): Spermatid 
retention at ≥60 mg/kg/day, however no effect observed in 
13-week study. The observations in the 4-week study were 
not associated with degenerative changes in testes or 
epididymides.
No spermatogenic abnormalities were observed in dogs.
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats.
Skeletal muscle toxicity
Rat (4-week study): Myofiber necrosis: myofiber 
degeneration/regeneration; fibroplasia, at 300 mg/kg/day in 
the soleus muscle.
Participant Monitoring: Creatinine phosphokinase (CPK) 
levels will be taken before and after dosing. 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Seizures and 
convulsions
Rats (micronucleus and comet study): convulsions observed 
at ≥600 mg/kg/day. Convulsions were not related to Cmax, 
nor occurred at any predictable time from dose administration.
Dogs: No central nervous system (CNS) findings at 
12 mg/kg/day in the dog 7-day EEG/CV study. In other 
compounds in the same series, convulsions have been 
observed.
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment,
including a history of seizure disorder or stroke within the last 
5 years will be excluded from the study. 
Low food consumption 
Dogs (4-week study): 30 mg/kg/day reduced food 
consumption. Two males were terminated early (Day 10) due 
to extremely reduced food consumption.
Rats (4-week study): 300 mg/kg/day had decreased food 
consumption.
Participant Monitoring: Weight will be monitored.
Effects on 
macrophages 
(Phospholipid 
accumulation)
Inconsistent effects observed in Rats (4-week study):
60 mg/kg/day in the lung (prominent alveolar macrophages); 
300 mg/kg/day in the mesenteric lymph node (increased 
cellularity of sinus macrophages) and thymus (macrophage 
vacuolation; increased thymus weight). Consistent with 
phospholipid accumulation (phospholipidosis) based on 
ultrastructural appearance of mesenteric lymph nodes at 
300 mg/kg/day. Findings were not associated with 
degenerative changes. In 13-week studies in rats, these 
effects were not observed.
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats.
Theoretical Risk:
Potential effects on 
vasoregulation .
TRPV4 mediates prostaglandin release from isolated human 
endothelial cells and in vivo in rats, supporting the potential 
for TRPV4 blockade to modulate blood pressure via 
prostaglandin release. No effect of GSK2798745 on blood 
Participant Monitoring: Blood pressure will be monitored 
throughout the study.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pressure was observed in preclinical or clinical studies. 
Theoretical Risk:
Potential effect on 
hearing.
Genetic deletion of TRPV4 in mice has been shown to effect 
hearing. TRPV4 knockout (KO) mice at age 8 weeks 
exhibited normal hearing thresholds, but at age 24 weeks, 
had delayed-onset hearing loss; additionally, the cochlea was 
found to be vulnerable to acoustic injury with sound 
overexposure [Tabuchi, 2005]. Patients with Charcot-Marie-
Tooth Disease Type 2C (CMT2C), an autosomal dominant 
axonal neuropathy related to TRPV4 gene mutations, 
demonstrate symptoms that include hearing loss caused by 
nerve damage in the inner ear (sensorineural hearing loss).
These are predominantly gain of function TRPV4 
abnormalities, in which the hearing loss is sporadic among 
family members; and relegated to some TRPV4 defects, but 
not in others. Although the exact mechanism is unclear, it 
has been suggested that the TRPV4 channel plays an 
important role in peripheral nerve function and that the 
alterations in TRPV4 in CMT2C may be due to increased 
channel activity leading to excessive calcium influx and a 
calcium overload. There is potential for benefit with 
GSK2798745, in that with cells (HEK293) expressing the 
CMT2C mutant channel, inhibitors of the TRPV4 channel 
were found to block the increased intracellular calcium 
concentrations and resultant cell death [Landouré, 2010]. In a 
study evaluating effects on heart failure with similar dosing 
exposure, a week-long duration and comprising an older 
participant demographic, audiometry testing was conducted. 
Although a variety of changes were observed, primarily 
Participant Exposure: Dosing will be limited to a short duration 
of a single day. 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
sporadic, low frequency and single frequency changes in 
those on treatment as well as placebo, none were assessed 
as a signal for concern by the reviewing expert audiologist.
Theoretical risk:  
Potential suicidal 
ideation
GSK2798745 is considered to be a CNS-active drug. There 
has been some concern that some CNS-active drugs may be 
associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with certain 
conditions. GSK considers it important to monitor for such 
events before or during clinical studies with CNS-active 
compounds.  Participants being treated with GSK2798745 
should be assessed at screening for suicidality.
Participant Selection: The risk of such an event would be very 
low in single-day dose trials in healthy volunteers; however,
participants who, in the investigator/designee's judgement, 
poses a significant suicide risk, will be excluded from the 
study.  A C-SSRS questionnaire will be completed before and 
after dosing. 
Study procedures-related
Risk of adverse events 
following delivery of 
LPS
Previously reported segmental LPS related adverse events 
include pleuritic pain, pyrexia, head ache, nausea and 
alveolitis [Hohlfeld, 2008; Holz, 2015]. 
It is known that LPS and pro-inflammatory mediators can 
cause gut permeability [Al-Sadi, 2014; Guo, 2013].  We 
expect the systemic exposure to LPS and systemic 
inflammatory response to LPS to be minimal following the 
segmental topical dose of 4ng/kg LPS.  As such, we assess 
the risk to increased gut permeability, and potential increased 
bioavailability, with this regimen to be low.
Participant Monitoring: Participants will be monitored with 
safety assessments, including clinical laboratory tests, 
physical examination, ECGs, vital signs (including 
temperature), pulse oximetry and spirometry during the study.
Experienced site staff will conduct the procedures. 
Participants will be carefully monitored and managed with 
standard procedures in the event of complications.
Risks associated with 
bronchoscopy and BAL 
sampling:
Procedure related complications include cough, transient 
fever, chills and myalgias, transient infiltrates, bronchospasm, 
transient fall of lung function, transient decrease in baseline 
PaO2 (partial pressure of oxygen in arterial blood).
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Risk associated with 
blood draws
Fainting, mild pain, bruising, irritation or redness.
Experienced site staff will follow standard approaches for 
managing events related to blood draws.
Risks associated with 
spirometry
Shortness of breath, coughing, light-headedness or fainting, 
and/or chest tightness may be induced by spirometry testing.
Participants experiencing any of these symptoms will receive 
standard medical treatment by the study investigator.
 
 
 
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3.3.2.
Benefit Assessment
There will be no intended therapeutic clinical benefit to the participants taking part in the 
study as it is a healthy volunteer study. However, participants will undergo a medical 
evaluation during screening including physical exams, electrocardiograms (ECGs) and 
laboratory assessments which may provide important health information.
By taking part in this study, the participant will be contributing to the development of 
GSK2798745 for the treatment of ARDS, a syndrome with significant unmet need.
3.3.3.
Overall Benefit:Risk Conclusion
No benefit to healthy participants is expected. The study activities have risks, however 
these risks are mitigated by: exclusion of participants with identified comorbidities; short 
(single day) duration of dosing with GSK2798745; exposure limited to previously 
approved exposure levels; and inclusion of safety margins, as well as safety monitoring 
by trained staff. The study will provide important information towards future 
development of TRPV4 blockers that may help patients with ARDS.
The design of the study is considered low risk to the participants and justified based on 
the safety information from the nonclinical studies and the previous clinical trials carried 
out on GSK2798745.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To investigate the effect of
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers.

Baseline adjusted total protein 
concentration in bronchoalveolar 
lavage (BAL) samples at 24 h after 
segmental LPS challenge.
Secondary

To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs.

Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge.

To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers.

Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry 
(forced expiratory volume in 1 
second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood
test (FOBT).

To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers 

PK parameters of GSK2798745 in 
plasma (AUC [0-26] and Cmax).
Exploratory

To assess concentration of 
GSK2798745 in BAL.

Levels of GSK2798745 in BAL 
samples at 2 and 26 h after dosing.

To investigate the effect of 
GSK2798745 on exploratory 
markers of endothelial barrier 
permeability and/or injury, and
inflammation, in LPS-challenged 
lungs.

Baseline adjusted levels of 
exploratory biomarkers in blood 
and/or BAL.

To possibly assess metabolite 
GSK3526876 (major metabolite of 
GSK2798745) in plasma and BAL 
samples.

Plasma and BAL concentrations of 
metabolite GSK3526876.
 
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Objectives
Endpoints

To compare the PK of GSK2798745 
with the effect of prophylactic 
dosing on alveolar-septal barrier 
permeability following LPS 
challenge in healthy volunteers.

To investigate the effect of 
GSK2798745 on white blood cell 
levels (except neutrophils) in 
LPS-challenged lungs.

Comparison of PK parameters of 
GSK2798745 in plasma with 
baseline corrected total protein 
concentration in BAL.

Baseline adjusted total and 
differential cell count of white blood 
cells (except neutrophils) in BAL 
samples at 24 h after segmental LPS 
challenge.
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.  
Participants will be randomised 1:1 to take 2 single doses (3 tablets total): either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later. Participants will undergo segmental LPS challenge to the 
lungs at 2 h after the first dose.  BAL samples will be taken after dosing:  immediately 
before and at 24 h after the LPS and saline challenge.  Blood samples will be taken before 
and after dosing and the challenge.  Safety will be monitored throughout.  A schematic of 
the study is provided in Figure 2.
Figure 2
Study schematic
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic.
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2).  The first dose will be 
administered on Day 1 at 2 h before baseline BAL sampling from a segment in the left 
lower lobe. 4 ng/kg LPS will subsequently be instilled into the right middle segment and
saline control into the lingula segment of the contralateral side. The second dose of study 
treatment will be administered 10 hours after LPS challenge followed by post-dose BAL 
sampling on Day 2. Participants will receive a follow up phone call 2 days after 
discharge, and return to the study site on Day 8 (1 day) for a follow-up visit.
 
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5.2.
Number of Participants
Sufficient healthy participants will be screened to ensure that a maximum of 60 evaluable
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted (as described in Section 10.3.4), to assess the 
difference, if any, between treatments in the primary endpoint.  There are two interim 
analyses planned, depending on the results of the interim analyses, recruitment may be 
stopped.  Participants who prematurely discontinue the study, and whose data are not 
evaluable (i.e. those for whom results of the primary analysis cannot be determined), may 
be replaced. Recruitment into the study can continue whilst interim analyses are taking 
place. 
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design

Use of a placebo:  The randomised, placebo-controlled study design is a 
well-established methodology to evaluate potential treatment effects in experimental 
studies. The use of a placebo arm allows for a valid evaluation of changes in PD 
markers attributable to treatment versus those independent of treatment.  Given that 
participants are healthy and treatment is not being withheld, the use of placebo is 
considered acceptable.

Parallel group:  The use of a parallel group design is considered to limit the burden 
of procedures and exposure of LPS to participants. A crossover design only 
minimally decreases the required number of evaluable participants and owing to the 
expected dropout rate in a crossover study, and the burden of procedures for each 
participant, a parallel group design was selected.

Blinding:  A double blind design is a standard methodology for randomised, 
controlled studies to avoid bias. 

Selection of primary endpoint:  Changes in total protein concentrations to monitor 
influx of proteinaceous fluid into the lung has been used in several LPS challenge 
studies. Evidence points to the involvement of TRPV4 in changes to alveolar 
capillary barrier following LPS administration, with subsequent leak of proteinaceous 
fluid as measured by total protein. Given the influx of fluid with high concentrations 
of protein observed in ARDS patients, monitoring total protein changes is considered
an acceptable surrogate to assess for target engagement of GSK2798745 and for 
potential effects in ARDS patients. 

Timing of primary endpoint:  As previous studies show that total protein 
concentrations peak at 24 h after segmental LPS challenge [O’Grady, 2001; 
Holz, 2015], post-challenge BAL samples will be taken at 24 h after the challenge. 
 
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
Timing of challenge:  Baseline BAL sampling prior to administration of study drug is 
not considered feasible due to the burden of bronchoscopy (i.e. two procedures 
required – one pre and one post dose to instil LPS). A baseline bronchoscopy is 
planned 2 h after administration of the first dose, with the aim of maximising 
exposure to GSK2798745 (in healthy volunteers, the median [range] Time to reach 
maximum plasma concentration (Tmax) of the tablet formulation of GSK2798745 to 
be used in this study is 1.5 h [1–3 h]). Drug on board at the time of baseline BAL 
fluid sampling is expected to have little to no effect on baseline BAL total protein 
concentrations as TRPV4 channels are quiescent until stimulated and blockade of 
these channels does not affect barrier permeability of ‘healthy’ endothelial cells 
[internal data].  The effects of LPS to induce endothelial permeability are believed to 
occur rapidly.  Investigation of LPS induced permeability and markers of cell 
activation and inflammation over time consistently indicates that the initial events 
leading to increased barrier permeability and inflammation occur within first 2 h post 
intratracheal (i.t.) LPS exposure; where any earlier measurements are limited. LPS 
induces intracellular stress fibre formation within 5 min in both human dermal 
microvascular endothelial cells (HMVEC) endothelial and A549 epithelial cells 
[Ngamsri, 2010].  Increased levels of TNFα following i.t. LPS instillation are 
observed within 2 h in man [O’Grady, 2001] and other pro-inflammatory mediators 
within 4 h in a mouse model of acute lung injury (ALI) [Bosmann, 2012].  
Permeability across an endothelial monolayer is observed after 0.5 h and peaks at 2 h 
post-LPS [Bannerman, 1998].  BAL total protein increases following LPS i.t. 
challenge in man as early as 2 h and reaches significance at 6 h post-LPS [Matthay
, 2012] with significant increases in neutrophil counts also observed as early as 2 h.  
Looking to a systemic LPS model of sepsis with a higher LPS insult, earlier sampling 
is possible and high levels of inflammatory mediators are measured within 1 h, which 
reach plateau by 3 h. Therefore, despite our conservative treatment effect prediction 
(see Section 5.5), we expect that high plasma and/or alveolar fluid concentrations of 
GSK2798745 will be required at the time of and/or soon after the challenge, in order 
to inhibit the effects of LPS. Therefore, LPS will be administered shortly after time of 
Tmax (1.5-hours) to ensure sufficient drug on board. 
5.5.
Dose Justification
5.5.1.
Dose Rationale
The first time in human study (TR4113787) for GSK2798745 evaluated doses from 
0.25 mg to 12.5 mg as single doses, and 5 mg once daily repeat dosing for 14 days in 
healthy volunteers in cohorts 1–3.  Cohorts 4 and 5 of the study were administered once 
daily 2.4 mg dose of capsules with food for 7 days to stable heart failure participants.  
Exposure from different tablet formulations administered with or without food was 
characterised in another clinical study in healthy volunteers (204725).  Exposure from all 
available clinical data to date was analysed with a population pharmacokinetic (POP PK) 
approach accounting for participant weight, formulation, impact of food amongst other 
variables.  Trial simulations were performed with this POP PK model with differing 
dosing regimen. 
 
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The estimated human IC50 of 2.1–3.2 ng/mL was derived from data from a rat study, 
which was conducted to assess the ability of different doses of GSK2798745 infusion to 
reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist.  The IC50 
was also corrected for species differences using protein binding data and TRPV4 potency 
differences in invitro assays. To evaluate drug activity/efficacy at the intended dosing 
regimen, the percentage pulmonary oedema blockade was estimated using the population 
model and the corrected potency values derived from the rat pulmonary study. 
Based on the simulations, the intended dosing scheme for this study is a 4.8 mg dose 
followed by a 2.4 mg dose at 12 h. Table 1 lists the predicted average percentage 
pulmonary oedema blockade over the 24-h period based on this potency range.  The 
schematic in Figure 3 also depicts the range of GSK2798745 systemic exposure and the 
predicted percent inhibition by TRPV4 with the intended regimen.  At 26 h post the first 
dose, when the primary endpoint sample will be taken, the predicted TRPV4 inhibition is 
71.1% (44.4–86.3) [median (95% prediction interval)].
The intended dosing regimen also limits the daily ceiling human exposure at individual 
participant level to 30-fold of the exposure observed at the no observed adverse effect 
level (NOAEL) dose of 3 mg/kg from the 3-month dog safety study (D70496G). The 
current clinical doses are selected so that no participant intentionally exceeds the daily 
AUC of 513 ng*hr/mL and Cmax of 50 ng.hr/mL.  The likelihood of one or more 
participants of the 30 participants to be dosed with this regimen exceeding the threshold 
is listed in Table 1.
 
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Figure 3
Predicted GSK2798745 exposure and corresponding effect on 
pulmonary oedema after doses of 4.8 mg then 2.4 mg, 12 h apart
Note:  percentage inhibition based on the rat, agonist-driven, pulmonary oedema model.
Table 1
Predicted exposure, probability of exceeding threshold and 
predicted efficacy after doses of 4.8 mg then 2.4 mg, 12 h apart, 
administered to 30 participants
Percentage 
pulmonary oedema 
blockade over 24 h
(median 
[95% PI])
Predicted exposure
(median [95% PI])
% Probability that ≥1 of 30 
participants will exceed the 
toxicokinetic limit1
AUC0–24 h
(ng.h/mL)
Cmax 
(50 ng/mL)
AUC0–24 h 
(513 ng.h/mL)
Cmax 
(50 ng/mL)
79.1 
[66.5–87.1]
272.4 
[176.2–400.9]
23.1 
[15.2–34.4]
5.6
1.6
PI:  predicted interval.  
1.
The percentage of the 500 simulated studies (of 30 subjects each) in which ≥ 1 subject exceeds the toxicokinetic 
limit.
5.5.2.
Treatment Effect Rationale
Data from a systemic LPS model [Dalsgaard, 2016] , and from other models of lung 
injury (chlorine gas exposed mice [Suresh, 2015], pulmonary venous pressure induced 
 
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injury of isolated mouse lungs [Narita, 2015], and a mouse model of intratracheal 
instillation of hydrochloric acid [Hamanaka, 2007]) suggest that TRPV4 blockade 
contributes 20–80% to a reduction in total protein in BAL fluid after the injury.  
Averaging the effect from those studies, the maximum effect possible in this segmental 
LPS model is estimated to be approximately 50%, assuming total TRPV4 channel 
blockade.  Therefore, with estimated exposure expected to reduce total protein by 
approximately 71% in a pure agonist driven challenge, a median treatment effect of 35% 
might be expected in this LPS challenge.  Based on pragmatic reasons and given some of 
the uncertainty around TRPV4 contribution to proteinaceous fluid influx as measured by 
total protein in a segmental LPS challenge, an estimated 30% treatment effect was 
nominally selected for sample size calculations.
 
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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Volunteers who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests (including a normal 
coagulation profile), ECGs, vital signs and spirometry.
Note:  In the event of out-of-range results of safety tests, the tests may be repeated 
once within the screening window.  If a retest result is again outside the reference 
range and considered clinically significant by the investigator and GSK medical 
monitor, the participant will be considered a screen failure.  
3.
Normal spirometry (FEV1 ≥80% of predicted, FEV1/FVC ratio ≥70%) at screening
and before dosing.
WEIGHT
4.
Body weight 50 kg and body mass index (BMI) within the range 19–29.9 kg/m2
(inclusive).
SEX
5.
Male or female.
a. Male participants:
A male participant must agree to use contraception, as described in Appendix 5, 
during the treatment period and for at least 7 days after the last dose of study 
treatment and refrain from donating sperm during this period.
b. Female participants: 
A female is eligible to participate if she is not of childbearing potential, as defined 
in Appendix 5.
INFORMED CONSENT
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
 
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6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTC INTERVAL)
1.
Significant history of or current cardiovascular, respiratory (eg asthma, chronic 
obstructive pulmonary disorder (COPD), bronchiectasis, active Tuberculosis [TB]), 
hepatic, renal, gastrointestinal, endocrine, hematological, autoimmune or 
neurological disorders capable of significantly altering the absorption, metabolism, 
or elimination of drugs; constituting a risk when taking the study treatment; or 
interfering with the interpretation of data.
2.
Participant who, in the investigator/designee's judgement, poses a significant suicide 
risk. Evidence of serious suicide risk may include any history of suicidal behaviour 
and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on 
the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years. 
3.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive
faecal occult blood test [FOBT] at screening).
4.
Values outside of the following ranges; 90-140 mmHg for systolic blood pressure, 
50-90 mmHg for diastolic blood pressure and 50-90 beats/minute for heart rate.
5.
An AV block greater than Grade 1.
6.
ALT or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%). 
7.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
8.
QTc >450 msec
NOTES:  the QTc is the QT interval corrected for heart rate according Fridericia’s 
formula (QTcF).
9.
At risk of Torsades de pointes (e.g. a personal history or a family history of sudden 
unexplained death, long QT, familial cardiac syndrome, or cardiomyopathy).
10. Chronic or acute infection within the 4 weeks before dosing, (e.g. upper and lower 
respiratory infection within the 4 weeks before dosing).
11. Major (as per investigator judgment) surgery within the last 12 weeks prior to 
randomisation or planned within 3 months of screening.
PRIOR/CONCOMITANT THERAPY
12. Use of prescription or non-prescription drugs (except paracetamol), including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
or 5 half-lives (whichever is longer) before the first dose of study medication, 
unless, in the opinion of the investigator and GSK Medical Monitor, the medication 
will not interfere with the study procedures or compromise participant safety.
13. History of sensitivity to any of the study medications, or components thereof or a 
 
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PRIOR/CONCOMITANT THERAPY
history of drug or other allergy that, in the opinion of the investigator and/or GSK
Medical Monitor, contraindicates their participation.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
15. The participant has participated in a clinical trial and has received an investigational 
product within the following time period before 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).
16. Exposure to more than four new chemical entities within 12 months before the first 
dosing day.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
17. Presence of hepatitis B surface antigen (HBsAg) at screening
18. Positive hepatitis C antibody test result at screening. 
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA)
test is obtained.
19. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
20. A positive pre-study drug/alcohol/cotinine screen.  
21. A positive test for immunodeficiency virus (HIV) antibody.
22. Regular use of known drugs of abuse.
OTHER EXCLUSIONS
23. 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. 
24. Current smoker or a history of smoking within 6 months of screening, or a total 
pack year history of >5 pack years. [number of pack years = (number of cigarettes 
per day/20) x number of years smoked].
 
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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants are not permitted to consume red wine, Seville oranges, grapefruit or 
grapefruit juice, and/or pomelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days before the start of study treatment until discharge from the clinical unit.

Participants will be required to fast from midnight before the bronchoscopies on 
Day 1 and 2 until after the procedure and for at least 2 hours before dosing. 
6.3.2.
Caffeine, Alcohol, and Tobacco

During the Treatment Period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) and/or pharmacodynamic sample.

During the Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 

Only non-smokers may be recruited into this study. 
6.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Participants may be rescreened once.  If rescreening is preformed, participants must be 
assigned a different unique participant identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment 
Name:
GSK2798745
Matching Placebo
Challenge Agent:
GMP grade 
lipopolysaccharide 
from Escherichia coli
(E. Coli Group 
0113:H10:K Negative) 
for the segmental LPS 
challenge
Dosage formulation:
White to slightly 
coloured, round 
biconvex tablet.
Product: AP, Tab-
A  
White to slightly 
coloured, round 
biconvex tablet.
Product code: 
CET, Tab-A..
LPS is available from 
stock lyophilized in a 
1 microgram vial, 
formulated in 1% lactose 
and 0.1% PEG6000. 
Clear solution. 
Unit dose 
strength(s)/Dosage 
level(s):
Unit dose strength
2.4 mg.
Dosage Levels: 
4.8 mg and 
2.4 mg
Not applicable
4 ng/kg
Route of 
Administration 
Oral
Oral
Direct application to the 
lung segment, via 
bronchoscopy
Dosing instructions:
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later.
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later. 
One single instillation of 
10 mL by bronchoscopy 
2 hours after dosing with 
GSK2798745 or placebo 
on Day 1. 
 
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Study Treatment 
Name:
GSK2798745
Matching Placebo
Challenge Agent:
GMP grade 
lipopolysaccharide 
from Escherichia coli
(E. Coli Group 
0113:H10:K Negative) 
for the segmental LPS 
challenge
Packaging and 
Labeling
GSK2798745 
tablets will be 
provided in high-
density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement.
Placebo tablets will 
be provided in 
high-density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement.
-
Manufacturer
GSK
GSK
List Laboratories, Inc.
Sterile saline (0.9%) for control challenge will be sourced by the clinical site.
7.1.1.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.2.
Challenge Agents
Bacterial endotoxin is a component of the cell wall of Gram-negative bacteria present in a
variety of occupational and general environmental settings.
The dose of LPS used in this study is 4 ng/kg, which is 100 times lower than doses used
in inhalation models of endotoxin-induced lung inflammation. This dose was chosen
based on the data published by O’Grady et al [O’Grady, 2001].  In this study, lavage after
24-h in subjects challenged with 4 ng/kg of endotoxin revealed a localised inflammatory
response that was neutrophil-predominant. The site performing this study has experience 
with this model. The LPS challenge agent to be used for the procedure is Good 
Manufacturing Practice (GMP)-grade product and will be sourced from List Laboratories, 
Inc. A certificate of analysis will be provided for each batch of the LPS challenge agent 
to ensure its quality and safety.
 
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Reconstitution will be done under the responsibility and supervision of the investigator or 
qualified site staff who performs the bronchoscopy and administers the reconstituted LPS 
in individual dilution to the subject. The reconstitution will be done on the day of
bronchoscopy immediately before the procedure (within 1 hour). If more than one subject 
per day will be investigated, the first process of reconstitution and administration of LPS 
has to be completed before a second process is started.
The reconstitution process is described as an example for the nominal dose of 10,000 EU 
of endotoxin per vial. Each vial of LPS contains a lyophilized solid containing 
10,000 EU of endotoxin. Upon reconstitution with 5 mL of sterile saline 0.9%, the vial 
will contain 2,000 EU/mL = 2 EU/μL. Forty (40) μL/kg body weight will be withdrawn 
from the vial and transferred into a sterile endotoxin-free 30 mL-sample vial (Acila AG, 
Weiterstadt, Germany). Sterile saline 0.9% will be added to give a final volume of 
20 mL. Ten (10) mL of this solution contains the application dose of 40 EU (4 ng)/kg, 
and will be filled into a 10 mL-syringe. This individual dilution will be administered to 
the participant by segmental pulmonary application during the bronchoscopy. The 
remaining 10 mL will be stored frozen (-20°C) as a retention sample.
The negative control will be performed with 10 mL of sterile saline 0.9% only. The 
reconstitution process will be adapted to the actual endotoxin content as determined in 
the Certificate of Analysis. The Investigator Site File will contain the current instructions 
for reconstitution in order to ensure the application dose of 40 EU/kg.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information and instructions for the 
IWRS will be provided to each site.  Participants will be registered using the IWRS, and 
assigned a unique number (randomisation number).  The randomisation number encodes 
the participant’s treatment (GSK2798745 or placebo), according to the randomization 
schedule generated prior to the study by the Statistics Department at GSK.  Each 
participant will be dispensed blinded study treatment, labelled with his/her unique 
randomisation number.
7.4.
Blinding
This will be double blind study.  All study staff involved in clinical assessments (which 
includes the investigator, sub-investigators, other site staff) and the participant will be 
blinded to the treatment allocated to individual participants and to post challenge total 
protein in BAL sample results. Selected sponsor study team members (and delegates if 
programming activities are outsourced) will be unblinded to perform the interim analysis.  
This may include the medical monitor, study statistician, study programmer (and 
delegates) and study pharmacokineticist.  Access to unblinded data will be kept to the 
minimum set of individuals required to implement any interim analyses, but may include 
GSK management/review committees if alterations to the study conduct are required.  
Details of who were unblinded to what data and when will be included in the clinical 
study report. The IWRS will be programmed with blind-breaking instructions. In case of 
an emergency, the investigator has the sole responsibility for determining if unblinding of 
 
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a participant’s treatment assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior
to unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded GSK 
must be notified within 24 hours after breaking the blind.  The date and reason that the 
blind was broken must be recorded in the source documentation and CRF, as applicable.
A participant whose treatment assignment is inadvertently unblinded (either to 
investigative staff or the participant themselves) will be permitted to remain in the study, 
although the accidental unblinding will be recorded as a protocol deviation and hence the 
participant will be subject to review as to their inclusion in analyses.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
1.
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorised site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the
preparation of the dose will be confirmed by a second member of the study site staff. 
 
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
When participants are dosed at the 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.

GSK2798745 and the placebo will be orally administered to participants at the site.  
7.7.
Concomitant Therapy
7.7.1.
Permitted Medications
Paracetamol, at doses of 2 grams/day, is permitted for use any time during the study.  
Rescue medication, such as salbutamol, is also permitted after bronchoscopy or 
spirometry procedure, if required, and other medication, such as midazolam, may be 
taken during bronchoscopies to aid the procedure. Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required.
7.7.2.
Prohibited Medications
Except for the permitted medications noted above (Section 7.7.1), participants must 
abstain from taking prescription or non-prescription drugs (including vitamins and dietary 
or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study treatment until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study. 
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the
study because only healthy volunteers are eligible for study participation.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Individual Stopping Criteria
8.1.1.
Liver Chemistry Stopping Criteria
Increased monitoring criteria have been designed to assure participant safety and 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance). These protocol guidelines are in alignment with FDA premarketing 
clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Increased monitoring will be performed for a participant if liver chemistry stopping 
criteria are met.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6
8.1.2.
QTc Stopping Criteria
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
A participant who meets either bulleted criterion below will be withdrawn from study:

QTcF >500 msec

Change from baseline of QTc >60 msec
8.1.3.
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria
8.1.3.1.
Asymptomatic Participant
Cardiac troponin (cTn) will be measured before and at the end of the study.  If any cTn 
assessment is >ULN or >2 times the participant’s baseline value (Day −1), the participant 
should be contacted immediately to assess for symptoms of cardiac ischemia.
8.1.3.2.
Symptomatic Participant
If a participant experiences symptoms of cardiac ischaemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  The participant should be evaluated by a cardiologist and undergo any 
clinically appropriate testing.  The participant should be followed up until symptoms are 
resolved.  If the event occurs after the first dose, but before the second, the participant
should not receive the second dose.
 
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8.1.4.
Bronchoscopy Stopping Criteria
A participant will be withdrawn from the study if they experience symptomatic 
bradycardia or tachycardia requiring treatment as a consequence of bronchoscopy, BAL 
and LPS instillation. In addition, participants who have the following may also be 
withdrawn at the discretion of the investigator:

Oxygen saturation <90% (on oxygen)

Prolonged somnolence following administration of midazolam

Significant hypertension/hypotension
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA (Section 2.3) for data to be collected at the time of withdrawal.
8.3.
Study Stopping Criteria
If there is a serious unexpected adverse event considered at least possibly related to the 
investigational product administration in one participant; or a severe non-serious AEs 
considered as, at least, possibly related to the investigational product administration in 
two participants, the study will be temporarily halted until full review of the events. In 
participants, significant changes from baseline measurements will be reviewed and 
participants will be followed until resolved. Participants who have been dosed at the time 
of the study halt will continue in the study, as planned. Further participants may be dosed 
only if, after review, the sponsor and investigator consider it safe to do so and only after 
ethics and regulatory approval of a substantial amendment.
8.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.
 
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
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the Schedule of Activities 
(SoA). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Bronchoscopy
Bronchoscopy will be performed in accordance with site standard operating procedures
(SOPs), at 2 hours and 26 hours. These SOPs will reflect current standards
of practice in hospital care and will include (but are not limited to) the following items:

Oxygen supplementation will be given to all participants.

Pulmonary function will be monitored before the bronchoscopy and after the
bronchoscopy until FEV1 is within 20% of the pre-procedure value.

All participants will be monitored in a recovery/holding room post bronchoscopy.
Participants will be discharged only after approval is obtained from the 
supervising physician, and participants will be given a 24-hour contact number. 
Admission facilities will be available in the event a participant is not deemed fit 
for discharge or if overnight observation is deemed necessary by the study 
physician or site-specific policies.
Following bronchoscopies, participants will be monitored for at least 4 hours. However,
should the investigator have any concern for participant safety, participants may be 
requested to remain resident for further observation.
 
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9.2.
Segmental lung challenge
Participants will undergo segmental challenge to the lungs, via bronchoscopy, at 2 hours 
after the first dose of investigational medicinal product (IMP):  10 mL LPS (4 ng/kg) will 
be instilled into the right middle segment and 10 mL saline control will be instilled into 
the lingula segment of the contralateral side.
Local SOPs will be followed and further details about the segmental LPS/saline challenge 
are provided in the SRM. 
9.3.
Pharmacodynamic Assessments
BAL samples will be taken, via bronchoscopy, to measure total protein and neutrophils 
counts. Baseline samples will be taken immediately before the LPS and saline 
challenges, from a segment in the left lower lobe, and post-challenge samples will be 
taken at 24 h after the LPS and saline challenges, from the challenged segments.  
Details of BAL sample collection, processing, storage and shipping procedures are 
provided in the SRM.
9.4.
Pharmacokinetics
Blood and BAL samples for assay of GSK2798745 will be collected at the time points 
indicated in the SoA (Section 2.2).  Details of sample collection, processing, storage and 
shipping procedures are provided in the SRM.
PK analysis will be performed under the control of Platform Technologies and
Science-IVIVT (PTS-IVIVT)/GlaxoSmithKline.  Plasma and BAL concentrations of 
GSK2798745 will be determined using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Plasma and BAL samples may be analysed for the metabolite GSK3526876, GSK will 
store the remaining plasma and/or BAL for future possible metabolite investigations.  
Analysis of compound-related metabolites may be reported under a separate protocol.
9.5.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8). 
Adverse event/serious adverse event reporting will meet the requirements set out in 
Section 12.2.4 of the ICH E3 Guidelines.
 
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9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit.  
However, any SAEs assessed as related to study participation (e.g. study 
treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product, will be recorded from the time a 
participant consents to participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit.

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.5.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.5.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE/SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.4). Further information on follow-up procedures is given in 
Appendix 4.
9.5.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
 
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under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg: summary or listing of SAE) from the
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.5.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 12.5.
9.6.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2798745 can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.7.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
 
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9.7.1.
Physical Examinations

A complete physical examination will include, at a minimum, measuring weight 
and assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.7.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes’ rest and 
will include temperature, systolic and diastolic blood pressure and heart rate

At each time point before dosing, 3 readings of blood pressure and heart rate
will be taken. The first reading should be rejected. The second and third 
readings should be averaged to give the measurement to be recorded in the CRF.
At all other time points, single measurements will be taken. 
9.7.3.
Pulse Oximetry

Pulse oximetry will be monitored during each bronchoscopy. Clinically 
significant results will be recorded as AEs.
9.7.4.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at each time point before dosing. At all 
other time-points a single 12-lead ECG will be obtained as outlined in the SoA 
(see Section 2) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.

ECG to be measured in a semi-supine position after 5 minutes’ rest.
9.7.5.
Spirometry
Spirometry assessments will be performed from screening through the final visit as 
indicated in the SoA (Section 2).  The following parameters will be assessed:

Forced expiratory volume in one second (FEV1)

Forced vital capacity (FVC)
Measurements will be made in triplicate and the best recording (i.e. the highest FEV1 and 
the highest FVC) from 3 technically acceptable manoeuvres will be recorded in the CRF. 
To fulfill the entry criteria, FEV1 should be ≥80% of predicted and FEV1/FVC ratio
≥70%) at screening and pre-dose. 
Details on performing the spirometry assessments are provided in the SRM.
 
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9.7.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. 

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study (until the follow-up visit) should be repeated 
until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE), then the results must be recorded in the CRF.
9.7.7.
Faecal Occult Blood Test (FOBT)
Based on the preclinical finding of gastric erosions, FOBT will be performed before and 
after dosing (See Section 2). Details on FOBT are provided in the SRM. 
9.7.8.
Columbia Suicide Severity Rating Scale (C-SSRS)
Based on preclinical studies that have been conducted, GSK2798745 is considered to be a 
central nervous system (CNS)-active drug. There has been some concern that some
CNS-active drugs may be associated with an increased risk of suicidal thinking or
behaviour when given to some patients with certain conditions. Although GSK2798745
has not been shown to be associated with an increased risk of suicidal thinking or
behaviour, GSK considers it important to monitor for such events.
The C-SSRS is a measure of suicidal ideation and behaviour, with demonstrated
predictive validity and reliability. Sections of the C-SSRS include suicidal ideation,
intensity of ideation, suicidal behaviour, and actual suicide attempt(s). The C-SSRS
assesses lifetime and current suicidal thoughts and behaviours across these categories
based on an increasing severity of a 1- to 5-rating scale. The semi-structured
questionnaire is completed by a trained and experienced neurologist, psychiatrist, or
neuropsychologist, or another trained and experienced person approved by the Sponsor, 
who may be the Principal Investigator or a sub-investigator for the study. See SRM for 
details of the scale.
The C-SSRS will be performed at screening and after dosing before discharge (See 
Section 2). 
 
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9.8.
Exploratory biomarkers
Blood and BAL samples for exploratory biomarker analysis of endothelial barrier 
permeability and/or injury and inflammation will be collected at the time points indicated
in the SoA (Section 2). 
Samples may also be used for research to develop methods or support identification of 
prognostic/diagnostic biomarkers associated with clinical outcomes in ARDS and related 
diseases.
Details of sample collection, processing, storage and shipping procedures are provided in 
the SRM.
Exploratory biomarker results may be entered into the clinical study database before or 
after database lock and unblinding, or may be reported separately.
9.9.
Genetics
Genetics are not evaluated in this study.
 
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10.
STATISTICAL CONSIDERATIONS
The primary study objective is to investigate the effect of GSK2798745 relative to 
placebo on BAL total protein at 24 hours after segmental LPS challenge. In this study a 
Bayesian framework will be used (with non-informative priors) to estimate the posterior 
probability of any percentage reduction in mean 24 h post-LPS BAL protein level 
(GSK2798745 relative to placebo). It is anticipated that BAL total protein will be loge
transformed to improve normality before model fitting. Following back-transformation 
treatment comparisons will be expressed as percentage changes.
10.1.
Sample Size Determination
The sample size of 30 participants per arm (1:1 allocation) is based on an upper limit of 
feasibility. Figure 4 illustrates the probability of study success for a range of sample sizes 
and assumed true treatment effects unconditional on variability.
Assuming a true treatment effect of a 30% reduction in mean BAL total protein in 
participants receiving GSK2798745 relative to placebo at 24 h after segmental LPS 
challenge to the lung, the probability of study success for the study is 82% (this excludes 
the possibility of success from a review of secondary data), unconditional on the 
variability of BAL total protein in segmental LPS challenged lungs. Outright end of study 
success is defined as at least a 95% posterior probability that the percentage reduction in 
the mean 24 h post-LPS BAL total protein level (GSK2798745 relative to placebo) 
exceeds zero.
Despite limited historical information for guidance on the true treatment effect for 
GSK2798745, 30% is believed to be a rational estimate.  However, probability of study 
success is sensitive to the true treatment effect – for example, the probability of study 
success reduces to 50% if the true treatment effect is 20% (GSK2798745 relative to 
placebo) with a sample size of 30 per arm but increases to 96% if the true treatment effect 
is 40%.
 
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Figure 4
Probability of Study Success (Unconditional on Variance) for a 
Range of Treatment Profiles and Sample Sizes
Estimates for the mean and variance of BAL total protein in segmental LPS challenged 
lungs were obtained from data in an observational study assessing the variability of the 
inflammatory response to segmental LPS challenge by the Fraunhofer Institute of 
Toxicology and Experimental Medicine, Germany [Holz, 2015] using a random effects 
model with total protein levels from 11 participants measured at baseline and 24 h over 2 
study periods.  The data were assumed to be representative of future segmental-LPS 
challenged lungs to be observed in this study.
The estimate of the mean BAL protein in 24 h post-LPS challenged lungs on the loge
scale is 5.47 (95% CI 5.23, 5.72).  The variance estimate on the loge scale is 0.25 (95% 
CI 0.13, 0.69).  A posterior distribution was formed for the standard deviation and for 
each possible value of standard deviation from this distribution the power of the study 
was calculated and multiplied by its probability.  The resulting values were all summed to 
 
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give probability of study success unconditional on variance, which is a more accurate 
representation of the probability of study success rather than assuming a single variance 
estimate with no uncertainty.
Figure 5 shows the minimum observed treatment effect in the study that would achieve 
success (expressed as a percentage reduction in BAL total protein for GSK2798745 
relative to placebo) for a number of sample sizes. Assuming the variance in the study is 
the median obtained from the historical data, the minimum treatment effect to trigger 
success is 19% for a sample size of 30 participants per arm. As the sample size increases, 
the minimum observed treatment effect that would trigger success decreases due to the 
decreasing standard error (greater confidence in the observed treatment effect). This 
figure gives rationale for including the data review region since it is probable that 
moderate observed treatment effects will not achieve success with a sample size of 30 per 
arm.
Figure 5
Minimum Detectable Effect for Range of Sample Sizes
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF.
Evaluable
All participants for whom results of the primary analysis can be 
determined.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Other populations, such as Per-Protocol population, may be defined in the RAP.
 
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10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The mean percentage reduction in BAL total protein (µg/mL) in segmental 
LPS challenged lungs, at 24 h post-challenge, for GSK2798745 relative to
placebo, will be assessed using an analysis of covariance (ANCOVA) model 
(fitted in a Bayesian framework with non-informative priors for model 
parameters) testing that there is at least 95% posterior probability that the 
percentage reduction in 24 hour post-challenge mean BAL total protein 
(GSK2798745 relative to placebo) exceeds zero , adjusting for baseline BAL 
total protein. A sensitivity analysis will include 24 h BAL total protein in the 
saline segment (saline challenge will be administered to the contralateral 
lobe) as a covariate. Additional factors may be included as covariates if 
deemed appropriate.
Secondary
See Section 10.3.2 and Section 10.3.3
Exploratory
Will be described in the reporting and analysis plan.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
For the safety data, no formal hypotheses will be tested. Safety data such as 
adverse events, electrocardiogram (ECG), physical examinations, vital signs, 
spirometry, FEV1 and FVC will be displayed in the form of listings, frequencies, 
summary statistics and graphs. Interpretation will be aided by clinical expertise. 
Full details, including example outputs, will be documented in the RAP.
10.3.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses
will be presented separately from the main clinical study report (CSR). 
10.3.4.
Interim Analyses
An interim analysis will occur once approximately 10 participants per arm have 
completed the treatment period to assess if the study should stop for futility or continue. 
Subsequently, if the decision at the first interim is to continue, an interim analysis will 
occur once approximately 20 participants per arm have completed the treatment period to 
assess whether the study should continue or stop for success or futility.  If at this point the 
 
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study continues, the maximum 30 participants per arm will be recruited. The study then 
either meets the success criteria, undergoes analysis of secondary data (review) or is 
declared a failure. Enrolment into the study will continue whilst interim analyses are 
taking place.
This interim framework is being used to allow the possibility to reduce the number of 
participants enrolled into the study, either in the case of an overwhelming observed 
treatment effect or no/poor treatment effect. The interim stopping criteria for success is 
based on the probability of the study going on to meet the success criteria (predictive 
probability that the posterior probability is at least 0.95) whilst the stopping criteria for 
futility is based on the probability of the study going on to declare success or review
(predictive probability that the posterior probability is at least 0.75, see Table 2).
Table 2
Interim Decision Criteria
Interim 
Analysis
Success
Futility
10 subjects 
per arm
N/A – cannot stop for success at the 
first interim.
Predictive Prob ( PP ≥ 0.75) ≤ 0.075
20 subjects 
per arm
Predictive Prob (PP ≥ 0.95) ≥ 0.85
Predictive Prob ( PP ≥ 0.75) ≤ 0.15
At each interim, the probability of the study going on to meet these criteria will be 
calculated.  This probability value may be used to assist in determining whether there is 
sufficient rationale to continue/discontinue the study.  If the probability of study success 
is sufficiently high, then the study may stop for success.  Conversely, if the probability of 
study success or review is sufficiently low then the study may stop for futility. The
probability thresholds for success and futility have been calibrated to balance the risk of 
declaring success despite a placebo-like drug (type 1 error) and declaring failure despite a 
positive true underlying treatment effect for GSK2798745 relative to placebo (type 2 
error).
The predictive probability at each interim is calculated using predictive inference 
methods.  The observed data at the interim is used to obtain estimates of the mean and 
standard error of the treatment effect for GSK2798745 relative to placebo.  These 
estimates are then used to predict the treatment effect for participants in the remainder of 
the study using the predictive interim distribution. These two parts of data (observed and 
predicted) are combined to create a complete study. The end of study success criteria is 
then applied to this complete data set made up of observed and predicted participants.  
This process is performed 10,000 times to account for the uncertainty in the estimated 
treatment effect at the interim – i.e. the same observed data is combined with thousands 
of permutations for the remainder of the study, and each time the end of study success 
criteria is applied.  The proportion of complete studies that meet the pre-defined success 
criteria gives the predicted probability of success if the study was to continue at the 
interim.
 
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To inform the study design, a range of scenarios were reviewed to assess the operating 
characteristics when changing the total sample size, interim decision rules, interim 
analysis time points and assumed true treatment effects. Characteristics such as the 
overall probability of study success/failure, probability of success/failure at each interim, 
and the expected number of participants to be recruited were reviewed under a variety of 
design options.
Figure 6 show the operating characteristics of the chosen study design under true 
percentage reductions in total BAL protein for GSK2798745 relative to placebo of 0%, 
15%, 30% and 50%, respectively, unconditional on variability.  The schematic 
demonstrates all possible decision pathways the study may take.  To obtain the operating 
characteristics of a given study design, 10,000 studies were simulated with each one 
taking a particular pathway and finishing in one of the pockets on the left or right of the 
diagram, or indeterminate (additional data review). The overall proportion of simulated 
studies reaching a particular conclusion gives the probability of a single study reaching 
that conclusion.
A stricter posterior probability futility threshold is implemented at the first interim to 
reduce the probability of incorrectly declaring futility. Furthermore, a minimum of 20 
participants per arm must be recruited before declaring success. These rules are shown 
within the left (success) and right (futile) arrows.  Under this design, assuming a true 
treatment effect of 30%, the overall probability of study success is approximately 83%, 
unconditional on variability.  In addition, the probability of requiring a maximum of 20 
participants per arm is approximately 61% (under the same assumption of true treatment 
effect of 30%).  In the case of a placebo-like drug the probability of incorrectly declaring 
success is approximately 6% (akin to type 1 error rate). The blue boxes at the bottom of 
the charts show the probability that a study goes to data review.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
 
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Figure 6
Interim Analysis Framework for Range of True Treatment Effects
 
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11.
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Holter JF, Weiland HE, Pacht ER, Gadek JE. Protein Permeability in the Adult 
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peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4. 
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Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by 
Heart Failure. Pulmonary edema. 2012;4:159ra148. 
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Endothelial Permeability. Microcirculation. 2006;13:693-708. 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
ANCOVA
Analysis of covariance
ARDS
Acute respiratory distress syndrome
AST
Aspartate aminotransferase
AUC
Area under concentration-time curve
AUC0–24
Area under the curve during 24 hours
AUC0–26
Area under the curve during 26 hours
AV
Atrioventricular
BAL
Bronchoalveolar Lavage
BMI
Body mass index
BUN
Blood urea nitrogen
Ca2+
Calcium
Cmax
Maximum observed plasma concentration
CMT2C
Charcot-Marie-Tooth Disease Type 2C
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disorder
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicide Severity Rating Scale
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EU
Endotoxin Unit
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FVC
Forced vital capacity
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GMP
Good Manufacturing Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HCl
Hydrochloric acid
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HMVEC
Human Dermal Microvascular Endothelial Cells
 
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HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IC50
50% maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IMP
Investigational medicinal product
IP
Investigational Product
i.t.
Intratracheal
IRB
Institutional Review Board
IWRS
Interactive Web Response System
Kg
Kilogram
KO
Knockout
LDH
Lactate dehydrogenase
LPS
Lipopolysaccharide
MCH
Mean corpuscular haemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
Msec
Milliseconds
mSV
MilliSievert
Ng
Nanogram
NOAEL
No observed adverse effect level
PK
Pharmacokinetic
POP PK
Population Pharmacokinetic
PTS-DMPK
Platform Technologies and Science-Drug Metabolism and 
Pharmacokinetics
QC
Quality control
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)
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TLR 4
Toll-like receptor 4
Tmax
Time to reach maximum plasma concentration
 
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TRALI
Transfusion Related Acute Lung Injury
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None 
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory. 

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
CRP 
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting 
not required)
Calcium
Alkaline 
phosphatase
CPK
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin (cTn)

Coagulation profile (Quick/INR, PTT and thrombocytes)

Faecal Occult Blood Test (FOBT)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
 
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Laboratory 
Assessments
Parameters
hepatitis C virus antibody)

Alcohol, cotinine and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines).
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 6 All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Substantial amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
 
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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the source document 
agreement (to be signed by the investigator (or delegate) at the site).
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
 
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leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
 
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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor (who is also the SAE coordinator).

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1:

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 4 when having penile-vaginal 
intercourse with a woman of childbearing potential 
 
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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm from the time of 
first dose of study treatment until 2 weeks after last dose of study treatment.
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
 
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Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry increased monitoring criteria and required follow up 
assessments
Liver Chemistry Increased Monitoring Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or haepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 48hrs of last 
dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:
 
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Liver Chemistry Increased Monitoring Criteria 
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: 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 
 
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12.7.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Protocol Amendment 1 02-FEB-2018
Overall Rationale for the Amendment: The primary reason for amending the protocol 
is to update the number of time-points for exploratory biomarkers. The number of blood 
samples for exploratory biomarkers has been reduced.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 2.2 
Treatment Period 
of Schedule of 
Activities 
Removal of time-points (Pre-dose, 
6h, 12h, 14h) for exploratory 
biomarker blood sample. 
No longer required.
Section 3.3.1
Risk Assessment
Vascular lesions:
The following correction was 
made under Summary of 
Data/Rationale for Risk: 
Dogs (1213-week study): At 
10 mg/kg/day, 1 male and 1 
female had arterial lesions.
Error corrected from previous version.
Section 4 
Exploratory 
Objectives and 
Endpoints
The following was added: 
Objective: To possibly assess 
metabolite GSK3526876 (major 
metabolite of GSK2798745) in 
plasma and BAL samples.
Endpoint: Plasma and BAL
concentrations of metabolite 
GSK3526876.
Updated to also include BAL. Amended 
to allow flexibility, depending on the 
availability of an assay. 
Section 5.4 
Scientific 
Rationale for 
study design
The following correction was 
made: Drug on board at the time 
of baseline BAL fluid sampling is 
expected to have little to no effect 
on baseline BAL total protein 
concentrations as TRPV4 
channels are quiescent until 
stimulated and blockade of these 
channels does not affect barrier 
permeability of ‘healthy’ 
endothelial cells [internal data].
Error corrected from previous version.
5.5.2
Treatment Effect 
Rational
Data from a the systemic LPS 
model described in Section 
5.4[Shyamsundar, 2009]
[Dalsgaard, 2016].
Error corrected from previous version.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.2 
Challenge Agents
Removal of wording:
The LPS challenge agent to be 
used for the procedure is Good 
Manufacturing Practice (GMP)-
grade product and will be sourced 
by GSK from List Laboratories, 
Inc.
Wording not required.
Section 7.7.1 
Permitted 
Medications 
The following was added: 
Rescue medication, such as 
salbutamol, is also permitted after 
bronchoscopy or spirometry 
procedure, if required, and other 
medication, such as midazolam, 
may be taken during 
bronchoscopies to aid the 
procedure.
Text added on use of midazolam during 
bronchoscopy as a rescue medication. 
9.4 
Pharmacokinetics
The following changes were 
made:
Plasma and BAL samples will 
also may be analysed for the 
metabolite GSK3526876,
Amended to allow flexibility, depending 
on the availability of an assay. 
 
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GlaxoSmithKline group of companies
207464
1
TITLE PAGE
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of 
GSK2798745 in healthy participants
Protocol Number: 207464 / Amendment 01
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model
Compound Number:
GSK2798745
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):  2017-002388-16
Approval Date: 02-FEB-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 1 (2016N304618_01)
02-FEB-2018
Original Protocol (2016N304618_00)
24-OCT-2017
The original protocol (24-Oct-2017) was published internally only, it was not reviewed
by the competent authority or the research ethics committee.
Protocol Amendment 1 02-FEB-2018
Overall Rationale for the Amendment: The primary reason for amending the protocol 
is to update the number of time-points for exploratory biomarkers. The number of blood 
samples for exploratory biomarkers has been reduced. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 2.2
Treatment Period
of Schedule of 
Activities 
Removal of time-points (Pre-dose, 
6h, 12h, 14h) for exploratory 
biomarker blood sample. 
No longer required.
Section 3.3.1
Risk Assessment
Vascular lesions:
The following correction was 
made under Summary of 
Data/Rationale for Risk: 
Dogs (1213-week study): At 
10 mg/kg/day, 1 male and 1 
female had arterial lesions.
Error corrected from previous version.
Section 4 
Exploratory 
Objectives and 
Endpoints
The following was added:
Objective: To possibly assess 
metabolite GSK3526876 (major 
metabolite of GSK2798745) in 
plasma and BAL samples.
Endpoint: Plasma and BAL
concentrations of metabolite 
GSK3526876.
Updated to also include BAL. Amended 
to allow flexibility, depending on the 
availability of an assay. 
Section 5.4 
Scientific 
Rationale for 
study design
The following correction was 
made: Drug on board at the time 
of baseline BAL fluid sampling is 
expected to have little to no effect 
on baseline BAL total protein 
concentrations as TRPV4 
channels are quiescent until 
stimulated and blockade of these 
channels does not affect barrier 
permeability of ‘healthy’ 
endothelial cells [internal data].
Error corrected from previous version.
5.5.2
Treatment Effect 
Rational
Data from a the systemic LPS 
model described in Section 
5.4[Shyamsundar, 2009]
[Dalsgaard, 2016].
Error corrected from previous version.
Section 7.2 
Challenge Agents
Removal of wording:
The LPS challenge agent to be 
used for the procedure is Good 
Wording not required.
 
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Section # and 
Name
Description of Change
Brief Rationale
Manufacturing Practice (GMP)-
grade product and will be sourced 
by GSK from List Laboratories, 
Inc.
Section 7.7.1 
Permitted 
Medications 
The following was added: 
Rescue medication, such as 
salbutamol, is also permitted after 
bronchoscopy or spirometry 
procedure, if required, and other 
medication, such as midazolam, 
may be taken during 
bronchoscopies to aid the 
procedure.
Text added on use of midazolam during 
bronchoscopy as a rescue medication. 
9.4 
Pharmacokinetics
The following changes were
made:
Plasma and BAL samples will 
also may be analysed for the 
metabolite GSK3526876,
Amended to allow flexibility, depending 
on the availability of an assay. 
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................12
2.1.
Screening ...................................................................................................13
2.2.
Treatment period ........................................................................................14
2.3.
Follow-up/Early Withdrawal ........................................................................16
3.
INTRODUCTION....................................................................................................17
3.1.
Study Rationale ..........................................................................................17
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................19
3.3.2.
Benefit Assessment.....................................................................27
3.3.3.
Overall Benefit:Risk Conclusion...................................................27
4.
OBJECTIVES AND ENDPOINTS...........................................................................27
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................29
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
5.5.1.
Dose Rationale ............................................................................31
5.5.2.
Treatment Effect Rationale ..........................................................33
6.
STUDY POPULATION...........................................................................................33
6.1.
Inclusion Criteria.........................................................................................33
6.2.
Exclusion Criteria........................................................................................34
6.3.
Lifestyle Restrictions...................................................................................36
6.3.1.
Meals and Dietary Restrictions ....................................................36
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................36
6.3.3.
Activity .........................................................................................37
6.4.
Screen Failures...........................................................................................37
7.
TREATMENTS.......................................................................................................37
7.1.
Treatments Administered............................................................................38
7.1.1.
Dose Modification ........................................................................39
7.2.
Challenge Agents .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................39
7.4.
Blinding.......................................................................................................40
7.5.
Preparation/Handling/Storage/Accountability..............................................40
7.6.
Treatment Compliance................................................................................41
7.7.
Concomitant Therapy..................................................................................41
7.7.1.
Permitted Medications .................................................................41
 
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7.7.2.
Prohibited Medications.................................................................41
7.8.
Treatment after the End of the Study ..........................................................42
8.
DISCONTINUATION CRITERIA.............................................................................42
8.1.
Individual Stopping Criteria .........................................................................42
8.1.1.
Liver Chemistry Stopping Criteria ................................................42
8.1.2.
QTc Stopping Criteria ..................................................................42
8.1.3.
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria........................................42
8.1.3.1.
Asymptomatic Participant ...........................................42
8.1.3.2.
Symptomatic Participant.............................................42
8.1.4.
Bronchoscopy Stopping Criteria...................................................43
8.2.
Withdrawal from the Study..........................................................................43
8.3.
Study Stopping Criteria...............................................................................43
8.4.
Lost to Follow Up........................................................................................43
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
9.1.
Bronchoscopy.............................................................................................44
9.2.
Segmental lung challenge...........................................................................45
9.3.
Pharmacodynamic Assessments ................................................................45
9.4.
Pharmacokinetics .......................................................................................45
9.5.
Adverse Events...........................................................................................45
9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................46
9.5.2.
Method of Detecting AEs and SAEs.............................................46
9.5.3.
Follow-up of AEs and SAEs.........................................................46
9.5.4.
Regulatory Reporting Requirements for SAEs .............................47
9.6.
Treatment of Overdose...............................................................................47
9.7.
Safety Assessments ...................................................................................48
9.7.1.
Physical Examinations.................................................................48
9.7.2.
Vital Signs....................................................................................48
9.7.3.
Pulse Oximetry ............................................................................48
9.7.4.
Electrocardiograms......................................................................48
9.7.5.
Spirometry ...................................................................................48
9.7.6.
Clinical Safety Laboratory Assessments ......................................49
9.7.7.
Faecal Occult Blood Test (FOBT) ................................................49
9.7.8.
Columbia Suicide Severity Rating Scale (C-SSRS) .....................49
9.8.
Exploratory biomarkers...............................................................................50
9.9.
Genetics .....................................................................................................50
10. STATISTICAL CONSIDERATIONS........................................................................50
10.1.
Sample Size Determination ........................................................................50
10.2.
Populations for Analyses ............................................................................52
10.3.
Statistical Analyses.....................................................................................53
10.3.1.
Efficacy Analyses.........................................................................53
10.3.2.
Safety Analyses...........................................................................53
10.3.3.
Other Analyses ............................................................................54
10.3.4.
Interim Analyses ..........................................................................54
11. REFERENCES.......................................................................................................57
 
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12. APPENDICES........................................................................................................60
12.1.
Appendix 1: Abbreviations and Trademarks................................................60
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................63
12.3.
Appendix 3: Study Governance Considerations..........................................65
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................69
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................74
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................77
12.7.
Appendix 7: Protocol Amendment History...................................................79
 
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1.
SYNOPSIS
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of GSK2798745 in 
healthy participants
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model
Rationale:  
The influx of protein-rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function, is a fundamental underlying 
defect in Acute Respiratory Distress Syndrome (ARDS).  In this Phase 1,
proof-of-mechanism study, a segmental lipopolysaccharide (LPS) challenge will be used 
as a surrogate injury model to investigate the effects of Transient receptor potential 
vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man.  
The LPS model has been widely used for the evaluation of anti-inflammatory agents, and 
will aid in the characterization of TRPV4 blockade on lung permeability and 
inflammation. It is hypothesised that TRPV4 inhibitors modulate the LPS response by 
reducing LPS induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4)
mediated activation of endothelial cells] or indirectly [e.g. autocrine cytokine 
activation]).  The assessment of TRPV4 mediated effects on LPS induced lung barrier 
damage in healthy volunteers is considered a viable strategy before conducting studies in 
an ARDS patient population.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To investigate the effect of 
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers.

Baseline adjusted total protein 
concentration in 
bronchoalveolar lavage (BAL) 
samples at 24 h after segmental LPS 
challenge.
Secondary

To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs.

Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge.
 
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Objectives
Endpoints

To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers.

Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry
(forced expiratory volume in 
1 second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood
test (FOBT).

To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers 

PK parameters of GSK2798745 in 
plasma (AUC (0-24) and Cmax).
Overall Design:
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.  
Participants will be randomised 1:1 to take 2 single doses (3 tablets total):  either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later. The first dose will be administered on Day 1 at 2 h before 
baseline BAL sampling from a segment in the left lower lobe.  4 ng/kg LPS will 
subsequently be instilled into the right middle segment and saline control into the lingula 
segment of the contralateral side.  The second dose of study treatment will be 
administered 10 hours after LPS challenge followed by post-dose BAL sampling on 
Day 2.  A schematic of the study is provided in Figure 1.
Figure 1
Study schematic
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic.
 
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Number of Participants:
Sufficient participants will be screened to ensure that a maximum of 60 evaluable 
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted, to assess the difference, if any, between treatments in 
the primary endpoint. Recruitment can continue whilst interim analyses are conducted.
Depending on the results of the interim analyses, recruitment may be stopped.  
Treatment Groups and Duration:
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2). Participants will receive a 
follow up phone call 2 days after discharge, and return to the study site on Day 8 
(1 day) for a follow-up visit.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamics and exploratory biomarker assessments 
may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The IRB/IEC will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the informed consent form (ICF).
 
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2.1.
Screening
Screening 
(Days –28 to –2)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination 
X
Height and weight
X
Medical history 
X
Past and current medical conditions  
X
HIV, Hepatitis B and C screening
X
FSH and oestradiol1
X
Drug, alcohol and cotinine screen
X
C-SSRS
X
Laboratory assessments2
X
12-lead ECG3
X
Vital signs4
X
Spirometry5
X
FOBT6
X
C-SSRS:  Columbia Suicide Severity Rating Scale; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; HIV:  human immunodeficiency virus.
1.
Postmenopausal females whose postmenopausal status is in doubt only.
2.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile. 
3.
In triplicate.
4.
Blood pressure and heart rate in triplicate.  Single temperature measurement.
5.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form.
6.
May be measured during the screening window or on Day –1.  FOBT cards will be provided at screening and must be returned to the laboratory and analysed before dosing.
 
 
 
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2.2.
Treatment period
Day –12
Day 11
Day 21
Pre-
dose
0 h
1 h
2 h
3 h
6 h
8 h
12 h
14 h
25.5 h
26 h
30 h
Day 4
Inpatient stay2
===============================================================
Telephone call3
X
Drug, alcohol and cotinine screen
X
Laboratory assessments4
X
X
12-lead ECG5
X
X
X
Blood pressure and heart rate5
X
X
X
X
X
X
X
Temperature6
X
X
X
X
X
X
X
X
X
Spirometry7
X
X
X
X
X
C-SSRS
X
Randomisation
X
Study treatment
X
X
Pulse oximetry8
X
X
Bronchoscopy, baseline BAL and
challenge9
X
Bronchoscopy and post-challenge 
BAL10
X
Blood sample for exploratory 
biomarkers11
X11
X
X
X11
Blood sample for PK
See footnote 12
AE review
========================================================================
SAE review
=================================================================================
Concomitant medication review
=================================================================================
AE:  adverse event; BAL:  bronchoalveolar lavage; ECG:  electrocardiogram; PK:  pharmacokinetic; SAE:  serious adverse event, C-SSRS:  Columbia Suicide Severity Rating Scale.
1.
Time points relative to the first dose on Day 1.
2.
Admission on Day –1, at a time to allow all Day –1 procedures to be done; discharge on Day 2, at least 4 h after the bronchoscopy.
 
 
 
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3.
To check for any AEs.
4.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile. 
5.
Triplicate on Day-1 and pre-dose. Single measurements at time points after dosing. 
6.
Immediately before BAL sampling/LPS challenge at the 2-h time point.
7.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurements at each time point, the highest of which should be recorded in the case 
report form.
8.
Pulse oximetry to be measured during bronchoscopy procedures. Only AEs to be recorded. 
9.
BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers. Baseline BAL sample from a segment in the left lower lobe, followed by segmental 
challenge of the lungs:  LPS in right middle segment; saline control in the lingula segment of the contralateral side.  Challenges to be done as close as possible to 2 h post-dose.   
10. BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers.  Baseline and post-dose measurements to be done by the same person, where 
possible.
11. Blood samples for exploratory biomarkers. The 2- and 26-h blood samples should be taken immediately before BAL sampling.
12. PK samples will be taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 h after the first dose.  The 2- and 26-h blood sample should be taken 
immediately before BAL sampling
 
 
 
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2.3.
Follow-up/Early Withdrawal
Follow-up/Early Withdrawal
(Day 8 [1 day])
Outpatient visit
X
Full physical examination 
X
Weight
X
Laboratory assessments1
X
12-lead ECG2
X
Vital signs3
X
Spirometry4
X
FOBT5
X
AE review
X
SAE review
X
Concomitant medication review
X
AE:  adverse event; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; SAE: serious adverse event.
1.
Haematology, clinical chemistry (including liver chemistry), cardiac troponins and urinalysis.
2.
Single measurement.
3.
Blood pressure, heart rate, temperature.  Single measurement.
4.
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form.
5.
FOBT cards will be provided upon discharge from the unit and should be returned by the follow-up/early withdrawal visit. 
 
 
 
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3.
INTRODUCTION
GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) 
channel blocker being investigated for the treatment of acute respiratory distress 
syndrome (ARDS). TRPV4 blockade is expected to ameliorate the injury inflicted to the 
alveolar capillary barrier in ARDS patients and reduce the leakage of protein and fluid 
into the alveolar space. Studies investigating administration of GSK2798745 have been 
conducted in healthy volunteers and in patients with chronic heart failure.
GSK2798745 has been administered orally to healthy participants as single doses ranging 
from 0.25 to 12.5 mg. A dosage of 5 mg once daily has been administered for up to 
14 days in healthy participants.  Further, GSK2798745 at a dose of 2.4 mg has been 
evaluated as a single dose and subsequently as repeated doses for 7 days in participants 
with heart failure.
No clinically significant safety concerns were observed with single or repeat 
administration of GSK2798745 in either healthy volunteers or participants with heart 
failure. 
3.1.
Study Rationale
The influx of protein rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function is a fundamental underlying 
defect in ARDS. In this Phase 1 proof of mechanism study, a segmental
lipopolysaccharide (LPS) challenge will be used as a surrogate injury model to 
investigate the effects of TRPV4 channel blockade on alveolar-septal barrier permeability 
in man. The LPS model has been widely used for the evaluation of anti-inflammatory 
agents [Zielen, 2015], and will aid in the characterization of TRPV4 blockade on lung 
permeability and inflammation. 
Segmental LPS challenge, in which a small quantity of the endotoxin, LPS, is 
administered directly to one segment of the lung, is a model of focal and self-limiting 
lung inflammation.  LPS induces pulmonary endothelial cell permeability [Fu, 2009] via 
calcium dependent cytoskeleton rearrangement [Bannerman, 1998; Gandhirajan, 2013]. 
LPS may also directly act on endothelial cells to cause permeability by degrading 
intercellular junctions [Bannerman, 1998].  The upregulation of a pro-inflammatory 
signalling cascade via NF-kB leading to endothelial activation and pro-inflammatory 
mediator release [Bosmann, 2012] may be regulated by the influx of calcium
[Kandasamy, 2013], and may also induce further calcium influx and endothelial 
permeability [Lush, 2000; Tiruppathi, 2006].  
Under normal conditions, concentrations of total protein in alveolar fluid are low. LPS 
induced endothelial damage leads to accumulation of protein rich fluid into the lung due 
to the migration of large molecules, such as albumin, from blood to the alveolar space. 
Preclinical and clinical studies have shown a positive correlation between amount of 
protein the bronchoalveolar lavage and extent of lung damage [Holter, 1986; Moazed, 
2016; Yu, 2015]. In the lung, TRPV4, a Ca2+-permeable non-selective cation channel, is 
widely expressed in cells involved in ARDS, namely microvascular endothelium, 
 
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alveolar epithelium, alveolar macrophages, and circulating neutrophils and monocytes,
and is a known regulator of endothelial permeability [Narita, 2015; Suresh, 2015; 
Huh, 2012] and pulmonary oedema [Balakrishna, 2014; Hamanaka, 2007]. Therefore,
TRPV4 may play an important role in LPS-induced alveolar permeability.  The relevance 
of the TRPV4 channel to LPS induced injury has been confirmed in a mouse sepsis 
model. In this severe injury model, administration of a TRPV4 inhibitor 1 h prior to LPS 
injection (i.p.) increased survival by 70%.  Although this study was not specifically 
designed to evaluate bronchoalveolar lavage (BAL) protein levels, total protein 
concentrations in BAL fluid of mice pre-treated with a TRPV4 inhibitor were reduced by 
approximately 20% after the LPS challenge in TRPV4 treated mice compared with 
controls [Dalsgaard, 2016].  
It is hypothesised that TRPV4 inhibitors modulate the LPS response by reducing LPS 
induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4) mediated 
activation of endothelial cells] or indirectly [e.g. autocrine cytokine activation]).
Given the link to ARDS of endothelial damage and fluid leak, assessment of TRPV4 
mediated effects on LPS induced lung barrier damage in healthy volunteers is important 
to establish whether beneficial effects may be observed in an ARDS patient population.  
3.2.
Background
ARDS is an acute inflammatory lung injury, associated with increased pulmonary 
vascular permeability, increased lung weight, and loss of aerated lung tissue [Bellani,
2016]. Treatment options remain limited to supportive care including mechanical 
ventilation and ARDS represents a significant unmet need accounting for over 10% of 
intensive care unit (ICU) admissions and a mortality rate of up to 40% [Bellani, 2016; 
Matthay, 2012].  The syndrome is characterised by acute hypoxemic respiratory failure 
and non-cardiogenic pulmonary oedema and may be precipitated by direct (e.g. 
pneumonia and aspiration) and indirect insults (e.g. sepsis and transfusion related acute 
lung injury ([TRALI]) to the lung. Dysregulated inflammation, inappropriate 
accumulation and activity of leukocytes and platelets, uncontrolled activation of 
coagulation pathways, and altered permeability of alveolar endothelial and epithelial 
barriers are central to the pathophysiology of ARDS [Matthay, 2012]. Damage to the 
alveolar-capillary membrane leads to increased vascular permeability, and the 
development of interstitial and alveolar protein rich oedema, leading to reduced gas 
exchange, ventilation perfusion mismatching and arterial hypoxaemia. 
TRPV4 has been implicated as a key regulator of lung endothelial barrier integrity, and 
specifically, the integrity of the lung alveolar-capillary endothelium, which is most 
relevant to alveolar flooding associated with acute lung injury. TRPV4 activation by 
hydrostatic stretch in lung microvessels leads to increased endothelial Ca2+ concentration 
and a diverse set of vascular responses, including an increase in endothelial permeability 
[Morty, 2014]. The importance of TRPV4 in maintaining pulmonary barrier function has 
been demonstrated in the settings of elevated pulmonary venous [Thorneloe, 2012] or 
airway pressure [Hamanaka, 2007], and following treatment with chemical and biological 
toxins such as Hydrochloric acid (HCl) and platelet activating factor [Balakrishna, 2014; 
Morty, 2014; Yin, 2016] . In these studies, TRPV4 blockade limited lung damage by 
 
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reducing plasma fluid leak into the alveolar space (thus increasing arterial oxygenation), 
and by modulating neutrophil and macrophage recruitment and activity and reducing 
overall mortality in response to LPS [Balakrishna, 2014; Morty, 2014; Yin, 2016; 
Dalsgaard, 2016].  This evidence suggests TRPV4 channel blockade may benefit patients 
with ARDS where alveolar capillary leak is a primary driver of injury, by reducing fluid 
leak, reducing ventilation perfusion mismatching, improving oxygenation and reducing
the need for mechanical ventilation with potential reductions in mortality.
3.3.
Benefit/Risk Assessment
3.3.1.
Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2798745 may be found in the Investigator’s 
Brochure.
All potential risks of GSK2798745 are based on pre-clinical data. No risks have been 
identified in the clinical studies of GSK2798745 conducted before the effective date of 
this protocol.
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2798745]
Vascular lesions
Dogs (4-week study): at 30 mg/kg/day, 2 males had arterial 
lesions
One male: Heart – Coronary artery inflammation; Thymus 
– Arteriole inflammation with fibroplasia 
One male: Epididymides – Artery degeneration/necrosis 
with inflammation
Dogs (13-week study): At 10 mg/kg/day, 1 male and 1 female 
had arterial lesions
One male: Epididymides – Arteriole degeneration/necrosis 
with lymphocytic inflammation
One female: Bladder – Arteriole degeneration/necrosis 
with lymphocytic inflammation
Participant Monitoring: The arterial lesions noted in heart, 
thymus, epididymides, and urinary bladder cannot be 
monitored directly. There is currently no human translation 
biomarker or understanding of the underlying mechanism.
Participant Exposure: Since these effects cannot be 
monitored directly in clinical studies, coverage of ≥30 fold will 
be maintained from the no-effect dose (3 mg/kg/day); 
exposure will not intentionally exceed the average daily area 
under concentration-time curve (AUC) of 0.513 hr*µg/mL 
and/or maximum observed plasma concentration (Cmax) of 
0.050 µg/mL on an individual basis.
Myocardial toxicity
Dogs (4-week study): at 30 mg/kg/day, myofibre
degeneration/necrosis and inflammation (2 animals)
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment,
including relevant history of acute coronary syndromes 
(including unstable angina), coronary angioplasty, or stenting,
will be excluded.
Participant Monitoring: Cardiac troponin levels will be 
monitored and ECGs will be done during the study.
Participant Exposure: Exposure levels will be maintained 
below the threshold detailed in the Dose Justification Section 
(see Section 5.5).
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Mortality/moribund 
condition; poor viability
Dogs (4-week study): at 30 mg/kg/day, one male terminated 
early (Day 6) due to poor clinical condition. Another male had 
transient whole body shaking on Days 8 and 9.
Dogs (13-week study): at 10 mg/kg/day one male was 
terminated early (Day 74) due to welfare reasons.
Rats (micronucleus and comet study): mortality occurred 
following 1 to 3 doses at ≥600mg/kg/day
Participant Monitoring: Weight and adverse events reported 
by participants will be monitored.
Gastrointestinal (GI) 
and/or hepatic toxicity
GI toxicity: ≥3 mg/kg/day in dogs and at 30 and 300 
mg/kg/day in rats, consisting of mucosal erosion/ulceration in 
the stomach and/or duodenum.
Hepatic Toxicity: Biliary epithelial hypertrophy/hyperplasia 
and periductal mixed inflammatory cell infiltrate into the liver 
was observed at 300 mg/kg/day in rat (7-day study) and focal 
hepatocellular degeneration in 1 male dog at 30 mg/kg/day 
(4-week study)
Participant Selection: Participants with active ulcer disease or 
GI bleeding or those who are taking concomitant medications, 
including nonsteroidal anti-inflammatory drugs (NSAIDs) and 
steroids, will be excluded. Assessment of faecal occult blood 
will be performed before and after dosing.
Participant Monitoring: Participants will be monitored for GI 
intolerance (e.g by adverse events such as abdominal 
discomfort) and sequential clinical chemistry analysis, 
including liver enzymes. Follow-up faecal occult blood test
(FOBT) will be conducted.
Testicular toxicity
Inconsistent finding in rats (4-week study): Spermatid 
retention at ≥60 mg/kg/day, however no effect observed in 
13-week study. The observations in the 4-week study were 
not associated with degenerative changes in testes or 
epididymides.
No spermatogenic abnormalities were observed in dogs.
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats.
Skeletal muscle toxicity
Rat (4-week study): Myofiber necrosis: myofiber 
degeneration/regeneration; fibroplasia, at 300 mg/kg/day in 
the soleus muscle.
Participant Monitoring: Creatinine phosphokinase (CPK) 
levels will be taken before and after dosing. 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Seizures and 
convulsions
Rats (micronucleus and comet study): convulsions observed 
at ≥600 mg/kg/day. Convulsions were not related to Cmax, 
nor occurred at any predictable time from dose administration.
Dogs: No central nervous system (CNS) findings at 
12 mg/kg/day in the dog 7-day EEG/CV study. In other 
compounds in the same series, convulsions have been 
observed.
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment,
including a history of seizure disorder or stroke within the last 
5 years will be excluded from the study. 
Low food consumption 
Dogs (4-week study): 30 mg/kg/day reduced food 
consumption. Two males were terminated early (Day 10) due 
to extremely reduced food consumption.
Rats (4-week study): 300 mg/kg/day had decreased food 
consumption.
Participant Monitoring: Weight will be monitored.
Effects on 
macrophages 
(Phospholipid 
accumulation)
Inconsistent effects observed in Rats (4-week study):
60 mg/kg/day in the lung (prominent alveolar macrophages); 
300 mg/kg/day in the mesenteric lymph node (increased 
cellularity of sinus macrophages) and thymus (macrophage 
vacuolation; increased thymus weight). Consistent with 
phospholipid accumulation (phospholipidosis) based on 
ultrastructural appearance of mesenteric lymph nodes at 
300 mg/kg/day. Findings were not associated with 
degenerative changes. In 13-week studies in rats, these 
effects were not observed.
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Theoretical Risk:
Potential effects on 
vasoregulation .
TRPV4 mediates prostaglandin release from isolated human 
endothelial cells and in vivo in rats, supporting the potential 
for TRPV4 blockade to modulate blood pressure via 
prostaglandin release. No effect of GSK2798745 on blood 
pressure was observed in preclinical or clinical studies. 
Participant Monitoring: Blood pressure will be monitored 
throughout the study.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Theoretical Risk:
Potential effect on 
hearing.
Genetic deletion of TRPV4 in mice has been shown to effect 
hearing. TRPV4 knockout (KO) mice at age 8 weeks 
exhibited normal hearing thresholds, but at age 24 weeks, 
had delayed-onset hearing loss; additionally, the cochlea was 
found to be vulnerable to acoustic injury with sound 
overexposure [Tabuchi, 2005]. Patients with Charcot-Marie-
Tooth Disease Type 2C (CMT2C), an autosomal dominant 
axonal neuropathy related to TRPV4 gene mutations, 
demonstrate symptoms that include hearing loss caused by 
nerve damage in the inner ear (sensorineural hearing loss).
These are predominantly gain of function TRPV4 
abnormalities, in which the hearing loss is sporadic among 
family members; and relegated to some TRPV4 defects, but 
not in others. Although the exact mechanism is unclear, it 
has been suggested that the TRPV4 channel plays an 
important role in peripheral nerve function and that the 
alterations in TRPV4 in CMT2C may be due to increased 
channel activity leading to excessive calcium influx and a 
calcium overload. There is potential for benefit with 
GSK2798745, in that with cells (HEK293) expressing the 
CMT2C mutant channel, inhibitors of the TRPV4 channel 
were found to block the increased intracellular calcium 
concentrations and resultant cell death [Landouré, 2010]. In a 
study evaluating effects on heart failure with similar dosing 
exposure, a week-long duration and comprising an older 
participant demographic, audiometry testing was conducted. 
Although a variety of changes were observed, primarily 
sporadic, low frequency and single frequency changes in 
those on treatment as well as placebo, none were assessed 
as a signal for concern by the reviewing expert audiologist.
Participant Exposure: Dosing will be limited to a short duration 
of a single day. 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Theoretical risk:  
Potential suicidal 
ideation
GSK2798745 is considered to be a CNS-active drug. There 
has been some concern that some CNS-active drugs may be 
associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with certain 
conditions. GSK considers it important to monitor for such 
events before or during clinical studies with CNS-active 
compounds.  Participants being treated with GSK2798745 
should be assessed at screening for suicidality.
Participant Selection: The risk of such an event would be very 
low in single-day dose trials in healthy volunteers; however,
participants who, in the investigator/designee's judgement, 
poses a significant suicide risk, will be excluded from the 
study.  A C-SSRS questionnaire will be completed before and 
after dosing. 
Study procedures-related
Risk of adverse events 
following delivery of 
LPS
Previously reported segmental LPS related adverse events 
include pleuritic pain, pyrexia, head ache, nausea and 
alveolitis [Hohlfeld, 2008; Holz, 2015]. 
It is known that LPS and pro-inflammatory mediators can 
cause gut permeability [Al-Sadi, 2014; Guo, 2013].  We 
expect the systemic exposure to LPS and systemic 
inflammatory response to LPS to be minimal following the 
segmental topical dose of 4ng/kg LPS.  As such, we assess 
the risk to increased gut permeability, and potential increased 
bioavailability, with this regimen to be low.
Participant Monitoring: Participants will be monitored with 
safety assessments, including clinical laboratory tests, 
physical examination, ECGs, vital signs (including 
temperature), pulse oximetry and spirometry during the study.
Experienced site staff will conduct the procedures. 
Participants will be carefully monitored and managed with 
standard procedures in the event of complications.
Risks associated with 
bronchoscopy and BAL 
sampling:
Procedure related complications include cough, transient 
fever, chills and myalgias, transient infiltrates, bronchospasm, 
transient fall of lung function, transient decrease in baseline 
PaO2 (partial pressure of oxygen in arterial blood).
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Risk associated with 
blood draws
Fainting, mild pain, bruising, irritation or redness.
Experienced site staff will follow standard approaches for 
managing events related to blood draws.
Risks associated with 
spirometry
Shortness of breath, coughing, light-headedness or fainting, 
and/or chest tightness may be induced by spirometry testing.
Participants experiencing any of these symptoms will receive 
standard medical treatment by the study investigator.
 
 
 
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3.3.2.
Benefit Assessment
There will be no intended therapeutic clinical benefit to the participants taking part in the 
study as it is a healthy volunteer study. However, participants will undergo a medical 
evaluation during screening including physical exams, electrocardiograms (ECGs) and 
laboratory assessments which may provide important health information.
By taking part in this study, the participant will be contributing to the development of 
GSK2798745 for the treatment of ARDS, a syndrome with significant unmet need.
3.3.3.
Overall Benefit:Risk Conclusion
No benefit to healthy participants is expected. The study activities have risks, however 
these risks are mitigated by: exclusion of participants with identified comorbidities; short 
(single day) duration of dosing with GSK2798745; exposure limited to previously 
approved exposure levels; and inclusion of safety margins, as well as safety monitoring 
by trained staff. The study will provide important information towards future 
development of TRPV4 blockers that may help patients with ARDS.
The design of the study is considered low risk to the participants and justified based on 
the safety information from the nonclinical studies and the previous clinical trials carried 
out on GSK2798745.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To investigate the effect of
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers.

Baseline adjusted total protein 
concentration in bronchoalveolar 
lavage (BAL) samples at 24 h after 
segmental LPS challenge.
Secondary

To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs.

Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge.

To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers.

Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry 
(forced expiratory volume in 1 
second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood
test (FOBT).
 
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Objectives
Endpoints

To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers 

PK parameters of GSK2798745 in 
plasma (AUC (0-24) and Cmax).
Exploratory

To assess concentration of 
GSK2798745 in BAL.

Levels of GSK2798745 in BAL 
samples at 2 and 26 h after dosing.

To investigate the effect of 
GSK2798745 on exploratory 
markers of endothelial barrier 
permeability and/or injury, and
inflammation, in LPS-challenged 
lungs.

Baseline adjusted levels of 
exploratory biomarkers in blood 
and/or BAL.

To possibly assess metabolite 
GSK3526876 (major metabolite of 
GSK2798745) in plasma and BAL 
samples.

Plasma and BAL concentrations of 
metabolite GSK3526876.

To compare the PK of GSK2798745 
with the effect of prophylactic 
dosing on alveolar-septal barrier 
permeability following LPS 
challenge in healthy volunteers.

To investigate the effect of 
GSK2798745 on white blood cell 
levels (except neutrophils) in 
LPS-challenged lungs.

Comparison of PK parameters of 
GSK2798745 in plasma with 
baseline corrected total protein 
concentration in BAL.

Baseline adjusted total and 
differential cell count of white blood 
cells (except neutrophils) in BAL 
samples at 24 h after segmental LPS 
challenge.
5.
STUDY DESIGN
5.1.
Overall Design
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.  
Participants will be randomised 1:1 to take 2 single doses (3 tablets total): either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later. Participants will undergo segmental LPS challenge to the 
lungs at 2 h after the first dose.  BAL samples will be taken after dosing:  immediately 
before and at 24 h after the LPS and saline challenge.  Blood samples will be taken before 
and after dosing and the challenge.  Safety will be monitored throughout.  A schematic of 
the study is provided in Figure 2.
 
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Figure 2
Study schematic
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic.
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2).  The first dose will be 
administered on Day 1 at 2 h before baseline BAL sampling from a segment in the left 
lower lobe. 4 ng/kg LPS will subsequently be instilled into the right middle segment and
saline control into the lingula segment of the contralateral side. The second dose of study 
treatment will be administered 10 hours after LPS challenge followed by post-dose BAL 
sampling on Day 2. Participants will receive a follow up phone call 2 days after 
discharge, and return to the study site on Day 8 (1 day) for a follow-up visit.
5.2.
Number of Participants
Sufficient healthy participants will be screened to ensure that a maximum of 60 evaluable
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted (as described in Section 10.3.4), to assess the 
difference, if any, between treatments in the primary endpoint.  There are two interim 
analyses planned, depending on the results of the interim analyses, recruitment may be 
stopped.  Participants who prematurely discontinue the study, and whose data are not 
evaluable (i.e. those for whom results of the primary analysis cannot be determined), may 
be replaced. Recruitment into the study can continue whilst interim analyses are taking 
place. 
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design

Use of a placebo:  The randomised, placebo-controlled study design is a 
well-established methodology to evaluate potential treatment effects in experimental 
studies. The use of a placebo arm allows for a valid evaluation of changes in PD 
markers attributable to treatment versus those independent of treatment.  Given that 
participants are healthy and treatment is not being withheld, the use of placebo is 
considered acceptable.

Parallel group:  The use of a parallel group design is considered to limit the burden 
of procedures and exposure of LPS to participants. A crossover design only 
minimally decreases the required number of evaluable participants and owing to the 
expected dropout rate in a crossover study, and the burden of procedures for each 
participant, a parallel group design was selected.

Blinding:  A double blind design is a standard methodology for randomised, 
controlled studies to avoid bias. 

Selection of primary endpoint:  Changes in total protein concentrations to monitor 
influx of proteinaceous fluid into the lung has been used in several LPS challenge 
studies. Evidence points to the involvement of TRPV4 in changes to alveolar 
capillary barrier following LPS administration, with subsequent leak of proteinaceous 
fluid as measured by total protein. Given the influx of fluid with high concentrations 
of protein observed in ARDS patients, monitoring total protein changes is considered
an acceptable surrogate to assess for target engagement of GSK2798745 and for 
potential effects in ARDS patients. 

Timing of primary endpoint:  As previous studies show that total protein 
concentrations peak at 24 h after segmental LPS challenge [O’Grady, 2001; 
Holz, 2015], post-challenge BAL samples will be taken at 24 h after the challenge. 

Timing of challenge:  Baseline BAL sampling prior to administration of study drug is 
not considered feasible due to the burden of bronchoscopy (i.e. two procedures 
required – one pre and one post dose to instil LPS). A baseline bronchoscopy is 
planned 2 h after administration of the first dose, with the aim of maximising 
exposure to GSK2798745 (in healthy volunteers, the median [range] Time to reach 
maximum plasma concentration (Tmax) of the tablet formulation of GSK2798745 to 
be used in this study is 1.5 h [1–3 h]). Drug on board at the time of baseline BAL 
fluid sampling is expected to have little to no effect on baseline BAL total protein 
concentrations as TRPV4 channels are quiescent until stimulated and blockade of 
these channels does not affect barrier permeability of ‘healthy’ endothelial cells 
[internal data].  The effects of LPS to induce endothelial permeability are believed to 
occur rapidly.  Investigation of LPS induced permeability and markers of cell 
activation and inflammation over time consistently indicates that the initial events 
leading to increased barrier permeability and inflammation occur within first 2 h post 
 
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intratracheal (i.t.) LPS exposure; where any earlier measurements are limited. LPS 
induces intracellular stress fibre formation within 5 min in both human dermal 
microvascular endothelial cells (HMVEC) endothelial and A549 epithelial cells 
[Ngamsri, 2010].  Increased levels of TNFα following i.t. LPS instillation are 
observed within 2 h in man [O’Grady, 2001] and other pro-inflammatory mediators 
within 4 h in a mouse model of acute lung injury (ALI) [Bosmann, 2012].  
Permeability across an endothelial monolayer is observed after 0.5 h and peaks at 2 h 
post-LPS [Bannerman, 1998].  BAL total protein increases following LPS i.t. 
challenge in man as early as 2 h and reaches significance at 6 h post-LPS [Matthay
, 2012] with significant increases in neutrophil counts also observed as early as 2 h.  
Looking to a systemic LPS model of sepsis with a higher LPS insult, earlier sampling 
is possible and high levels of inflammatory mediators are measured within 1 h, which 
reach plateau by 3 h. Therefore, despite our conservative treatment effect prediction 
(see Section 5.5), we expect that high plasma and/or alveolar fluid concentrations of 
GSK2798745 will be required at the time of and/or soon after the challenge, in order 
to inhibit the effects of LPS. Therefore, LPS will be administered shortly after time of 
Tmax (1.5-hours) to ensure sufficient drug on board. 
5.5.
Dose Justification
5.5.1.
Dose Rationale
The first time in human study (TR4113787) for GSK2798745 evaluated doses from 
0.25 mg to 12.5 mg as single doses, and 5 mg once daily repeat dosing for 14 days in 
healthy volunteers in cohorts 1–3.  Cohorts 4 and 5 of the study were administered once 
daily 2.4 mg dose of capsules with food for 7 days to stable heart failure participants.  
Exposure from different tablet formulations administered with or without food was 
characterised in another clinical study in healthy volunteers (204725).  Exposure from all 
available clinical data to date was analysed with a population pharmacokinetic (POP PK) 
approach accounting for participant weight, formulation, impact of food amongst other 
variables.  Trial simulations were performed with this POP PK model with differing 
dosing regimen. 
The estimated human IC50 of 2.1–3.2 ng/mL was derived from data from a rat study, 
which was conducted to assess the ability of different doses of GSK2798745 infusion to 
reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist.  The IC50 
was also corrected for species differences using protein binding data and TRPV4 potency 
differences in invitro assays. To evaluate drug activity/efficacy at the intended dosing 
regimen, the percentage pulmonary oedema blockade was estimated using the population 
model and the corrected potency values derived from the rat pulmonary study. 
Based on the simulations, the intended dosing scheme for this study is a 4.8 mg dose 
followed by a 2.4 mg dose at 12 h. Table 1 lists the predicted average percentage 
pulmonary oedema blockade over the 24-h period based on this potency range.  The 
schematic in Figure 3 also depicts the range of GSK2798745 systemic exposure and the 
predicted percent inhibition by TRPV4 with the intended regimen.  At 26 h post the first 
dose, when the primary endpoint sample will be taken, the predicted TRPV4 inhibition is 
71.1% (44.4–86.3) [median (95% prediction interval)].
 
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The intended dosing regimen also limits the daily ceiling human exposure at individual 
participant level to 30-fold of the exposure observed at the no observed adverse effect 
level (NOAEL) dose of 3 mg/kg from the 3-month dog safety study (D70496G). The 
current clinical doses are selected so that no participant intentionally exceeds the daily 
AUC of 513 ng*hr/mL and Cmax of 50 ng.hr/mL.  The likelihood of one or more 
participants of the 30 participants to be dosed with this regimen exceeding the threshold 
is listed in Table 1.
Figure 3
Predicted GSK2798745 exposure and corresponding effect on 
pulmonary oedema after doses of 4.8 mg then 2.4 mg, 12 h apart
Note:  percentage inhibition based on the rat, agonist-driven, pulmonary oedema model.
 
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Table 1
Predicted exposure, probability of exceeding threshold and 
predicted efficacy after doses of 4.8 mg then 2.4 mg, 12 h apart, 
administered to 30 participants
Percentage 
pulmonary oedema 
blockade over 24 h
(median 
[95% PI])
Predicted exposure
(median [95% PI])
% Probability that ≥1 of 30 
participants will exceed the 
toxicokinetic limit1
AUC0–24 h
(ng.h/mL)
Cmax 
(50 ng/mL)
AUC0–24 h 
(513 ng.h/mL)
Cmax 
(50 ng/mL)
79.1 
[66.5–87.1]
272.4 
[176.2–400.9]
23.1 
[15.2–34.4]
5.6
1.6
PI:  predicted interval.  
1.
The percentage of the 500 simulated studies (of 30 subjects each) in which ≥ 1 subject exceeds the toxicokinetic 
limit.
5.5.2.
Treatment Effect Rationale
Data from a systemic LPS model [Dalsgaard, 2016] , and from other models of lung 
injury (chlorine gas exposed mice [Suresh, 2015], pulmonary venous pressure induced 
injury of isolated mouse lungs [Narita, 2015], and a mouse model of intratracheal 
instillation of hydrochloric acid [Hamanaka, 2007]) suggest that TRPV4 blockade 
contributes 20–80% to a reduction in total protein in BAL fluid after the injury.  
Averaging the effect from those studies, the maximum effect possible in this segmental 
LPS model is estimated to be approximately 50%, assuming total TRPV4 channel 
blockade.  Therefore, with estimated exposure expected to reduce total protein by 
approximately 71% in a pure agonist driven challenge, a median treatment effect of 35% 
might be expected in this LPS challenge.  Based on pragmatic reasons and given some of 
the uncertainty around TRPV4 contribution to proteinaceous fluid influx as measured by 
total protein in a segmental LPS challenge, an estimated 30% treatment effect was 
nominally selected for sample size calculations.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Volunteers who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests (including a normal 
coagulation profile), ECGs, vital signs and spirometry.
 
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Note:  In the event of out-of-range results of safety tests, the tests may be repeated 
once within the screening window.  If a retest result is again outside the reference 
range and considered clinically significant by the investigator and GSK medical 
monitor, the participant will be considered a screen failure.  
3.
Normal spirometry (FEV1 ≥80% of predicted, FEV1/FVC ratio ≥70%) at screening
and before dosing.
WEIGHT
4.
Body weight 50 kg and body mass index (BMI) within the range 19–29.9 kg/m2
(inclusive).
SEX
5.
Male or female.
a. Male participants:
A male participant must agree to use contraception, as described in Appendix 5, 
during the treatment period and for at least 7 days after the last dose of study 
treatment and refrain from donating sperm during this period.
b. Female participants: 
A female is eligible to participate if she is not of childbearing potential, as defined 
in Appendix 5.
INFORMED CONSENT
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTC INTERVAL)
1.
Significant history of or current cardiovascular, respiratory (eg asthma, chronic 
obstructive pulmonary disorder (COPD), bronchiectasis, active Tuberculosis [TB]), 
hepatic, renal, gastrointestinal, endocrine, hematological, autoimmune or 
neurological disorders capable of significantly altering the absorption, metabolism, 
or elimination of drugs; constituting a risk when taking the study treatment; or 
interfering with the interpretation of data.
2.
Participant who, in the investigator/designee's judgement, poses a significant suicide 
risk. Evidence of serious suicide risk may include any history of suicidal behaviour 
and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on 
the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years. 
 
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3.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive
faecal occult blood test [FOBT] at screening).
4.
Abnormal blood pressure as determined by the investigator.
5.
ALT or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
7.
QTc >450 msec
NOTES:  the QTc is the QT interval corrected for heart rate according Fridericia’s 
formula (QTcF).
8.
At risk of Torsades de pointes (e.g. a personal history or a family history of sudden 
unexplained death, long QT, familial cardiac syndrome, or cardiomyopathy).
9.
Chronic or acute infection within the 4 weeks before dosing, (e.g. upper and lower 
respiratory infection within the 4 weeks before dosing).
10. Major (as per investigator judgment) surgery within the last 12 weeks prior to 
randomisation or planned within 3 months of screening.
PRIOR/CONCOMITANT THERAPY
11. Use of prescription or non-prescription drugs (except paracetamol), including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
or 5 half-lives (whichever is longer) before the first dose of study medication, 
unless, in the opinion of the investigator and GSK Medical Monitor, the medication 
will not interfere with the study procedures or compromise participant safety.
12. 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 and/or GSK 
Medical Monitor, contraindicates their participation.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
13. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
14. The participant has participated in a clinical trial and has received an investigational 
product within the following time period before 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).
15. Exposure to more than four new chemical entities within 12 months before the first 
dosing day.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
16. Presence of hepatitis B surface antigen (HBsAg) at screening
 
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17. Positive hepatitis C antibody test result at screening. 
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA)
test is obtained.
18. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
19. A positive pre-study drug/alcohol/cotinine screen.  
20. A positive test for immunodeficiency virus (HIV) antibody.
21. Regular use of known drugs of abuse.
OTHER EXCLUSIONS
22. 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. 
23. Current smoker or a history of smoking within 6 months of screening, or a total 
pack year history of >5 pack years.  [number of pack years = (number of cigarettes 
per day/20) x number of years smoked].
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants are not permitted to consume red wine, Seville oranges, grapefruit or 
grapefruit juice, and/or pomelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days before the start of study treatment until discharge from the clinical unit.

Participants will be required to fast from midnight before the bronchoscopies on 
Day 1 and 2 until after the procedure and for at least 2 hours before dosing. 
6.3.2.
Caffeine, Alcohol, and Tobacco

During the Treatment Period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) and/or pharmacodynamic sample.

During the Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 

Only non-smokers may be recruited into this study. 
 
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6.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Participants may be rescreened once.  If rescreening is preformed, participants must be 
assigned a different unique participant identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
 
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7.1.
Treatments Administered
Study Treatment 
Name:
GSK2798745
Matching Placebo
Challenge Agent:
GMP grade 
lipopolysaccharide 
from Escherichia coli
(E. Coli Group 
0113:H10:K Negative) 
for the segmental LPS 
challenge
Dosage formulation:
White to slightly 
coloured, round 
biconvex tablet.
Product: AP, Tab-
A  
White to slightly 
coloured, round 
biconvex tablet.
Product code: 
CET, Tab-A..
LPS is available from 
stock lyophilized in a 
1 microgram vial, 
formulated in 1% lactose 
and 0.1% PEG6000. 
Clear solution. 
Unit dose 
strength(s)/Dosage 
level(s):
Unit dose strength
2.4 mg.
Dosage Levels: 
4.8 mg and 
2.4 mg
Not applicable
4 ng/kg
Route of 
Administration 
Oral
Oral
Direct application to the 
lung segment, via 
bronchoscopy
Dosing instructions:
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later.
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later. 
One single instillation of 
10 mL by bronchoscopy 
2 hours after dosing with 
GSK2798745 or placebo 
on Day 1. 
Packaging and 
Labeling
GSK2798745 
tablets will be 
provided in high-
density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement.
Placebo tablets will 
be provided in 
high-density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement.
-
Manufacturer
GSK
GSK
List Laboratories, Inc.
 
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Sterile saline (0.9%) for control challenge will be sourced by the clinical site.
7.1.1.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.2.
Challenge Agents
Bacterial endotoxin is a component of the cell wall of Gram-negative bacteria present in a
variety of occupational and general environmental settings.
The dose of LPS used in this study is 4 ng/kg, which is 100 times lower than doses used
in inhalation models of endotoxin-induced lung inflammation. This dose was chosen
based on the data published by O’Grady et al [O’Grady, 2001].  In this study, lavage after
24-h in subjects challenged with 4 ng/kg of endotoxin revealed a localised inflammatory
response that was neutrophil-predominant. The site performing this study has experience 
with this model. The LPS challenge agent to be used for the procedure is Good 
Manufacturing Practice (GMP)-grade product and will be sourced from List Laboratories, 
Inc. A certificate of analysis will be provided for each batch of the LPS challenge agent 
to ensure its quality and safety.
Reconstitution will be done under the responsibility and supervision of the investigator or 
qualified site staff who performs the bronchoscopy and administers the reconstituted LPS 
in individual dilution to the subject. The reconstitution will be done on the day of
bronchoscopy immediately before the procedure (within 1 hour). If more than one subject 
per day will be investigated, the first process of reconstitution and administration of LPS 
has to be completed before a second process is started.
The reconstitution process is described as an example for the nominal dose of 10,000 EU 
of endotoxin per vial. Each vial of LPS contains a lyophilized solid containing 
10,000 EU of endotoxin. Upon reconstitution with 5 mL of sterile saline 0.9%, the vial 
will contain 2,000 EU/mL = 2 EU/μL. Forty (40) μL/kg body weight will be withdrawn 
from the vial and transferred into a sterile endotoxin-free 30 mL-sample vial (Acila AG, 
Weiterstadt, Germany). Sterile saline 0.9% will be added to give a final volume of 
20 mL. Ten (10) mL of this solution contains the application dose of 40 EU (4 ng)/kg, 
and will be filled into a 10 mL-syringe. This individual dilution will be administered to 
the participant by segmental pulmonary application during the bronchoscopy. The 
remaining 10 mL will be stored frozen (-20°C) as a retention sample.
The negative control will be performed with 10 mL of sterile saline 0.9% only. The 
reconstitution process will be adapted to the actual endotoxin content as determined in 
the Certificate of Analysis. The Investigator Site File will contain the current instructions 
for reconstitution in order to ensure the application dose of 40 EU/kg.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information and instructions for the 
 
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IWRS will be provided to each site.  Participants will be registered using the IWRS, and 
assigned a unique number (randomisation number).  The randomisation number encodes 
the participant’s treatment (GSK2798745 or placebo), according to the randomization 
schedule generated prior to the study by the Statistics Department at GSK.  Each 
participant will be dispensed blinded study treatment, labelled with his/her unique 
randomisation number.
7.4.
Blinding
This will be double blind study.  All study staff involved in clinical assessments (which 
includes the investigator, sub-investigators, other site staff) and the participant will be 
blinded to the treatment allocated to individual participants and to post challenge PD 
results. Selected sponsor study team members (and delegates if programming activities 
are outsourced) will be unblinded to perform the interim analysis.  This may include the 
medical monitor, study statistician, study programmer (and delegates) and study 
pharmacokineticist.  Access to unblinded data will be kept to the minimum set of 
individuals required to implement any interim analyses, but may include GSK 
management/review committees if alterations to the study conduct are required.  Details 
of who were unblinded to what data and when will be included in the clinical study 
report. The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s treatment assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded GSK 
must be notified within 24 hours after breaking the blind.  The date and reason that the 
blind was broken must be recorded in the source documentation and CRF, as applicable.
A participant whose treatment assignment is inadvertently unblinded (either to 
investigative staff or the participant themselves) will be permitted to remain in the study, 
although the accidental unblinding will be recorded as a protocol deviation and hence the 
participant will be subject to review as to their inclusion in analyses.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
1.
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
 
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automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorised site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.

GSK2798745 and the placebo will be orally administered to participants at the site.  
7.7.
Concomitant Therapy
7.7.1.
Permitted Medications
Paracetamol, at doses of 2 grams/day, is permitted for use any time during the study.  
Rescue medication, such as salbutamol, is also permitted after bronchoscopy or 
spirometry procedure, if required, and other medication, such as midazolam, may be 
taken during bronchoscopies to aid the procedure. Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required.
7.7.2.
Prohibited Medications
Except for the permitted medications noted above (Section 7.7.1), participants must 
abstain from taking prescription or non-prescription drugs (including vitamins and dietary 
or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study treatment until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study. 
 
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7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the
study because only healthy volunteers are eligible for study participation.
8.
DISCONTINUATION CRITERIA
8.1.
Individual Stopping Criteria
8.1.1.
Liver Chemistry Stopping Criteria
Increased monitoring criteria have been designed to assure participant safety and 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance). These protocol guidelines are in alignment with FDA premarketing 
clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Increased monitoring will be performed for a participant if liver chemistry stopping 
criteria are met.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6
8.1.2.
QTc Stopping Criteria
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A participant who meets either bulleted criterion below will be withdrawn from study:

QTcF >500 msec

Change from baseline of QTc >60 msec
8.1.3.
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria
8.1.3.1.
Asymptomatic Participant
Cardiac troponin (cTn) will be measured before and at the end of the study.  If any cTn 
assessment is >ULN or >2 times the participant’s baseline value (Day −1), the participant 
should be contacted immediately to assess for symptoms of cardiac ischemia.
8.1.3.2.
Symptomatic Participant
If a participant experiences symptoms of cardiac ischaemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  The participant should be evaluated by a cardiologist and undergo any 
clinically appropriate testing.  The participant should be followed up until symptoms are 
 
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resolved.  If the event occurs after the first dose, but before the second, the participant
should not receive the second dose.
8.1.4.
Bronchoscopy Stopping Criteria
A participant will be withdrawn from the study if they experience symptomatic 
bradycardia or tachycardia requiring treatment as a consequence of bronchoscopy, BAL 
and LPS instillation. In addition, participants who have the following may also be 
withdrawn at the discretion of the investigator:

Oxygen saturation <90% (on oxygen)

Prolonged somnolence following administration of midazolam

Significant hypertension/hypotension
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA (Section 2.3) for data to be collected at the time of withdrawal.
8.3.
Study Stopping Criteria
If there is a serious unexpected adverse event considered at least possibly related to the 
investigational product administration in one participant; or a severe non-serious AEs 
considered as, at least, possibly related to the investigational product administration in 
two participants, the study will be temporarily halted until full review of the events. In 
participants, significant changes from baseline measurements will be reviewed and 
participants will be followed until resolved.
8.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.
 
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
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the Schedule of Activities 
(SoA). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Bronchoscopy
Bronchoscopy will be performed in accordance with site standard operating procedures
(SOPs), at 2 hours and 26 hours. These SOPs will reflect current standards
of practice in hospital care and will include (but are not limited to) the following items:

Oxygen supplementation will be given to all participants.

Pulmonary function will be monitored before the bronchoscopy and after the
bronchoscopy until FEV1 is within 20% of the pre-procedure value.

All participants will be monitored in a recovery/holding room post bronchoscopy.
Participants will be discharged only after approval is obtained from the 
 
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supervising physician, and participants will be given a 24-hour contact number. 
Admission facilities will be available in the event a participant is not deemed fit 
for discharge or if overnight observation is deemed necessary by the study 
physician or site-specific policies.
Following bronchoscopies, participants will be monitored for at least 4 hours. However,
should the investigator have any concern for participant safety, participants may be 
requested to remain resident for further observation.
9.2.
Segmental lung challenge
Participants will undergo segmental challenge to the lungs, via bronchoscopy, at 2 hours 
after the first dose of investigational medicinal product (IMP):  10 mL LPS (4 ng/kg) will 
be instilled into the right middle segment and 10 mL saline control will be instilled into 
the lingula segment of the contralateral side.
Local SOPs will be followed and further details about the segmental LPS/saline challenge 
are provided in the SRM. 
9.3.
Pharmacodynamic Assessments
BAL samples will be taken, via bronchoscopy, to measure total protein and neutrophils 
counts. Baseline samples will be taken immediately before the LPS and saline 
challenges, from a segment in the left lower lobe, and post-challenge samples will be 
taken at 24 h after the LPS and saline challenges, from the challenged segments.  
Details of BAL sample collection, processing, storage and shipping procedures are 
provided in the SRM.
9.4.
Pharmacokinetics
Blood and BAL samples for assay of GSK2798745 will be collected at the time points 
indicated in the SoA (Section 2.2).  Details of sample collection, processing, storage and 
shipping procedures are provided in the SRM.
PK analysis will be performed under the control of Platform Technologies and
Science-IVIVT (PTS-IVIVT)/GlaxoSmithKline.  Plasma and BAL concentrations of 
GSK2798745 will be determined using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Plasma and BAL samples may be analysed for the metabolite GSK3526876, GSK will 
store the remaining plasma and/or BAL for future possible metabolite investigations.  
Analysis of compound-related metabolites may be reported under a separate protocol.
9.5.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
 
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The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8). 
9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit.  
However, any SAEs assessed as related to study participation (e.g. study 
treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product, will be recorded from the time a 
participant consents to participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit.

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.5.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.5.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.4). Further information on follow-up procedures is given in 
Appendix 4.
 
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9.5.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg: summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.5.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 12.5.
9.6.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2798745 can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
 
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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.7.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
9.7.1.
Physical Examinations

A complete physical examination will include, at a minimum, measuring weight 
and assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.7.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes’ rest and 
will include temperature, systolic and diastolic blood pressure and heart rate

At each time point before dosing, 3 readings of blood pressure and heart rate
will be taken. The first reading should be rejected. The second and third 
readings should be averaged to give the measurement to be recorded in the CRF.
At all other time points, single measurements will be taken. 
9.7.3.
Pulse Oximetry

Pulse oximetry will be monitored during each bronchoscopy. Clinically 
significant results will be recorded as AEs.
9.7.4.
Electrocardiograms

Triplicate 12-lead ECGs will be obtained at each time point before dosing. At all 
other time-points a single 12-lead ECG will be obtained as outlined in the SoA 
(see Section 2) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.

ECG to be measured in a semi-supine position after 5 minutes’ rest.
9.7.5.
Spirometry
Spirometry assessments will be performed from screening through the final visit as 
indicated in the SoA (Section 2).  The following parameters will be assessed:

Forced expiratory volume in one second (FEV1)

Forced vital capacity (FVC)
 
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Measurements will be made in triplicate and the best recording (i.e. the highest FEV1 and 
the highest FVC) from 3 technically acceptable manoeuvres will be recorded in the CRF. 
To fulfill the entry criteria, FEV1 should be ≥80% of predicted and FEV1/FVC ratio 
≥70%) at screening and pre-dose. 
Details on performing the spirometry assessments are provided in the SRM.
9.7.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. 

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study (until the follow-up visit) should be repeated 
until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE), then the results must be recorded in the CRF.
9.7.7.
Faecal Occult Blood Test (FOBT)
Based on the preclinical finding of gastric erosions, FOBT will be performed before and 
after dosing (See Section 2). Details on FOBT are provided in the SRM. 
9.7.8.
Columbia Suicide Severity Rating Scale (C-SSRS)
Based on preclinical studies that have been conducted, GSK2798745 is considered to be a 
central nervous system (CNS)-active drug. There has been some concern that some
CNS-active drugs may be associated with an increased risk of suicidal thinking or
behaviour when given to some patients with certain conditions. Although GSK2798745
has not been shown to be associated with an increased risk of suicidal thinking or
behaviour, GSK considers it important to monitor for such events.
The C-SSRS is a measure of suicidal ideation and behaviour, with demonstrated
predictive validity and reliability. Sections of the C-SSRS include suicidal ideation,
intensity of ideation, suicidal behaviour, and actual suicide attempt(s). The C-SSRS
assesses lifetime and current suicidal thoughts and behaviours across these categories
based on an increasing severity of a 1- to 5-rating scale. The semi-structured
questionnaire is completed by a trained and experienced neurologist, psychiatrist, or
 
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neuropsychologist, or another trained and experienced person approved by the Sponsor, 
who may be the Principal Investigator or a sub-investigator for the study. See SRM for 
details of the scale.
The C-SSRS will be performed at screening and after dosing before discharge (See 
Section 2). 
9.8.
Exploratory biomarkers
Blood and BAL samples for exploratory biomarker analysis of endothelial barrier 
permeability and/or injury and inflammation will be collected at the time points indicated 
in the SoA (Section 2). 
Samples may also be used for research to develop methods or support identification of 
prognostic/diagnostic biomarkers associated with clinical outcomes in ARDS and related 
diseases.
Details of sample collection, processing, storage and shipping procedures are provided in 
the SRM.
Exploratory biomarker results may be entered into the clinical study database before or 
after database lock and unblinding, or may be reported separately.
9.9.
Genetics
Genetics are not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The primary study objective is to investigate the effect of GSK2798745 relative to 
placebo on BAL total protein at 24 hours after segmental LPS challenge. In this study a 
Bayesian framework will be used (with non-informative priors) to estimate the posterior 
probability of any percentage reduction in mean 24 h post-LPS BAL protein level 
(GSK2798745 relative to placebo). It is anticipated that BAL total protein will be loge
transformed to improve normality before model fitting. Following back-transformation 
treatment comparisons will be expressed as percentage changes.
10.1.
Sample Size Determination
The sample size of 30 participants per arm (1:1 allocation) is based on an upper limit of 
feasibility. Figure 4 illustrates the probability of study success for a range of sample sizes 
and assumed true treatment effects unconditional on variability.
Assuming a true treatment effect of a 30% reduction in mean BAL total protein in 
participants receiving GSK2798745 relative to placebo at 24 h after segmental LPS 
challenge to the lung, the probability of study success for the study is 82% (this excludes 
the possibility of success from a review of secondary data), unconditional on the 
variability of BAL total protein in segmental LPS challenged lungs. Outright end of study 
success is defined as at least a 95% posterior probability that the percentage reduction in 
 
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the mean 24 h post-LPS BAL total protein level (GSK2798745 relative to placebo) 
exceeds zero.
Despite limited historical information for guidance on the true treatment effect for 
GSK2798745, 30% is believed to be a rational estimate.  However, probability of study 
success is sensitive to the true treatment effect – for example, the probability of study 
success reduces to 50% if the true treatment effect is 20% (GSK2798745 relative to 
placebo) with a sample size of 30 per arm but increases to 96% if the true treatment effect 
is 40%.
Figure 4
Probability of Study Success (Unconditional on Variance) for a 
Range of Treatment Profiles and Sample Sizes
Estimates for the mean and variance of BAL total protein in segmental LPS challenged 
lungs were obtained from data in an observational study assessing the variability of the 
inflammatory response to segmental LPS challenge by the Fraunhofer Institute of 
 
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Toxicology and Experimental Medicine, Germany [Holz, 2015] using a random effects 
model with total protein levels from 11 participants measured at baseline and 24 h over 2 
study periods.  The data were assumed to be representative of future segmental-LPS 
challenged lungs to be observed in this study.
The estimate of the mean BAL protein in 24 h post-LPS challenged lungs on the loge
scale is 5.47 (95% CI 5.23, 5.72).  The variance estimate on the loge scale is 0.25 (95% 
CI 0.13, 0.69).  A posterior distribution was formed for the standard deviation and for 
each possible value of standard deviation from this distribution the power of the study 
was calculated and multiplied by its probability.  The resulting values were all summed to 
give probability of study success unconditional on variance, which is a more accurate 
representation of the probability of study success rather than assuming a single variance 
estimate with no uncertainty.
Figure 5 shows the minimum observed treatment effect in the study that would achieve 
success (expressed as a percentage reduction in BAL total protein for GSK2798745 
relative to placebo) for a number of sample sizes. Assuming the variance in the study is 
the median obtained from the historical data, the minimum treatment effect to trigger 
success is 19% for a sample size of 30 participants per arm. As the sample size increases, 
the minimum observed treatment effect that would trigger success decreases due to the 
decreasing standard error (greater confidence in the observed treatment effect). This 
figure gives rationale for including the data review region since it is probable that 
moderate observed treatment effects will not achieve success with a sample size of 30 per 
arm.
Figure 5
Minimum Detectable Effect for Range of Sample Sizes
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
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Population
Description
Enrolled 
All participants who sign the ICF.
Evaluable
All participants for whom results of the primary analysis can be 
determined.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Other populations, such as Per-Protocol population, may be defined in the RAP.
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The mean percentage reduction in BAL total protein (µg/mL) in segmental 
LPS challenged lungs, at 24 h post-challenge, for GSK2798745 relative to
placebo, will be assessed using an analysis of covariance (ANCOVA) model 
(fitted in a Bayesian framework with non-informative priors for model 
parameters) testing that there is at least 95% posterior probability that the 
percentage reduction in 24 hour post-challenge mean BAL total protein 
(GSK2798745 relative to placebo) exceeds zero , adjusting for baseline BAL 
total protein. A sensitivity analysis will include 24 h BAL total protein in the 
saline segment (saline challenge will be administered to the contralateral 
lobe) as a covariate. Additional factors may be included as covariates if 
deemed appropriate.
Secondary
See Section 10.3.2 and Section 10.3.3
Exploratory
Will be described in the reporting and analysis plan.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
For the safety data, no formal hypotheses will be tested. Safety data such as 
adverse events, electrocardiogram (ECG), physical examinations, vital signs, 
spirometry, FEV1 and FVC will be displayed in the form of listings, frequencies, 
summary statistics and graphs. Interpretation will be aided by clinical expertise. 
Full details, including example outputs, will be documented in the RAP.
 
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10.3.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses
will be presented separately from the main clinical study report (CSR). 
10.3.4.
Interim Analyses
An interim analysis will occur once approximately 10 participants per arm have 
completed the treatment period to assess if the study should stop for futility or continue. 
Subsequently, if the decision at the first interim is to continue, an interim analysis will 
occur once approximately 20 participants per arm have completed the treatment period to 
assess whether the study should continue or stop for success or futility.  If at this point the 
study continues, the maximum 30 participants per arm will be recruited. The study then 
either meets the success criteria, undergoes analysis of secondary data (review) or is 
declared a failure. Enrolment into the study will continue whilst interim analyses are 
taking place.
This interim framework is being used to allow the possibility to reduce the number of 
participants enrolled into the study, either in the case of an overwhelming observed 
treatment effect or no/poor treatment effect. The interim stopping criteria for success is 
based on the probability of the study going on to meet the success criteria (predictive 
probability that the posterior probability is at least 0.95) whilst the stopping criteria for 
futility is based on the probability of the study going on to declare success or review
(predictive probability that the posterior probability is at least 0.75, see Table 2).
Table 2
Interim Decision Criteria
Interim 
Analysis
Success
Futility
10 subjects 
per arm
N/A – cannot stop for success at the 
first interim.
Predictive Prob ( PP ≥ 0.75) ≤ 0.075
20 subjects 
per arm
Predictive Prob (PP ≥ 0.95) ≥ 0.85
Predictive Prob ( PP ≥ 0.75) ≤ 0.15
At each interim, the probability of the study going on to meet these criteria will be 
calculated.  This probability value may be used to assist in determining whether there is 
sufficient rationale to continue/discontinue the study.  If the probability of study success 
is sufficiently high, then the study may stop for success.  Conversely, if the probability of 
study success or review is sufficiently low then the study may stop for futility. The 
probability thresholds for success and futility have been calibrated to balance the risk of 
declaring success despite a placebo-like drug (type 1 error) and declaring failure despite a 
positive true underlying treatment effect for GSK2798745 relative to placebo (type 2 
error).
 
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The predictive probability at each interim is calculated using predictive inference 
methods.  The observed data at the interim is used to obtain estimates of the mean and 
standard error of the treatment effect for GSK2798745 relative to placebo.  These 
estimates are then used to predict the treatment effect for participants in the remainder of 
the study using the predictive interim distribution. These two parts of data (observed and 
predicted) are combined to create a complete study.  The end of study success criteria is 
then applied to this complete data set made up of observed and predicted participants.  
This process is performed 10,000 times to account for the uncertainty in the estimated 
treatment effect at the interim – i.e. the same observed data is combined with thousands 
of permutations for the remainder of the study, and each time the end of study success 
criteria is applied.  The proportion of complete studies that meet the pre-defined success 
criteria gives the predicted probability of success if the study was to continue at the 
interim.
To inform the study design, a range of scenarios were reviewed to assess the operating 
characteristics when changing the total sample size, interim decision rules, interim 
analysis time points and assumed true treatment effects. Characteristics such as the 
overall probability of study success/failure, probability of success/failure at each interim, 
and the expected number of participants to be recruited were reviewed under a variety of 
design options.
Figure 6 show the operating characteristics of the chosen study design under true 
percentage reductions in total BAL protein for GSK2798745 relative to placebo of 0%, 
15%, 30% and 50%, respectively, unconditional on variability.  The schematic 
demonstrates all possible decision pathways the study may take.  To obtain the operating 
characteristics of a given study design, 10,000 studies were simulated with each one 
taking a particular pathway and finishing in one of the pockets on the left or right of the 
diagram, or indeterminate (additional data review). The overall proportion of simulated 
studies reaching a particular conclusion gives the probability of a single study reaching 
that conclusion.
A stricter posterior probability futility threshold is implemented at the first interim to 
reduce the probability of incorrectly declaring futility. Furthermore, a minimum of 20 
participants per arm must be recruited before declaring success. These rules are shown 
within the left (success) and right (futile) arrows.  Under this design, assuming a true 
treatment effect of 30%, the overall probability of study success is approximately 83%, 
unconditional on variability.  In addition, the probability of requiring a maximum of 20 
participants per arm is approximately 61% (under the same assumption of true treatment 
effect of 30%).  In the case of a placebo-like drug the probability of incorrectly declaring 
success is approximately 6% (akin to type 1 error rate). The blue boxes at the bottom of 
the charts show the probability that a study goes to data review.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
 
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Figure 6
Interim Analysis Framework for Range of True Treatment Effects
 
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11.
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Bosmann M, Russkamp NF, Ward PA. Fingerprinting of the TLR4-induced acute 
inflammatory response. Exp Mol Pathol. 2012;93:319-23. 
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inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function 
and increase survival in septic mice. Sci Rep. 2016;6:338-41. 
Fu P, Birukova AA, Xing J, Sammani S, Murley JS, Garcia JG,et al. Amifostine reduces 
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H, et al. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced
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Holter JF, Weiland HE, Pacht ER, Gadek JE. Protein Permeability in the Adult 
Respiratory Distress Syndrome, Loss of Size Selectivity of the Alveolar Epithelium. J. 
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variability of the inflammatory response to segmental endotoxin challenge in healthy 
volunteers. Pulmonary Pharmacology & Therapeutics. 2015;35:50-9. 
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disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Kandasamy K, Bezavada L, Escue RB, Parthasarathi K. Lipopolysaccharide Induces 
Endoplasmic Store Ca2+-Dependent Inflammatory Responses in Lung Microvessels. 
PLoS ONE. 2013;8:e63465. 
Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H et al. 
Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 
2010;42(2):170-4.
Lush CW, Cepinskas G, Kvietys PR. LPS tolerance in human endothelial cells: reduced 
PMN adhesion, E-selectin expression, and NF-kB mobilization. Am J Physiol Heart Circ 
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Cigarette smokers have exaggerated alveolar barrier disruption in response to 
lipopolysaccharide inhalation. Thorax. 2016;71:1130-6. 
Morty RE, Kuebler WM. TRPV4: an exciting new target to promote alveolocapillary 
barrier function. Am J Physiol Lung Cell Mol Physio. 2014;307:L817-21. 
Narita K, Sasamoto S, Koizumi S, Okazaki S, Nakamura H, Inoue T,et al. TRPV4 
regulates the integrity of the blood-cerebrospinal fluid barrier and modulates 
transepithelial protein transport. FASEB J. 2015;29:2247-59. 
Ngamsri K-C, Wagner R, Vollmer I, Stark S, Reutershan J. Adenosine Receptor A1 
Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in 
Lipopolysaccharide-Induced Lung Injury. The Journal of Immunology. 2010;185:4374-
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O’Grady NP, Preas II HL, Pugin J, Fiuza C, Tropea M, Reda D,et al. Local Inflammatory 
Responses following Bronchial Endotoxin Instillation in Humans. . 2001;163:1591-8. Am 
J Respir Crit Care Med. 2001;163:1591-8. 
Shyamsundar M, McKeown STW, O’Kane CM, Craig TR, Brown V, Thickett DR,et al. 
Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy 
Volunteers. Am J Respir Crit Care Med. 2009;179:1107-1114. 
Suresh K, Servinsky L, Reyes J, Baksh S, Undem C, Caterina M,et al. Hydrogen 
peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4. 
Am J Physiol Lung Cell Mol Physiol. 2015;309:L1467-77. 
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. 
Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian M-Y,et al. An Orally 
Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by 
Heart Failure. Pulmonary edema. 2012;4:159ra148. 
Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB. Ca2+ Signaling, TRP Channels, and 
Endothelial Permeability. Microcirculation. 2006;13:693-708. 
Yin J, Michalick L, Tang C, Tabuchi A, Goldenberg N, Dan Q,et al. Role of Transient 
Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury. Am J 
Respir Cell Mol Biol. 2016;54:370-83. 
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activity of novel asymmetric C66 analogs as anti-inflammatory agents for the treatment 
of acute lung injury. European Journal of Medicinal Chemistry. 2015;436-46
Zielen S, Trischler J, Schubert R. Lipopolysaccharide challenge:  immunological effects 
and safety in humans. Expert Review of Clinical Immunology. 2015;11:409-18. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
ANCOVA
Analysis of covariance
ARDS
Acute respiratory distress syndrome
AST
Aspartate aminotransferase
AUC
Area under concentration-time curve
AUC0–24
Area under the curve during 24 hours
BAL
Bronchoalveolar Lavage
BMI
Body mass index
BUN
Blood urea nitrogen
Ca2+
Calcium
Cmax
Maximum observed plasma concentration
CMT2C
Charcot-Marie-Tooth Disease Type 2C
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disorder
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicide Severity Rating Scale
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EU
Endotoxin Unit
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FVC
Forced vital capacity
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GMP
Good Manufacturing Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HCl
Hydrochloric acid
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HMVEC
Human Dermal Microvascular Endothelial Cells
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
 
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IC50
50% maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IMP
Investigational medicinal product
IP
Investigational Product
i.t.
Intratracheal
IRB
Institutional Review Board
IWRS
Interactive Web Response System
Kg
Kilogram
KO
Knockout
LDH
Lactate dehydrogenase
LPS
Lipopolysaccharide
MCH
Mean corpuscular haemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Msec
Milliseconds
mSV
MilliSievert
Ng
Nanogram
NOAEL
No observed adverse effect level
PK
Pharmacokinetic
POP PK
Population Pharmacokinetic
PTS-DMPK
Platform Technologies and Science-Drug Metabolism and 
Pharmacokinetics
QC
Quality control
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)
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TLR 4
Toll-like receptor 4
Tmax
Time to reach maximum plasma concentration
TRALI
Transfusion Related Acute Lung Injury
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
 
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WBC
White blood cells
WOCBP
Women of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None 
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory. 

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
CRP 
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting 
not required)
Calcium
Alkaline 
phosphatase
CPK
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin (cTn)

Coagulation profile (Quick/INR, PTT and thrombocytes)

Faecal Occult Blood Test (FOBT)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
 
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Laboratory 
Assessments
Parameters
hepatitis C virus antibody)

Alcohol, cotinine and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines).
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 6 All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Substantial amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
 
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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the source document 
agreement (to be signed by the investigator (or delegate) at the site).
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
 
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leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
 
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reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor (who is also the SAE coordinator).

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1:

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 4 when having penile-vaginal 
intercourse with a woman of childbearing potential 
 
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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm from the time of 
first dose of study treatment until 2 weeks after last dose of study treatment.
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
 
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Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry increased monitoring criteria and required follow up 
assessments
Liver Chemistry Increased Monitoring Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or haepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 48hrs of last 
dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:
 
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Liver Chemistry Increased Monitoring Criteria 
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: 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 
 
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12.7.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
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GlaxoSmithKline group of companies
207464
1
TITLE PAGE
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of 
GSK2798745 in healthy participants
Protocol Number: 207464
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model
Compound Number:
GSK2798745
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):  2017-002388-16
Approval Date: 24-OCT-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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CONFIDENTIAL 
 
 
 
 
207464 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 6 
2. 
SCHEDULE OF ACTIVITIES (SOA) ......................................................................... 9 
2.1. 
Screening ................................................................................................... 10 
2.2. 
Treatment period ........................................................................................ 11 
2.3. 
Follow-up/Early Withdrawal ........................................................................ 13 
3. 
INTRODUCTION .................................................................................................... 14 
3.1. 
Study Rationale .......................................................................................... 14 
3.2. 
Background ................................................................................................ 15 
3.3. 
Benefit/Risk Assessment ............................................................................ 16 
3.3.1. 
Risk Assessment ......................................................................... 16 
3.3.2. 
Benefit Assessment ..................................................................... 24 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 24 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 24 
5. 
STUDY DESIGN .................................................................................................... 25 
5.1. 
Overall Design ............................................................................................ 25 
5.2. 
Number of Participants ............................................................................... 26 
5.3. 
Participant and Study Completion ............................................................... 27 
5.4. 
Scientific Rationale for Study Design .......................................................... 27 
5.5. 
Dose Justification ........................................................................................ 28 
5.5.1. 
Dose Rationale ............................................................................ 28 
5.5.2. 
Treatment Effect Rationale .......................................................... 30 
6. 
STUDY POPULATION ........................................................................................... 30 
6.1. 
Inclusion Criteria ......................................................................................... 30 
6.2. 
Exclusion Criteria ........................................................................................ 31 
6.3. 
Lifestyle Restrictions ................................................................................... 33 
6.3.1. 
Meals and Dietary Restrictions .................................................... 33 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 33 
6.3.3. 
Activity ......................................................................................... 34 
6.4. 
Screen Failures........................................................................................... 34 
7. 
TREATMENTS ....................................................................................................... 34 
7.1. 
Treatments Administered ............................................................................ 35 
7.1.1. 
Dose Modification ........................................................................ 36 
7.2. 
Challenge Agents ....................................................................................... 36 
7.3. 
Method of Treatment Assignment ............................................................... 36 
7.4. 
Blinding ....................................................................................................... 37 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 37 
7.6. 
Treatment Compliance ................................................................................ 38 
7.7. 
Concomitant Therapy.................................................................................. 38 
7.7.1. 
Permitted Medications ................................................................. 38 
7.7.2. 
Prohibited Medications ................................................................. 38 
7.8. 
Treatment after the End of the Study .......................................................... 39 
 
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8. 
DISCONTINUATION CRITERIA ............................................................................. 39 
8.1. 
Individual Stopping Criteria ......................................................................... 39 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 39 
8.1.2. 
QTc Stopping Criteria .................................................................. 39 
8.1.3. 
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria ........................................ 39 
8.1.3.1. 
Asymptomatic Participant ........................................... 39 
8.1.3.2. 
Symptomatic Participant ............................................. 39 
8.1.4. 
Bronchoscopy Stopping Criteria ................................................... 40 
8.2. 
Withdrawal from the Study .......................................................................... 40 
8.3. 
Study Stopping Criteria ............................................................................... 40 
8.4. 
Lost to Follow Up ........................................................................................ 40 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 41 
9.1. 
Bronchoscopy ............................................................................................. 41 
9.2. 
Segmental lung challenge ........................................................................... 42 
9.3. 
Pharmacodynamic Assessments ................................................................ 42 
9.4. 
Pharmacokinetics ....................................................................................... 42 
9.5. 
Adverse Events........................................................................................... 42 
9.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 43 
9.5.2. 
Method of Detecting AEs and SAEs ............................................. 43 
9.5.3. 
Follow-up of AEs and SAEs ......................................................... 43 
9.5.4. 
Regulatory Reporting Requirements for SAEs ............................. 44 
9.6. 
Treatment of Overdose ............................................................................... 44 
9.7. 
Safety Assessments ................................................................................... 45 
9.7.1. 
Physical Examinations ................................................................. 45 
9.7.2. 
Vital Signs .................................................................................... 45 
9.7.3. 
Pulse Oximetry ............................................................................ 45 
9.7.4. 
Electrocardiograms ...................................................................... 45 
9.7.5. 
Spirometry ................................................................................... 45 
9.7.6. 
Clinical Safety Laboratory Assessments ...................................... 46 
9.7.7. 
Faecal Occult Blood Test (FOBT) ................................................ 46 
9.7.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................... 46 
9.8. 
Exploratory biomarkers ............................................................................... 47 
9.9. 
Genetics ..................................................................................................... 47 
10. STATISTICAL CONSIDERATIONS ........................................................................ 47 
10.1. 
Sample Size Determination ........................................................................ 47 
10.2. 
Populations for Analyses ............................................................................ 49 
10.3. 
Statistical Analyses ..................................................................................... 50 
10.3.1. 
Efficacy Analyses ......................................................................... 50 
10.3.2. 
Safety Analyses ........................................................................... 50 
10.3.3. 
Other Analyses ............................................................................ 51 
10.3.4. 
Interim Analyses .......................................................................... 51 
11. REFERENCES ....................................................................................................... 54 
12. APPENDICES ........................................................................................................ 57 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 57 
12.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 60 
 
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12.3. 
Appendix 3: Study Governance Considerations .......................................... 62 
12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 66 
12.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 71 
12.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 74 
 
 
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1. 
SYNOPSIS 
Protocol Title:  A randomised, placebo-controlled, double-blind (sponsor open), 
segmental LPS challenge study to investigate the pharmacodynamics of GSK2798745 in 
healthy participants  
Short Title: Effects of GSK2798745 on alveolar barrier disruption in a segmental LPS 
challenge model  
Rationale:   
The influx of protein-rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function, is a fundamental underlying 
defect in Acute Respiratory Distress Syndrome (ARDS).  In this Phase 1, 
proof-of-mechanism study, a segmental lipopolysaccharide (LPS) challenge will be used 
as a surrogate injury model to investigate the effects of Transient receptor potential 
vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man.  
The LPS model has been widely used for the evaluation of anti-inflammatory agents, and 
will aid in the characterization of TRPV4 blockade on lung permeability and 
inflammation. It is hypothesised that TRPV4 inhibitors modulate the LPS response by 
reducing LPS induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4) 
mediated activation of endothelial cells] or indirectly [e.g. autocrine cytokine 
activation]).  The assessment of TRPV4 mediated effects on LPS induced lung barrier 
damage in healthy volunteers is considered a viable strategy before conducting studies in 
an ARDS patient population.   
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To investigate the effect of 
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers. 
• 
Baseline adjusted total protein 
concentration in 
bronchoalveolar lavage (BAL) 
samples at 24 h after segmental LPS 
challenge. 
Secondary 
• 
To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs. 
• 
Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge. 
 
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Objectives 
Endpoints 
• 
To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers. 
 
• 
Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry 
(forced expiratory volume in 
1 second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood 
test (FOBT). 
• 
To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers  
• 
PK parameters of GSK2798745 in 
plasma (AUC (0-24) and Cmax). 
 
Overall Design: 
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.   
Participants will be randomised 1:1 to take 2 single doses (3 tablets total):  either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later.  The first dose will be administered on Day 1 at 2 h before 
baseline BAL sampling from a segment in the left lower lobe.  4 ng/kg LPS will 
subsequently be instilled into the right middle segment and saline control into the lingula 
segment of the contralateral side.  The second dose of study treatment will be 
administered 10 hours after LPS challenge followed by post-dose BAL sampling on 
Day 2.  A schematic of the study is provided in Figure 1. 
 
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Figure 1 
Study schematic 
 
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic. 
Number of Participants: 
Sufficient participants will be screened to ensure that a maximum of 60 evaluable 
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted, to assess the difference, if any, between treatments in 
the primary endpoint. Recruitment can continue whilst interim analyses are conducted. 
Depending on the results of the interim analyses, recruitment may be stopped.   
Treatment Groups and Duration: 
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2). Participants will receive a 
follow up phone call 2 days after discharge, and return to the study site on Day 8 
(± 1 day) for a follow-up visit. 
 
 
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2. 
SCHEDULE OF ACTIVITIES (SOA) 
• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamics and exploratory biomarker assessments 
may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.  
• 
Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The IRB/IEC will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the informed consent form (ICF). 
 
 
 
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2.1. 
Screening 
 
Screening  
(Days –28 to –2) 
Outpatient visit 
X 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Full physical examination  
X 
Height and weight 
X 
Medical history  
X 
Past and current medical conditions   
X 
HIV, Hepatitis B and C screening 
X 
FSH and oestradiol1 
X 
Drug, alcohol and cotinine screen 
X 
C-SSRS 
X 
Laboratory assessments2 
X 
12-lead ECG3 
X 
Vital signs4 
X 
Spirometry5 
X 
FOBT6 
X 
C-SSRS:  Columbia Suicide Severity Rating Scale; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; HIV:  human immunodeficiency virus. 
1. 
Postmenopausal females whose postmenopausal status is in doubt only. 
2. 
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile.  
3. 
In triplicate. 
4. 
Blood pressure and heart rate in triplicate.  Single temperature measurement. 
5. 
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form. 
6. 
May be measured during the screening window or on Day –1.  FOBT cards will be provided at screening and must be returned to the laboratory and analysed before dosing. 
 
 
 
 
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2.2. 
Treatment period 
 
Day –12 
Day 11 
Day 21 
 
Pre-
dose 
0 h 
1 h 
2 h 
3 h 
6 h 
8 h 
12 h 
14 h 
25.5 h 
26 h 
30 h 
Day 4 
Inpatient stay2 
 
←===============================================================→ 
 
Telephone call3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug, alcohol and cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments4 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG5 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood pressure and heart rate5 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
Temperature6 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
X 
 
Spirometry7 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pulse oximetry8 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Bronchoscopy, baseline BAL and 
challenge9 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Bronchoscopy and post-challenge 
BAL10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample for exploratory 
biomarkers11 
 
X 
 
 
X11 
X 
X 
X 
X 
X 
 
X11 
 
 
Blood sample for PK 
 
See footnote 12 
 
 
AE review 
 
←========================================================================→ 
SAE review 
←=================================================================================→ 
Concomitant medication review 
←=================================================================================→ 
 AE:  adverse event; BAL:  bronchoalveolar lavage; ECG:  electrocardiogram; PK:  pharmacokinetic; SAE:  serious adverse event, C-SSRS:  Columbia Suicide Severity Rating Scale. 
1. 
Time points relative to the first dose on Day 1. 
2. 
Admission on Day –1, at a time to allow all Day –1 procedures to be done; discharge on Day 2, at least 4 h after the bronchoscopy. 
 
 
 
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3. 
To check for any AEs. 
4. 
Haematology, clinical chemistry (including liver chemistry), cardiac troponins, urinalysis and coagulation profile.  
5. 
Triplicate on Day-1 and pre-dose. Single measurements at time points after dosing.  
6. 
Immediately before BAL sampling/LPS challenge at the 2-h time point.  
7. 
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurements at each time point, the highest of which should be recorded in the case 
report form. 
8. 
Pulse oximetry to be measured during bronchoscopy procedures. Only AEs to be recorded.  
9. 
BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers. Baseline BAL sample from a segment in the left lower lobe, followed by segmental 
challenge of the lungs:  LPS in right middle segment; saline control in the lingula segment of the contralateral side.  Challenges to be done as close as possible to 2 h post-dose.    
10. BAL samples for total protein, neutrophil counts, GSK2798745 and exploratory biomarkers.  Baseline and post-dose measurements to be done by the same person, where 
possible. 
11. Blood samples for exploratory biomarkers. The 2- and 26-h blood samples should be taken immediately before BAL sampling. 
12. PK samples will be taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 h after the first dose.  The 2- and 26-h blood sample should be taken 
immediately before BAL sampling 
 
 
 
 
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2.3. 
Follow-up/Early Withdrawal 
 
Follow-up/Early Withdrawal 
(Day 8 [± 1 day]) 
Outpatient visit 
X 
Full physical examination  
X 
Weight 
X 
Laboratory assessments1 
X 
12-lead ECG2 
X 
Vital signs3 
X 
Spirometry4 
X 
FOBT5 
X 
AE review 
X 
SAE review 
X 
Concomitant medication review 
X 
AE:  adverse event; ECG:  electrocardiogram; FOBT:  Faecal Occult Blood Test; SAE: serious adverse event. 
1. 
Haematology, clinical chemistry (including liver chemistry), cardiac troponins and urinalysis. 
2. 
Single measurement. 
3. 
Blood pressure, heart rate, temperature.  Single measurement. 
4. 
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).  Triplicate measurement, the highest of which should be recorded in the case report form. 
5. 
FOBT cards will be provided upon discharge from the unit and should be returned by the follow-up/early withdrawal visit.  
 
 
 
 
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3. 
INTRODUCTION 
GSK2798745 is a potent and selective transient receptor potential vanilloid 4 (TRPV4) 
channel blocker being investigated for the treatment of acute respiratory distress 
syndrome (ARDS). TRPV4 blockade is expected to ameliorate the injury inflicted to the 
alveolar capillary barrier in ARDS patients and reduce the leakage of protein and fluid 
into the alveolar space. Studies investigating administration of GSK2798745 have been 
conducted in healthy volunteers and in patients with chronic heart failure. 
GSK2798745 has been administered orally to healthy participants as single doses ranging 
from 0.25 to 12.5 mg. A dosage of 5 mg once daily has been administered for up to 
14 days in healthy participants.  Further, GSK2798745 at a dose of 2.4 mg has been 
evaluated as a single dose and subsequently as repeated doses for 7 days in participants 
with heart failure. 
No clinically significant safety concerns were observed with single or repeat 
administration of GSK2798745 in either healthy volunteers or participants with heart 
failure.  
3.1. 
Study Rationale 
The influx of protein rich fluid into the lung due to damage to the alveolar capillary 
barrier, with resultant adverse effects on respiratory function is a fundamental underlying 
defect in ARDS.  In this Phase 1 proof of mechanism study, a segmental 
lipopolysaccharide (LPS) challenge will be used as a surrogate injury model to 
investigate the effects of TRPV4 channel blockade on alveolar-septal barrier permeability 
in man.  The LPS model has been widely used for the evaluation of anti-inflammatory 
agents [Zielen, 2015], and will aid in the characterization of TRPV4 blockade on lung 
permeability and inflammation.  
Segmental LPS challenge, in which a small quantity of the endotoxin, LPS, is 
administered directly to one segment of the lung, is a model of focal and self-limiting 
lung inflammation.  LPS induces pulmonary endothelial cell permeability [Fu, 2009]  via 
calcium dependent cytoskeleton rearrangement [Bannerman, 1998; Gandhirajan, 2013]. 
LPS may also directly act on endothelial cells to cause permeability by degrading 
intercellular junctions [Bannerman, 1998].  The upregulation of a pro-inflammatory 
signalling cascade via NF-kB leading to endothelial activation and pro-inflammatory 
mediator release [Bosmann, 2012] may be regulated by the influx of calcium 
[Kandasamy, 2013], and may also induce further calcium influx and endothelial 
permeability [Lush, 2000; Tiruppathi, 2006].   
Under normal conditions, concentrations of total protein in alveolar fluid are low. LPS 
induced endothelial damage leads to accumulation of protein rich fluid into the lung due 
to the migration of large molecules, such as albumin, from blood to the alveolar space. 
Preclinical and clinical studies have shown a positive correlation between amount of 
protein the bronchoalveolar lavage and extent of lung damage [Holter, 1986; Moazed, 
2016; Yu, 2015].  In the lung, TRPV4, a Ca2+-permeable non-selective cation channel, is 
widely expressed in cells involved in ARDS, namely microvascular endothelium, 
 
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alveolar epithelium, alveolar macrophages, and circulating neutrophils and monocytes, 
and is a known regulator of endothelial permeability [Narita, 2015; Suresh, 2015; 
Huh, 2012] and pulmonary oedema [Balakrishna, 2014; Hamanaka, 2007]. Therefore, 
TRPV4 may play an important role in LPS-induced alveolar permeability.  The relevance 
of the TRPV4 channel to LPS induced injury has been confirmed in a mouse sepsis 
model. In this severe injury model, administration of a TRPV4 inhibitor 1 h prior to LPS 
injection (i.p.) increased survival by 70%.  Although this study was not specifically 
designed to evaluate bronchoalveolar lavage (BAL) protein levels, total protein 
concentrations in BAL fluid of mice pre-treated with a TRPV4 inhibitor were reduced by 
approximately 20% after the LPS challenge in TRPV4 treated mice compared with 
controls [Dalsgaard, 2016].   
It is hypothesised that TRPV4 inhibitors modulate the LPS response by reducing LPS 
induced calcium influx (either directly [e.g. via Toll-like receptor 4 (TLR4) mediated 
activation of endothelial cells] or indirectly [e.g. autocrine cytokine activation]). 
Given the link to ARDS of endothelial damage and fluid leak, assessment of TRPV4 
mediated effects on LPS induced lung barrier damage in healthy volunteers is important 
to establish whether beneficial effects may be observed in an ARDS patient population.   
3.2. 
Background 
ARDS is an acute inflammatory lung injury, associated with increased pulmonary 
vascular permeability, increased lung weight, and loss of aerated lung tissue [Bellani, 
2016]. Treatment options remain limited to supportive care including mechanical 
ventilation and ARDS represents a significant unmet need accounting for over 10% of 
intensive care unit (ICU) admissions and a mortality rate of up to 40% [Bellani, 2016; 
Matthay, 2012].  The syndrome is characterised by acute hypoxemic respiratory failure 
and non-cardiogenic pulmonary oedema and may be precipitated by direct (e.g. 
pneumonia and aspiration) and indirect insults (e.g. sepsis and transfusion related acute 
lung injury ([TRALI]) to the lung.  Dysregulated inflammation, inappropriate 
accumulation and activity of leukocytes and platelets, uncontrolled activation of 
coagulation pathways, and altered permeability of alveolar endothelial and epithelial 
barriers are central to the pathophysiology of ARDS [Matthay, 2012].  Damage to the 
alveolar-capillary membrane leads to increased vascular permeability, and the 
development of interstitial and alveolar protein rich oedema, leading to reduced gas 
exchange, ventilation perfusion mismatching and arterial hypoxaemia.   
TRPV4 has been implicated as a key regulator of lung endothelial barrier integrity, and 
specifically, the integrity of the lung alveolar-capillary endothelium, which is most 
relevant to alveolar flooding associated with acute lung injury. TRPV4 activation by 
hydrostatic stretch in lung microvessels leads to increased endothelial Ca2+ concentration 
and a diverse set of vascular responses, including an increase in endothelial permeability 
[Morty, 2014]. The importance of TRPV4 in maintaining pulmonary barrier function has 
been demonstrated in the settings of elevated pulmonary venous [Thorneloe, 2012] or 
airway pressure [Hamanaka, 2007], and following treatment with chemical and biological 
toxins such as Hydrochloric acid (HCl) and platelet activating factor [Balakrishna, 2014; 
Morty, 2014; Yin, 2016] .  In these studies, TRPV4 blockade limited lung damage by 
 
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reducing plasma fluid leak into the alveolar space (thus increasing arterial oxygenation), 
and by modulating neutrophil and macrophage recruitment and activity and reducing 
overall mortality in response to LPS [Balakrishna, 2014; Morty, 2014; Yin, 2016; 
Dalsgaard, 2016].  This evidence suggests TRPV4 channel blockade may benefit patients 
with ARDS where alveolar capillary leak is a primary driver of injury, by reducing fluid 
leak, reducing ventilation perfusion mismatching, improving oxygenation and reducing 
the need for mechanical ventilation with potential reductions in mortality. 
3.3. 
Benefit/Risk Assessment 
3.3.1. 
Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2798745 may be found in the Investigator’s 
Brochure.  
All potential risks of GSK2798745 are based on pre-clinical data. No risks have been 
identified in the clinical studies of GSK2798745 conducted before the effective date of 
this protocol. 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Investigational Product (IP) [GSK2798745] 
Vascular lesions 
Dogs (4-week study):  at 30 mg/kg/day, 2 males had arterial 
lesions 
• One male:  Heart – Coronary artery inflammation; Thymus 
– Arteriole inflammation with fibroplasia  
• One male:  Epididymides – Artery degeneration/necrosis 
with inflammation 
Dogs (12-week study):  At 10 mg/kg/day, 1 male and 1 female 
had arterial lesions 
• One male: Epididymides – Arteriole degeneration/necrosis 
with lymphocytic inflammation 
• One female: Bladder – Arteriole degeneration/necrosis 
with lymphocytic inflammation 
Participant Monitoring: The arterial lesions noted in heart, 
thymus, epididymides, and urinary bladder cannot be 
monitored directly.  There is currently no human translation 
biomarker or understanding of the underlying mechanism. 
Participant Exposure: Since these effects cannot be 
monitored directly in clinical studies, coverage of ≥30 fold will 
be maintained from the no-effect dose (3 mg/kg/day); 
exposure will not intentionally exceed the average daily area 
under concentration-time curve (AUC) of 0.513 hr*µg/mL 
and/or maximum observed plasma concentration (Cmax) of 
0.050 µg/mL on an individual basis. 
Myocardial toxicity 
Dogs (4-week study):  at 30 mg/kg/day, myofibre 
degeneration/necrosis and inflammation (2 animals) 
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment, 
including relevant history of acute coronary syndromes 
(including unstable angina), coronary angioplasty, or stenting, 
will be excluded. 
Participant Monitoring: Cardiac troponin levels will be 
monitored and ECGs will be done during the study. 
Participant Exposure: Exposure levels will be maintained 
below the threshold detailed in the Dose Justification Section 
(see Section 5.5). 
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Mortality/moribund 
condition; poor viability 
Dogs (4-week study):  at 30 mg/kg/day, one male terminated 
early (Day 6) due to poor clinical condition.  Another male had 
transient whole body shaking on Days 8 and 9. 
Dogs (13-week study):  at 10 mg/kg/day one male was 
terminated early (Day 74) due to welfare reasons. 
Rats (micronucleus and comet study):  mortality occurred 
following 1 to 3 doses at ≥600mg/kg/day 
Participant Monitoring: Weight and adverse events reported 
by participants will be monitored. 
 
Gastrointestinal (GI) 
and/or hepatic toxicity 
GI toxicity:  ≥3 mg/kg/day in dogs and at 30 and 300 
mg/kg/day in rats, consisting of mucosal erosion/ulceration in 
the stomach and/or duodenum. 
Hepatic Toxicity:  Biliary epithelial hypertrophy/hyperplasia 
and periductal mixed inflammatory cell infiltrate into the liver 
was observed at 300 mg/kg/day in rat (7-day study) and focal 
hepatocellular degeneration in 1 male dog at 30 mg/kg/day 
(4-week study) 
Participant Selection: Participants with active ulcer disease or 
GI bleeding or those who are taking concomitant medications, 
including nonsteroidal anti-inflammatory drugs (NSAIDs) and 
steroids, will be excluded.  Assessment of faecal occult blood 
will be performed before and after dosing.  
Participant Monitoring: Participants will be monitored for GI 
intolerance (e.g by adverse events such as abdominal 
discomfort) and sequential clinical chemistry analysis, 
including liver enzymes.  Follow-up faecal occult blood test 
(FOBT) will be conducted. 
Testicular toxicity 
Inconsistent finding in rats (4-week study):  Spermatid 
retention at ≥60 mg/kg/day, however no effect observed in 
13-week study.  The observations in the 4-week study were 
not associated with degenerative changes in testes or 
epididymides. 
No spermatogenic abnormalities were observed in dogs. 
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats. 
Skeletal muscle toxicity Rat (4-week study):  Myofiber necrosis: myofiber 
degeneration/regeneration; fibroplasia, at 300 mg/kg/day in 
the soleus muscle. 
Participant Monitoring: Creatinine phosphokinase (CPK) 
levels will be taken before and after dosing.  
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Seizures and 
convulsions 
Rats (micronucleus and comet study):  convulsions observed 
at ≥600 mg/kg/day.  Convulsions were not related to Cmax, 
nor occurred at any predictable time from dose administration. 
Dogs:  No central nervous system (CNS) findings at 
12 mg/kg/day in the dog 7-day EEG/CV study.  In other 
compounds in the same series, convulsions have been 
observed. 
Participant Selection: Participants with any history or current 
disease constituting a risk when taking the study treatment, 
including a history of seizure disorder or stroke within the last 
5 years will be excluded from the study.  
 
Low food consumption  
Dogs (4-week study):  30 mg/kg/day reduced food 
consumption.  Two males were terminated early (Day 10) due 
to extremely reduced food consumption. 
Rats (4-week study):  300 mg/kg/day had decreased food 
consumption. 
Participant Monitoring: Weight will be monitored. 
Effects on 
macrophages 
(Phospholipid 
accumulation) 
Inconsistent effects observed in Rats (4-week study):  
≥60 mg/kg/day in the lung (prominent alveolar macrophages); 
300 mg/kg/day in the mesenteric lymph node (increased 
cellularity of sinus macrophages) and thymus (macrophage 
vacuolation; increased thymus weight).  Consistent with 
phospholipid accumulation (phospholipidosis) based on 
ultrastructural appearance of mesenteric lymph nodes at 
300 mg/kg/day.  Findings were not associated with 
degenerative changes. In 13-week studies in rats, these 
effects were not observed. 
Participant Exposure: A safety margin of ≥40 fold will be 
maintained from the no effect dose (60 mg/kg/day) in rats. 
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Theoretical Risk:  
Potential effects on 
vasoregulation . 
TRPV4 mediates prostaglandin release from isolated human 
endothelial cells and in vivo in rats, supporting the potential 
for TRPV4 blockade to modulate blood pressure via 
prostaglandin release. No effect of GSK2798745 on blood 
pressure was observed in preclinical or clinical studies.  
Participant Monitoring: Blood pressure will be monitored 
throughout the study.  
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Theoretical Risk:  
Potential effect on 
hearing. 
Genetic deletion of TRPV4 in mice has been shown to effect 
hearing.  TRPV4 knockout (KO) mice at age 8 weeks 
exhibited normal hearing thresholds, but at age 24 weeks, 
had delayed-onset hearing loss; additionally, the cochlea was 
found to be vulnerable to acoustic injury with sound 
overexposure [Tabuchi, 2005].  Patients with Charcot-Marie-
Tooth Disease Type 2C (CMT2C), an autosomal dominant 
axonal neuropathy related to TRPV4 gene mutations, 
demonstrate symptoms that include hearing loss caused by 
nerve damage in the inner ear (sensorineural hearing loss).  
These are predominantly gain of function TRPV4 
abnormalities, in which the hearing loss is sporadic among 
family members; and relegated to some TRPV4 defects, but 
not in others.  Although the exact mechanism is unclear, it 
has been suggested that the TRPV4 channel plays an 
important role in peripheral nerve function and that the 
alterations in TRPV4 in CMT2C may be due to increased 
channel activity leading to excessive calcium influx and a 
calcium overload. There is potential for benefit with 
GSK2798745, in that with cells (HEK293) expressing the 
CMT2C mutant channel, inhibitors of the TRPV4 channel 
were found to block the increased intracellular calcium 
concentrations and resultant cell death [Landouré, 2010]. In a 
study evaluating effects on heart failure with similar dosing 
exposure, a week-long duration and comprising an older 
participant demographic, audiometry testing was conducted. 
Although a variety of changes were observed, primarily 
sporadic, low frequency and single frequency changes in 
those on treatment as well as placebo, none were assessed 
as a signal for concern by the reviewing expert audiologist. 
Participant Exposure: Dosing will be limited to a short duration 
of a single day.  
 
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Theoretical risk:  
Potential suicidal 
ideation 
GSK2798745 is considered to be a CNS-active drug. There 
has been some concern that some CNS-active drugs may be 
associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with certain 
conditions. GSK considers it important to monitor for such 
events before or during clinical studies with CNS-active 
compounds.  Participants being treated with GSK2798745 
should be assessed at screening for suicidality. 
Participant Selection: The risk of such an event would be very 
low in single dose trials in healthy volunteers however 
participants who, in the investigator/designee's judgement, 
poses a significant suicide risk, will be excluded from the 
study.  A C-SSRS questionnaire will be completed before and 
after dosing.  
Study procedures-related 
Risk of adverse events 
following delivery of 
LPS 
Previously reported segmental LPS related adverse events 
include pleuritic pain, pyrexia, head ache, nausea and 
alveolitis [Hohlfeld, 2008; Holz, 2015].  
It is known that LPS and pro-inflammatory mediators can 
cause gut permeability [Al-Sadi, 2014; Guo, 2013].  We 
expect the systemic exposure to LPS and systemic 
inflammatory response to LPS to be minimal following the 
segmental topical dose of 4ng/kg LPS.  As such, we assess 
the risk to increased gut permeability, and potential increased 
bioavailability, with this regimen to be low. 
Participant Monitoring: Participants will be monitored with 
safety assessments, including clinical laboratory tests, 
physical examination, ECGs, vital signs (including 
temperature), pulse oximetry and spirometry during the study.  
Experienced site staff will conduct the procedures.  
Participants will be carefully monitored and managed with 
standard procedures in the event of complications. 
Risks associated with 
bronchoscopy and BAL 
sampling: 
 
Procedure related complications include cough, transient 
fever, chills and myalgias, transient infiltrates, bronchospasm, 
transient fall of lung function, transient decrease in baseline 
PaO2 (partial pressure of oxygen in arterial blood). 
 
 
 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Risk associated with 
blood draws 
Fainting, mild pain, bruising, irritation or redness. 
Experienced site staff will follow standard approaches for 
managing events related to blood draws. 
Risks associated with 
spirometry 
Shortness of breath, coughing, light-headedness or fainting, 
and/or chest tightness may be induced by spirometry testing. 
Participants experiencing any of these symptoms will receive 
standard medical treatment by the study investigator. 
 
 
 
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3.3.2. 
Benefit Assessment 
There will be no intended therapeutic clinical benefit to the participants taking part in the 
study as it is a healthy volunteer study. However, participants will undergo a medical 
evaluation during screening including physical exams, electrocardiograms (ECGs) and 
laboratory assessments which may provide important health information. 
By taking part in this study, the participant will be contributing to the development of 
GSK2798745 for the treatment of ARDS, a syndrome with significant unmet need. 
3.3.3. 
Overall Benefit:Risk Conclusion 
No benefit to healthy participants is expected. The study activities have risks, however 
these risks are mitigated by exclusion of participants with identified comorbidities, short 
(single day) duration of dosing with GSK2798745 and exposure limited to previously 
approved exposure levels and inclusion of safety margins, as well as safety monitoring by 
trained staff. The study will provide important information towards future development 
of TRPV4 blockers that may help patients with ARDS. 
The design of the study is considered low risk to the participants and justified based on 
the safety information from the nonclinical studies and the previous clinical trials carried 
out on GSK2798745. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To investigate the effect of 
GSK2798745 on alveolar-septal 
barrier permeability following LPS 
challenge in healthy volunteers. 
• 
Baseline adjusted total protein 
concentration in bronchoalveolar 
lavage (BAL) samples at 24 h after 
segmental LPS challenge. 
Secondary 
• 
To investigate the effect of 
GSK2798745 on neutrophil levels in 
LPS-challenged lungs. 
• 
Baseline adjusted total and 
differential cell count of neutrophils 
in BAL samples at 24 h after 
segmental LPS challenge. 
• 
To assess the safety and tolerability 
of GSK2798745 in LPS-challenged, 
healthy volunteers. 
 
• 
Adverse events (AEs), laboratory 
safety assessments, 12-lead 
electrocardiogram (ECG), physical 
examination, vital signs, spirometry 
(forced expiratory volume in 1 
second [FEV1] and forced vital 
capacity [FVC]), faecal occult blood 
test (FOBT). 
 
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Objectives 
Endpoints 
• 
To assess the pharmacokinetics (PK) 
of GSK2798745 in plasma in 
LPS-challenged, healthy volunteers  
• 
PK parameters of GSK2798745 in 
plasma (AUC (0-24) and Cmax). 
Exploratory 
• 
To assess concentration of 
GSK2798745 in BAL. 
• 
Levels of GSK2798745 in BAL 
samples at 2 and 26 h after dosing. 
• 
To investigate the effect of 
GSK2798745 on exploratory 
markers of endothelial barrier 
permeability and/or injury, and 
inflammation, in LPS-challenged 
lungs. 
• 
Baseline adjusted levels of 
exploratory biomarkers in blood 
and/or BAL. 
• 
To assess metabolite GSK3526876 
(major metabolite of GSK2798745) 
in plasma. 
• 
Plasma concentrations of metabolite 
GSK3526876. 
• 
To compare the PK of GSK2798745 
with the effect of prophylactic 
dosing on alveolar-septal barrier 
permeability following LPS 
challenge in healthy volunteers. 
• 
To investigate the effect of 
GSK2798745 on white blood cell 
levels (except neutrophils) in 
LPS-challenged lungs. 
• 
Comparison of PK parameters of 
GSK2798745 in plasma with 
baseline corrected total protein 
concentration in BAL. 
 
• 
Baseline adjusted total and 
differential cell count of white blood 
cells (except neutrophils) in BAL 
samples at 24 h after segmental LPS 
challenge. 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), 
segmental LPS challenge study of GSK2798745 in healthy participants.   
Participants will be randomised 1:1 to take 2 single doses (3 tablets total): either 4.8 mg 
GSK2798745, then 2.4 mg GSK2798745 12 h later; or a dose of placebo, then another 
dose of placebo 12 h later. Participants will undergo segmental LPS challenge to the 
lungs at 2 h after the first dose.  BAL samples will be taken after dosing:  immediately 
before and at 24 h after the LPS and saline challenge.  Blood samples will be taken before 
and after dosing and the challenge.  Safety will be monitored throughout.  A schematic of 
the study is provided in Figure 2. 
 
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Figure 2 
Study schematic 
 
BAL:  bronchoalveolar lavage; LPS:  lipopolysaccharide; PD:  pharmacodynamic; PK:  pharmacokinetic. 
Each participant will take up to approximately 5 weeks to complete the study.  
Participants will be screened within 28 days before dosing and remain on site from the 
day before dosing (Day −1) until the day after dosing (Day 2).  The first dose will be 
administered on Day 1 at 2 h before baseline BAL sampling from a segment in the left 
lower lobe.  4 ng/kg LPS will subsequently be instilled into the right middle segment and 
saline control into the lingula segment of the contralateral side. The second dose of study 
treatment will be administered 10 hours after LPS challenge followed by post-dose BAL 
sampling on Day 2. Participants will receive a follow up phone call 2 days after 
discharge, and return to the study site on Day 8 (± 1 day) for a follow-up visit. 
5.2. 
Number of Participants 
Sufficient healthy participants will be screened to ensure that a maximum of 60 evaluable 
participants (defined as all participants for whom results of the primary analysis can be 
determined) are enrolled onto the study:  30 for GSK2798745 and 30 for placebo.  
Interim analyses will be conducted (as described in Section 10.3.4), to assess the 
difference, if any, between treatments in the primary endpoint.  There are two interim 
analyses planned, depending on the results of the interim analyses, recruitment may be 
stopped.  Participants who prematurely discontinue the study, and whose data are not 
evaluable (i.e. those for whom results of the primary analysis cannot be determined), may 
be replaced. Recruitment into the study can continue whilst interim analyses are taking 
place.  
 
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5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4. 
Scientific Rationale for Study Design 
• Use of a placebo:  The randomised, placebo-controlled study design is a 
well-established methodology to evaluate potential treatment effects in experimental 
studies. The use of a placebo arm allows for a valid evaluation of changes in PD 
markers attributable to treatment versus those independent of treatment.  Given that 
participants are healthy and treatment is not being withheld, the use of placebo is 
considered acceptable. 
• Parallel group:  The use of a parallel group design is considered to limit the burden 
of procedures and exposure of LPS to participants.  A crossover design only 
minimally decreases the required number of evaluable participants and owing to the 
expected dropout rate in a crossover study, and the burden of procedures for each 
participant, a parallel group design was selected. 
• Blinding:  A double blind design is a standard methodology for randomised, 
controlled studies to avoid bias.   
• Selection of primary endpoint:  Changes in total protein concentrations to monitor 
influx of proteinaceous fluid into the lung has been used in several LPS challenge 
studies. Evidence points to the involvement of TRPV4 in changes to alveolar 
capillary barrier following LPS administration, with subsequent leak of proteinaceous 
fluid as measured by total protein. Given the influx of fluid with high concentrations 
of protein observed in ARDS patients, monitoring total protein changes is considered 
an acceptable surrogate to assess for target engagement of GSK2798745 and for 
potential effects in ARDS patients.  
• Timing of primary endpoint:  As previous studies show that total protein 
concentrations peak at 24 h after segmental LPS challenge [O’Grady, 2001; 
Holz, 2015], post-challenge BAL samples will be taken at 24 h after the challenge.  
• Timing of challenge:  Baseline BAL sampling prior to administration of study drug is 
not considered feasible due to the burden of bronchoscopy (i.e. two procedures 
required – one pre and one post dose to instil LPS). A baseline bronchoscopy is 
planned 2 h after administration of the first dose, with the aim of maximising 
exposure to GSK2798745 (in healthy volunteers, the median [range] Time to reach 
maximum plasma concentration (Tmax) of the tablet formulation of GSK2798745 to 
be used in this study is 1.5 h [1–3 h]).  Drug on board at the time of baseline BAL 
fluid sampling is expected to have little to no effect on baseline BAL total protein 
concentrations as TRPV4 channels are quiescent until stimulated and blockade of 
these channels does affect barrier permeability of ‘healthy’ endothelial cells [internal 
data].  The effects of LPS to induce endothelial permeability are believed to occur 
rapidly.  Investigation of LPS induced permeability and markers of cell activation and 
inflammation over time consistently indicates that the initial events leading to 
increased barrier permeability and inflammation occur within first 2 h post 
 
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intratracheal (i.t.) LPS exposure; where any earlier measurements are limited.  LPS 
induces intracellular stress fibre formation within 5 min in both human dermal 
microvascular endothelial cells (HMVEC) endothelial and A549 epithelial cells 
[Ngamsri, 2010].  Increased levels of TNFα following i.t. LPS instillation are 
observed within 2 h in man [O’Grady, 2001] and other pro-inflammatory mediators 
within 4 h in a mouse model of acute lung injury (ALI) [Bosmann, 2012].  
Permeability across an endothelial monolayer is observed after 0.5 h and peaks at 2 h 
post-LPS [Bannerman, 1998].  BAL total protein increases following LPS i.t. 
challenge in man as early as 2 h and reaches significance at 6 h post-LPS [Matthay 
, 2012] with significant increases in neutrophil counts also observed as early as 2 h.  
Looking to a systemic LPS model of sepsis with a higher LPS insult, earlier sampling 
is possible and high levels of inflammatory mediators are measured within 1 h, which 
reach plateau by 3 h.  Therefore, despite our conservative treatment effect prediction 
(see Section 5.5), we expect that high plasma and/or alveolar fluid concentrations of 
GSK2798745 will be required at the time of and/or soon after the challenge, in order 
to inhibit the effects of LPS. Therefore, LPS will be administered shortly after time of 
Tmax (1.5-hours) to ensure sufficient drug on board.  
5.5. 
Dose Justification 
5.5.1. 
Dose Rationale 
The first time in human study (TR4113787) for GSK2798745 evaluated doses from 
0.25 mg to 12.5 mg as single doses, and 5 mg once daily repeat dosing for 14 days in 
healthy volunteers in cohorts 1–3.  Cohorts 4 and 5 of the study were administered once 
daily 2.4 mg dose of capsules with food for 7 days to stable heart failure participants.  
Exposure from different tablet formulations administered with or without food was 
characterised in another clinical study in healthy volunteers (204725).  Exposure from all 
available clinical data to date was analysed with a population pharmacokinetic (POP PK) 
approach accounting for participant weight, formulation, impact of food amongst other 
variables.  Trial simulations were performed with this POP PK model with differing 
dosing regimen.  
The estimated human IC50 of 2.1–3.2 ng/mL was derived from data from a rat study, 
which was conducted to assess the ability of different doses of GSK2798745 infusion to 
reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist.  The IC50 
was also corrected for species differences using protein binding data and TRPV4 potency 
differences in invitro assays.  To evaluate drug activity/efficacy at the intended dosing 
regimen, the percentage pulmonary oedema blockade was estimated using the population 
model and the corrected potency values derived from the rat pulmonary study.  
Based on the simulations, the intended dosing scheme for this study is a 4.8 mg dose 
followed by a 2.4 mg dose at 12 h. Table 1 lists the predicted average percentage 
pulmonary oedema blockade over the 24-h period based on this potency range.  The 
schematic in Figure 3 also depicts the range of GSK2798745 systemic exposure and the 
predicted percent inhibition by TRPV4 with the intended regimen.  At 26 h post the first 
dose, when the primary endpoint sample will be taken, the predicted TRPV4 inhibition is 
71.1% (44.4–86.3) [median (95% prediction interval)]. 
 
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The intended dosing regimen also limits the daily ceiling human exposure at individual 
participant level to 30-fold of the exposure observed at the no observed adverse effect 
level (NOAEL) dose of 3 mg/kg from the 3-month dog safety study (D70496G). The 
current clinical doses are selected so that no participant intentionally exceeds the daily 
AUC of 513 ng*hr/mL and Cmax of 50 ng.hr/mL.  The likelihood of one or more 
participants of the 30 participants to be dosed with this regimen exceeding the threshold 
is listed in Table 1. 
Figure 3 
Predicted GSK2798745 exposure and corresponding effect on 
pulmonary oedema after doses of 4.8 mg then 2.4 mg, 12 h apart 
 
Note:  percentage inhibition based on the rat, agonist-driven, pulmonary oedema model. 
 
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Table 1 
Predicted exposure, probability of exceeding threshold and 
predicted efficacy after doses of 4.8 mg then 2.4 mg, 12 h apart, 
administered to 30 participants 
Percentage 
pulmonary oedema 
blockade over 24 h 
(median  
[95% PI]) 
Predicted exposure 
(median [95% PI]) 
% Probability that ≥1 of 30 
participants will exceed the 
toxicokinetic limit1 
AUC0–24 h 
(ng.h/mL) 
Cmax  
(50 ng/mL) 
AUC0–24 h  
(513 ng.h/mL) 
Cmax  
(50 ng/mL) 
79.1  
 [66.5–87.1] 
272.4  
[176.2–400.9] 
23.1  
[15.2–34.4] 
5.6 
1.6 
PI:  predicted interval.   
1. The percentage of the 500 simulated studies (of 30 subjects each) in which ≥ 1 subject exceeds the toxicokinetic 
limit. 
5.5.2. 
Treatment Effect Rationale 
Data from the systemic LPS model described in Section 5.4 [Shyamsundar, 2009] , and 
from other models of lung injury (chlorine gas exposed mice [Suresh, 2015], pulmonary 
venous pressure induced injury of isolated mouse lungs [Narita, 2015], and a mouse 
model of intratracheal instillation of hydrochloric acid [Hamanaka, 2007]) suggest that 
TRPV4 blockade contributes 20–80% to a reduction in total protein in BAL fluid after 
the injury.  Averaging the effect from those studies, the maximum effect possible in this 
segmental LPS model is estimated to be approximately 50%, assuming total TRPV4 
channel blockade.  Therefore, with estimated exposure expected to reduce total protein by 
approximately 71% in a pure agonist driven challenge, a median treatment effect of 35% 
might be expected in this LPS challenge.  Based on pragmatic reasons and given some of 
the uncertainty around TRPV4 contribution to proteinaceous fluid influx as measured by 
total protein in a segmental LPS challenge, an estimated 30% treatment effect was 
nominally selected for sample size calculations. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1. Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent. 
 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Volunteers who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests (including a normal 
coagulation profile), ECGs, vital signs and spirometry. 
 
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Note:  In the event of out-of-range results of safety tests, the tests may be repeated 
once within the screening window.  If a retest result is again outside the reference 
range and considered clinically significant by the investigator and GSK medical 
monitor, the participant will be considered a screen failure.   
3. Normal spirometry (FEV1 ≥80% of predicted, FEV1/FVC ratio ≥70%) at screening 
and before dosing. 
 
WEIGHT 
4. Body weight ≥50 kg and body mass index (BMI) within the range 19–29.9 kg/m2 
(inclusive). 
 
SEX 
5. Male or female. 
a. Male participants: 
A male participant must agree to use contraception, as described in Appendix 5, 
during the treatment period and for at least 7 days after the last dose of study 
treatment and refrain from donating sperm during this period. 
b. Female participants:  
A female is eligible to participate if she is not of childbearing potential, as defined 
in Appendix 5. 
 
 
INFORMED CONSENT 
6. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTC INTERVAL) 
1. Significant history of or current cardiovascular, respiratory (eg asthma, chronic 
obstructive pulmonary disorder (COPD), bronchiectasis, active Tuberculosis [TB]), 
hepatic, renal, gastrointestinal, endocrine, hematological, autoimmune or 
neurological disorders capable of significantly altering the absorption, metabolism, 
or elimination of drugs; constituting a risk when taking the study treatment; or 
interfering with the interpretation of data. 
2. Participant who, in the investigator/designee's judgement, poses a significant suicide 
risk.  Evidence of serious suicide risk may include any history of suicidal behaviour 
and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on 
the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years.  
 
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3. Active ulcer disease or gastrointestinal bleeding at the time of screening (positive 
faecal occult blood test [FOBT] at screening). 
4. Abnormal blood pressure as determined by the investigator. 
5. ALT or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%).  
6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
7. QTc >450 msec 
NOTES:  the QTc is the QT interval corrected for heart rate according Fridericia’s 
formula (QTcF). 
8. At risk of Torsades de pointes (e.g. a personal history or a family history of sudden 
unexplained death, long QT, familial cardiac syndrome, or cardiomyopathy). 
9. Chronic or acute infection within the 4 weeks before dosing, (e.g. upper and lower 
respiratory infection within the 4 weeks before dosing). 
10. Major (as per investigator judgment) surgery within the last 12 weeks prior to 
randomisation or planned within 3 months of screening. 
 
PRIOR/CONCOMITANT THERAPY 
11. Use of prescription or non-prescription drugs (except paracetamol), including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
or 5 half-lives (whichever is longer) before the first dose of study medication, 
unless, in the opinion of the investigator and GSK Medical Monitor, the medication 
will not interfere with the study procedures or compromise participant safety. 
12. 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 and/or GSK 
Medical Monitor, contraindicates their participation. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
13. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months. 
14. The participant has participated in a clinical trial and has received an investigational 
product within the following time period before 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). 
15. Exposure to more than four new chemical entities within 12 months before the first 
dosing day. 
 
 
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA 
16. Presence of hepatitis B surface antigen (HBsAg) at screening 
 
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17. Positive hepatitis C antibody test result at screening.  
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) 
test is obtained. 
18. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment. 
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing. 
19. A positive pre-study drug/alcohol/cotinine screen.   
20. A positive test for immunodeficiency virus (HIV) antibody. 
21. Regular use of known drugs of abuse. 
 
 
 
OTHER EXCLUSIONS 
22. 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.  
23. Current smoker or a history of smoking within 6 months of screening, or a total 
pack year history of >5 pack years.  [number of pack years = (number of cigarettes 
per day/20) x number of years smoked]. 
 
 
6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
• 
Participants are not permitted to consume red wine, Seville oranges, grapefruit or 
grapefruit juice, and/or pomelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days before the start of study treatment until discharge from the clinical unit.  
• 
Participants will be required to fast from midnight before the bronchoscopies on 
Day 1 and 2 until after the procedure and for at least 2 hours before dosing.  
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During the Treatment Period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) and/or pharmacodynamic sample. 
• 
During the Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample.  
• 
Only non-smokers may be recruited into this study.  
 
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6.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 72 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
Participants may be rescreened once.  If rescreening is preformed, participants must be 
assigned a different unique participant identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details. 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
 
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7.1. 
Treatments Administered 
Study Treatment 
Name: 
 
GSK2798745 
Matching Placebo Challenge Agent: 
GMP grade 
lipopolysaccharide 
from Escherichia coli 
(E. Coli Group 
0113:H10:K Negative) 
for the segmental LPS 
challenge 
Dosage formulation: 
 
White to slightly 
coloured, round 
biconvex tablet. 
Product: AP, Tab- 
A   
White to slightly 
coloured, round 
biconvex tablet.  
Product code: 
CET, Tab-A.. 
LPS is available from 
stock lyophilized in a 
1 microgram vial, 
formulated in 1% lactose 
and 0.1% PEG6000. 
Clear solution.  
Unit dose 
strength(s)/Dosage 
level(s): 
Unit dose strength 
2.4 mg. 
Dosage Levels: 
4.8 mg and 
2.4 mg 
Not applicable 
4 ng/kg 
Route of 
Administration  
Oral 
Oral 
Direct application to the 
lung segment, via 
bronchoscopy 
Dosing instructions: 
 
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later. 
Two tablets to be 
taken on the 
morning of Day 1, 
then one tablet to 
be taken 12 hours 
later.  
One single instillation of 
10 mL by bronchoscopy 
2 hours after dosing with 
GSK2798745 or placebo 
on Day 1.  
Packaging and 
Labeling 
GSK2798745 
tablets will be 
provided in high-
density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement. 
Placebo tablets will 
be provided in 
high-density 
polyethylene 
(HDPE) bottles 
with child-resistant 
closures that 
include induction-
seal liners.  Each 
bottle will be 
labelled as 
required per 
country 
requirement. 
- 
Manufacturer 
GSK 
GSK 
List Laboratories, Inc. 
 
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Sterile saline (0.9%) for control challenge will be sourced by the clinical site. 
7.1.1. 
Dose Modification 
No dose modifications are permitted without submission of a substantial amendment to 
the protocol. 
7.2. 
Challenge Agents 
Bacterial endotoxin is a component of the cell wall of Gram-negative bacteria present in a 
variety of occupational and general environmental settings. 
The dose of LPS used in this study is 4 ng/kg, which is 100 times lower than doses used 
in inhalation models of endotoxin-induced lung inflammation. This dose was chosen 
based on the data published by O’Grady et al [O’Grady, 2001].  In this study, lavage after 
24-h in subjects challenged with 4 ng/kg of endotoxin revealed a localised inflammatory 
response that was neutrophil-predominant. The site performing this study has experience 
with this model. The LPS challenge agent to be used for the procedure is Good 
Manufacturing Practice (GMP)-grade product and will be sourced by GSK from List 
Laboratories, Inc.  A certificate of analysis will be provided for each batch of the LPS 
challenge agent to ensure its quality and safety. 
Reconstitution will be done under the responsibility and supervision of the investigator or 
qualified site staff who performs the bronchoscopy and administers the reconstituted LPS 
in individual dilution to the subject. The reconstitution will be done on the day of 
bronchoscopy immediately before the procedure (within 1 hour). If more than one subject 
per day will be investigated, the first process of reconstitution and administration of LPS 
has to be completed before a second process is started. 
The reconstitution process is described as an example for the nominal dose of 10,000 EU 
of endotoxin per vial.  Each vial of LPS contains a lyophilized solid containing 
10,000 EU of endotoxin. Upon reconstitution with 5 mL of sterile saline 0.9%, the vial 
will contain 2,000 EU/mL = 2 EU/μL. Forty (40) μL/kg body weight will be withdrawn 
from the vial and transferred into a sterile endotoxin-free 30 mL-sample vial (Acila AG, 
Weiterstadt, Germany). Sterile saline 0.9% will be added to give a final volume of 
20 mL. Ten (10) mL of this solution contains the application dose of 40 EU (4 ng)/kg, 
and will be filled into a 10 mL-syringe. This individual dilution will be administered to 
the participant by segmental pulmonary application during the bronchoscopy.  The 
remaining 10 mL will be stored frozen (-20°C) as a retention sample. 
The negative control will be performed with 10 mL of sterile saline 0.9% only. The 
reconstitution process will be adapted to the actual endotoxin content as determined in 
the Certificate of Analysis. The Investigator Site File will contain the current instructions 
for reconstitution in order to ensure the application dose of 40 EU/kg. 
7.3. 
Method of Treatment Assignment 
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS).  Before the study is initiated, the log in information and instructions for the 
 
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IWRS will be provided to each site.  Participants will be registered using the IWRS, and 
assigned a unique number (randomisation number).  The randomisation number encodes 
the participant’s treatment (GSK2798745 or placebo), according to the randomization 
schedule generated prior to the study by the Statistics Department at GSK.  Each 
participant will be dispensed blinded study treatment, labelled with his/her unique 
randomisation number. 
7.4. 
Blinding 
This will be double blind study.  All study staff involved in clinical assessments (which 
includes the investigator, sub-investigators, other site staff) and the participant will be 
blinded to the treatment allocated to individual participants and to post challenge PD 
results. Selected sponsor study team members (and delegates if programming activities 
are outsourced) will be unblinded to perform the interim analysis.  This may include the 
medical monitor, study statistician, study programmer (and delegates) and study 
pharmacokineticist.  Access to unblinded data will be kept to the minimum set of 
individuals required to implement any interim analyses, but may include GSK 
management/review committees if alterations to the study conduct are required.  Details 
of who were unblinded to what data and when will be included in the clinical study 
report. The IWRS will be programmed with blind-breaking instructions.  In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s treatment assignment is warranted.  Participant safety must always be the 
first consideration in making such a determination.  If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant.  If a participant’s treatment assignment is unblinded GSK 
must be notified within 24 hours after breaking the blind.  The date and reason that the 
blind was broken must be recorded in the source documentation and CRF, as applicable. 
A participant whose treatment assignment is inadvertently unblinded (either to 
investigative staff or the participant themselves) will be permitted to remain in the study, 
although the accidental unblinding will be recorded as a protocol deviation and hence the 
participant will be subject to review as to their inclusion in analyses. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
7.5. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
 
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automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorised site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 
5. Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 
6. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
7.6. 
Treatment Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• 
When participants are dosed at the 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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested. 
• 
GSK2798745 and the placebo will be orally administered to participants at the site.   
7.7. 
Concomitant Therapy 
7.7.1. 
Permitted Medications 
Paracetamol, at doses of ≤2 grams/day, is permitted for use any time during the study.  
Rescue medication, such as salbutamol, is also permitted after bronchoscopy or 
spirometry procedure, if required.  Other concomitant medication may be considered on a 
case-by-case basis by the investigator in consultation with the Medical Monitor if 
required. 
7.7.2. 
Prohibited Medications 
Except for the permitted medications noted above (Section 7.7.1), participants must 
abstain from taking prescription or non-prescription drugs (including vitamins and dietary 
or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study treatment until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study.  
 
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7.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Individual Stopping Criteria 
8.1.1. 
Liver Chemistry Stopping Criteria 
Increased monitoring criteria have been designed to assure participant safety and 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance). These protocol guidelines are in alignment with FDA premarketing 
clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Increased monitoring will be performed for a participant if liver chemistry stopping 
criteria are met. 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6 
8.1.2. 
QTc Stopping Criteria 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.   
A participant who meets either bulleted criterion below will be withdrawn from study: 
• QTcF >500 msec 
• Change from baseline of QTc >60 msec 
8.1.3. 
Symptoms of Cardiac Ischaemia and Cardiac Troponin 
Stopping/Increased monitoring Criteria 
8.1.3.1. 
Asymptomatic Participant 
Cardiac troponin (cTn) will be measured before and at the end of the study.  If any cTn 
assessment is >ULN or >2 times the participant’s baseline value (Day −1), the participant 
should be contacted immediately to assess for symptoms of cardiac ischemia. 
8.1.3.2. 
Symptomatic Participant 
If a participant experiences symptoms of cardiac ischaemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  The participant should be evaluated by a cardiologist and undergo any 
clinically appropriate testing.  The participant should be followed up until symptoms are 
 
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resolved.  If the event occurs after the first dose, but before the second, the participant 
should not receive the second dose. 
8.1.4. 
Bronchoscopy Stopping Criteria 
A participant will be withdrawn from the study if they experience symptomatic 
bradycardia or tachycardia requiring treatment as a consequence of bronchoscopy, BAL 
and LPS instillation. In addition, participants who have the following may also be 
withdrawn at the discretion of the investigator: 
 
• Oxygen saturation <90% (on oxygen) 
• Prolonged somnolence following administration of midazolam 
• Significant hypertension/hypotension 
8.2. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• 
Refer to the SoA (Section 2.3) for data to be collected at the time of withdrawal. 
8.3. 
Study Stopping Criteria 
If there is a serious unexpected adverse event considered at least possibly related to the 
investigational product administration in one participant; or a severe non-serious AEs 
considered as, at least, possibly related to the investigational product administration in 
two participants, the study will be temporarily halted until full review of the events. In 
participants, significant changes from baseline measurements will be reviewed and 
participants will be followed until resolved. 
8.4. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
 
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• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the Schedule of Activities 
(SoA).  
• 
Protocol waivers or exemptions are not allowed.  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• 
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
9.1. 
Bronchoscopy 
Bronchoscopy will be performed in accordance with site standard operating procedures 
(SOPs), at 2 hours and 26 hours. These SOPs will reflect current standards 
of practice in hospital care and will include (but are not limited to) the following items: 
• Oxygen supplementation will be given to all participants. 
 
• Pulmonary function will be monitored before the bronchoscopy and after the 
bronchoscopy until FEV1 is within 20% of the pre-procedure value.  
 
• All participants will be monitored in a recovery/holding room post bronchoscopy. 
Participants will be discharged only after approval is obtained from the 
 
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supervising physician, and participants will be given a 24-hour contact number. 
Admission facilities will be available in the event a participant is not deemed fit 
for discharge or if overnight observation is deemed necessary by the study 
physician or site-specific policies. 
Following bronchoscopies, participants will be monitored for at least 4 hours. However, 
should the investigator have any concern for participant safety, participants may be 
requested to remain resident for further observation. 
9.2. 
Segmental lung challenge 
Participants will undergo segmental challenge to the lungs, via bronchoscopy, at 2 hours 
after the first dose of investigational medicinal product (IMP):  10 mL LPS (4 ng/kg) will 
be instilled into the right middle segment and 10 mL saline control will be instilled into 
the lingula segment of the contralateral side.  
Local SOPs will be followed and further details about the segmental LPS/saline challenge 
are provided in the SRM.  
9.3. 
Pharmacodynamic Assessments 
BAL samples will be taken, via bronchoscopy, to measure total protein and neutrophils 
counts.  Baseline samples will be taken immediately before the LPS and saline 
challenges, from a segment in the left lower lobe, and post-challenge samples will be 
taken at 24 h after the LPS and saline challenges, from the challenged segments.   
Details of BAL sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.4. 
Pharmacokinetics 
Blood and BAL samples for assay of GSK2798745 will be collected at the time points 
indicated in the SoA (Section 2.2).  Details of sample collection, processing, storage and 
shipping procedures are provided in the SRM. 
PK analysis will be performed under the control of Platform Technologies and 
Science-IVIVT (PTS-IVIVT)/GlaxoSmithKline.  Plasma and BAL concentrations of 
GSK2798745 will be determined using the currently approved bioanalytical 
methodology.  Raw data will be archived at the bioanalytical site (detailed in the SRM). 
Plasma samples will also be analysed for the metabolite GSK3526876, GSK will store 
the remaining plasma and/or BAL for future possible metabolite investigations.  Analysis 
of compound-related metabolites may be reported under a separate protocol. 
9.5. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
 
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The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8).  
9.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the start of treatment until the follow-up visit.  
However, any SAEs assessed as related to study participation (e.g. study 
treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product, will be recorded from the time a 
participant consents to participate in the study.  
• 
All AEs will be collected from the start of treatment until the follow-up visit. 
• 
Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4. 
9.5.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
9.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.4). Further information on follow-up procedures is given in 
Appendix 4. 
 
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9.5.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg: summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
9.5.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit. 
• 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 12.5. 
9.6. 
Treatment of Overdose 
GSK does not recommend specific treatment for an overdose.  The investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2798745 can no longer be detected systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
 
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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
9.7. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA). 
9.7.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, measuring weight 
and assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. Height will be measured at screening only. 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
9.7.2. 
Vital Signs 
• 
Vital signs will be measured in a semi-supine position after 5 minutes’ rest and 
will include temperature, systolic and diastolic blood pressure and heart rate  
• 
At each time point before dosing, 3 readings of blood pressure and heart rate 
will be taken. The first reading should be rejected. The second and third 
readings should be averaged to give the measurement to be recorded in the CRF. 
At all other time points, single measurements will be taken.  
9.7.3. 
Pulse Oximetry 
• Pulse oximetry will be monitored during each bronchoscopy. Clinically 
significant results will be recorded as AEs. 
9.7.4. 
Electrocardiograms 
• Triplicate 12-lead ECGs will be obtained at each time point before dosing. At all 
other time-points a single 12-lead ECG will be obtained as outlined in the SoA 
(see Section 2) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary. 
• ECG to be measured in a semi-supine position after 5 minutes’ rest. 
9.7.5. 
Spirometry 
Spirometry assessments will be performed from screening through the final visit as 
indicated in the SoA (Section 2).  The following parameters will be assessed: 
• Forced expiratory volume in one second (FEV1) 
• Forced vital capacity (FVC) 
 
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Measurements will be made in triplicate and the best recording (i.e. the highest FEV1 and 
the highest FVC) from 3 technically acceptable manoeuvres will be recorded in the CRF. 
To fulfill the entry criteria, FEV1 should be ≥80% of predicted and FEV1/FVC ratio 
≥70%) at screening and pre-dose.  
Details on performing the spirometry assessments are provided in the SRM. 
9.7.6. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents.  
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study (until the follow-up visit) should be repeated 
until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified. 
• 
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE), then the results must be recorded in the CRF.  
9.7.7. 
Faecal Occult Blood Test (FOBT) 
Based on the preclinical finding of gastric erosions, FOBT will be performed before and 
after dosing (See Section 2). Details on FOBT are provided in the SRM.  
9.7.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Based on preclinical studies that have been conducted, GSK2798745 is considered to be a 
central nervous system (CNS)-active drug. There has been some concern that some 
CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with certain conditions. Although GSK2798745 
has not been shown to be associated with an increased risk of suicidal thinking or 
behaviour, GSK considers it important to monitor for such events. 
 
The C-SSRS is a measure of suicidal ideation and behaviour, with demonstrated 
predictive validity and reliability. Sections of the C-SSRS include suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual suicide attempt(s). The C-SSRS 
assesses lifetime and current suicidal thoughts and behaviours across these categories 
based on an increasing severity of a 1- to 5-rating scale. The semi-structured 
questionnaire is completed by a trained and experienced neurologist, psychiatrist, or 
 
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neuropsychologist, or another trained and experienced person approved by the Sponsor, 
who may be the Principal Investigator or a sub-investigator for the study. See SRM for 
details of the scale. 
The C-SSRS will be performed at screening and after dosing before discharge (See 
Section 2).  
9.8. 
Exploratory biomarkers 
Blood and BAL samples for exploratory biomarker analysis of endothelial barrier 
permeability and/or injury and inflammation will be collected at the time points indicated 
in the SoA (Section 2).  
Samples may also be used for research to develop methods or support identification of 
prognostic/diagnostic biomarkers associated with clinical outcomes in ARDS and related 
diseases. 
Details of sample collection, processing, storage and shipping procedures are provided in 
the SRM. 
Exploratory biomarker results may be entered into the clinical study database before or 
after database lock and unblinding, or may be reported separately. 
9.9. 
Genetics 
Genetics are not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
The primary study objective is to investigate the effect of GSK2798745 relative to 
placebo on BAL total protein at 24 hours after segmental LPS challenge. In this study a 
Bayesian framework will be used (with non-informative priors) to estimate the posterior 
probability of any percentage reduction in mean 24 h post-LPS BAL protein level 
(GSK2798745 relative to placebo). It is anticipated that BAL total protein will be loge 
transformed to improve normality before model fitting. Following back-transformation 
treatment comparisons will be expressed as percentage changes. 
10.1. 
Sample Size Determination 
The sample size of 30 participants per arm (1:1 allocation) is based on an upper limit of 
feasibility. Figure 4 illustrates the probability of study success for a range of sample sizes 
and assumed true treatment effects unconditional on variability. 
Assuming a true treatment effect of a 30% reduction in mean BAL total protein in 
participants receiving GSK2798745 relative to placebo at 24 h after segmental LPS 
challenge to the lung, the probability of study success for the study is 82% (this excludes 
the possibility of success from a review of secondary data), unconditional on the 
variability of BAL total protein in segmental LPS challenged lungs. Outright end of study 
success is defined as at least a 95% posterior probability that the percentage reduction in 
 
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the mean 24 h post-LPS BAL total protein level (GSK2798745 relative to placebo) 
exceeds zero. 
Despite limited historical information for guidance on the true treatment effect for 
GSK2798745, 30% is believed to be a rational estimate.  However, probability of study 
success is sensitive to the true treatment effect – for example, the probability of study 
success reduces to 50% if the true treatment effect is 20% (GSK2798745 relative to 
placebo) with a sample size of 30 per arm but increases to 96% if the true treatment effect 
is 40%. 
Figure 4 
Probability of Study Success (Unconditional on Variance) for a 
Range of Treatment Profiles and Sample Sizes 
 
Estimates for the mean and variance of BAL total protein in segmental LPS challenged 
lungs were obtained from data in an observational study assessing the variability of the 
inflammatory response to segmental LPS challenge by the Fraunhofer Institute of 
 
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Toxicology and Experimental Medicine, Germany [Holz, 2015] using a random effects 
model with total protein levels from 11 participants measured at baseline and 24 h over 2 
study periods.  The data were assumed to be representative of future segmental-LPS 
challenged lungs to be observed in this study. 
The estimate of the mean BAL protein in 24 h post-LPS challenged lungs on the loge 
scale is 5.47 (95% CI 5.23, 5.72).  The variance estimate on the loge scale is 0.25 (95% 
CI 0.13, 0.69).  A posterior distribution was formed for the standard deviation and for 
each possible value of standard deviation from this distribution the power of the study 
was calculated and multiplied by its probability.  The resulting values were all summed to 
give probability of study success unconditional on variance, which is a more accurate 
representation of the probability of study success rather than assuming a single variance 
estimate with no uncertainty. 
Figure 5 shows the minimum observed treatment effect in the study that would achieve 
success (expressed as a percentage reduction in BAL total protein for GSK2798745 
relative to placebo) for a number of sample sizes. Assuming the variance in the study is 
the median obtained from the historical data, the minimum treatment effect to trigger 
success is 19% for a sample size of 30 participants per arm. As the sample size increases, 
the minimum observed treatment effect that would trigger success decreases due to the 
decreasing standard error (greater confidence in the observed treatment effect). This 
figure gives rationale for including the data review region since it is probable that 
moderate observed treatment effects will not achieve success with a sample size of 30 per 
arm. 
Figure 5 
Minimum Detectable Effect for Range of Sample Sizes 
 
10.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 
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Population 
Description 
Enrolled  
All participants who sign the ICF. 
Evaluable 
All participants for whom results of the primary analysis can be 
determined. 
Safety 
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received. 
Other populations, such as Per-Protocol population, may be defined in the RAP. 
10.3. 
Statistical Analyses 
10.3.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The mean percentage reduction in BAL total protein (µg/mL) in segmental 
LPS challenged lungs, at 24 h post-challenge, for GSK2798745 relative to 
placebo, will be assessed using an analysis of covariance (ANCOVA) model 
(fitted in a Bayesian framework with non-informative priors for model 
parameters) testing that there is at least 95% posterior probability that the 
percentage reduction in 24 hour post-challenge mean BAL total protein 
(GSK2798745 relative to placebo) exceeds zero , adjusting for baseline BAL 
total protein. A sensitivity analysis will include 24 h BAL total protein in the 
saline segment (saline challenge will be administered to the contralateral 
lobe) as a covariate. Additional factors may be included as covariates if 
deemed appropriate. 
Secondary 
See Section 10.3.2 and Section 10.3.3 
Exploratory 
Will be described in the reporting and analysis plan. 
10.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Secondary 
For the safety data, no formal hypotheses will be tested. Safety data such as 
adverse events, electrocardiogram (ECG), physical examinations, vital signs, 
spirometry, FEV1 and FVC will be displayed in the form of listings, frequencies, 
summary statistics and graphs. Interpretation will be aided by clinical expertise. 
Full details, including example outputs, will be documented in the RAP. 
 
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10.3.3. 
Other Analyses 
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses 
will be presented separately from the main clinical study report (CSR).  
10.3.4. 
Interim Analyses 
An interim analysis will occur once approximately 10 participants per arm have 
completed the treatment period to assess if the study should stop for futility or continue. 
Subsequently, if the decision at the first interim is to continue, an interim analysis will 
occur once approximately 20 participants per arm have completed the treatment period to 
assess whether the study should continue or stop for success or futility.  If at this point the 
study continues, the maximum 30 participants per arm will be recruited. The study then 
either meets the success criteria, undergoes analysis of secondary data (review) or is 
declared a failure. Enrolment into the study will continue whilst interim analyses are 
taking place. 
This interim framework is being used to allow the possibility to reduce the number of 
participants enrolled into the study, either in the case of an overwhelming observed 
treatment effect or no/poor treatment effect. The interim stopping criteria for success is 
based on the probability of the study going on to meet the success criteria (predictive 
probability that the posterior probability is at least 0.95) whilst the stopping criteria for 
futility is based on the probability of the study going on to declare success or review 
(predictive probability that the posterior probability is at least 0.75, see Table 2). 
Table 2 
Interim Decision Criteria 
Interim 
Analysis 
Success 
Futility 
10 subjects 
per arm 
N/A – cannot stop for success at the 
first interim. 
Predictive Prob ( PP ≥ 0.75) ≤ 0.075 
20 subjects 
per arm 
Predictive Prob (PP ≥ 0.95) ≥ 0.85 
Predictive Prob ( PP ≥ 0.75) ≤ 0.15 
 
At each interim, the probability of the study going on to meet these criteria will be 
calculated.  This probability value may be used to assist in determining whether there is 
sufficient rationale to continue/discontinue the study.  If the probability of study success 
is sufficiently high, then the study may stop for success.  Conversely, if the probability of 
study success or review is sufficiently low then the study may stop for futility. The 
probability thresholds for success and futility have been calibrated to balance the risk of 
declaring success despite a placebo-like drug (type 1 error) and declaring failure despite a 
positive true underlying treatment effect for GSK2798745 relative to placebo (type 2 
error). 
 
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The predictive probability at each interim is calculated using predictive inference 
methods.  The observed data at the interim is used to obtain estimates of the mean and 
standard error of the treatment effect for GSK2798745 relative to placebo.  These 
estimates are then used to predict the treatment effect for participants in the remainder of 
the study using the predictive interim distribution. These two parts of data (observed and 
predicted) are combined to create a complete study.  The end of study success criteria is 
then applied to this complete data set made up of observed and predicted participants.  
This process is performed 10,000 times to account for the uncertainty in the estimated 
treatment effect at the interim – i.e. the same observed data is combined with thousands 
of permutations for the remainder of the study, and each time the end of study success 
criteria is applied.  The proportion of complete studies that meet the pre-defined success 
criteria gives the predicted probability of success if the study was to continue at the 
interim. 
To inform the study design, a range of scenarios were reviewed to assess the operating 
characteristics when changing the total sample size, interim decision rules, interim 
analysis time points and assumed true treatment effects. Characteristics such as the 
overall probability of study success/failure, probability of success/failure at each interim, 
and the expected number of participants to be recruited were reviewed under a variety of 
design options. 
Figure 6 show the operating characteristics of the chosen study design under true 
percentage reductions in total BAL protein for GSK2798745 relative to placebo of 0%, 
15%, 30% and 50%, respectively, unconditional on variability.  The schematic 
demonstrates all possible decision pathways the study may take.  To obtain the operating 
characteristics of a given study design, 10,000 studies were simulated with each one 
taking a particular pathway and finishing in one of the pockets on the left or right of the 
diagram, or indeterminate (additional data review). The overall proportion of simulated 
studies reaching a particular conclusion gives the probability of a single study reaching 
that conclusion. 
A stricter posterior probability futility threshold is implemented at the first interim to 
reduce the probability of incorrectly declaring futility. Furthermore, a minimum of 20 
participants per arm must be recruited before declaring success. These rules are shown 
within the left (success) and right (futile) arrows.  Under this design, assuming a true 
treatment effect of 30%, the overall probability of study success is approximately 83%, 
unconditional on variability.  In addition, the probability of requiring a maximum of 20 
participants per arm is approximately 61% (under the same assumption of true treatment 
effect of 30%).  In the case of a placebo-like drug the probability of incorrectly declaring 
success is approximately 6% (akin to type 1 error rate). The blue boxes at the bottom of 
the charts show the probability that a study goes to data review. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail. 
 
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Figure 6 
Interim Analysis Framework for Range of True Treatment Effects 
 
 
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11. 
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lipopolysaccharide inhalation. Thorax. 2016;71:1130-6.  
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barrier function. Am J Physiol Lung Cell Mol Physio. 2014;307:L817-21.  
Narita K, Sasamoto S, Koizumi S, Okazaki S, Nakamura H, Inoue T,et al. TRPV4 
regulates the integrity of the blood-cerebrospinal fluid barrier and modulates 
transepithelial protein transport. FASEB J. 2015;29:2247-59.  
Ngamsri K-C, Wagner R, Vollmer I, Stark S, Reutershan J. Adenosine Receptor A1 
Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in 
Lipopolysaccharide-Induced Lung Injury. The Journal of Immunology. 2010;185:4374-
84.  
 
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O’Grady NP, Preas II HL, Pugin J, Fiuza C, Tropea M, Reda D,et al. Local Inflammatory 
Responses following Bronchial Endotoxin Instillation in Humans. . 2001;163:1591-8. Am 
J Respir Crit Care Med. 2001;163:1591-8.  
Shyamsundar M, McKeown STW, O’Kane CM, Craig TR, Brown V, Thickett DR,et al. 
Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy 
Volunteers. Am J Respir Crit Care Med. 2009;179:1107-1114.  
Suresh K, Servinsky L, Reyes J, Baksh S, Undem C, Caterina M,et al. Hydrogen 
peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4. 
Am J Physiol Lung Cell Mol Physiol. 2015;309:L1467-77.  
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8.  
Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian M-Y,et al. An Orally 
Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by 
Heart Failure. Pulmonary edema. 2012;4:159ra148.  
Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB. Ca2+ Signaling, TRP Channels, and 
Endothelial Permeability. Microcirculation. 2006;13:693-708.  
Yin J, Michalick L, Tang C, Tabuchi A, Goldenberg N, Dan Q,et al. Role of Transient 
Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury. Am J 
Respir Cell Mol Biol. 2016;54:370-83.  
Yu P, Dong L, Zhang Y, Chen W, Xu S, Wang Z,et al. Design, synthesis and biological 
activity of novel asymmetric C66 analogs as anti-inflammatory agents for the treatment 
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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
AUC 
Area under concentration-time curve 
AUC0–24  
Area under the curve during 24 hours 
BAL 
Bronchoalveolar Lavage 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
Ca2+ 
Calcium 
Cmax 
Maximum observed plasma concentration 
CMT2C 
Charcot-Marie-Tooth Disease Type 2C 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disorder 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CV 
Cardiovascular 
CSSRS 
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
EU 
Endotoxin Unit 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in One Second 
FVC 
Forced vital capacity 
FOBT 
Faecal Occult Blood Test 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
GSK 
GlaxoSmithKline 
HBsAg 
Hepatitis B surface antigen 
HCl 
Hydrochloric acid 
HDPE 
High-density polyethylene 
HIV 
Human Immunodeficiency Virus 
HMVEC 
Human Dermal Microvascular Endothelial Cells 
HPLC 
High performance liquid chromatography 
IB 
Investigator’s Brochure 
 
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IC50 
50% maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IP 
Investigational Product 
i.t. 
Intratracheal 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
Kg 
Kilogram 
KO 
Knockout 
LDH 
Lactate dehydrogenase 
LPS 
Lipopolysaccharide 
MCH 
Mean corpuscular haemogloin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliter 
MSDS 
Material Safety Data Sheet 
Msec 
Milliseconds 
mSV 
MilliSievert 
Ng 
Nanogram 
NOAEL 
No observed adverse effect level 
PK 
Pharmacokinetic 
POP PK 
Population Pharmacokinetic 
PTS-DMPK 
Platform Technologies and Science-Drug Metabolism and 
Pharmacokinetics 
QC 
Quality control 
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) 
SOA 
Schedule of Activities 
SRM 
Study Reference Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TB 
Tuberculosis 
TLR 4 
Toll-like receptor 4 
Tmax 
Time to reach maximum plasma concentration 
TRALI 
Transfusion Related Acute Lung Injury 
TRPV4 
Transient receptor potential vanilloid 4  
ULN 
Upper Limit of Normal 
 
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WBC 
White blood cells 
WOCBP 
Women of Child Bearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
None  
 
 
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12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 3 will be performed by the local laboratory.  
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 3 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
CRP  
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (fasting 
not required) 
Calcium 
Alkaline 
phosphatase 
CPK 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• Cardiac troponin (cTn) 
• Coagulation profile (Quick/INR, PTT and thrombocytes) 
• Faecal Occult Blood Test (FOBT) 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
 
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Laboratory 
Assessments 
Parameters 
hepatitis C virus antibody)  
• Alcohol, cotinine and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines). 
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 6 All events of ALT ≥3 × upper limit of normal 
(ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
 
 
 
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12.3. 
Appendix 3: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Substantial amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
 
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• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
 
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Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate. 
• GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
 
 
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Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in the source document 
agreement (to be signed by the investigator (or delegate) at the site). 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 
 
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12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
 
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leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
 
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reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
 
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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
 
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Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone. 
• 
Contacts for SAE reporting can be found in SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor (who is also the SAE coordinator). 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in SRM. 
 
 
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12.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1:  
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
• 
Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 4 when having penile-vaginal 
intercourse with a woman of childbearing potential  
 
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• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame. 
• 
In addition, male participants must refrain from donating sperm from the time of 
first dose of study treatment until 2 weeks after last dose of study treatment. 
Table 4 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation  
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and
the preferred and usual lifestyle of the participant.)  
NOTES:  
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.  
 
 
 
 
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Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure.  
 
 
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12.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry increased monitoring criteria and required follow up 
assessments 
Liver Chemistry Increased Monitoring Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2 ≥ 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin ≥ 2xULN  or INR 
>1.5 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24 hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or haepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 48hrs of last 
dose4  
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin≥2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
If ALT≥3xULN AND bilirubin ≥ 2xULN  or 
INR >1.5: 
 
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Liver Chemistry Increased Monitoring Criteria  
72 hrs 
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT ≥ 3xULN and bilirubin ≥ 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants 
3. Includes: 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  
 
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