A Placebo-controlled, Double-blind (Sponsor Open), Randomized, Crossover Study to Assess the Efficacy, Safety, and Tolerability of GSK2798745 in Participants With Chronic Cough
Phase: PHASE1
Conditions: Cough
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
207702
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TITLE PAGE
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised,
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in 
participants with chronic cough
Protocol Number: 207702
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Compound Number:
GSK2798745
Development Phase:
2
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): 2017-002265-21
Approval Date: 31-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................8
2.1.
Screening and Follow-up Schedule of Activities............................................8
2.2.
Treatment Period 1 and 2 Schedule of Activities.........................................10
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................14
3.3.
Benefit/Risk Assessment ............................................................................14
3.3.1.
Risk Assessment .........................................................................15
3.3.2.
Benefit Assessment.....................................................................21
3.3.3.
Overall Benefit:Risk Conclusion...................................................21
4.
OBJECTIVES AND ENDPOINTS...........................................................................21
5.
STUDY DESIGN ....................................................................................................22
5.1.
Overall Design ............................................................................................22
5.2.
Number of Participants ...............................................................................22
5.3.
Participant and Study Completion...............................................................23
5.4.
Scientific Rationale for Study Design ..........................................................23
5.5.
Dose Justification........................................................................................23
6.
STUDY POPULATION...........................................................................................26
6.1.
Inclusion Criteria.........................................................................................26
6.2.
Exclusion Criteria........................................................................................27
6.3.
Lifestyle Restrictions...................................................................................29
6.3.1.
Meals and Dietary Restrictions ....................................................29
6.3.2.
Alcohol and Tobacco ...................................................................29
6.3.3.
Activity .........................................................................................29
6.4.
Screen Failures...........................................................................................29
7.
TREATMENTS.......................................................................................................30
7.1.
Treatments Administered............................................................................30
7.1.1.
Medical Devices...........................................................................30
7.2.
Dose Modification .......................................................................................31
7.3.
Method of Treatment Assignment ...............................................................31
7.4.
Blinding.......................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability..............................................32
7.6.
Treatment Compliance................................................................................33
7.7.
Concomitant Therapy..................................................................................33
7.7.1.
Permitted Medications .................................................................33
7.7.2.
Prohibited Medications.................................................................33
7.8.
Treatment after the End of the Study ..........................................................34
8.
DISCONTINUATION CRITERIA.............................................................................35
8.1.
Discontinuation of Study Treatment ............................................................35
8.1.1.
Liver Chemistry Stopping Criteria ................................................35
8.1.1.1.
Rechallenge ...............................................................36
 
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8.1.2.
QTc Stopping Criteria ..................................................................36
8.1.3.
Symptoms of Cardiac Ischemia and Cardiac Troponin 
Stopping Criteria..........................................................................37
8.1.3.1.
Symptomatic Participant:............................................37
8.1.3.2.
Asymptomatic Participant: ..........................................37
8.2.
Withdrawal from the Study..........................................................................37
8.3.
Lost to Follow Up........................................................................................38
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................38
9.1.
Efficacy Assessments.................................................................................39
9.1.1.
Cough Counting...........................................................................39
9.1.2.
Cough Visual Analogue Scale (VAS) ...........................................39
9.1.2.1.
Cough Severity VAS...................................................39
9.1.2.2.
Urge to Cough VAS....................................................40
9.1.3.
Leicester Cough Questionnaire (LCQ).........................................40
9.2.
Adverse Events...........................................................................................40
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................40
9.2.2.
Method of Detecting AEs and SAEs.............................................41
9.2.3.
Follow-up of AEs and SAEs.........................................................41
9.2.4.
Regulatory Reporting Requirements for SAEs .............................41
9.2.5.
Cardiovascular and Death Events................................................41
9.2.6.
Pregnancy ...................................................................................42
9.3.
Treatment of Overdose...............................................................................42
9.4.
Safety Assessments ...................................................................................42
9.4.1.
Physical Examinations.................................................................43
9.4.2.
Vital Signs....................................................................................43
9.4.3.
Electrocardiograms......................................................................43
9.4.4.
Audiometry ..................................................................................43
9.4.5.
Simplified Nutritional Appetite Questionnaire (SNAQ)..................43
9.4.6.
Chest Imaging .............................................................................44
9.4.7.
FEV1 ............................................................................................44
9.4.8.
Clinical Safety Laboratory Assessments ......................................44
9.4.9.
Faecal Occult Blood Test.............................................................44
9.4.10.
Columbia Suicidality Severity Rating Scale (CSSRS) ..................45
9.4.11.
Diary card ....................................................................................45
9.5.
Pharmacokinetics .......................................................................................45
9.6.
Pharmacodynamics ....................................................................................46
9.7.
Genetics .....................................................................................................46
10. STATISTICAL CONSIDERATIONS........................................................................46
10.1.
Sample Size Determination ........................................................................47
10.2.
Populations for Analyses ............................................................................48
10.3.
Statistical Analyses.....................................................................................48
10.3.1.
Efficacy Analyses.........................................................................48
10.3.2.
Safety Analyses...........................................................................49
10.3.3.
Interim Analyses ..........................................................................49
10.3.4.
Exploratory Analyses ...................................................................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................52
 
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12.1.
Appendix 1: Abbreviations and Trademarks................................................52
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................55
12.3.
Appendix 3: Study Governance Considerations..........................................56
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................60
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................66
12.6.
Appendix 6: Genetics..................................................................................69
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................70
 
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1.
SYNOPSIS
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised,
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in 
participants with chronic cough
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Rationale:
Chronic cough is a disease with high unmet medical need. It is hypothesised that chronic 
cough reflects a state of neuronal hypersensitivity involving exaggerated spinal and 
cortical responses to afferent sensory signals originating from mechanosensitive and 
chemosensitive neurons. It is thought that cough reflexes are triggered by adenosine 
triphosphate (ATP) through P2X purinoceptor 3 (P2X3) receptors.  Transient receptor 
potential vanilloid 4 (TRPV4) activation has been shown to cause ATP release from 
airway macrophages and airway epithelial cells, and studies have established a role for 
TRPV4-mediated ATP release and the P2X3 receptor in TRPV4-mediated activation of 
airway afferents.  ATP-stimulated cough is of particular interest as there are data to 
suggest that ATP levels are increased in the airways of patients with asthma and chronic 
obstructive pulmonary disease (COPD) – diseases in which cough is a prevalent 
symptom.  It is hypothesised, therefore, that a TRPV4-ATP-P2X3 axis contributes to the 
evolution and persistence of chronic cough.
GSK2798745 is a potent and selective TRPV4 channel blocker being investigated for the 
treatment of chronic cough. The aim of this study is to evaluate whether blockade of 
TRPV4 channels is effective in reducing cough in participants with idiopathic or 
treatment-resistant chronic cough.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment-
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
 
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Overall Design:
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Study Design Overview
Number of Participants:
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. However, following a sample-size re-
estimation when approximately 50% of the target sample size has completed the study, 
the sample size may be revised upwards or downwards.  Following the sample size re-
estimation, the target number of evaluable participants will not exceed 40 and the number 
of participants randomised will not exceed 48. 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening and Follow-up Schedule of Activities
Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage, and 
family history of premature cardiovascular (CV) 
disease
X
Substances: Drugs, Alcohol, tobacco
Full physical exam, including height and weight
X
X
Height to be measured at screening only.  
Chest imaging (chest x-ray [CXR] or computed 
tomography [CT] scan)
X
Not required if chest imaging has been conducted within 
12 months of screening with no significant findings.
Simplified Nutritional Appetite Questionnaire (SNAQ)
X
Columbia Suicidality Severity Rating Scale (CSSRS)
X
Use ‘Baseline’ CSSRS.
Human immunodeficiency virus (HIV), hepatitis B 
(Hep B) and Hepatitis C (Hep C) screen
X
Clinical chemistry, haematology and urinalysis
(including cardiac troponin)
X
X
Non Fasting 
Follicle-stimulating hormone and estradiol 
X
As needed in women of non-childbearing potential only
Faecal Occult Blood Test (FOBT)
X
FOBT cards will be provided at screening and must be 
returned to the laboratory and analysed before Day -1.
Vital signs (blood pressure, heart rate and 
temperature)
X
X
Triplicate vital signs required at screening. 
12-lead ECG
X
X
Triplicate ECG required at screening.
Forced Expiratory Volume in One Second (FEV1)
X
Not required if documented evidence of FEV1 ≥ 80% and 
120% within the 6 months before screening.
 
 
 
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Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Cough Severity & Urge to Cough Visual Analogue 
Scale (VAS)
X (Severity only)
X (Severity & Urge)
Urge to cough VAS will not be completed at screening.
Audiometry
X
Audiometry to be done anytime between end of Treatment 
Period 2 and Follow-up.
Concomitant Medication review 
X
X
Adverse event (AE)/serious adverse event (SAE)
review
X
X
SAEs collected from the time of consent.  AEs collected 
from the time of first dose (see Section 9.2.1).
1.
Screening assessments may be conducted at multiple visits, if required, but all samples for laboratory safety tests to be collected at one visit (unless repeats).
 
 
 
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2.2.
Treatment Period 1 and 2 Schedule of Activities
Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Study Treatment
Randomisation
X (TP1 only)
Can be done on Day –1 or Pre-dose Day 1.  
Participants will be stratified based on inclusion in a 
cough study within the last 12 months (defined as 
taking an investigational product in a cough study 
within the last 12 months).
Study Treatment dispensed
X
Study Treatment dosing
X
X
X
Home dosing on Days 2-6.  Dosing to be at about the 
same time each day (2 hours relative to dosing on 
Day 1).
Diary Card dispensed
X
X (TP1 only)
Diary card used to collect dosing information, AEs 
and concomitant medications.  Diary card dispensed 
on Day 7 in Treatment Period 1 only (to collect AEs 
and concomitant medications during washout period).
Efficacy Assessments
24- hour Cough Counting Starts
X
X
On Day 7, the cough counter must be attached 
immediately after dosing.  
Participant to be advised to avoid noisy environments 
whilst wearing the counter, and to stay awake for 
10 h after attachment of the monitor.
24- hour Cough Counting Ends
X
X
On Day 1, the cough counter must be removed 
before dosing.
Cough Severity & Urge to Cough VAS
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.2).
Leicester Cough Questionnaire (LCQ)
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.3).
Safety Assessments
Brief physical exam 
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
Weight
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
 
 
 
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Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Vital signs (blood pressure, heart rate and 
temperature)
X (pre-dose)
X
Single measurements
12-lead ECG
X (pre-dose)
X
Single measurements
Clinical chemistry, haematology and urinalysis 
(including cardiac troponin)
X (pre-dose)
X
Can be done on Day –1 or Pre-dose Day 1.  Non-
fasting.
FOBT
X
FOBT cards will be provided on Day 7 and returned 
on Day 8, if possible (or returned by post).
CSSRS
X
X
Use the ‘Since Last Visit’ CSSRS questionnaire.
The pre-dose CSSRS in each Treatment Period can 
be done on Day –1 or Pre-dose Day 1.
SNAQ
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
Audiometry
X
Pre-Treatment Period 1 audiometry can be done 
anytime between Screening and Treatment Period 1, 
Day 1, pre-dose. 
Pre-Treatment Period 2 audiometry can be done any 
time during the washout period (up to Treatment 
Period 2, Day 1 pre-dose).
Concomitant Medication review 
X
X
X
X
X
Concomitant medications collected in Diary Card 
during washout period.
SAE/AE review
X
X
X
X
X
AEs collected in Diary Card during washout period.
Other Assessments
PK blood samples 
X
X
X
Day 1 and Day 7:  predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 
3, 3.5 h post dose
Day 8:  24 h post dose
For participants taking atorvastatin, an extra sample 
will be taken at each time-point.
Optional Genetic Sample
X
Can be taken any time after consent has been signed 
and the participant has been randomised.
 
 
 
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
The Cough Severity & Urge to Cough VAS should be completed before the LCQ, and both questionnaires should be completed 
before any other assessments.  

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned study assessments, including:  safety and pharmacokinetic 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 ICF.
 
 
 
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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 chronic cough.
GSK2798745 is a potent in vitro blocker of recombinant human TRPV4 channels, with:

agonist-evoked Ca2+ influx 50% maximal inhibitory concentration (IC50) value of 
1.6 to 2.0 nM;

hypotonicity-evoked Ca2+ influx IC50 value of 1.6 to 2.0 nM; and 

blocks native human endothelial TRPV4 channels (agonist-evoked impedance 
reduction in the presence of human whole blood IC50=6.5nM).  
GSK2798745 is a potent in vivo blocker of rat TRPV4 channels where full block of 
TRPV4-induced pulmonary edema was observed at a 38 nM total plasma concentration. 
Further information regarding the pre-clinical and clinical studies performed with 
GSK2798745 is available in the investigator brochure (IB) (GSK Document Number 
2013N162862_03).
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 a repeat dose for 7 days in participants
with heart failure.
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745.  Review of data in 
participants with heart failure indicates that there are no clinically significant safety 
concerns with repeat administration up to 7 days. 
TRPV4 is widely expressed in the respiratory tract and is activated by a wide range of 
stimuli including temperature, pH and osmolarity [Toft-Bertelsen, 2017]. It is 
hypothesized that chronic cough reflects a state of neuronal hypersensitivity involving 
exaggerated spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) [Basoglu, 2005] through P2X purinoceptor 3
(P2X3) receptors [Ford, 2013]. TRPV4 activation causes ATP release from airway
epithelial cells [Baxter, 2014], and studies have established a role for TRPV4-mediated 
ATP release and P2X3 receptor in activation of airway afferents.  ATP-stimulated cough 
is of particular interest as there are data to suggest that ATP levels are increased in the 
airways of patients with asthma [Idzko, 2007] and chronic obstructive pulmonary disease 
(COPD) [Baxter, 2014], diseases in which cough is a prevalent symptom. It is 
hypothesized, therefore, that a TRPV4-ATP-P2X3 axis contributes to the evolution and 
persistence of chronic cough [Bonvini, 2016].
3.1.
Study Rationale
The aim of this study is to evaluate whether blockade of TRPV4 channels is effective in 
reducing cough in participants with idiopathic or treatment refractory chronic cough.  
 
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TRPV4 and P2X3 antagonists have been shown to reduce cough effectively in a pre-
clinical cough model in guinea pigs [Bonvini, 2016].  Moreover, clinical data suggest that 
pharmacological inhibition of P2X3 receptors reduces cough frequency and improves 
patient reported outcomes and quality of life in a subset of patients with chronic cough
[Abdulqawi, 2015].
Therefore, blocking TRPV4 channels may be a viable therapeutic strategy for treating 
chronic idiopathic or treatment-resistant cough.
3.2.
Background
Chronic cough is defined in clinical practice as cough lasting greater than 8 weeks. It is 
highly prevalent worldwide and is a leading cause of unplanned visits to the doctor’s 
office [Schappert, 2006]. Chronic cough patients can be broadly divided into 3 groups:  
those with idiopathic cough, those with treatment refractory cough secondary to 
otherwise controlled triggers such as allergic rhinitis or mild asthma, and those with 
cough associated with underlying chronic lung diseases, such as COPD or Idiopathic 
Pulmonary Fibrosis (IPF) [Smith, 2017]. 
Large epidemiological studies that include all 3 patient groups suggest that the prevalence 
of chronic cough is as high as 10% worldwide. The epidemiology of idiopathic and 
treatment refractory chronic cough is more difficult to determine precisely, though it is 
probable that these groups of patients represent a minority of the total compared with 
diseases such as COPD. However, the amount of coughing (coughs per hour) measured 
in patients with idiopathic or treatment refractory chronic cough tends to be much higher 
than in patients with COPD [Abdulqawi, 2015; Sumner, 2013]. Moreover, cough 
suppression in suppurative lung diseases such as COPD may carry additional risks that 
would require establishing a benefit risk ratio in a dedicated study. Therefore, 
demonstrating efficacy in idiopathic and treatment refractory chronic cough populations 
is a logical first step before exploring other populations.
Regardless of etiology, chronic cough is by nature difficult to treat and significantly 
diminishes quality of life. The commonly used therapies for cough are opioid-derived 
over-the-counter medicines, which tend to be relatively ineffective when compared with 
placebo. In addition, these medicines have significant side-effects and potential for abuse 
that limit their usability. Likewise, the opiate codeine is among the most commonly 
prescribed medicines for cough despite similar limitations to its clinical efficacy and even 
greater potential for abuse. Overall, there is a significant unmet medical need for safe 
and effective medicines to treat chronic cough.
3.3.
Benefit/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 IB.
 
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3.3.1.
Risk Assessment
All potential risks of GSK2798745 are based on pre-clinical data.  No risks have been identified in the clinical studies of GSK2798745 
conducted prior to the effective date of this protocol.
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*ug/mL and/or maximum observed 
plasma concentration (Cmax) of 0.050 ug/mL on 
an individual basis.
Myocardial toxicity
Dogs (4-week study):  at 30 mg/kg/day, myofiber 
degeneration/necrosis and inflammation (2 
animals)
Participant Selection: Participants with history 
of acute coronary syndromes (including unstable 
angina), coronary angioplasty, or stenting within 
the past 6 months will be excluded.
Participant Monitoring: Cardiac troponin levels 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
will be monitored throughout the study.
Participant Exposure: Exposure levels will be 
maintained below the threshold detailed in the 
Dose Justification Section (see Section 5.5).
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 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 gastrointestinal (GI) bleeding will 
be excluded.  
Participant Monitoring: Assessment of faecal
occult blood will be performed at screening and 
at the end of each study period.
Participants will be monitored for GI intolerance 
and sequential clinical chemistry analysis,
including liver enzymes.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 monitored 
throughout the study.
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 
Electroencephalography (EEG)/CV study.  In 
other compounds in the same series, 
convulsions have been observed.
Participant Selection: Participants with 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 and appetite 
will be monitored.  The Simplified Nutritional 
Appetite Questionnaire (SNAQ) will be used to 
monitor appetite. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 pressure was observed in preclinical 
studies. 
Participant Monitoring: Blood pressure will be 
monitored throughout the study.
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 
Participant Monitoring: Despite the very low 
risk that hearing will be affected, audiometry will 
be conducted during the study at baseline in 
each Treatment Period and at the Follow Up 
Visit.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
However, these findings are academic, and have 
not been observed in any drug induced model. 
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].
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Risk associated with blood draws 
Fainting, mild pain, bruising, irritation or redness 
at a phlebotomy site may be associated with 
blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Risk associated with cough monitoring
Mild contact dermatitis (skin irritation) or redness 
may be associated at the sites where a 
microphone is adhered.
Site staff will follow standard approaches for 
managing events related to application of self-
adherent pads.
Risks associated with chest imaging (if required
for participant selection)
The approximate effective radiation dose for a 
chest X-ray is 0.1 milliSievert (mSv) and 7 mSv 
for a chest CT-scan.
If a participant has had chest imaging within the 
12 months prior to starting the study, the 
procedure does not need to be repeated.
 
 
 
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3.3.2.
Benefit Assessment

Potential benefit of receiving GSK2798745 that may have clinical utility during 
study duration.

Medical evaluations and assessments associated with study procedures, e.g. physical 
examination, electrocardiogram, laboratory assessments, chest x-ray (CXR) (if 
applicable).

Contributing to the process of developing new therapies in idiopathic or treatment 
resistant chronic cough, an area of unmet medical need. 
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study 
(e.g. dose selection, careful participant selection and risk monitoring), the potential risks 
identified in association with GSK2798745 are justified by the anticipated benefits that 
may be afforded to participants with idiopathic or treatment resistant chronic cough.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Exploratory

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts over 24 hours following 
7 days of dosing

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo at improving 
patient reported outcomes in participants 
with idiopathic or treatment-resistant 
chronic cough

Change from baseline cough severity and 
urge to cough visual analogue scale (VAS)

Change from baseline Leicester Cough 
Questionnaire (LCQ) score

To evaluate the pharmacokinetics (PK) of 
GSK2798745 and its M1 metabolite in 
participants with idiopathic or treatment-
resistant chronic cough

Plasma concentrations of GSK2798745, 
and derived PK parameters, as data permit
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Figure 1
Study Design Overview
5.2.
Number of Participants
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. A participant will be considered evaluable 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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if they have completed at least one Treatment Period and have evaluable cough counting 
data from at least one Treatment Period.  A sample-size re-estimation will be conducted 
when approximately 50% of the target sample size has completed the study.  The sample 
size may be revised upwards or downwards (see Section 10.3.3).  Following the sample 
size re-estimation, the target number of evaluable participants will not exceed 40 and the 
number of participants randomised will not exceed 48.
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

A multicentre, randomised, double-blind, placebo-controlled crossover trial is a well-
established strategy to evaluate efficacy and safety of investigational medicinal 
products, such as GSK2798745. 

A placebo arm is included to determine the absolute effect of GSK2798745. In 
addition, the placebo-controlled design is appropriate as there are no effective, 
currently approved prescription medicines for chronic cough, and over-the-counter 
cough medicines have generally not shown benefit over placebo.  

Cough will be measured using a VitaloJAK cough device which is a validated, 
dedicated high fidelity recording device that provides ambulatory objective 
monitoring of cough with post-recording signal processing and expert systems to 
analyse coughs. Coughs will be recorded for 24 hours prior to dosing of each 
treatment period (baseline) and for 24 hours following dosing on Day 7 of each 
treatment period. 

The crossover design will be employed to minimise, as much as possible, the 
potential for variability in randomisation in a relatively small sample size.  

As chronic cough can significantly impact physical and emotional wellbeing, patient 
reported outcomes are important factors in determining the impact of a cough 
treatment. The Leicester Cough Questionnaire (LCQ) will be utilised as it is an 
established self-completed health related quality of life measure of chronic cough. 
The LCQ is a valid, repeatable 19 item self-completed quality of life measure of 
chronic cough which is responsive to change [Birring, 2003].
5.5.
Dose Justification
In this study, participants will take a 4.8 mg starting dose on Day 1, followed by a 2.4 mg 
GSK2798745 (tablet) once daily for remaining 6 days.
 
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In the first time in human study with GSK2798745 (GlaxoSmithKline [GSK] study 
TR4113787), single doses up to 12.5 mg, and repeat doses of 5 mg once daily for 
14 days, were tested in healthy participants.  In addition, participants with heart failure
were treated for 7 days with once daily doses of 2.4 mg GSK2798745 (as a capsule with 
food).  There were no serious adverse events (SAEs) in study TR4117387. In other 
studies, with GSK2798745, there has been only one SAE to date. A participant with 
heart failure (Study 201881) had orthostatic hypotension during the washout period 
between the 2 treatment periods. The Principal Investigator (PI) deemed it not related to 
study treatment.
Another healthy participant study was conducted to compare the pharmacokinetics (PK)
of different tablet formulations administered with or without food (GSK study 204725).  
A population PK (POP PK) approach was used to analyse all available clinical PK data 
(taking into consideration participant weight, formulation, impact of food, and other 
variables).  Trial simulations were performed with this POP PK model with different 
dosing regimen.
A rat study was conducted assessing the ability of different doses of GSK2798745 
infusion to reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist, 
GSK1016790.  Based on this study, the estimated human IC50 is 2.1–3.2 ng/mL.  To 
evaluate drug activity/efficacy at the intended dosing regimen, TRPV4 blockade was
estimated using the population model, and the potency values derived from the rat 
pulmonary study. 
Based on the simulations, the intended dosing scheme for this study with up to 40 
evaluable participants is a 4.8 mg dose on Day 1 followed by a 2.4 mg dose once daily 
for the following 6 days.  Table 1 lists the predicted average TRPV4 inhibition over the 
24-hour period on Day 7 based on this potency range.  The schematic in Figure 2 also 
depicts the range of GSK2798745 systemic exposure and the predicted percent inhibition 
of TRPV4 with the intended regimen.  With a loading dose of 4.8 mg, both GSK2798745 
exposure and TRPV4 inhibition reach steady state from the first dose, compared with 
after 4 to 6 days without the loading dose.
This dose regimen was selected to ensure that no participant intentionally exceeds the 
daily AUC of 513 ng*hr/mL and Cmax of 50 ng/mL while simultaneously providing 
sufficiently high channel blockade.  That is the exposure observed at the no observed 
adverse effect level (NOAEL) of 3 mg/kg in the 3-month dog safety study with a 30-fold 
safety margin.  The likelihood of one or more participants of the 40 participants to be 
dosed with this regimen, exceeding the threshold on Day 1 and Day 7 is listed in Table 1.
Food does not significantly impact the predicted exposures of GSK2798745 and the 
resulting TRPV4 inhibition as displayed in Table 1.  So, GSK2798745 can be 
administered with or without food. 
 
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Figure 2
GSK2798745 exposure and % TRPV4 inhibition
Table 1
Predicted exposure, probability of exceeding threshold and TRPV4 
percent inhibition
4.8 mg on 
Day 1 and 
2.4 mg 
OD 
Days 2–7
24 h
exposure
Median (95% PI)
% Probability that ≥ 
1 of 40 participants 
exceed threshold of
%TRPV4 
inhibition over 
24-hour period
Median (95% 
PI)
AUC24 
(ng*hr/mL)
Cmax (ug/mL)
AUC24
(513 
ng*hr/mL)
Cmax
(50 
ng/mL)
With food
Day 1
201.5 (127.5 –
302.8)
18.7 (11.2 –
29.8)
0
0
72.0 (56.5 –
82.6)
Day 7
147.6 (79.4 –
281.1)
13.1 (7.5 –
22.8)
2.0
0.2
67.3 (46.6 –
83.6)
Without 
food
Day 1
202.0 (128.3 –
303.5)
22.7 (15.3 –
34.2)
0
0.6
72.0 (55.3 –
83.4)
Day 7
141.5 (76.6 –
269.7)
14.9 (9.1 –
24.8)
1.8
0.4
65.7 (44.2 –
82.7)
 
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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 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Chronic idiopathic cough for ≥1 year (before screening), defined as:

a cough that is unresponsive to at least 8 weeks of targeted treatment, or

a cough for which no objective evidence of an underlying trigger has been 
determined, despite medical investigations.
3.
No significant findings on chest imaging (CXR or CT scan) within 12 months before 
screening (participants with an abnormal CXR within 12 months, from a temporary 
process, will be allowed to participate if a repeat CXR is normal). 
4.
FEV1 ≥80% and 120% of the predicted normal value (at screening), or documented 
evidence of FEV1 ≥80% and 120% within the 6 months before screening.
5.
Score of ≥40 mm on the Cough Severity VAS at Screening.
WEIGHT
6.
Body weight ≥50 kg and body mass index (BMI) within the range 18 to 32 kg/m2
(inclusive) at screening.
SEX
7.
Male or female
a.Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this
protocol from the time of first dose of study treatment until 2 weeks after last dose of 
study treatment, and refrain from donating sperm during this period.
b.Female participants: 
A female participant is eligible to participate if she is not of childbearing potential
as defined in Appendix 5.
 
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INFORMED CONSENT
8.
Capable of giving signed informed consent as described in Appendix 3, 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:
MEDICAL CONDITIONS
1.
History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on 
permitted therapies or that would, in the opinion of the investigator or the medical 
monitor, make the participant unsuitable for inclusion in this study.
2.
History or current evidence of chronic productive cough.
3.
History of acute coronary syndromes (including unstable angina), coronary 
angioplasty, or stenting within the 6 months before screening.
4.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive 
fecal occult blood test [FOBT] at screening).
5.
History of stroke or seizure disorder within 5 years of screening.
6.
Respiratory tract infection within 6 weeks of screening.
7.
Participant who, in the investigator’s opinion, 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 Suicidality Severity Rating Scale (C-SSRS) in the last 6 months (assessed 
at screening).
8.
Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
9.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at screening.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
11. QTc >450 msec or QTc >480 msec in participants with bundle branch block at 
screening.
NOTE: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method.  It is either 
machine-read or manually over-read.
 
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PRIOR/CONCOMITANT THERAPY
12. Use of a listed prohibited medication (Section 7.7) within the restricted timeframe 
relative to the first dose of study treatment.
13. Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (Section 7.7).
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months of screening.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. Current enrollment or past participation within the 3 months before screening in any 
clinical study involving an investigational study treatment or any other type of 
medical research.
DIAGNOSTIC ASSESSMENTS 
17. Positive human immunodeficiency virus (HIV) antibody test at screening.
18. Presence of Hepatitis B surface antigen (HBsAg) at screening.
19. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
20. 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.
21. Cardiac troponin at screening > ULN for the assay.
OTHER EXCLUSIONS
22. History of alcohol abuse within 6 months of screening, in the opinion of the 
investigator.
23. Current smoker or history of smoking within the 6 months before screening, or a 
cumulative history of ≥20 pack years.
Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked)
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study.
 
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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 pummelos, exotic citrus fruits, grapefruit hybrids or fruit 
juices from 7 days before the start of study treatment until the end of study treatment 
(in both Treatment Periods).
6.3.2.
Alcohol and Tobacco

During each Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample on Day 7.

Only non-smokers may be recruited into this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities (e.g. walking, watching television, reading).

Participants will be instructed to avoid noisy environments 24 hours before the 
audiometry assessments.

Participants will be asked to stay awake for 10 hours after attachment of the cough 
monitor, and to avoid noisy environments whilst wearing the cough monitor
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 SAEs.
Participants may be rescreened once.  If rescreening is performed, participants must be 
assigned a different unique subject identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.  
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 
subject will be considered a screen failure.
 
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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
Dosage formulation:
White to almost white, round, 
film-coated tablet.  
Tablet A (micronized active 
pharmaceutical ingredient 
[API])
White to almost white, round, 
film-coated tablet
Unit dose strength:
2.4 mg
Not applicable
Route of Administration 
Oral
Oral
Dosing instructions:
Two tablets to be taken on 
Day 1. One tablet to be taken 
on Days 2 to 7.  All doses to 
be taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Two tablets to be taken on 
Day 1. One tablet to be taken 
on Days 2 to 7.  All doses to 
be taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Packaging and Labelling
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
7.1.1.
Medical Devices

The VitaloJAK (Model 7100; manufactured by Vitalograph Ltd) will be used to 
sense and record coughs for up to 24 hours (baseline and Day 7 in each treatment 
period).  The VitaloJAK has a CE mark, indicating compliance to the Medical 
Devices Directive of the European Community (see Section 9.1.1).

Instructions for using the VitaloJAK will be provided in a study-specific manual 
provided by Vitalograph.
 
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7.2.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.3.
Method of Treatment Assignment
All participants will be centrally randomised 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 assignment to one of the 2 treatment sequences shown in Table 2, 
according to the randomisation schedule generated prior to the study by the Clinical 
Statistics Department at GSK.  In the randomisation, participants will be stratified based 
on inclusion in a cough study within the last 12 months (defined as taking an 
investigational product in a cough study within the last 12 months).  Each participant will 
be dispensed blinded study treatment, labelled with his/her unique randomisation number.
Table 2
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
AB
Placebo tablets for 7 days
GSK2798745 tablets for 7 days
BA
GSK2798745 tablets for 7 days
Placebo tablets for 7 days
Study treatment will be dispensed at the study visits summarized in the Schedule of 
Activities (SOA) (Section 2.2).  Returned study treatment should not be re-dispensed.
7.4.
Blinding
This will be a double blind (sponsor open) 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.  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;
however, only the statistician and programmer (and delegates) will have access to 
individual participant level data.  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 
 
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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 Case Report Form 
(CRF), as applicable.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
A participant whose treatment sequence 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 (i.e. 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.
 
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7.6.
Treatment Compliance
Participants will take the study treatment at home on Day 2 to 6.  Compliance will be 
assessed at the end of each Treatment Period by reviewing the participant diary card and 
questioning the participant.  A record of the number of tablets dispensed to and taken by 
each participant must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates will be recorded in the CRF for Day 1, 6 and 7 of 
each Treatment Period.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements), approved by the investigator, in consultation with 
the GSK Medical Monitor, that the participant is receiving at the time of enrolment, or 
receives during the study, must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications
Paracetamol at doses of ≤3 grams/day is permitted for use any time during the study.
Other concomitant medication will be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
Stable use of some medications may be permitted if the dose is stable for at least 28 days 
prior to Day 1, and the medication was prescribed for an indication other than cough. 
The dose should remain constant throughout the study. Changes in dose are not 
permitted, unless required for safety or tolerability. These willl be considered on a case 
by case basis by the investigator in consultation with the GSK Medical Monitor.
7.7.2.
Prohibited Medications
Except for the permitted medication noted above and those approved by the investigator 
in consultation with the GSK Medical Monitor (Section 7.7.1), participants must abstain 
from taking prescription and 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) or 30 days for ACE inhibitors, before the first dose 
of study treatment until completion of the follow-up visit, unless in the opinion of the 
investigator and GSK Medical Monitor the medication will not interfere with the study.
During the study, participants should not use drugs that are strong inhibitors or inducers
of Cytochrome P450 (CYP) 3A4 or p-glycoprotein (P-gp), because they may alter 
 
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GSK2798745 concentrations.  The list of background therapy/drugs may be modified 
based on emerging data. These include, but are not limited to, those listed in Table 3.
Table 3
Strong inducers/inhibitors of CYP3A4 and P-gp
Antiretrovirals:
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir, 
boceprevir
Antibiotics:
clarithromycin, telithromycin, troleandomycin, rifampin
Oral antifungals:
ketoconazole, itraconazole, voriconazole
Antidepressant
nefazadone 
Immunosuppressant
cyclosporine
Anti-Epileptic
carbamazepine, phenytoin
GSK2798745 has weak CYP3A4 inhibition potential. It is possible that concentrations of 
drugs that are substrates of CYP3A4 may be increased. HMG-CoA reductase inhibitors, 
such as atorvastatin and simvastatin, are examples of CYP3A4 substrates that might be 
taken by the eligible participants. Participants being treated with simvastatin will be 
allowed to participate in the study, as long as their dose is 20 mg once daily.  
Participants being treated with >20 mg once daily simvastatin will be considered on a 
case basis by the investigator in consultation with the GSK Medical Monitor.  
Participants being treated with atorvastatin of any therapeutic dose are allowed to 
participate in the study.  The concentration of atorvastatin may be evaluated after the 
study.  The investigators may also consider substitutions of these medications.
It is strongly recommended that participants avoid using drugs that are sensitive 
substrates of Cytochrome P450 (CYP) 3A4 and/or P-gp or that have a low therapeutic 
index because concentrations of these substrates may be increased by GSK2798745. If 
co-administration of medications with interaction potential with GSK2798745 is 
necessary, investigators should monitor participants for loss of efficacy or consider 
substitutions of these medications.  
All concomitant medications may be reviewed by the Medical Monitor and it will be up 
to the discretion of the Investigator in consultation with the GSK Medical Monitor, 
whether the medication can be continued and/or the participant can participate in 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 the indication being studied is not life threatening or seriously debilitating.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who withdraw or who are withdrawn from study treatment will be withdrawn 
from the study.  See the SoA (Section 2.1) for assessments to be performed at early 
withdrawal.
Participants who start taking a prohibited medication during the study will be withdrawn, 
unless approved by the investigator in consultation with the GSK Medical Monitor.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm; or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.
 
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Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7.
8.1.1.1.
Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.1.2.
QTc Stopping Criteria
If a participant meets either bulleted criterion below, two further ECG recordings should 
be done (obtained over a brief [e.g. 5 to 10 minute] recording period).  A participant who 
meets either bulleted criterion, based on the average of the triplicate ECG readings, will 
be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
 
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For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  
8.1.3.
Symptoms of Cardiac Ischemia and Cardiac Troponin Stopping 
Criteria
8.1.3.1.
Symptomatic Participant:
If a participant experiences symptoms of cardiac ischemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  GSK2798745 should be discontinued permanently.  The participant should 
be evaluated by a cardiologist and undergo any clinically appropriate testing.  The 
participant should be followed up until symptoms are resolved.
8.1.3.2.
Asymptomatic Participant:
Cardiac troponin will be measured pre-dose and at the end of dosing, in each Treatment 
Period.  If any cardiac troponin assessment is >ULN or >2 times the participant’s 
baseline value (screening value), the participant should be assessed for symptoms of 
cardiac ischemia (as above).  If the participant is asymptomatic, the participant can 
continue in the study after discussion with the Medical Monitor and close monitoring for
symptoms.
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.
 
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
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 for data to be collected at the time of withdrawal (early withdrawal 
visit).
8.3.
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.

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 summarised in the SoA. 

Protocol waivers or exemptions are not allowed 

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. 
 
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
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.
Efficacy Assessments
9.1.1.
Cough Counting
Cough monitoring will be conducted at the beginning and end of each treatment period, 
as shown in Section 2 (SOA).
The VitaloJAK cough monitor will be used.  The VitaloJAK cough monitor was 
developed by Prof 
 Dr 
 and Prof 
 at 
University Hospital of South Manchester NHS Foundation Trust (UHSM), and has been 
fully validated in clinical studies.  The VitaloJAK cough monitor has CE registration and 
Food and Drug Administration (FDA) 510K clearance.
The VitaloJAK Cough Monitor requires a disposable, single use chest sensor that is 
attached to the participant’s chest, and a ‘lapel microphone’ that is attached to the 
participant’s clothing. The monitor collects high fidelity recordings, recording all sound 
frequencies required for the semi-automated analysis of cough.  The recording 
automatically stops at 24 hours.  
Kits will be supplied by Vitalograph to the site containing all items required for each 24-
hour recording, including the monitor, memory card and battery packs. 
Recordings from the VitaloJAK Cough Monitor will be sent to Vitalograph for analysis 
via the Vitalograph Web Portal.  Recordings will be processed through the semi-
automated cough analysis system developed by UHSM. Vitalograph will QC check the 
recordings on receipt.  The recording will then be processed to remove non-cough sounds 
and silences, leaving a set of segmented files for analysis by a Cough Analyst at 
Vitalograph. 
9.1.2.
Cough Visual Analogue Scale (VAS)
Participants will be asked to complete 2 VAS forms, one each to rate the severity of their 
cough, and their urge to cough (see SRM).  
The VAS forms should be completed before other clinical assessments (and before the 
LCQ), and participants should be given instructions on how to complete the form.  The 
forms will be provided by GSK – the site should not make photocopies of the forms, or 
print from the PDF file.
9.1.2.1.
Cough Severity VAS
The participant will be asked:  ‘How severe was your cough today?’ 
 
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The participant will place a mark on a 100 mm horizontal line, rating the severity of their 
cough from ‘Not at all’ to ‘Extremely’.
9.1.2.2.
Urge to Cough VAS
The participant will be asked:  ‘Please rate the intensity of your urge to cough today’ 
The participant will place a mark on a 100 mm horizontal line, rating their urge to cough 
from ‘No urge’ to ‘Severe urge’.
9.1.3.
Leicester Cough Questionnaire (LCQ)
The LCQ is a validated, self-completed, quality of life measure of chronic cough
[Birring, 2003].  The questionnaire is designed to assess the impact of cough on various 
aspects of the participant’s life.  
The LCQ should be completed after the Cough VAS, but before other clinical 
assessments, and participants should be given instructions on how to complete the 
questionnaire.  The participant will be asked to read 19 statements, and rate their answer 
on a 7 point Likert response scale (see SRM).  
9.2.
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). 
9.2.1.
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 immediately and 
under no circumstance should this exceed 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.
 
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
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.
9.2.2.
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. 
9.2.3.
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 8.3). Further information on follow-up procedures is given in
Appendix 4.
9.2.4.
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 e.g. 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.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
 
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The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
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 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
9.3.
Treatment of Overdose
For this study, any dose of GSK2798745 greater than the planned dose in the protocol,
will be considered an 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 24 h 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 will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
 
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9.4.1.
Physical Examinations

A full physical examination will include, at a minimum, measuring weight, and 
assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 

A brief physical examination will include, at a minimum, measuring weight, and 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).

Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
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 screening, three readings of blood pressure and pulse 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.
9.4.3.
Electrocardiograms

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.

At screening, triplicate ECG are required:  3 individual ECG tracings should be 
obtained over a brief (e.g. 5 to 10 minute) recording period.
9.4.4.
Audiometry
Audiometry will be performed by authorised, trained staff using standard audiometry 
techniques.  Participants will be instructed to avoid noisy environments 24 h prior to the 
audiometry assessments.  Only air conductance will be performed.  It will be at the 
discretion of the Investigator, Medical Monitor and/or the audiologist to determine if 
significant changes from baseline are seen and if a bone conductance test should be 
performed.  Details of the audiometry testing are in the SRM.
9.4.5.
Simplified Nutritional Appetite Questionnaire (SNAQ)
The SNAQ is a participant completed, short questionnaire (4 questions) to assess appetite 
[Wilson, 2005] (see SRM).  
 
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9.4.6.
Chest Imaging
Chest imaging (CXR or CT scan) is only required if a participant has not had chest 
imaging within 12 months of screening. If a participant has had an abnormal CXR within 
12 months, from a temporary process, the CXR may be repeated to determine eligibility.  
Chest imaging will be performed by authorised, trained staff.  
9.4.7.
FEV1

FEV1 will be measured to assess eligibility.  It does not need to be repeated if there 
is documented evidence of FEV1 ≥80% and 120% within the 6 months before 
screening.

Spirometry assessments will be performed whilst the subject is in a seated position 
(if the assessment is done on a bed, the subject’s legs should be over the edge).

Spirometry assessments will be repeated until 3 technically acceptable measurements 
have been made.  
9.4.8.
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. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 to 10 days after the last dose of study treatment 
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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
9.4.9.
Faecal Occult Blood Test
Based on the preclinical finding of gastric erosions (See Section 3.3.1), FOBT will be 
performed to determine eligibility and assess any possible study treatment-related GI 
blood loss. 
 
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At each time-point, participants will be given 2 FOBT cards with instructions for 
completing (using 2 different bowel movements) and returning the tests (in person or by 
post).
9.4.10.
Columbia Suicidality Severity Rating Scale (CSSRS)
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.
Participants being treated with GSK2798745 should be assessed and monitored 
appropriately for suicidality and unusual changes in behaviour.  Consideration should be 
given to discontinuing GSK2798745 in participants who experience signs of suicidal 
ideation or behaviour.
The CSSRS is a measure of suicidal ideation and behaviour, with demonstrated 
predictive validity and reliability.  Sections of the CSSRS include suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual suicide attempt(s).  The CSSRS 
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.
At screening, the ‘Baseline’ CSSRS questionnaire will be completed.  At all other time-
points, the ‘Since Last Visit’ CSSRS questionnaire will be used (see Section 2, SOA).
9.4.11.
Diary card
In each Treatment Period, a diary card will be used to collect:

dosing information for Days 2 to 6 (Date and Time of Dose); 

AEs; and 

concomitant medications.
Between Treatment Periods 1 and 2 (the ‘Washout Period’), a diary card will be used to 
collect AEs and concomitant medications.
Paper diary cards will be used (see SRM).
9.5.
Pharmacokinetics

Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the 
timepoints indicated in the SOA (Section 2).
 
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
Approximately 2 mL of blood will be collected in ethylenediaminetetraacetic acid 
(EDTA) tubes. The actual date and time of each blood sample collection will be 
recorded. 

The timing and volume of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure adequate PK monitoring of GSK2798745 
and, if possible, any relevant GSK2798745 metabolites.  

Additional collection, processing, storage and shipping procedures are provided in 
the laboratory manual.

PK analysis will be performed under the control of Platform Technologies and
Science-In Vitro/In Vivo Translation (PTS-IVIVT)/ and Third Party Resourcing 
(TPR) GlaxoSmithKline.  Plasma 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 may be analyzed for the metabolite M1.  GSK may store the 
remaining plasma from the PK plasma samples for future possible additional 
metabolite analysis.  Additional analysis of compound-related metabolites may be
reported under a separate protocol.

For participants taking atorvastatin, an extra sample will be taken at each PK time-
point for analysis of atorvastatin concentration, and possible analysis of atorvastatin 
metabolites.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Laboratory 
Manual.
10.
STATISTICAL CONSIDERATIONS
This study is designed to estimate the effect of GSK2798745 relative to placebo on day-
time cough count totals following seven days of dosing. Day-time cough count totals 
will be derived from the total number of coughs during the first 10 hours following 
dosing, during which time the participant is expected to be awake. 
 
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The inference to be carried out will be with respect to the following hypothesis:

Treatment with GSK2798745 leads to an improvement in day-time 10-hour cough 
count totals compared with placebo.
The above hypothesis will be investigated in this study by means of a Bayesian approach, 
which will assume a non-informative prior distribution. It is anticipated that the day-time
10-hour cough count totals will be log-transformed before statistical analysis, and hence 
the treatment effect will be evaluated in terms of a ratio of day-time cough count totals 
(GSK2798745 / placebo). A day-time cough count total of at least 30% less for
GSK2798745 than for placebo is of interest. The posterior probability that the true ratio 
of the mean effect size of the test treatment and the mean effect size of the reference 
treatment (test) / (reference), is less than 0.7, and corresponding 90% credible 
intervals, will be obtained. The posterior probability that the true ratio is less than 0.7 
will be referred to as PP (ratio<0.7).
10.1.
Sample Size Determination
A simulation approach has been employed to investigate the chance of correctly 
determining a positive study with the planned number of participants. An estimate of 
0.28 for the within subject variability in cough count totals was obtained from previous 
studies and this estimate was used in the simulations. 
A treatment ratio (active:placebo) of 0.7 is considered to indicate an effective treatment. 
A treatment ratio of 0.5 is considered to represent a very effective treatment.
A positive study will be declared if the posterior probability that the true treatment ratio 
is less than 0.7 is more than 70% (PP(ratio <0.7) >70%). Given the planned sample size 
of 24 participants, if our variability assumptions are correct, then if the true treatment 
ratio is 0.5, there is a 95.3% probability of correctly declaring success. Conversely, if the 
true treatment ratio is 1, there is a 0.2% probability of declaring success at the end of the 
study. 
An unblinded sample size re-estimation is planned in addition to the final analysis. This 
will be performed when at least 12 participants have completed both dosing periods and
key assessment data is available. Cleaned efficacy data will be provided by Data 
Management to the unblinded study statistician. 
Estimated treatment ratio of day-time cough counts between GSK2798745 and placebo 
will be calculated together with 90% credible intervals assuming a non-informative prior. 
This analysis will be supplemented by deriving predictive and/or conditional power in 
order to support sample size re-estimation. As a result of the sample size re-estimation, 
the sample size could be revised either upwards or downwards from the planned sample 
size of 24 evaluable participants, but the target number of evaluable participants will not 
exceed 40 participants.
Full details of the plan for the sample size re-estimation will be described in the 
Reporting and Analysis Plan (RAP).
 
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10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database.
All Subjects
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Pharmacokinetic
All randomised participants who take at least 1 dose of study 
treatment and for whom a pharmacokinetic sample was obtained 
and analysed.
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Day-time 10-hour cough counts following seven days’ dosing of 
GSK2798745 as compared with placebo will be analysed by first log 
transforming the day-time 10-hour cough counts recorded on day 7 of each 
dosing period. The difference between GSK2798745 and placebo in log-
transformed count rates will be investigated using a mixed effects model with 
fixed effects terms for treatment and period. Centre effects and the effect of 
whether or not the participant has participated in a cough clinical trial (which 
will be included as a stratification factor in the randomisation) in the previous 
12 months will also be investigated. Baseline cough counts may be included 
in the model as a covariate. Participant will be treated as a random effect in 
the model. The posterior probability and corresponding 90% credible
intervals that the ratio of the mean effect size of the test treatment and the 
mean effect size of the placebo treatment μ(test) - μ(placebo), is less than 1 
will be constructed. In addition, the posterior probability true effect size 
distribution will be used to obtain estimates for the probabilities that the true 
effect size falls below thresholds of interest (e.g. what is the probability the 
true ratio is less than 0.7 and less than 0.5).
The presence of carryover effects or treatment by period interaction will also 
be investigated and, if deemed appropriate, an analysis by period will be 
undertaken. 
Exploratory
Will be described in the reporting and analysis plan.
 
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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 are being tested and no statistical
analyses will be performed.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards.
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram 
(ECG) will be summarized by treatment and time-point.
10.3.3.
Interim Analyses
At least one interim analysis will be conducted during the course of the study. The 
treatment level results will be made available to the GSK study team who will review the 
available cough count data before making a decision on whether to:
i) stop the study on the grounds of futility
ii) adjust the sample size, in the event that futility criteria have not been met. 
The interim analysis will also include a preliminary assessment of whether there is any 
evidence for the presence of carryover effects or treatment by period interaction.
Following the interim analysis, any adjustment to the sample size will be communicated 
to the sites.
The interim analysis will be conducted after at least 12 participants have completed both 
dosing periods and will look at day-time 10-hour cough count data only. 
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statisticians (including QC statistician) and programmers will have access to 
individual participant data.  However, the findings of the interim analysis will be shared 
with the entire GSK study team. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.3.4.
Exploratory Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics
Modelling & Simulation Department within GlaxoSmithKline. Calculations will be 
based on the actual sampling times recorded during the study. The systemic 
concentrations of GSK2798745, any metabolites, and atorvastatin will be summarised, as 
data permit. The details of the PK analysis will be listed in the RAP. 
 
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11.
REFERENCES
Abdulqawi R, R. Dockry, K. Holt et al. P2X3 receptor antagonist (AF-219) in refractory 
chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 
2015;385(9974):1198-205. 
Basoglu OK, A. Pelleg, S. Essilfie-Quaye, et al.,. Effects of Aerosolized Adenosine 5′-
Triphosphate vs Adenosine 5′-Monophosphate on Dyspnea and Airway Caliber in 
Healthy Nonsmokers and Patients With Asthma. Chest. 2005;128(4):1905-1909. 
Baxter M, S. Eltom, B. Dekkak, et al. Role of transient receptor potential and pannexin 
channels in cigarette smoke-triggered ATP release in the lung. Thorax. 
2014;69(12):1080-1089. 
Birring S, B Prudon, A J Carr, S J Singh, M D L Morgan, I D Pavord. Development of a 
symptom specific health status measure for patients with chronic cough:  Leicester Cough 
Questionnaire (LCQ). Thorax, 2003 58(4):339-343.
Bonvini SJ, M.A. Birrell, M.S. Grace, et al. Transient receptor potential cation channel, 
subfamily V, member 4 and airway sensory afferent activation: Role of adenosine 
triphosphate. J Allergy Clin Immunol. 2016;138(1):249-261 e12. 
Ford AP, B.J. Undem. The therapeutic promise of ATP antagonism at P2X3 receptors in 
respiratory and urological disorders. Front Cell Neurosci. 2013;7:267. 
GlaxoSmithKline Document Number 2013N162862_03. Investigator’s Brochure (IB) for 
GSK2798745. Version 04, 2016-Jun-03.
Idzko M, H. Hammad, M. van Nimwegen, et al. Extracellular ATP triggers and maintains 
asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-
919. 
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. 
Schappert SM, C.W. Burt. Ambulatory care visits to physician offices, hospital outpatient 
departments, and emergency departments: United States, 2001-02. Vital Health Stat 13. 
2006;159:1-66. 
Smith JA, A. Woodcock. Chronic Cough. N Engl J Med. 2017;376(2):183-184. 
Sumner H, Woodcock A, Kolsum U, Dockry R, Lazaar AL, Singh D, Vestbo J, Smith 
JA. Predictors of objective cough frequency in chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med. 2013;187(9):943-9. 
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. 
 
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Toft-Bertelsen TL, D. Krízaj, and N. MacAulay. When size matters: transient receptor 
potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor. The Journal 
of Physiology. 2017:doi: 10.1113/JP274135. 
Wilson MMG, Thomas DR, Rubenstein LZ, Chibnall JT, Anderson S, Baxi A, et al. 
Appetite assessment: simple appetite questionnaire predicts weight loss in community-
dwelling adults and nursing home residents. Am J Clin Nutr. 2005;82:1074-81. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
ATP
Adenosine Triphosphate
AUC
Area under concentration-time curve
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 Disease
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicidality Severity Rating Scale
CT
Computed tomography
CXR
Chest X-ray
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IC50
50% maximal inhibitory concentration
ICF
Informed consent form
 
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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IVIVT
In Vitro/In Vivo Translations
IWRS
Interactive Web Response System
kg
kilogram
KO
Knockout
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
mSV
MilliSievert
NOAEL
No observed adverse effect level
nM
Nano Molar
P2X3
P2X purinoceptor 3
P-gp
p-glycoprotein
PK
Pharmacokinetic
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SNAQ
Simplified Nutritional Appetite Questionnaire
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TPR
Third Party Resourcing
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Vitalograph
VitaloJAK
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)
Total Protein
Glucose 
(Fasting not 
required)
Calcium
Alkaline phosphatase
Creatinine 
phosphokinase 
(CPK)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin
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 hepatitis C 
virus antibody)
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 7.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
 
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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 International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 

Any 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 authorised 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 authorised 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 centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised 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 
authorised 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 authorised 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 multi-centre 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 (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

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 authorised 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. 
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.
 
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
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 each 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
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 
 
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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 
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 (eg, 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, diarrhea, influenza, 
and accidental trauma (eg, 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
 
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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 
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism
Revascularization
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 
 
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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.
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 
 
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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, 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.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g. check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in the SRM.
 
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SAE Reporting to GSK via Paper CRF (only necessary when electronic data collection tool 
is not available)

The SAE paper CRF should be emailed to the medical monitor (who is also the SAE 
coordinator).

In rare circumstances, if email is not possible, 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.
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.
2.
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) and estradiol 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 and estradiol 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 5 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 Section 6.1.

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 5
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 2 weeks 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 fetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2798745 or chronic cough and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2798745 (or study treatments of this drug class), and chronic 
cough. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome.

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2798745 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2798745 (or study treatments of 
this class) or chronic cough continues, but no longer than 15 years after the last 
participant last visit or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

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 chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(defined as Day -1; Treatment Period 1) (see 
MONITORING below)

Do not restart/rechallenge participant with 
study treatment (not allowed under this 
protocol)  

Permanently discontinue study treatment 
and continue any protocol specified follow up 
assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis, 
within 24 hours after last dose5

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 
 
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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 h

Monitor participants twice weekly until liver
chemistries resolve, stabilize or return to 
within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) page 
For bilirubin or INR criteria:

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 pages.
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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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TITLE PAGE
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised, 
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in 
participants with chronic cough
Protocol Number: 207702
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Compound Number:
GSK2798745
Development Phase:
2
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): 2017-002265-21
Protocol Amendment Number: 01
Approval Date: 09-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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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Version
Document
Date
Protocol Amendment 1
2017N319286_01
09-OCT-2017
Original Protocol
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The original protocol (31-May-2017) was published internally only, it was not reviewed 
by the competent authority or the research ethics committee.
Protocol Amendment 1 09-OCT-2017
Overall Rationale for the Amendment: The primary reason for amending the protocol 
is the removal of the Simplified Nutritional Appetite Questionnaire (SNAQ).  The 
original protocol included the SNAQ, because of the preclinical finding of reduced food 
consumption in dogs (30 mg/kg/day) and rats (300 mg/kg/day).  Since the publication of 
the original protocol, data has been reviewed from a study of GSK2798745 in heart 
failure patients.  Participants took 2.4 mg GSK2798745 (n=10) or placebo (n=12) for 
7 days. As shown in the table below, there was no observable difference in weight and 
appetite in participants receiving GSK2798745 and placebo.  Therefore, the GSK Global 
Safety Board agreed to the removal of the SNAQ from future protocols.  Weight will be 
measured at screening, follow-up, and the beginning and end of each Treatment Period, 
and adverse events that may be associated with low food consumption will be reviewed.
Baseline (mean ± SD)
Day 7 (mean ± SD)
Change from Baseline
Weight (kg)
2.4 mg 
87.44 ± 18.54
87.67± 17.50
0.23
Placebo
83.58 ± 10.46
83.33 ± 10.56
-0.25
SNAQ Score (Maximum = 20)
2.4 mg
16.2 ± 1.69
16.7 ± 1.95
0.5 ± 1.18
Placebo
15.3 ± 1.83
16.2 ± 1.53
0.8 ± 1.11
 
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Section # and Name
Description of Change
Brief Rationale
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Removal of the SNAQ at the 
follow-up visit.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
The option for a CT scan at screening was 
included in the original protocol, in error.  If 
chest imaging (chest x-ray or CT scan) has 
not been conducted within 12 months of 
screening, a chest x-ray will be conducted.
Section 2.2 
(Treatment Period 1 
and 2 Schedule of 
Activities)
Removal of the SNAQ at 
Day -1 and Day 8, in each 
Treatment Period.
Rationale for removal of the SNAQ 
described above.
Section 3.3.1 (Risk 
Assessment)
Removal of the SNAQ.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
Rationale for removal of CT scan at 
screening described above.
Section 7.7.1 
(Permitted 
Medications)
The following change was 
made:  Stable use of some 
medications may be 
permitted if the dose is 
stable for at least 28 days
3 months prior to Day 1.
Time period of stable dose changed from 
28 days to 3 months, because 28 days 
might not be sufficient to achieve stable 
dosing of some permitted medications.
Section 8.1.3.2
(Symptoms of 
Cardiac Ischemia 
and Cardiac 
Troponin Stopping 
Criteria: 
Asymptomatic 
Participant)
The following change was 
made:  If any cardiac 
troponin assessment is 
>ULN or >2 times the 
participant’s baseline value 
(Screening Day -1, 
Treatment Period 1), the 
participant should be
assessed for symptoms of 
cardiac ischemia (as above).
Definition of baseline changed from 
Screening to Treatment Period 1, Day -1 to 
be consistent with the baseline used for 
other laboratory tests.
Section 9.4.5
(Simplified Nutritional 
Appetite 
Questionnaire)
Removal of complete 
section.
Rationale for removal of the SNAQ 
described above.
Section 9.4.6 (Chest 
Imaging)
Removal of the option for a 
CT scan at screening.
Rationale for removal of CT scan at 
screening described above.
 
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Section # and Name
Description of Change
Brief Rationale
Section 9.4.9 
(Columbia Suicidality 
Severity Rating 
Scale (CSSRS)
Addition of text stating that 
families of participants 
should be alerted about 
monitoring for emergence of 
suicidal ideation and 
behaviour.
New text added to ensure compliance with 
GSK’s Global Safety Board-Approved
Recommendations for Prospective 
Assessment of Suicidal Ideation and 
Behaviour in Relevant Clinical Studies.
Section 9.5
(Pharmacokinetics)
Blood sample volume 
removed.
Blood volume of sample removed, as this is 
still to be confirmed.  Sample collection 
instructions to be provided in the laboratory 
manual. 
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
Screening and Follow-up Schedule of Activities..........................................11
2.2.
Treatment Period 1 and 2 Schedule of Activities.........................................13
3.
INTRODUCTION....................................................................................................16
3.1.
Study Rationale ..........................................................................................16
3.2.
Background ................................................................................................17
3.3.
Benefit/Risk Assessment ............................................................................17
3.3.1.
Risk Assessment .........................................................................18
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 ...............................................................................25
5.3.
Participant and Study Completion...............................................................26
5.4.
Scientific Rationale for Study Design ..........................................................26
5.5.
Dose Justification........................................................................................26
6.
STUDY POPULATION...........................................................................................29
6.1.
Inclusion Criteria.........................................................................................29
6.2.
Exclusion Criteria........................................................................................30
6.3.
Lifestyle Restrictions...................................................................................32
6.3.1.
Meals and Dietary Restrictions ....................................................32
6.3.2.
Alcohol and Tobacco ...................................................................32
6.3.3.
Activity .........................................................................................32
6.4.
Screen Failures...........................................................................................32
7.
TREATMENTS.......................................................................................................33
7.1.
Treatments Administered............................................................................33
7.1.1.
Medical Devices...........................................................................33
7.2.
Dose Modification .......................................................................................34
7.3.
Method of Treatment Assignment ...............................................................34
7.4.
Blinding.......................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability..............................................35
7.6.
Treatment Compliance................................................................................36
7.7.
Concomitant Therapy..................................................................................36
7.7.1.
Permitted Medications .................................................................36
7.7.2.
Prohibited Medications.................................................................36
7.8.
Treatment after the End of the Study ..........................................................37
8.
DISCONTINUATION CRITERIA.............................................................................38
8.1.
Discontinuation of Study Treatment ............................................................38
 
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8.1.1.
Liver Chemistry Stopping Criteria ................................................38
8.1.1.1.
Rechallenge ...............................................................39
8.1.2.
QTc Stopping Criteria ..................................................................39
8.1.3.
Symptoms of Cardiac Ischemia and Cardiac Troponin 
Stopping Criteria..........................................................................39
8.1.3.1.
Symptomatic Participant:............................................39
8.1.3.2.
Asymptomatic Participant: ..........................................40
8.2.
Withdrawal from the Study..........................................................................40
8.3.
Lost to Follow Up........................................................................................40
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
9.1.
Efficacy Assessments.................................................................................41
9.1.1.
Cough Counting...........................................................................41
9.1.2.
Cough Visual Analogue Scale (VAS) ...........................................42
9.1.2.1.
Cough Severity VAS...................................................42
9.1.2.2.
Urge to Cough VAS....................................................42
9.1.3.
Leicester Cough Questionnaire (LCQ).........................................42
9.2.
Adverse Events...........................................................................................42
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................43
9.2.2.
Method of Detecting AEs and SAEs.............................................43
9.2.3.
Follow-up of AEs and SAEs.........................................................43
9.2.4.
Regulatory Reporting Requirements for SAEs .............................43
9.2.5.
Cardiovascular and Death Events................................................44
9.2.6.
Pregnancy ...................................................................................44
9.3.
Treatment of Overdose...............................................................................44
9.4.
Safety Assessments ...................................................................................45
9.4.1.
Physical Examinations.................................................................45
9.4.2.
Vital Signs....................................................................................45
9.4.3.
Electrocardiograms......................................................................45
9.4.4.
Audiometry ..................................................................................46
9.4.5.
Chest X-ray..................................................................................46
9.4.6.
FEV1 ............................................................................................46
9.4.7.
Clinical Safety Laboratory Assessments ......................................46
9.4.8.
Faecal Occult Blood Test.............................................................47
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS) ..................47
9.4.10.
Diary card ....................................................................................47
9.5.
Pharmacokinetics .......................................................................................48
9.6.
Pharmacodynamics ....................................................................................48
9.7.
Genetics .....................................................................................................48
10. STATISTICAL CONSIDERATIONS........................................................................49
10.1.
Sample Size Determination ........................................................................49
10.2.
Populations for Analyses ............................................................................50
10.3.
Statistical Analyses.....................................................................................51
10.3.1.
Efficacy Analyses.........................................................................51
10.3.2.
Safety Analyses...........................................................................51
10.3.3.
Interim Analyses ..........................................................................52
10.3.4.
Exploratory Analyses ...................................................................52
11. REFERENCES.......................................................................................................53
 
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12. APPENDICES........................................................................................................55
12.1.
Appendix 1: Abbreviations and Trademarks................................................55
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................58
12.3.
Appendix 3: Study Governance Considerations..........................................59
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................63
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................69
12.6.
Appendix 6: Genetics..................................................................................72
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................73
12.8.
Appendix 8: Protocol Amendment History...................................................75
 
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1.
SYNOPSIS
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised, 
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in 
participants with chronic cough
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Rationale: Chronic cough is a disease with high unmet medical need. It is hypothesised 
that chronic cough reflects a state of neuronal hypersensitivity involving exaggerated 
spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) through P2X purinoceptor 3 (P2X3) receptors.  
Transient receptor potential vanilloid 4 (TRPV4) activation has been shown to cause ATP 
release from airway macrophages and airway epithelial cells, and studies have established 
a role for TRPV4-mediated ATP release and the P2X3 receptor in TRPV4-mediated 
activation of airway afferents.  ATP-stimulated cough is of particular interest as there are 
data to suggest that ATP levels are increased in the airways of patients with asthma and 
chronic obstructive pulmonary disease (COPD) – diseases in which cough is a prevalent 
symptom.  It is hypothesised, therefore, that a TRPV4-ATP-P2X3 axis contributes to the 
evolution and persistence of chronic cough. 
GSK2798745 is a potent and selective TRPV4 channel blocker being investigated for the 
treatment of chronic cough. The aim of this study is to evaluate whether blockade of 
TRPV4 channels is effective in reducing cough in participants with idiopathic or 
treatment-resistant chronic cough.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment-
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Overall Design:
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
 
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Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Study Design Overview
Number of Participants:
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. However, following a sample-size re-
estimation when approximately 50% of the target sample size has completed the study, 
the sample size may be revised upwards or downwards.  Following the sample size re-
estimation, the target number of evaluable participants will not exceed 40 and the number 
of participants randomised will not exceed 48. 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening and Follow-up Schedule of Activities
Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage, and 
family history of premature cardiovascular (CV) 
disease
X
Substances: Drugs, Alcohol, tobacco
Full physical exam, including height and weight
X
X
Height to be measured at screening only.  
Chest x-ray [CXR]
X
Not required if chest imaging has been conducted within 
12 months of screening with no significant findings.
Columbia Suicidality Severity Rating Scale (CSSRS)
X
Use ‘Baseline’ CSSRS.
Human immunodeficiency virus (HIV), hepatitis B 
(Hep B) and Hepatitis C (Hep C) screen
X
Clinical chemistry, haematology and urinalysis
(including cardiac troponin)
X
X
Non Fasting 
Follicle-stimulating hormone and estradiol 
X
As needed in women of non-childbearing potential only
Faecal Occult Blood Test (FOBT)
X
FOBT cards will be provided at screening and must be 
returned to the laboratory and analysed before Day -1.
Vital signs (blood pressure, heart rate and 
temperature)
X
X
Triplicate vital signs required at screening. 
12-lead ECG
X
X
Triplicate ECG required at screening.
Forced Expiratory Volume in One Second (FEV1)
X
Not required if documented evidence of FEV1 ≥ 80% and 
120% within the 6 months before screening.
 
 
 
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Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Cough Severity & Urge to Cough Visual Analogue 
Scale (VAS)
X (Severity only)
X (Severity & Urge)
Urge to cough VAS will not be completed at screening.
Audiometry
X
Audiometry to be done anytime between end of Treatment 
Period 2 and Follow-up.
Concomitant Medication review 
X
X
Adverse event (AE)/serious adverse event (SAE) 
review
X
X
SAEs collected from the time of consent.  AEs collected 
from the time of first dose (see Section 9.2.1).
1.
Screening assessments may be conducted at multiple visits, if required, but all samples for laboratory safety tests to be collected at one visit (unless repeats).
 
 
 
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2.2.
Treatment Period 1 and 2 Schedule of Activities
Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Study Treatment
Randomisation
X (TP1 only)
Can be done on Day –1 or Pre-dose Day 1.  
Participants will be stratified based on inclusion in a 
cough study within the last 12 months (defined as 
taking an investigational product in a cough study 
within the last 12 months).
Study Treatment dispensed
X
Study Treatment dosing
X
X
X
Home dosing on Days 2-6.  Dosing to be at about the 
same time each day (2 hours relative to dosing on 
Day 1).
Diary Card dispensed
X
X (TP1 only)
Diary card used to collect dosing information, AEs 
and concomitant medications.  Diary card dispensed 
on Day 7 in Treatment Period 1 only (to collect AEs 
and concomitant medications during washout period).
Efficacy Assessments
24- hour Cough Counting Starts
X
X
On Day 7, the cough counter must be attached 
immediately after dosing.  
Participant to be advised to avoid noisy environments 
whilst wearing the counter, and to stay awake for 10 h 
after attachment of the monitor.
24- hour Cough Counting Ends
X
X
On Day 1, the cough counter must be removed before 
dosing.
Cough Severity & Urge to Cough VAS
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.2).
Leicester Cough Questionnaire (LCQ)
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.3).
Safety Assessments
Brief physical exam 
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
Weight
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
 
 
 
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Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Vital signs (blood pressure, heart rate and 
temperature)
X (pre-dose)
X
Single measurements
12-lead ECG
X (pre-dose)
X
Single measurements
Clinical chemistry, haematology and urinalysis 
(including cardiac troponin)
X (pre-dose)
X
Non-fasting.
FOBT
X
FOBT cards will be provided on Day 7 and returned 
on Day 8, if possible (or returned by post).
CSSRS
X
X
Use the ‘Since Last Visit’ CSSRS questionnaire.
The pre-dose CSSRS in each Treatment Period can 
be done on Day –1 or Pre-dose Day 1.
Audiometry
X
Pre-Treatment Period 1 audiometry can be done 
anytime between Screening and Treatment Period 1, 
Day 1, pre-dose. 
Pre-Treatment Period 2 audiometry can be done any 
time during the washout period (up to Treatment 
Period 2, Day 1 pre-dose).
Concomitant Medication review 
X
X
X
X
X
Concomitant medications collected in Diary Card 
during washout period.
SAE/AE review
X
X
X
X
X
AEs collected in Diary Card during washout period.
Other Assessments
PK blood samples 
X
X
X
Day 1 and Day 7:  predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 
3, 3.5 h post dose
Day 8:  24 h post dose
For participants taking atorvastatin, an extra sample 
will be taken at each time-point.
Optional Genetic Sample
X
Can be taken any time after consent has been signed 
and the participant has been randomised.
 
 
 
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
The Cough Severity & Urge to Cough VAS should be completed before the LCQ, and both questionnaires should be completed 
before any other assessments.  

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned study assessments, including:  safety and pharmacokinetic 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 ICF.
 
 
 
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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 chronic cough.
GSK2798745 is a potent in vitro blocker of recombinant human TRPV4 channels, with:

agonist-evoked Ca2+ influx 50% maximal inhibitory concentration (IC50) value of 
1.6 to 2.0 nM; 

hypotonicity-evoked Ca2+ influx IC50 value of 1.6 to 2.0 nM; and 

blocks native human endothelial TRPV4 channels (agonist-evoked impedance 
reduction in the presence of human whole blood IC50=6.5nM).  
GSK2798745 is a potent in vivo blocker of rat TRPV4 channels where full block of 
TRPV4-induced pulmonary edema was observed at a 38 nM total plasma concentration.  
Further information regarding the pre-clinical and clinical studies performed with 
GSK2798745 is available in the investigator brochure (IB) (GSK Document Number 
2013N162862_03). 
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 a repeat dose for 7 days in participants
with heart failure.
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745.  Review of data in 
participants with heart failure indicates that there are no clinically significant safety 
concerns with repeat administration up to 7 days. 
TRPV4 is widely expressed in the respiratory tract and is activated by a wide range of 
stimuli including temperature, pH and osmolarity [Toft-Bertelsen, 2017].  It is 
hypothesized that chronic cough reflects a state of neuronal hypersensitivity involving 
exaggerated spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) [Basoglu, 2005] through P2X purinoceptor 3 
(P2X3) receptors [Ford, 2013].  TRPV4 activation causes ATP release from airway
epithelial cells [Baxter, 2014], and studies have established a role for TRPV4-mediated 
ATP release and P2X3 receptor in activation of airway afferents.  ATP-stimulated cough 
is of particular interest as there are data to suggest that ATP levels are increased in the 
airways of patients with asthma [Idzko, 2007] and chronic obstructive pulmonary disease 
(COPD) [Baxter, 2014], diseases in which cough is a prevalent symptom. It is 
hypothesized, therefore, that a TRPV4-ATP-P2X3 axis contributes to the evolution and 
persistence of chronic cough [Bonvini, 2016].
3.1.
Study Rationale
The aim of this study is to evaluate whether blockade of TRPV4 channels is effective in 
reducing cough in participants with idiopathic or treatment refractory chronic cough.  
 
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TRPV4 and P2X3 antagonists have been shown to reduce cough effectively in a pre-
clinical cough model in guinea pigs [Bonvini, 2016].  Moreover, clinical data suggest that 
pharmacological inhibition of P2X3 receptors reduces cough frequency and improves 
patient reported outcomes and quality of life in a subset of patients with chronic cough
[Abdulqawi, 2015]. 
Therefore, blocking TRPV4 channels may be a viable therapeutic strategy for treating 
chronic idiopathic or treatment-resistant cough.
3.2.
Background
Chronic cough is defined in clinical practice as cough lasting greater than 8 weeks. It is 
highly prevalent worldwide and is a leading cause of unplanned visits to the doctor’s 
office [Schappert, 2006]. Chronic cough patients can be broadly divided into 3 groups:  
those with idiopathic cough, those with treatment refractory cough secondary to 
otherwise controlled triggers such as allergic rhinitis or mild asthma, and those with 
cough associated with underlying chronic lung diseases, such as COPD or Idiopathic 
Pulmonary Fibrosis (IPF) [Smith, 2017].  
Large epidemiological studies that include all 3 patient groups suggest that the prevalence 
of chronic cough is as high as 10% worldwide. The epidemiology of idiopathic and 
treatment refractory chronic cough is more difficult to determine precisely, though it is 
probable that these groups of patients represent a minority of the total compared with 
diseases such as COPD. However, the amount of coughing (coughs per hour) measured 
in patients with idiopathic or treatment refractory chronic cough tends to be much higher 
than in patients with COPD [Abdulqawi, 2015; Sumner, 2013]. Moreover, cough 
suppression in suppurative lung diseases such as COPD may carry additional risks that 
would require establishing a benefit risk ratio in a dedicated study. Therefore, 
demonstrating efficacy in idiopathic and treatment refractory chronic cough populations 
is a logical first step before exploring other populations.
Regardless of etiology, chronic cough is by nature difficult to treat and significantly 
diminishes quality of life. The commonly used therapies for cough are opioid-derived 
over-the-counter medicines, which tend to be relatively ineffective when compared with 
placebo. In addition, these medicines have significant side-effects and potential for abuse 
that limit their usability. Likewise, the opiate codeine is among the most commonly 
prescribed medicines for cough despite similar limitations to its clinical efficacy and even 
greater potential for abuse. Overall, there is a significant unmet medical need for safe 
and effective medicines to treat chronic cough.
3.3.
Benefit/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 IB.
 
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3.3.1.
Risk Assessment
All potential risks of GSK2798745 are based on pre-clinical data.  No risks have been identified in the clinical studies of GSK2798745 
conducted prior to the effective date of this protocol.
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*ug/mL and/or maximum observed 
plasma concentration (Cmax) of 0.050 ug/mL on 
an individual basis.
Myocardial toxicity
Dogs (4-week study):  at 30 mg/kg/day, myofiber 
degeneration/necrosis and inflammation (2 
animals)
Participant Selection: Participants with history 
of acute coronary syndromes (including unstable 
angina), coronary angioplasty, or stenting within 
the past 6 months will be excluded.
Participant Monitoring: Cardiac troponin levels 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
will be monitored throughout the study.
Participant Exposure: Exposure levels will be 
maintained below the threshold detailed in the 
Dose Justification Section (see Section 5.5).
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 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 gastrointestinal (GI) bleeding will 
be excluded.  
Participant Monitoring: Assessment of faecal
occult blood will be performed at screening and 
at the end of each study period.
Participants will be monitored for GI intolerance 
and sequential clinical chemistry analysis,
including liver enzymes.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 monitored 
throughout the study.
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 
Electroencephalography (EEG)/CV study.  In 
other compounds in the same series, 
convulsions have been observed.
Participant Selection: Participants with 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.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 pressure was observed in preclinical 
studies. 
Participant Monitoring: Blood pressure will be 
monitored throughout the study.
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 
Participant Monitoring: Despite the very low 
risk that hearing will be affected, audiometry will 
be conducted during the study at baseline in 
each Treatment Period and at the Follow Up 
Visit.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
However, these findings are academic, and have 
not been observed in any drug induced model. 
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].
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Risk associated with blood draws 
Fainting, mild pain, bruising, irritation or redness 
at a phlebotomy site may be associated with 
blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Risk associated with cough monitoring
Mild contact dermatitis (skin irritation) or redness 
may be associated at the sites where a 
microphone is adhered.
Site staff will follow standard approaches for 
managing events related to application of self-
adherent pads.
Risks associated with CXR (if required for 
participant selection)
The approximate effective radiation dose for a 
chest X-ray is 0.1 milliSievert (mSv).
If a participant has had chest imaging within the 
12 months prior to starting the study, the 
procedure does not need to be repeated.
 
 
 
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3.3.2.
Benefit Assessment

Potential benefit of receiving GSK2798745 that may have clinical utility during 
study duration.

Medical evaluations and assessments associated with study procedures, e.g. physical 
examination, electrocardiogram, laboratory assessments, chest x-ray (CXR) (if 
applicable).

Contributing to the process of developing new therapies in idiopathic or treatment 
resistant chronic cough, an area of unmet medical need. 
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study 
(e.g. dose selection, careful participant selection and risk monitoring), the potential risks 
identified in association with GSK2798745 are justified by the anticipated benefits that 
may be afforded to participants with idiopathic or treatment resistant chronic cough.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Exploratory

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts over 24 hours following 
7 days of dosing

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo at improving 
patient reported outcomes in participants 
with idiopathic or treatment-resistant 
chronic cough

Change from baseline cough severity and 
urge to cough visual analogue scale (VAS)

Change from baseline Leicester Cough 
Questionnaire (LCQ) score

To evaluate the pharmacokinetics (PK) of 
GSK2798745 and its M1 metabolite in 
participants with idiopathic or treatment-
resistant chronic cough

Plasma concentrations of GSK2798745, 
and derived PK parameters, as data permit
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Figure 1
Study Design Overview
5.2.
Number of Participants
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. A participant will be considered evaluable 
if they have completed at least one Treatment Period and have evaluable cough counting 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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data from at least one Treatment Period.  A sample-size re-estimation will be conducted 
when approximately 50% of the target sample size has completed the study.  The sample 
size may be revised upwards or downwards (see Section 10.3.3).  Following the sample 
size re-estimation, the target number of evaluable participants will not exceed 40 and the 
number of participants randomised will not exceed 48.
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

A multicentre, randomised, double-blind, placebo-controlled crossover trial is a well-
established strategy to evaluate efficacy and safety of investigational medicinal 
products, such as GSK2798745. 

A placebo arm is included to determine the absolute effect of GSK2798745. In 
addition, the placebo-controlled design is appropriate as there are no effective, 
currently approved prescription medicines for chronic cough, and over-the-counter 
cough medicines have generally not shown benefit over placebo.  

Cough will be measured using a VitaloJAK cough device which is a validated, 
dedicated high fidelity recording device that provides ambulatory objective 
monitoring of cough with post-recording signal processing and expert systems to 
analyse coughs. Coughs will be recorded for 24 hours prior to dosing of each 
treatment period (baseline) and for 24 hours following dosing on Day 7 of each 
treatment period. 

The crossover design will be employed to minimise, as much as possible, the 
potential for variability in randomisation in a relatively small sample size.  

As chronic cough can significantly impact physical and emotional wellbeing, patient 
reported outcomes are important factors in determining the impact of a cough 
treatment. The Leicester Cough Questionnaire (LCQ) will be utilised as it is an 
established self-completed health related quality of life measure of chronic cough. 
The LCQ is a valid, repeatable 19 item self-completed quality of life measure of 
chronic cough which is responsive to change [Birring, 2003].
5.5.
Dose Justification
In this study, participants will take a 4.8 mg starting dose on Day 1, followed by a 2.4 mg 
GSK2798745 (tablet) once daily for remaining 6 days.
In the first time in human study with GSK2798745 (GlaxoSmithKline [GSK] study 
TR4113787), single doses up to 12.5 mg, and repeat doses of 5 mg once daily for 
 
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14 days, were tested in healthy participants.  In addition, participants with heart failure 
were treated for 7 days with once daily doses of 2.4 mg GSK2798745 (as a capsule with 
food).  There were no serious adverse events (SAEs) in study TR4117387. In other 
studies, with GSK2798745, there has been only one SAE to date. A participant with 
heart failure (Study 201881) had orthostatic hypotension during the washout period 
between the 2 treatment periods. The Principal Investigator (PI) deemed it not related to 
study treatment.
Another healthy participant study was conducted to compare the pharmacokinetics (PK)
of different tablet formulations administered with or without food (GSK study 204725).  
A population PK (POP PK) approach was used to analyse all available clinical PK data 
(taking into consideration participant weight, formulation, impact of food, and other 
variables).  Trial simulations were performed with this POP PK model with different 
dosing regimen.
A rat study was conducted assessing the ability of different doses of GSK2798745 
infusion to reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist, 
GSK1016790.  Based on this study, the estimated human IC50 is 2.1–3.2 ng/mL.  To 
evaluate drug activity/efficacy at the intended dosing regimen, TRPV4 blockade was 
estimated using the population model, and the potency values derived from the rat 
pulmonary study. 
Based on the simulations, the intended dosing scheme for this study with up to 40 
evaluable participants is a 4.8 mg dose on Day 1 followed by a 2.4 mg dose once daily 
for the following 6 days.  Table 1 lists the predicted average TRPV4 inhibition over the 
24-hour period on Day 7 based on this potency range.  The schematic in Figure 2 also 
depicts the range of GSK2798745 systemic exposure and the predicted percent inhibition 
of TRPV4 with the intended regimen.  With a loading dose of 4.8 mg, both GSK2798745 
exposure and TRPV4 inhibition reach steady state from the first dose, compared with 
after 4 to 6 days without the loading dose.
This dose regimen was selected to ensure that no participant intentionally exceeds the 
daily AUC of 513 ng*hr/mL and Cmax of 50 ng/mL while simultaneously providing 
sufficiently high channel blockade.  That is the exposure observed at the no observed 
adverse effect level (NOAEL) of 3 mg/kg in the 3-month dog safety study with a 30-fold 
safety margin.  The likelihood of one or more participants of the 40 participants to be 
dosed with this regimen, exceeding the threshold on Day 1 and Day 7 is listed in Table 1.
Food does not significantly impact the predicted exposures of GSK2798745 and the 
resulting TRPV4 inhibition as displayed in Table 1.  So, GSK2798745 can be 
administered with or without food. 
 
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Figure 2
GSK2798745 exposure and % TRPV4 inhibition
Table 1
Predicted exposure, probability of exceeding threshold and TRPV4 
percent inhibition
4.8 mg on 
Day 1 and 
2.4 mg 
OD 
Days 2–7
24 h
exposure
Median (95% PI)
% Probability that ≥ 
1 of 40 participants 
exceed threshold of
%TRPV4 
inhibition over 
24-hour period
Median (95% 
PI)
AUC24 
(ng*hr/mL)
Cmax (ug/mL)
AUC24
(513 
ng*hr/mL)
Cmax
(50 
ng/mL)
With food
Day 1
201.5 (127.5 –
302.8)
18.7 (11.2 –
29.8)
0
0
72.0 (56.5 –
82.6)
Day 7
147.6 (79.4 –
281.1)
13.1 (7.5 –
22.8)
2.0
0.2
67.3 (46.6 –
83.6)
Without 
food
Day 1
202.0 (128.3 –
303.5)
22.7 (15.3 –
34.2)
0
0.6
72.0 (55.3 –
83.4)
Day 7
141.5 (76.6 –
269.7)
14.9 (9.1 –
24.8)
1.8
0.4
65.7 (44.2 –
82.7)
 
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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 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Chronic idiopathic cough for ≥1 year (before screening), defined as:

a cough that is unresponsive to at least 8 weeks of targeted treatment, or

a cough for which no objective evidence of an underlying trigger has been 
determined, despite medical investigations.
3.
No significant findings on chest imaging (CXR or CT scan) within 12 months before 
screening (participants with an abnormal CXR within 12 months, from a temporary 
process, will be allowed to participate if a repeat CXR is normal). 
4.
FEV1 ≥80% and 120% of the predicted normal value (at screening), or documented 
evidence of FEV1 ≥80% and 120% within the 6 months before screening.
5.
Score of ≥40 mm on the Cough Severity VAS at Screening.
WEIGHT
6.
Body weight ≥50 kg and body mass index (BMI) within the range 18 to 32 kg/m2
(inclusive) at screening.
SEX
7.
Male or female
a.Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol from the time of first dose of study treatment until 2 weeks after last dose of 
study treatment, and refrain from donating sperm during this period.
b.Female participants: 
A female participant is eligible to participate if she is not of childbearing potential
as defined in Appendix 5.
 
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INFORMED CONSENT
8.
Capable of giving signed informed consent as described in Appendix 3, 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:
MEDICAL CONDITIONS
1.
History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on 
permitted therapies or that would, in the opinion of the investigator or the medical 
monitor, make the participant unsuitable for inclusion in this study.
2.
History or current evidence of chronic productive cough.
3.
History of acute coronary syndromes (including unstable angina), coronary 
angioplasty, or stenting within the 6 months before screening.
4.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive 
fecal occult blood test [FOBT] at screening).
5.
History of stroke or seizure disorder within 5 years of screening.
6.
Respiratory tract infection within 6 weeks of screening.
7.
Participant who, in the investigator’s opinion, 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 Suicidality Severity Rating Scale (C-SSRS) in the last 6 months (assessed 
at screening).
8.
Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
9.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at screening.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
11. QTc >450 msec or QTc >480 msec in participants with bundle branch block at 
screening.
NOTE: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method.  It is either 
machine-read or manually over-read.
 
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PRIOR/CONCOMITANT THERAPY
12. Use of a listed prohibited medication (Section 7.7) within the restricted timeframe 
relative to the first dose of study treatment.
13. Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (Section 7.7).
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months of screening.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. Current enrollment or past participation within the 3 months before screening in any 
clinical study involving an investigational study treatment or any other type of 
medical research.
DIAGNOSTIC ASSESSMENTS 
17. Positive human immunodeficiency virus (HIV) antibody test at screening.
18. Presence of Hepatitis B surface antigen (HBsAg) at screening.
19. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
20. 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.
21. Cardiac troponin at screening > ULN for the assay.
OTHER EXCLUSIONS
22. History of alcohol abuse within 6 months of screening, in the opinion of the 
investigator.
23. Current smoker or history of smoking within the 6 months before screening, or a 
cumulative history of ≥ 20 pack years.
Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked)
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study.
 
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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 pummelos, exotic citrus fruits, grapefruit hybrids or fruit 
juices from 7 days before the start of study treatment until the end of study treatment 
(in both Treatment Periods).
6.3.2.
Alcohol and Tobacco

During each Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample on Day 7.

Only non-smokers may be recruited into this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities (e.g. walking, watching television, reading).

Participants will be instructed to avoid noisy environments 24 hours before the 
audiometry assessments.

Participants will be asked to stay awake for 10 hours after attachment of the cough 
monitor, and to avoid noisy environments whilst wearing the cough monitor
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 SAEs.
Participants may be rescreened once.  If rescreening is performed, participants must be 
assigned a different unique subject identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.  
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 
subject will be considered a screen failure.
 
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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
Dosage formulation:
White to almost white, round, 
film-coated tablet.  
Tablet A (micronized active 
pharmaceutical ingredient 
[API])
White to almost white, round, 
film-coated tablet
Unit dose strength:
2.4 mg
Not applicable
Route of Administration 
Oral
Oral
Dosing instructions:
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Packaging and Labelling
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
7.1.1.
Medical Devices

The VitaloJAK (Model 7100; manufactured by Vitalograph Ltd) will be used to 
sense and record coughs for up to 24 hours (baseline and Day 7 in each treatment 
period).  The VitaloJAK has a CE mark, indicating compliance to the Medical 
Devices Directive of the European Community (see Section 9.1.1).

Instructions for using the VitaloJAK will be provided in a study-specific manual 
provided by Vitalograph.
 
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7.2.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.3.
Method of Treatment Assignment
All participants will be centrally randomised 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 assignment to one of the 2 treatment sequences shown in Table 2, 
according to the randomisation schedule generated prior to the study by the Clinical 
Statistics Department at GSK.  In the randomisation, participants will be stratified based 
on inclusion in a cough study within the last 12 months (defined as taking an 
investigational product in a cough study within the last 12 months).  Each participant will 
be dispensed blinded study treatment, labelled with his/her unique randomisation number.
Table 2
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
AB
Placebo tablets for 7 days
GSK2798745 tablets for 7 days
BA
GSK2798745 tablets for 7 days
Placebo tablets for 7 days
Study treatment will be dispensed at the study visits summarized in the Schedule of 
Activities (SOA) (Section 2.2).  Returned study treatment should not be re-dispensed.
7.4.
Blinding
This will be a double blind (sponsor open) 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.  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;
however, only the statistician and programmer (and delegates) will have access to 
individual participant level data.  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 
 
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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 Case Report Form 
(CRF), as applicable.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
A participant whose treatment sequence 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 (i.e. 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.
 
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7.6.
Treatment Compliance
Participants will take the study treatment at home on Day 2 to 6.  Compliance will be 
assessed at the end of each Treatment Period by reviewing the participant diary card and 
questioning the participant.  A record of the number of tablets dispensed to and taken by 
each participant must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates will be recorded in the CRF for Day 1, 6 and 7 of 
each Treatment Period.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements), approved by the investigator, in consultation with 
the GSK Medical Monitor, that the participant is receiving at the time of enrolment, or 
receives during the study, must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications
Paracetamol at doses of ≤3 grams/day is permitted for use any time during the study.
Other concomitant medication will be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
Stable use of some medications may be permitted if the dose is stable for at least 3 
months prior to Day 1, and the medication was prescribed for an indication other than 
cough. The dose should remain constant throughout the study. Changes in dose are not 
permitted, unless required for safety or tolerability. These willl be considered on a case 
by case basis by the investigator in consultation with the GSK Medical Monitor.
7.7.2.
Prohibited Medications
Except for the permitted medication noted above and those approved by the investigator 
in consultation with the GSK Medical Monitor (Section 7.7.1), participants must abstain 
from taking prescription and 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) or 30 days for ACE inhibitors, before the first dose 
of study treatment until completion of the follow-up visit, unless in the opinion of the 
investigator and GSK Medical Monitor the medication will not interfere with the study.
During the study, participants should not use drugs that are strong inhibitors or inducers
of Cytochrome P450 (CYP) 3A4 or p-glycoprotein (P-gp), because they may alter 
 
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GSK2798745 concentrations.  The list of background therapy/drugs may be modified 
based on emerging data. These include, but are not limited to, those listed in Table 3.
Table 3
Strong inducers/inhibitors of CYP3A4 and P-gp
Antiretrovirals:
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir, 
boceprevir
Antibiotics:
clarithromycin, telithromycin, troleandomycin, rifampin
Oral antifungals:
ketoconazole, itraconazole, voriconazole
Antidepressant
nefazadone 
Immunosuppressant
cyclosporine
Anti-Epileptic
carbamazepine, phenytoin
GSK2798745 has weak CYP3A4 inhibition potential. It is possible that concentrations of 
drugs that are substrates of CYP3A4 may be increased. HMG-CoA reductase inhibitors, 
such as atorvastatin and simvastatin, are examples of CYP3A4 substrates that might be 
taken by the eligible participants. Participants being treated with simvastatin will be 
allowed to participate in the study, as long as their dose is 20 mg once daily.  
Participants being treated with >20 mg once daily simvastatin will be considered on a 
case basis by the investigator in consultation with the GSK Medical Monitor.  
Participants being treated with atorvastatin of any therapeutic dose are allowed to 
participate in the study.  The concentration of atorvastatin may be evaluated after the 
study.  The investigators may also consider substitutions of these medications.
It is strongly recommended that participants avoid using drugs that are sensitive 
substrates of Cytochrome P450 (CYP) 3A4 and/or P-gp or that have a low therapeutic 
index because concentrations of these substrates may be increased by GSK2798745. If 
co-administration of medications with interaction potential with GSK2798745 is 
necessary, investigators should monitor participants for loss of efficacy or consider 
substitutions of these medications.  
All concomitant medications may be reviewed by the Medical Monitor and it will be up 
to the discretion of the Investigator in consultation with the GSK Medical Monitor, 
whether the medication can be continued and/or the participant can participate in 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 the indication being studied is not life threatening or seriously debilitating.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who withdraw or who are withdrawn from study treatment will be withdrawn 
from the study.  See the SoA (Section 2.1) for assessments to be performed at early 
withdrawal.
Participants who start taking a prohibited medication during the study will be withdrawn, 
unless approved by the investigator in consultation with the GSK Medical Monitor.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm; or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.
Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
 
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Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7.
8.1.1.1.
Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.1.2.
QTc Stopping Criteria
If a participant meets either bulleted criterion below, two further ECG recordings should 
be done (obtained over a brief [e.g. 5 to 10 minute] recording period).  A participant who 
meets either bulleted criterion, based on the average of the triplicate ECG readings, will 
be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  
8.1.3.
Symptoms of Cardiac Ischemia and Cardiac Troponin Stopping 
Criteria
8.1.3.1.
Symptomatic Participant:
If a participant experiences symptoms of cardiac ischemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  GSK2798745 should be discontinued permanently.  The participant should 
be evaluated by a cardiologist and undergo any clinically appropriate testing.  The 
participant should be followed up until symptoms are resolved.
 
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8.1.3.2.
Asymptomatic Participant:
Cardiac troponin will be measured pre-dose and at the end of dosing, in each Treatment 
Period.  If any cardiac troponin assessment is >ULN or >2 times the participant’s 
baseline value (Day -1, Treatment Period 1), the participant should be assessed for 
symptoms of cardiac ischemia (as above).  If the participant is asymptomatic, the 
participant can continue in the study after discussion with the Medical Monitor and close 
monitoring for symptoms.
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 for data to be collected at the time of withdrawal (early withdrawal 
visit).
8.3.
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.

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 summarised in the SoA. 

Protocol waivers or exemptions are not allowed 

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. 

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.
Efficacy Assessments
9.1.1.
Cough Counting
Cough monitoring will be conducted at the beginning and end of each treatment period, 
as shown in Section 2 (SOA).
The VitaloJAK cough monitor will be used.  The VitaloJAK cough monitor was 
developed by Prof 
 Dr 
 and Prof 
 at 
University Hospital of South Manchester NHS Foundation Trust (UHSM), and has been 
fully validated in clinical studies.  The VitaloJAK cough monitor has CE registration and 
Food and Drug Administration (FDA) 510K clearance.
The VitaloJAK Cough Monitor requires a disposable, single use chest sensor that is 
attached to the participant’s chest, and a ‘lapel microphone’ that is attached to the 
participant’s clothing. The monitor collects high fidelity recordings, recording all sound 
frequencies required for the semi-automated analysis of cough.  The recording 
automatically stops at 24 hours.  
Kits will be supplied by Vitalograph to the site containing all items required for each 24-
hour recording, including the monitor, memory card and battery packs. 
Recordings from the VitaloJAK Cough Monitor will be sent to Vitalograph for analysis 
via the Vitalograph Web Portal.  Recordings will be processed through the semi-
automated cough analysis system developed by UHSM. Vitalograph will QC check the 
recordings on receipt.  The recording will then be processed to remove non-cough sounds 
 
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and silences, leaving a set of segmented files for analysis by a Cough Analyst at 
Vitalograph. 
9.1.2.
Cough Visual Analogue Scale (VAS)
Participants will be asked to complete 2 VAS forms, one each to rate the severity of their 
cough, and their urge to cough (see SRM).
The VAS forms should be completed before other clinical assessments (and before the 
LCQ), and participants should be given instructions on how to complete the form.  The 
forms will be provided by GSK – the site should not make photocopies of the forms, or 
print from the PDF file.
9.1.2.1.
Cough Severity VAS
The participant will be asked:  ‘How severe was your cough today?’ 
The participant will place a mark on a 100 mm horizontal line, rating the severity of their 
cough from ‘Not at all’ to ‘Extremely’.
9.1.2.2.
Urge to Cough VAS
The participant will be asked:  ‘Please rate the intensity of your urge to cough today’ 
The participant will place a mark on a 100 mm horizontal line, rating their urge to cough 
from ‘No urge’ to ‘Severe urge’.
9.1.3.
Leicester Cough Questionnaire (LCQ)
The LCQ is a validated, self-completed, quality of life measure of chronic cough
[Birring, 2003].  The questionnaire is designed to assess the impact of cough on various 
aspects of the participant’s life.  
The LCQ should be completed after the Cough VAS, but before other clinical 
assessments, and participants should be given instructions on how to complete the 
questionnaire.  The participant will be asked to read 19 statements, and rate their answer 
on a 7 point Likert response scale (see SRM).  
9.2.
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). 
 
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9.2.1.
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 immediately and 
under no circumstance should this exceed 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.
9.2.2.
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. 
9.2.3.
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 8.3). Further information on follow-up procedures is given in
Appendix 4.
9.2.4.
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 
 
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investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g. summary or listing of 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.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
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 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
9.3.
Treatment of Overdose
For this study, any dose of GSK2798745 greater than the planned dose in the protocol, 
will be considered an 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.
 
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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 24 h 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 will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A full physical examination will include, at a minimum, measuring weight, and 
assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 

A brief physical examination will include, at a minimum, measuring weight, and 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).

Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
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 screening, three readings of blood pressure and pulse 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.
9.4.3.
Electrocardiograms

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.

At screening, triplicate ECG are required:  3 individual ECG tracings should be 
obtained over a brief (e.g. 5 to 10 minute) recording period.
 
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9.4.4.
Audiometry
Audiometry will be performed by authorised, trained staff using standard audiometry 
techniques.  Participants will be instructed to avoid noisy environments 24 h prior to the 
audiometry assessments.  Only air conductance will be performed.  It will be at the 
discretion of the Investigator, Medical Monitor and/or the audiologist to determine if 
significant changes from baseline are seen and if a bone conductance test should be 
performed.  Details of the audiometry testing are in the SRM.
9.4.5.
Chest X-ray
CXR is only required if a participant has not had chest imaging within 12 months of 
screening. If a participant has had an abnormal CXR within 12 months, from a 
temporary process, the CXR may be repeated to determine eligibility.  
CXR will be performed by authorised, trained staff.  
9.4.6.
FEV1

FEV1 will be measured to assess eligibility.  It does not need to be repeated if there 
is documented evidence of FEV1 ≥80% and 120% within the 6 months before 
screening.

Spirometry assessments will be performed whilst the subject is in a seated position 
(if the assessment is done on a bed, the subject’s legs should be over the edge).

Spirometry assessments will be repeated until 3 technically acceptable measurements 
have been made.  
9.4.7.
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. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 to 10 days after the last dose of study treatment 
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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
 
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9.4.8.
Faecal Occult Blood Test
Based on the preclinical finding of gastric erosions (See Section 3.3.1), FOBT will be 
performed to determine eligibility and assess any possible study treatment-related GI 
blood loss. 
At each time-point, participants will be given 2 FOBT cards with instructions for 
completing (using 2 different bowel movements) and returning the tests (in person or by 
post).
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS)
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.
Participants being treated with GSK2798745 should be assessed and monitored 
appropriately for suicidality and unusual changes in behaviour.  Consideration should be 
given to discontinuing GSK2798745 in participants who experience signs of suicidal 
ideation or behaviour.  Families of participants being treated with GSK2798745 should 
be alerted about the need to monitor subjects for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour, and to report such 
symptoms immediately to the study investigator. 
The CSSRS is a measure of suicidal ideation and behaviour, with demonstrated 
predictive validity and reliability.  Sections of the CSSRS include suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual suicide attempt(s).  The CSSRS 
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.
At screening, the ‘Baseline’ CSSRS questionnaire will be completed.  At all other time-
points, the ‘Since Last Visit’ CSSRS questionnaire will be used (see Section 2, SOA).
9.4.10.
Diary card
In each Treatment Period, a diary card will be used to collect:

dosing information for Days 2 to 6 (Date and Time of Dose); 

AEs; and 

concomitant medications.
 
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Between Treatment Periods 1 and 2 (the ‘Washout Period’), a diary card will be used to 
collect AEs and concomitant medications.
Paper diary cards will be used (see SRM).
9.5.
Pharmacokinetics

Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the 
timepoints indicated in the SOA (Section 2).

Blood will be collected in ethylenediaminetetraacetic acid (EDTA) tubes.  The actual 
date and time of each blood sample collection will be recorded.  

The timing and volume of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure adequate PK monitoring of GSK2798745 
and, if possible, any relevant GSK2798745 metabolites.  

Additional collection, processing, storage and shipping procedures are provided in 
the laboratory manual.

PK analysis will be performed under the control of Platform Technologies and
Science-In Vitro/In Vivo Translation (PTS-IVIVT)/ and Third Party Resourcing 
(TPR) GlaxoSmithKline.  Plasma 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 may be analyzed for the metabolite M1.  GSK may store the 
remaining plasma from the PK plasma samples for future possible additional 
metabolite analysis.  Additional analysis of compound-related metabolites may be 
reported under a separate protocol.

For participants taking atorvastatin, an extra sample will be taken at each PK time-
point for analysis of atorvastatin concentration, and possible analysis of atorvastatin 
metabolites.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
 
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See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Laboratory 
Manual.
10.
STATISTICAL CONSIDERATIONS
This study is designed to estimate the effect of GSK2798745 relative to placebo on day-
time cough count totals following seven days of dosing. Day-time cough count totals 
will be derived from the total number of coughs during the first 10 hours following 
dosing, during which time the participant is expected to be awake. 
The inference to be carried out will be with respect to the following hypothesis:

Treatment with GSK2798745 leads to an improvement in day-time 10-hour cough 
count totals compared with placebo.
The above hypothesis will be investigated in this study by means of a Bayesian approach, 
which will assume a non-informative prior distribution.  It is anticipated that the day-time
10-hour cough count totals will be log-transformed before statistical analysis, and hence 
the treatment effect will be evaluated in terms of a ratio of day-time cough count totals 
(GSK2798745 / placebo).  A day-time cough count total of at least 30% less for 
GSK2798745 than for placebo is of interest.  The posterior probability that the true ratio 
of the mean effect size of the test treatment and the mean effect size of the reference 
treatment (test) / (reference), is less than 0.7, and corresponding 90% credible 
intervals, will be obtained.  The posterior probability that the true ratio is less than 0.7 
will be referred to as PP (ratio<0.7).
10.1.
Sample Size Determination
A simulation approach has been employed to investigate the chance of correctly 
determining a positive study with the planned number of participants. An estimate of 
0.28 for the within subject variability in cough count totals was obtained from previous 
studies and this estimate was used in the simulations. 
A treatment ratio (active:placebo) of 0.7 is considered to indicate an effective treatment.  
A treatment ratio of 0.5 is considered to represent a very effective treatment.
A positive study will be declared if the posterior probability that the true treatment ratio 
is less than 0.7 is more than 70% (PP(ratio <0.7) >70%). Given the planned sample size
of 24 participants, if our variability assumptions are correct, then if the true treatment 
ratio is 0.5, there is a 95.3% probability of correctly declaring success. Conversely, if the 
true treatment ratio is 1, there is a 0.2% probability of declaring success at the end of the 
study. 
An unblinded sample size re-estimation is planned in addition to the final analysis.  This 
will be performed when at least 12 participants have completed both dosing periods and 
key assessment data is available.  Cleaned efficacy data will be provided by Data 
Management to the unblinded study statistician. 
 
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Estimated treatment ratio of day-time cough counts between GSK2798745 and placebo 
will be calculated together with 90% credible intervals assuming a non-informative prior.  
This analysis will be supplemented by deriving predictive and/or conditional power in 
order to support sample size re-estimation. As a result of the sample size re-estimation, 
the sample size could be revised either upwards or downwards from the planned sample 
size of 24 evaluable participants, but the target number of evaluable participants will not 
exceed 40 participants.
Full details of the plan for the sample size re-estimation will be described in the 
Reporting and Analysis Plan (RAP).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database.
All Subjects
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Pharmacokinetic
All randomised participants who take at least 1 dose of study 
treatment and for whom a pharmacokinetic sample was obtained 
and analysed.
 
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10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Day-time 10-hour cough counts following seven days’ dosing of 
GSK2798745 as compared with placebo will be analysed by first log 
transforming the day-time 10-hour cough counts recorded on day 7 of each 
dosing period. The difference between GSK2798745 and placebo in log-
transformed count rates will be investigated using a mixed effects model with 
fixed effects terms for treatment and period. Centre effects and the effect of 
whether or not the participant has participated in a cough clinical trial (which 
will be included as a stratification factor in the randomisation) in the previous 
12 months will also be investigated. Baseline cough counts may be included 
in the model as a covariate. Participant will be treated as a random effect in 
the model. The posterior probability and corresponding 90% credible
intervals that the ratio of the mean effect size of the test treatment and the 
mean effect size of the placebo treatment μ(test) - μ(placebo), is less than 1 
will be constructed. In addition, the posterior probability true effect size 
distribution will be used to obtain estimates for the probabilities that the true 
effect size falls below thresholds of interest (e.g. what is the probability the 
true ratio is less than 0.7 and less than 0.5).
The presence of carryover effects or treatment by period interaction will also 
be investigated and, if deemed appropriate, an analysis by period will be 
undertaken. 
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 are being tested and no statistical 
analyses will be performed.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards.
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram 
(ECG) will be summarized by treatment and time-point.
 
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10.3.3.
Interim Analyses
At least one interim analysis will be conducted during the course of the study.  The 
treatment level results will be made available to the GSK study team who will review the 
available cough count data before making a decision on whether to:
i) stop the study on the grounds of futility
ii) adjust the sample size, in the event that futility criteria have not been met. 
The interim analysis will also include a preliminary assessment of whether there is any 
evidence for the presence of carryover effects or treatment by period interaction.
Following the interim analysis, any adjustment to the sample size will be communicated 
to the sites.
The interim analysis will be conducted after at least 12 participants have completed both 
dosing periods and will look at day-time 10-hour cough count data only. 
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statisticians (including QC statistician) and programmers will have access to 
individual participant data.  However, the findings of the interim analysis will be shared 
with the entire GSK study team. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.3.4.
Exploratory Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics
Modelling & Simulation Department within GlaxoSmithKline. Calculations will be 
based on the actual sampling times recorded during the study. The systemic 
concentrations of GSK2798745, any metabolites, and atorvastatin will be summarised, as 
data permit. The details of the PK analysis will be listed in the RAP. 
 
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11.
REFERENCES
Abdulqawi R, R. Dockry, K. Holt et al. P2X3 receptor antagonist (AF-219) in refractory 
chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 
2015;385(9974):1198-205. 
Basoglu OK, A. Pelleg, S. Essilfie-Quaye, et al.,. Effects of Aerosolized Adenosine 5′-
Triphosphate vs Adenosine 5′-Monophosphate on Dyspnea and Airway Caliber in 
Healthy Nonsmokers and Patients With Asthma. Chest. 2005;128(4):1905-1909. 
Baxter M, S. Eltom, B. Dekkak, et al. Role of transient receptor potential and pannexin 
channels in cigarette smoke-triggered ATP release in the lung. Thorax. 
2014;69(12):1080-1089. 
Birring S, B Prudon, A J Carr, S J Singh, M D L Morgan, I D Pavord. Development of a 
symptom specific health status measure for patients with chronic cough:  Leicester Cough 
Questionnaire (LCQ). Thorax, 2003 58(4):339-343.
Bonvini SJ, M.A. Birrell, M.S. Grace, et al. Transient receptor potential cation channel, 
subfamily V, member 4 and airway sensory afferent activation: Role of adenosine 
triphosphate. J Allergy Clin Immunol. 2016;138(1):249-261 e12. 
Ford AP, B.J. Undem. The therapeutic promise of ATP antagonism at P2X3 receptors in 
respiratory and urological disorders. Front Cell Neurosci. 2013;7:267. 
GlaxoSmithKline Document Number 2013N162862_03. Investigator’s Brochure (IB) for 
GSK2798745. Version 04, 2016-Jun-03.
Idzko M, H. Hammad, M. van Nimwegen, et al. Extracellular ATP triggers and maintains 
asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-
919. 
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. 
Schappert SM, C.W. Burt. Ambulatory care visits to physician offices, hospital outpatient 
departments, and emergency departments: United States, 2001-02. Vital Health Stat 13. 
2006;159:1-66. 
Smith JA, A. Woodcock. Chronic Cough. N Engl J Med. 2017;376(2):183-184. 
Sumner H, Woodcock A, Kolsum U, Dockry R, Lazaar AL, Singh D, Vestbo J, Smith 
JA. Predictors of objective cough frequency in chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med. 2013;187(9):943-9. 
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. 
 
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Toft-Bertelsen TL, D. Krízaj, and N. MacAulay. When size matters: transient receptor 
potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor. The Journal 
of Physiology. 2017:doi: 10.1113/JP274135. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
ATP
Adenosine Triphosphate
AUC
Area under concentration-time curve
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 Disease
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicidality Severity Rating Scale
CT
Computed tomography
CXR
Chest X-ray
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IC50
50% maximal inhibitory concentration
ICF
Informed consent form
 
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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IVIVT
In Vitro/In Vivo Translations
IWRS
Interactive Web Response System
kg
kilogram
KO
Knockout
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
mSV
MilliSievert
NOAEL
No observed adverse effect level
nM
Nano Molar
P2X3
P2X purinoceptor 3
P-gp
p-glycoprotein
PK
Pharmacokinetic
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TPR
Third Party Resourcing
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Vitalograph
VitaloJAK
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)
Total Protein
Glucose 
(Fasting not 
required)
Calcium
Alkaline phosphatase
Creatinine 
phosphokinase 
(CPK)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin
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 hepatitis C 
virus antibody)
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 7.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
 
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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 International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 

Any 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 authorised 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 authorised 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 centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised 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 
authorised 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 authorised 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 multi-centre 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 (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

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 authorised 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 each 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
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 
 
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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 
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 (eg, 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, diarrhea, influenza, 
and accidental trauma (eg, 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
 
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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 
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
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 
 
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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.
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 
 
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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, 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.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g. check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in the SRM.
 
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SAE Reporting to GSK via Paper CRF (only necessary when electronic data collection tool 
is not available)

The SAE paper CRF should be emailed to the medical monitor (who is also the SAE 
coordinator).

In rare circumstances, if email is not possible, 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.
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.
2.
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) and estradiol 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 and estradiol 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 5 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 Section 6.1.

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 5
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 2 weeks 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 fetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2798745 or chronic cough and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2798745 (or study treatments of this drug class), and chronic 
cough. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome.

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2798745 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2798745 (or study treatments of 
this class) or chronic cough continues, but no longer than 15 years after the last 
participant last visit or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

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 chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(defined as Day -1; Treatment Period 1) (see 
MONITORING below)

Do not restart/rechallenge participant with 
study treatment (not allowed under this 
protocol)  

Permanently discontinue study treatment 
and continue any protocol specified follow up 
assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis, 
within 24 hours after last dose5

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 
 
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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 h

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) page 
For bilirubin or INR criteria:

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 et al, 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 pages.
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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment 
(Protocol Amendment 1) is located directly before the Table of Contents (TOC).
 
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TITLE PAGE
Protocol Title: A placebo-controlled, double-blind (sponsor open), 
randomised,crossover study to assess the efficacy, safety, and tolerability of 
GSK2798745 in participants with chronic cough
Protocol Number: 207702 /Amendment 02
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Compound Number:
GSK2798745
Development Phase:
2
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): 2017-002265-21
Approval Date: 22-NOV-2017
Copyright 2017 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
Version
Document
Date
Protocol Amendment 2
2017N319286_02
22-NOV-2017
Protocol Amendment 1
2017N319286_01
09-OCT-2017
Original Protocol
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31-MAY-2017
The original protocol (31-May-2017) was published internally only, it was not reviewed 
by the competent authority or the research ethics committee.
Protocol Amendment 1 (09-OCT-2017) was submitted to both the competent authority 
and the research ethics committee.  The Summary of Changes table for Amendment 1 is 
in Section 12.8 (Appendix 8).
Protocol Amendment 2  (22-NOV-2017)
Overall Rationale for the Amendment: The protocol was amended in response to 
comments from the Medicines and Healthcare Products Regulatory Agency (MHRA).
Section # and Name
Description of Change
Brief Rationale
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Addition of the Columbia Suicidality Severity 
Rating Scale (CSSRS) at Follow-up.
Requested by the MHRA.
Section 7.4 (Blinding)
The following change was made:  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.  
Requested by the MHRA.
 
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Section # and Name
Description of Change
Brief Rationale
Section 8.1.1
(Adverse Event 
Stopping Criteria)
Addition of the following section:
8.1.1 Adverse Event Stopping Criteria
Participants who experience an adverse 
event, which in the opinion of the 
investigator could jeopardise the
participant’s safety, will be withdrawn from 
the study.
Requested by the MHRA.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
2.1.
Screening and Follow-up Schedule of Activities..........................................10
2.2.
Treatment Period 1 and 2 Schedule of Activities.........................................12
3.
INTRODUCTION....................................................................................................15
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................16
3.3.
Benefit/Risk Assessment ............................................................................16
3.3.1.
Risk Assessment .........................................................................17
3.3.2.
Benefit Assessment.....................................................................23
3.3.3.
Overall Benefit:Risk Conclusion...................................................23
4.
OBJECTIVES AND ENDPOINTS...........................................................................23
5.
STUDY DESIGN ....................................................................................................24
5.1.
Overall Design ............................................................................................24
5.2.
Number of Participants ...............................................................................24
5.3.
Participant and Study Completion...............................................................25
5.4.
Scientific Rationale for Study Design ..........................................................25
5.5.
Dose Justification........................................................................................25
6.
STUDY POPULATION...........................................................................................28
6.1.
Inclusion Criteria.........................................................................................28
6.2.
Exclusion Criteria........................................................................................29
6.3.
Lifestyle Restrictions...................................................................................31
6.3.1.
Meals and Dietary Restrictions ....................................................31
6.3.2.
Alcohol and Tobacco ...................................................................31
6.3.3.
Activity .........................................................................................31
6.4.
Screen Failures...........................................................................................31
7.
TREATMENTS.......................................................................................................32
7.1.
Treatments Administered............................................................................32
7.1.1.
Medical Devices...........................................................................32
7.2.
Dose Modification .......................................................................................33
7.3.
Method of Treatment Assignment ...............................................................33
7.4.
Blinding.......................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability..............................................34
7.6.
Treatment Compliance................................................................................34
7.7.
Concomitant Therapy..................................................................................35
7.7.1.
Permitted Medications .................................................................35
7.7.2.
Prohibited Medications.................................................................35
7.8.
Treatment after the End of the Study ..........................................................36
8.
DISCONTINUATION CRITERIA.............................................................................37
8.1.
Discontinuation of Study Treatment ............................................................37
 
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8.1.1.
Adverse Event Stopping Criteria..................................................37
8.1.2.
Liver Chemistry Stopping Criteria ................................................37
8.1.2.1.
Rechallenge ...............................................................38
8.1.3.
QTc Stopping Criteria ..................................................................38
8.1.4.
Symptoms of Cardiac Ischemia and Cardiac Troponin 
Stopping Criteria..........................................................................38
8.1.4.1.
Symptomatic Participant:............................................38
8.1.4.2.
Asymptomatic Participant: ..........................................39
8.2.
Withdrawal from the Study..........................................................................39
8.3.
Lost to Follow Up........................................................................................39
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
9.1.
Efficacy Assessments.................................................................................40
9.1.1.
Cough Counting...........................................................................40
9.1.2.
Cough Visual Analogue Scale (VAS) ...........................................41
9.1.2.1.
Cough Severity VAS...................................................41
9.1.2.2.
Urge to Cough VAS....................................................41
9.1.3.
Leicester Cough Questionnaire (LCQ).........................................41
9.2.
Adverse Events...........................................................................................41
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................42
9.2.2.
Method of Detecting AEs and SAEs.............................................42
9.2.3.
Follow-up of AEs and SAEs.........................................................42
9.2.4.
Regulatory Reporting Requirements for SAEs .............................42
9.2.5.
Cardiovascular and Death Events................................................43
9.2.6.
Pregnancy ...................................................................................43
9.3.
Treatment of Overdose...............................................................................43
9.4.
Safety Assessments ...................................................................................44
9.4.1.
Physical Examinations.................................................................44
9.4.2.
Vital Signs....................................................................................44
9.4.3.
Electrocardiograms......................................................................44
9.4.4.
Audiometry ..................................................................................45
9.4.5.
Chest X-ray..................................................................................45
9.4.6.
FEV1 ............................................................................................45
9.4.7.
Clinical Safety Laboratory Assessments ......................................45
9.4.8.
Faecal Occult Blood Test.............................................................46
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS) ..................46
9.4.10.
Diary card ....................................................................................46
9.5.
Pharmacokinetics .......................................................................................47
9.6.
Pharmacodynamics ....................................................................................47
9.7.
Genetics .....................................................................................................47
10. STATISTICAL CONSIDERATIONS........................................................................48
10.1.
Sample Size Determination ........................................................................48
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.
Interim Analyses ..........................................................................51
10.3.4.
Exploratory Analyses ...................................................................51
11. REFERENCES.......................................................................................................52
 
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12. APPENDICES........................................................................................................54
12.1.
Appendix 1: Abbreviations and Trademarks................................................54
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................57
12.3.
Appendix 3: Study Governance Considerations..........................................58
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................62
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................68
12.6.
Appendix 6: Genetics..................................................................................71
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................72
12.8.
Appendix 8: Protocol Amendment History...................................................74
 
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1.
SYNOPSIS
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised,crossover 
study to assess the efficacy, safety, and tolerability of GSK2798745 in participants with 
chronic cough
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Rationale: Chronic cough is a disease with high unmet medical need. It is hypothesised 
that chronic cough reflects a state of neuronal hypersensitivity involving exaggerated 
spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) through P2X purinoceptor 3 (P2X3) receptors.  
Transient receptor potential vanilloid 4 (TRPV4) activation has been shown to cause ATP 
release from airway macrophages and airway epithelial cells, and studies have established 
a role for TRPV4-mediated ATP release and the P2X3 receptor in TRPV4-mediated 
activation of airway afferents.  ATP-stimulated cough is of particular interest as there are 
data to suggest that ATP levels are increased in the airways of patients with asthma and 
chronic obstructive pulmonary disease (COPD) – diseases in which cough is a prevalent 
symptom.  It is hypothesised, therefore, that a TRPV4-ATP-P2X3 axis contributes to the 
evolution and persistence of chronic cough. 
GSK2798745 is a potent and selective TRPV4 channel blocker being investigated for the 
treatment of chronic cough. The aim of this study is to evaluate whether blockade of 
TRPV4 channels is effective in reducing cough in participants with idiopathic or 
treatment-resistant chronic cough.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment-
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Overall Design:
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
 
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Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Study Design Overview
Number of Participants:
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. However, following a sample-size re-
estimation when approximately 50% of the target sample size has completed the study, 
the sample size may be revised upwards or downwards.  Following the sample size re-
estimation, the target number of evaluable participants will not exceed 40 and the number 
of participants randomised will not exceed 48. 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening and Follow-up Schedule of Activities
Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage, and 
family history of premature cardiovascular (CV) 
disease
X
Substances: Drugs, Alcohol, tobacco
Full physical exam, including height and weight
X
X
Height to be measured at screening only.  
Chest x-ray [CXR]
X
Not required if chest imaging has been conducted within 
12 months of screening with no significant findings.
Columbia Suicidality Severity Rating Scale (CSSRS)
X
X
Use ‘Baseline’ CSSRS at Screening.  Use the ‘Since Last 
Visit’ CSSRS at Follow-up.
Human immunodeficiency virus (HIV), hepatitis B 
(Hep B) and Hepatitis C (Hep C) screen
X
Clinical chemistry, haematology and urinalysis
(including cardiac troponin)
X
X
Non Fasting 
Follicle-stimulating hormone and estradiol 
X
As needed in women of non-childbearing potential only
Faecal Occult Blood Test (FOBT)
X
FOBT cards will be provided at screening and must be 
returned to the laboratory and analysed before Day -1.
Vital signs (blood pressure, heart rate and 
temperature)
X
X
Triplicate vital signs required at screening. 
12-lead ECG
X
X
Triplicate ECG required at screening.
Forced Expiratory Volume in One Second (FEV1)
X
Not required if documented evidence of FEV1 ≥ 80% and 
120% within the 6 months before screening.
 
 
 
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Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Cough Severity & Urge to Cough Visual Analogue 
Scale (VAS)
X (Severity only)
X (Severity & Urge)
Urge to cough VAS will not be completed at screening.
Audiometry
X
Audiometry to be done anytime between end of Treatment 
Period 2 and Follow-up.
Concomitant Medication review 
X
X
Adverse event (AE)/serious adverse event (SAE) 
review
X
X
SAEs collected from the time of consent.  AEs collected 
from the time of first dose (see Section 9.2.1).
1.
Screening assessments may be conducted at multiple visits, if required, but all samples for laboratory safety tests to be collected at one visit (unless repeats).
 
 
 
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2.2.
Treatment Period 1 and 2 Schedule of Activities
Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Study Treatment
Randomisation
X (TP1 only)
Can be done on Day –1 or Pre-dose Day 1.  
Participants will be stratified based on inclusion in a 
cough study within the last 12 months (defined as 
taking an investigational product in a cough study 
within the last 12 months).
Study Treatment dispensed
X
Study Treatment dosing
X
X
X
Home dosing on Days 2-6.  Dosing to be at about the 
same time each day (2 hours relative to dosing on 
Day 1).
Diary Card dispensed
X
X (TP1 only)
Diary card used to collect dosing information, AEs 
and concomitant medications.  Diary card dispensed 
on Day 7 in Treatment Period 1 only (to collect AEs 
and concomitant medications during washout period).
Efficacy Assessments
24- hour Cough Counting Starts
X
X
On Day 7, the cough counter must be attached 
immediately after dosing.  
Participant to be advised to avoid noisy environments 
whilst wearing the counter, and to stay awake for 10 h 
after attachment of the monitor.
24- hour Cough Counting Ends
X
X
On Day 1, the cough counter must be removed before 
dosing.
Cough Severity & Urge to Cough VAS
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.2).
Leicester Cough Questionnaire (LCQ)
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.3).
Safety Assessments
Brief physical exam 
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
Weight
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
 
 
 
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Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Vital signs (blood pressure, heart rate and 
temperature)
X (pre-dose)
X
Single measurements
12-lead ECG
X (pre-dose)
X
Single measurements
Clinical chemistry, haematology and urinalysis 
(including cardiac troponin)
X (pre-dose)
X
Non-fasting.
FOBT
X
FOBT cards will be provided on Day 7 and returned 
on Day 8, if possible (or returned by post).
CSSRS
X
X
Use the ‘Since Last Visit’ CSSRS questionnaire.
The pre-dose CSSRS in each Treatment Period can 
be done on Day –1 or Pre-dose Day 1.
Audiometry
X
Pre-Treatment Period 1 audiometry can be done 
anytime between Screening and Treatment Period 1, 
Day 1, pre-dose. 
Pre-Treatment Period 2 audiometry can be done any 
time during the washout period (up to Treatment 
Period 2, Day 1 pre-dose).
Concomitant Medication review 
X
X
X
X
X
Concomitant medications collected in Diary Card 
during washout period.
SAE/AE review
X
X
X
X
X
AEs collected in Diary Card during washout period.
Other Assessments
PK blood samples 
X
X
X
Day 1 and Day 7:  predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 
3, 3.5 h post dose
Day 8:  24 h post dose
For participants taking atorvastatin, an extra sample 
will be taken at each time-point.
Optional Genetic Sample
X
Can be taken any time after consent has been signed 
and the participant has been randomised.
 
 
 
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
The Cough Severity & Urge to Cough VAS should be completed before the LCQ, and both questionnaires should be completed 
before any other assessments.  

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned study assessments, including:  safety and pharmacokinetic 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 ICF.
 
 
 
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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 chronic cough.
GSK2798745 is a potent in vitro blocker of recombinant human TRPV4 channels, with:

agonist-evoked Ca2+ influx 50% maximal inhibitory concentration (IC50) value of 
1.6 to 2.0 nM; 

hypotonicity-evoked Ca2+ influx IC50 value of 1.6 to 2.0 nM; and 

blocks native human endothelial TRPV4 channels (agonist-evoked impedance 
reduction in the presence of human whole blood IC50=6.5nM).  
GSK2798745 is a potent in vivo blocker of rat TRPV4 channels where full block of 
TRPV4-induced pulmonary edema was observed at a 38 nM total plasma concentration.  
Further information regarding the pre-clinical and clinical studies performed with 
GSK2798745 is available in the investigator brochure (IB) (GSK Document Number 
2013N162862_03). 
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 a repeat dose for 7 days in participants
with heart failure.
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745.  Review of data in 
participants with heart failure indicates that there are no clinically significant safety 
concerns with repeat administration up to 7 days. 
TRPV4 is widely expressed in the respiratory tract and is activated by a wide range of 
stimuli including temperature, pH and osmolarity [Toft-Bertelsen, 2017].  It is 
hypothesized that chronic cough reflects a state of neuronal hypersensitivity involving 
exaggerated spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) [Basoglu, 2005] through P2X purinoceptor 3 
(P2X3) receptors [Ford, 2013].  TRPV4 activation causes ATP release from airway
epithelial cells [Baxter, 2014], and studies have established a role for TRPV4-mediated 
ATP release and P2X3 receptor in activation of airway afferents.  ATP-stimulated cough 
is of particular interest as there are data to suggest that ATP levels are increased in the 
airways of patients with asthma [Idzko, 2007] and chronic obstructive pulmonary disease 
(COPD) [Baxter, 2014], diseases in which cough is a prevalent symptom. It is 
hypothesized, therefore, that a TRPV4-ATP-P2X3 axis contributes to the evolution and 
persistence of chronic cough [Bonvini, 2016].
3.1.
Study Rationale
The aim of this study is to evaluate whether blockade of TRPV4 channels is effective in 
reducing cough in participants with idiopathic or treatment refractory chronic cough.  
 
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TRPV4 and P2X3 antagonists have been shown to reduce cough effectively in a pre-
clinical cough model in guinea pigs [Bonvini, 2016].  Moreover, clinical data suggest that 
pharmacological inhibition of P2X3 receptors reduces cough frequency and improves 
patient reported outcomes and quality of life in a subset of patients with chronic cough
[Abdulqawi, 2015]. 
Therefore, blocking TRPV4 channels may be a viable therapeutic strategy for treating 
chronic idiopathic or treatment-resistant cough.
3.2.
Background
Chronic cough is defined in clinical practice as cough lasting greater than 8 weeks. It is 
highly prevalent worldwide and is a leading cause of unplanned visits to the doctor’s 
office [Schappert, 2006]. Chronic cough patients can be broadly divided into 3 groups:  
those with idiopathic cough, those with treatment refractory cough secondary to 
otherwise controlled triggers such as allergic rhinitis or mild asthma, and those with 
cough associated with underlying chronic lung diseases, such as COPD or Idiopathic 
Pulmonary Fibrosis (IPF) [Smith, 2017].  
Large epidemiological studies that include all 3 patient groups suggest that the prevalence 
of chronic cough is as high as 10% worldwide. The epidemiology of idiopathic and 
treatment refractory chronic cough is more difficult to determine precisely, though it is 
probable that these groups of patients represent a minority of the total compared with 
diseases such as COPD. However, the amount of coughing (coughs per hour) measured 
in patients with idiopathic or treatment refractory chronic cough tends to be much higher 
than in patients with COPD [Abdulqawi, 2015; Sumner, 2013]. Moreover, cough 
suppression in suppurative lung diseases such as COPD may carry additional risks that 
would require establishing a benefit risk ratio in a dedicated study. Therefore, 
demonstrating efficacy in idiopathic and treatment refractory chronic cough populations 
is a logical first step before exploring other populations.
Regardless of etiology, chronic cough is by nature difficult to treat and significantly 
diminishes quality of life. The commonly used therapies for cough are opioid-derived 
over-the-counter medicines, which tend to be relatively ineffective when compared with 
placebo. In addition, these medicines have significant side-effects and potential for abuse 
that limit their usability. Likewise, the opiate codeine is among the most commonly 
prescribed medicines for cough despite similar limitations to its clinical efficacy and even 
greater potential for abuse. Overall, there is a significant unmet medical need for safe 
and effective medicines to treat chronic cough.
3.3.
Benefit/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 IB.
 
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3.3.1.
Risk Assessment
All potential risks of GSK2798745 are based on pre-clinical data.  No risks have been identified in the clinical studies of GSK2798745 
conducted prior to the effective date of this protocol.
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*ug/mL and/or maximum observed 
plasma concentration (Cmax) of 0.050 ug/mL on 
an individual basis.
Myocardial toxicity
Dogs (4-week study):  at 30 mg/kg/day, myofiber 
degeneration/necrosis and inflammation (2 
animals)
Participant Selection: Participants with history 
of acute coronary syndromes (including unstable 
angina), coronary angioplasty, or stenting within 
the past 6 months will be excluded.
Participant Monitoring: Cardiac troponin levels 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
will be monitored throughout the study.
Participant Exposure: Exposure levels will be 
maintained below the threshold detailed in the 
Dose Justification Section (see Section 5.5).
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 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 gastrointestinal (GI) bleeding will 
be excluded.  
Participant Monitoring: Assessment of faecal
occult blood will be performed at screening and 
at the end of each study period.
Participants will be monitored for GI intolerance 
and sequential clinical chemistry analysis,
including liver enzymes.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 monitored 
throughout the study.
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 
Electroencephalography (EEG)/CV study.  In 
other compounds in the same series, 
convulsions have been observed.
Participant Selection: Participants with 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.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 pressure was observed in preclinical 
studies. 
Participant Monitoring: Blood pressure will be 
monitored throughout the study.
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 
Participant Monitoring: Despite the very low 
risk that hearing will be affected, audiometry will 
be conducted during the study at baseline in 
each Treatment Period and at the Follow Up 
Visit.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
However, these findings are academic, and have 
not been observed in any drug induced model. 
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].
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Risk associated with blood draws 
Fainting, mild pain, bruising, irritation or redness 
at a phlebotomy site may be associated with 
blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Risk associated with cough monitoring
Mild contact dermatitis (skin irritation) or redness 
may be associated at the sites where a 
microphone is adhered.
Site staff will follow standard approaches for 
managing events related to application of self-
adherent pads.
Risks associated with CXR (if required for 
participant selection)
The approximate effective radiation dose for a 
chest X-ray is 0.1 milliSievert (mSv).
If a participant has had chest imaging within the 
12 months prior to starting the study, the 
procedure does not need to be repeated.
 
 
 
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3.3.2.
Benefit Assessment

Potential benefit of receiving GSK2798745 that may have clinical utility during 
study duration.

Medical evaluations and assessments associated with study procedures, e.g. physical 
examination, electrocardiogram, laboratory assessments, chest x-ray (CXR) (if 
applicable).

Contributing to the process of developing new therapies in idiopathic or treatment 
resistant chronic cough, an area of unmet medical need. 
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study 
(e.g. dose selection, careful participant selection and risk monitoring), the potential risks 
identified in association with GSK2798745 are justified by the anticipated benefits that 
may be afforded to participants with idiopathic or treatment resistant chronic cough.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Exploratory

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts over 24 hours following 
7 days of dosing

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo at improving 
patient reported outcomes in participants 
with idiopathic or treatment-resistant 
chronic cough

Change from baseline cough severity and 
urge to cough visual analogue scale (VAS)

Change from baseline Leicester Cough 
Questionnaire (LCQ) score

To evaluate the pharmacokinetics (PK) of 
GSK2798745 and its M1 metabolite in 
participants with idiopathic or treatment-
resistant chronic cough

Plasma concentrations of GSK2798745, 
and derived PK parameters, as data permit
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Figure 1
Study Design Overview
5.2.
Number of Participants
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. A participant will be considered evaluable 
if they have completed at least one Treatment Period and have evaluable cough counting 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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data from at least one Treatment Period.  A sample-size re-estimation will be conducted 
when approximately 50% of the target sample size has completed the study.  The sample 
size may be revised upwards or downwards (see Section 10.3.3).  Following the sample 
size re-estimation, the target number of evaluable participants will not exceed 40 and the 
number of participants randomised will not exceed 48.
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

A multicentre, randomised, double-blind, placebo-controlled crossover trial is a well-
established strategy to evaluate efficacy and safety of investigational medicinal 
products, such as GSK2798745. 

A placebo arm is included to determine the absolute effect of GSK2798745. In 
addition, the placebo-controlled design is appropriate as there are no effective, 
currently approved prescription medicines for chronic cough, and over-the-counter 
cough medicines have generally not shown benefit over placebo.  

Cough will be measured using a VitaloJAK cough device which is a validated, 
dedicated high fidelity recording device that provides ambulatory objective 
monitoring of cough with post-recording signal processing and expert systems to 
analyse coughs. Coughs will be recorded for 24 hours prior to dosing of each 
treatment period (baseline) and for 24 hours following dosing on Day 7 of each 
treatment period. 

The crossover design will be employed to minimise, as much as possible, the 
potential for variability in randomisation in a relatively small sample size.  

As chronic cough can significantly impact physical and emotional wellbeing, patient 
reported outcomes are important factors in determining the impact of a cough 
treatment. The Leicester Cough Questionnaire (LCQ) will be utilised as it is an 
established self-completed health related quality of life measure of chronic cough. 
The LCQ is a valid, repeatable 19 item self-completed quality of life measure of 
chronic cough which is responsive to change [Birring, 2003].
5.5.
Dose Justification
In this study, participants will take a 4.8 mg starting dose on Day 1, followed by a 2.4 mg 
GSK2798745 (tablet) once daily for remaining 6 days.
In the first time in human study with GSK2798745 (GlaxoSmithKline [GSK] study 
TR4113787), single doses up to 12.5 mg, and repeat doses of 5 mg once daily for 
 
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14 days, were tested in healthy participants.  In addition, participants with heart failure 
were treated for 7 days with once daily doses of 2.4 mg GSK2798745 (as a capsule with 
food).  There were no serious adverse events (SAEs) in study TR4117387. In other 
studies, with GSK2798745, there has been only one SAE to date. A participant with 
heart failure (Study 201881) had orthostatic hypotension during the washout period 
between the 2 treatment periods. The Principal Investigator (PI) deemed it not related to 
study treatment.
Another healthy participant study was conducted to compare the pharmacokinetics (PK)
of different tablet formulations administered with or without food (GSK study 204725).  
A population PK (POP PK) approach was used to analyse all available clinical PK data 
(taking into consideration participant weight, formulation, impact of food, and other 
variables).  Trial simulations were performed with this POP PK model with different 
dosing regimen.
A rat study was conducted assessing the ability of different doses of GSK2798745 
infusion to reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist, 
GSK1016790.  Based on this study, the estimated human IC50 is 2.1–3.2 ng/mL.  To 
evaluate drug activity/efficacy at the intended dosing regimen, TRPV4 blockade was 
estimated using the population model, and the potency values derived from the rat 
pulmonary study. 
Based on the simulations, the intended dosing scheme for this study with up to 40 
evaluable participants is a 4.8 mg dose on Day 1 followed by a 2.4 mg dose once daily 
for the following 6 days.  Table 1 lists the predicted average TRPV4 inhibition over the 
24-hour period on Day 7 based on this potency range.  The schematic in Figure 2 also 
depicts the range of GSK2798745 systemic exposure and the predicted percent inhibition 
of TRPV4 with the intended regimen.  With a loading dose of 4.8 mg, both GSK2798745 
exposure and TRPV4 inhibition reach steady state from the first dose, compared with 
after 4 to 6 days without the loading dose.
This dose regimen was selected to ensure that no participant intentionally exceeds the 
daily AUC of 513 ng*hr/mL and Cmax of 50 ng/mL while simultaneously providing 
sufficiently high channel blockade.  That is the exposure observed at the no observed 
adverse effect level (NOAEL) of 3 mg/kg in the 3-month dog safety study with a 30-fold 
safety margin.  The likelihood of one or more participants of the 40 participants to be 
dosed with this regimen, exceeding the threshold on Day 1 and Day 7 is listed in Table 1.
Food does not significantly impact the predicted exposures of GSK2798745 and the 
resulting TRPV4 inhibition as displayed in Table 1.  So, GSK2798745 can be 
administered with or without food. 
 
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Figure 2
GSK2798745 exposure and % TRPV4 inhibition
Table 1
Predicted exposure, probability of exceeding threshold and TRPV4 
percent inhibition
4.8 mg on 
Day 1 and 
2.4 mg 
OD 
Days 2–7
24 h
exposure
Median (95% PI)
% Probability that ≥ 
1 of 40 participants 
exceed threshold of
%TRPV4 
inhibition over 
24-hour period
Median (95% 
PI)
AUC24 
(ng*hr/mL)
Cmax (ug/mL)
AUC24
(513 
ng*hr/mL)
Cmax
(50 
ng/mL)
With food
Day 1
201.5 (127.5 –
302.8)
18.7 (11.2 –
29.8)
0
0
72.0 (56.5 –
82.6)
Day 7
147.6 (79.4 –
281.1)
13.1 (7.5 –
22.8)
2.0
0.2
67.3 (46.6 –
83.6)
Without 
food
Day 1
202.0 (128.3 –
303.5)
22.7 (15.3 –
34.2)
0
0.6
72.0 (55.3 –
83.4)
Day 7
141.5 (76.6 –
269.7)
14.9 (9.1 –
24.8)
1.8
0.4
65.7 (44.2 –
82.7)
 
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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 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Chronic idiopathic cough for ≥1 year (before screening), defined as:

a cough that is unresponsive to at least 8 weeks of targeted treatment, or

a cough for which no objective evidence of an underlying trigger has been 
determined, despite medical investigations.
3.
No significant findings on chest imaging (CXR or CT scan) within 12 months before 
screening (participants with an abnormal CXR within 12 months, from a temporary 
process, will be allowed to participate if a repeat CXR is normal). 
4.
FEV1 ≥80% and 120% of the predicted normal value (at screening), or documented 
evidence of FEV1 ≥80% and 120% within the 6 months before screening.
5.
Score of ≥40 mm on the Cough Severity VAS at Screening.
WEIGHT
6.
Body weight ≥50 kg and body mass index (BMI) within the range 18 to 32 kg/m2
(inclusive) at screening.
SEX
7.
Male or female
a.Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol from the time of first dose of study treatment until 2 weeks after last dose of 
study treatment, and refrain from donating sperm during this period.
b.Female participants: 
A female participant is eligible to participate if she is not of childbearing potential
as defined in Appendix 5.
 
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INFORMED CONSENT
8.
Capable of giving signed informed consent as described in Appendix 3, 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:
MEDICAL CONDITIONS
1.
History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on 
permitted therapies or that would, in the opinion of the investigator or the medical 
monitor, make the participant unsuitable for inclusion in this study.
2.
History or current evidence of chronic productive cough.
3.
History of acute coronary syndromes (including unstable angina), coronary 
angioplasty, or stenting within the 6 months before screening.
4.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive 
fecal occult blood test [FOBT] at screening).
5.
History of stroke or seizure disorder within 5 years of screening.
6.
Respiratory tract infection within 6 weeks of screening.
7.
Participant who, in the investigator’s opinion, 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 Suicidality Severity Rating Scale (C-SSRS) in the last 6 months (assessed 
at screening).
8.
Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
9.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at screening.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
11. QTc >450 msec or QTc >480 msec in participants with bundle branch block at 
screening.
NOTE: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method.  It is either 
machine-read or manually over-read.
 
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PRIOR/CONCOMITANT THERAPY
12. Use of a listed prohibited medication (Section 7.7) within the restricted timeframe 
relative to the first dose of study treatment.
13. Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (Section 7.7).
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months of screening.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. Current enrollment or past participation within the 3 months before screening in any 
clinical study involving an investigational study treatment or any other type of 
medical research.
DIAGNOSTIC ASSESSMENTS 
17. Positive human immunodeficiency virus (HIV) antibody test at screening.
18. Presence of Hepatitis B surface antigen (HBsAg) at screening.
19. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
20. 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.
21. Cardiac troponin at screening > ULN for the assay.
OTHER EXCLUSIONS
22. History of alcohol abuse within 6 months of screening, in the opinion of the 
investigator.
23. Current smoker or history of smoking within the 6 months before screening, or a 
cumulative history of ≥ 20 pack years.
Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked)
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study.
 
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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 pummelos, exotic citrus fruits, grapefruit hybrids or fruit 
juices from 7 days before the start of study treatment until the end of study treatment 
(in both Treatment Periods).
6.3.2.
Alcohol and Tobacco

During each Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample on Day 7.

Only non-smokers may be recruited into this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities (e.g. walking, watching television, reading).

Participants will be instructed to avoid noisy environments 24 hours before the 
audiometry assessments.

Participants will be asked to stay awake for 10 hours after attachment of the cough 
monitor, and to avoid noisy environments whilst wearing the cough monitor
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 SAEs.
Participants may be rescreened once.  If rescreening is performed, participants must be 
assigned a different unique subject identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.  
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 
subject will be considered a screen failure.
 
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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
Dosage formulation:
White to almost white, round, 
film-coated tablet.  
Tablet A (micronized active 
pharmaceutical ingredient 
[API])
White to almost white, round, 
film-coated tablet
Unit dose strength:
2.4 mg
Not applicable
Route of Administration 
Oral
Oral
Dosing instructions:
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Packaging and Labelling
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
7.1.1.
Medical Devices

The VitaloJAK (Model 7100; manufactured by Vitalograph Ltd) will be used to 
sense and record coughs for up to 24 hours (baseline and Day 7 in each treatment 
period).  The VitaloJAK has a CE mark, indicating compliance to the Medical 
Devices Directive of the European Community (see Section 9.1.1).

Instructions for using the VitaloJAK will be provided in a study-specific manual 
provided by Vitalograph.
 
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7.2.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.3.
Method of Treatment Assignment
All participants will be centrally randomised 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 assignment to one of the 2 treatment sequences shown in Table 2, 
according to the randomisation schedule generated prior to the study by the Clinical 
Statistics Department at GSK.  In the randomisation, participants will be stratified based 
on inclusion in a cough study within the last 12 months (defined as taking an 
investigational product in a cough study within the last 12 months).  Each participant will 
be dispensed blinded study treatment, labelled with his/her unique randomisation number.
Table 2
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
AB
Placebo tablets for 7 days
GSK2798745 tablets for 7 days
BA
GSK2798745 tablets for 7 days
Placebo tablets for 7 days
Study treatment will be dispensed at the study visits summarized in the Schedule of 
Activities (SOA) (Section 2.2).  Returned study treatment should not be re-dispensed.
7.4.
Blinding
This will be a double blind (sponsor open) 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.  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;
however, only the statistician and programmer (and delegates) will have access to 
individual participant level data.  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 a participant’s treatment 
assignment is unblinded GSK must be notified within 24 hours after breaking the blind.  
 
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The date and reason that the blind was broken must be recorded in the source 
documentation and Case Report Form (CRF), as applicable.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
A participant whose treatment sequence 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 (i.e. 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
Participants will take the study treatment at home on Day 2 to 6.  Compliance will be 
assessed at the end of each Treatment Period by reviewing the participant diary card and 
questioning the participant.  A record of the number of tablets dispensed to and taken by 
each participant must be maintained and reconciled with study treatment and compliance 
 
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records.  Treatment start and stop dates will be recorded in the CRF for Day 1, 6 and 7 of 
each Treatment Period.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements), approved by the investigator, in consultation with 
the GSK Medical Monitor, that the participant is receiving at the time of enrolment, or 
receives during the study, must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications
Paracetamol at doses of ≤3 grams/day is permitted for use any time during the study.
Other concomitant medication will be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
Stable use of some medications may be permitted if the dose is stable for at least 3 
months prior to Day 1, and the medication was prescribed for an indication other than 
cough. The dose should remain constant throughout the study. Changes in dose are not 
permitted, unless required for safety or tolerability. These willl be considered on a case 
by case basis by the investigator in consultation with the GSK Medical Monitor.
7.7.2.
Prohibited Medications
Except for the permitted medication noted above and those approved by the investigator 
in consultation with the GSK Medical Monitor (Section 7.7.1), participants must abstain 
from taking prescription and 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) or 30 days for ACE inhibitors, before the first dose 
of study treatment until completion of the follow-up visit, unless in the opinion of the 
investigator and GSK Medical Monitor the medication will not interfere with the study.
During the study, participants should not use drugs that are strong inhibitors or inducers
of Cytochrome P450 (CYP) 3A4 or p-glycoprotein (P-gp), because they may alter 
GSK2798745 concentrations.  The list of background therapy/drugs may be modified 
based on emerging data. These include, but are not limited to, those listed in Table 3.
 
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Table 3
Strong inducers/inhibitors of CYP3A4 and P-gp
Antiretrovirals:
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir, 
boceprevir
Antibiotics:
clarithromycin, telithromycin, troleandomycin, rifampin
Oral antifungals:
ketoconazole, itraconazole, voriconazole
Antidepressant
nefazadone 
Immunosuppressant
cyclosporine
Anti-Epileptic
carbamazepine, phenytoin
GSK2798745 has weak CYP3A4 inhibition potential. It is possible that concentrations of 
drugs that are substrates of CYP3A4 may be increased. HMG-CoA reductase inhibitors, 
such as atorvastatin and simvastatin, are examples of CYP3A4 substrates that might be 
taken by the eligible participants. Participants being treated with simvastatin will be 
allowed to participate in the study, as long as their dose is 20 mg once daily.  
Participants being treated with >20 mg once daily simvastatin will be considered on a 
case basis by the investigator in consultation with the GSK Medical Monitor.  
Participants being treated with atorvastatin of any therapeutic dose are allowed to 
participate in the study.  The concentration of atorvastatin may be evaluated after the 
study.  The investigators may also consider substitutions of these medications.
It is strongly recommended that participants avoid using drugs that are sensitive 
substrates of Cytochrome P450 (CYP) 3A4 and/or P-gp or that have a low therapeutic 
index because concentrations of these substrates may be increased by GSK2798745. If 
co-administration of medications with interaction potential with GSK2798745 is 
necessary, investigators should monitor participants for loss of efficacy or consider 
substitutions of these medications.  
All concomitant medications may be reviewed by the Medical Monitor and it will be up 
to the discretion of the Investigator in consultation with the GSK Medical Monitor, 
whether the medication can be continued and/or the participant can participate in 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 the indication being studied is not life threatening or seriously debilitating.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who withdraw or who are withdrawn from study treatment will be withdrawn 
from the study.  See the SoA (Section 2.1) for assessments to be performed at early 
withdrawal.
Participants who start taking a prohibited medication during the study will be withdrawn, 
unless approved by the investigator in consultation with the GSK Medical Monitor.
8.1.1.
Adverse Event Stopping Criteria
Participants who experience an adverse event, which in the opinion of the investigator 
could jeopardise the participant’s safety, will be withdrawn from the study.
8.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm; or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.
Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
 
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Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7.
8.1.2.1.
Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.1.3.
QTc Stopping Criteria
If a participant meets either bulleted criterion below, two further ECG recordings should 
be done (obtained over a brief [e.g. 5 to 10 minute] recording period).  A participant who 
meets either bulleted criterion, based on the average of the triplicate ECG readings, will 
be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  
8.1.4.
Symptoms of Cardiac Ischemia and Cardiac Troponin Stopping 
Criteria
8.1.4.1.
Symptomatic Participant:
If a participant experiences symptoms of cardiac ischemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  GSK2798745 should be discontinued permanently.  The participant should 
be evaluated by a cardiologist and undergo any clinically appropriate testing.  The 
participant should be followed up until symptoms are resolved.
 
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8.1.4.2.
Asymptomatic Participant:
Cardiac troponin will be measured pre-dose and at the end of dosing, in each Treatment 
Period.  If any cardiac troponin assessment is >ULN or >2 times the participant’s 
baseline value (Day -1, Treatment Period 1), the participant should be assessed for 
symptoms of cardiac ischemia (as above).  If the participant is asymptomatic, the 
participant can continue in the study after discussion with the Medical Monitor and close 
monitoring for symptoms.
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 for data to be collected at the time of withdrawal (early withdrawal 
visit).
8.3.
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.

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 summarised in the SoA. 

Protocol waivers or exemptions are not allowed 

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. 

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.
Efficacy Assessments
9.1.1.
Cough Counting
Cough monitoring will be conducted at the beginning and end of each treatment period, 
as shown in Section 2 (SOA).
The VitaloJAK cough monitor will be used.  The VitaloJAK cough monitor was 
developed by Prof 
 Dr 
 and Prof 
 at 
University Hospital of South Manchester NHS Foundation Trust (UHSM), and has been 
fully validated in clinical studies.  The VitaloJAK cough monitor has CE registration and 
Food and Drug Administration (FDA) 510K clearance.
The VitaloJAK Cough Monitor requires a disposable, single use chest sensor that is 
attached to the participant’s chest, and a ‘lapel microphone’ that is attached to the 
participant’s clothing. The monitor collects high fidelity recordings, recording all sound 
frequencies required for the semi-automated analysis of cough.  The recording 
automatically stops at 24 hours.  
Kits will be supplied by Vitalograph to the site containing all items required for each 24-
hour recording, including the monitor, memory card and battery packs. 
Recordings from the VitaloJAK Cough Monitor will be sent to Vitalograph for analysis 
via the Vitalograph Web Portal.  Recordings will be processed through the semi-
automated cough analysis system developed by UHSM. Vitalograph will QC check the 
recordings on receipt.  The recording will then be processed to remove non-cough sounds 
 
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and silences, leaving a set of segmented files for analysis by a Cough Analyst at 
Vitalograph. 
9.1.2.
Cough Visual Analogue Scale (VAS)
Participants will be asked to complete 2 VAS forms, one each to rate the severity of their 
cough, and their urge to cough (see SRM).
The VAS forms should be completed before other clinical assessments (and before the 
LCQ), and participants should be given instructions on how to complete the form.  The 
forms will be provided by GSK – the site should not make photocopies of the forms, or 
print from the PDF file.
9.1.2.1.
Cough Severity VAS
The participant will be asked:  ‘How severe was your cough today?’ 
The participant will place a mark on a 100 mm horizontal line, rating the severity of their 
cough from ‘Not at all’ to ‘Extremely’.
9.1.2.2.
Urge to Cough VAS
The participant will be asked:  ‘Please rate the intensity of your urge to cough today’ 
The participant will place a mark on a 100 mm horizontal line, rating their urge to cough 
from ‘No urge’ to ‘Severe urge’.
9.1.3.
Leicester Cough Questionnaire (LCQ)
The LCQ is a validated, self-completed, quality of life measure of chronic cough
[Birring, 2003].  The questionnaire is designed to assess the impact of cough on various 
aspects of the participant’s life.  
The LCQ should be completed after the Cough VAS, but before other clinical 
assessments, and participants should be given instructions on how to complete the 
questionnaire.  The participant will be asked to read 19 statements, and rate their answer 
on a 7 point Likert response scale (see SRM).  
9.2.
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). 
 
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9.2.1.
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 immediately and 
under no circumstance should this exceed 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.
9.2.2.
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. 
9.2.3.
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 8.3). Further information on follow-up procedures is given in
Appendix 4.
9.2.4.
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 
 
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investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g. summary or listing of 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.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
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 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
9.3.
Treatment of Overdose
For this study, any dose of GSK2798745 greater than the planned dose in the protocol, 
will be considered an 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.
 
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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 24 h 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 will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A full physical examination will include, at a minimum, measuring weight, and 
assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 

A brief physical examination will include, at a minimum, measuring weight, and 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).

Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
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 screening, three readings of blood pressure and pulse 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.
9.4.3.
Electrocardiograms

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 8.1.3 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

At screening, triplicate ECG are required:  3 individual ECG tracings should be 
obtained over a brief (e.g. 5 to 10 minute) recording period.
 
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9.4.4.
Audiometry
Audiometry will be performed by authorised, trained staff using standard audiometry 
techniques.  Participants will be instructed to avoid noisy environments 24 h prior to the 
audiometry assessments.  Only air conductance will be performed.  It will be at the 
discretion of the Investigator, Medical Monitor and/or the audiologist to determine if 
significant changes from baseline are seen and if a bone conductance test should be 
performed.  Details of the audiometry testing are in the SRM.
9.4.5.
Chest X-ray
CXR is only required if a participant has not had chest imaging within 12 months of 
screening. If a participant has had an abnormal CXR within 12 months, from a 
temporary process, the CXR may be repeated to determine eligibility.  
CXR will be performed by authorised, trained staff.  
9.4.6.
FEV1

FEV1 will be measured to assess eligibility.  It does not need to be repeated if there 
is documented evidence of FEV1 ≥80% and 120% within the 6 months before 
screening.

Spirometry assessments will be performed whilst the subject is in a seated position 
(if the assessment is done on a bed, the subject’s legs should be over the edge).

Spirometry assessments will be repeated until 3 technically acceptable measurements 
have been made.  
9.4.7.
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. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 to 10 days after the last dose of study treatment 
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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
 
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9.4.8.
Faecal Occult Blood Test
Based on the preclinical finding of gastric erosions (See Section 3.3.1), FOBT will be 
performed to determine eligibility and assess any possible study treatment-related GI 
blood loss. 
At each time-point, participants will be given 2 FOBT cards with instructions for 
completing (using 2 different bowel movements) and returning the tests (in person or by 
post).
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS)
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.
Participants being treated with GSK2798745 should be assessed and monitored 
appropriately for suicidality and unusual changes in behaviour.  Consideration should be 
given to discontinuing GSK2798745 in participants who experience signs of suicidal 
ideation or behaviour.  Families of participants being treated with GSK2798745 should 
be alerted about the need to monitor subjects for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour, and to report such 
symptoms immediately to the study investigator. 
The CSSRS is a measure of suicidal ideation and behaviour, with demonstrated 
predictive validity and reliability.  Sections of the CSSRS include suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual suicide attempt(s).  The CSSRS 
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.
At screening, the ‘Baseline’ CSSRS questionnaire will be completed.  At all other time-
points, the ‘Since Last Visit’ CSSRS questionnaire will be used (see Section 2, SOA).
9.4.10.
Diary card
In each Treatment Period, a diary card will be used to collect:

dosing information for Days 2 to 6 (Date and Time of Dose); 

AEs; and 

concomitant medications.
 
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Between Treatment Periods 1 and 2 (the ‘Washout Period’), a diary card will be used to 
collect AEs and concomitant medications.
Paper diary cards will be used (see SRM).
9.5.
Pharmacokinetics

Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the 
timepoints indicated in the SOA (Section 2).

Blood will be collected in ethylenediaminetetraacetic acid (EDTA) tubes.  The actual 
date and time of each blood sample collection will be recorded.  

The timing and volume of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure adequate PK monitoring of GSK2798745 
and, if possible, any relevant GSK2798745 metabolites.  

Additional collection, processing, storage and shipping procedures are provided in 
the laboratory manual.

PK analysis will be performed under the control of Platform Technologies and
Science-In Vitro/In Vivo Translation (PTS-IVIVT)/ and Third Party Resourcing 
(TPR) GlaxoSmithKline.  Plasma 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 may be analyzed for the metabolite M1.  GSK may store the 
remaining plasma from the PK plasma samples for future possible additional 
metabolite analysis.  Additional analysis of compound-related metabolites may be 
reported under a separate protocol.

For participants taking atorvastatin, an extra sample will be taken at each PK time-
point for analysis of atorvastatin concentration, and possible analysis of atorvastatin 
metabolites.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
 
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See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Laboratory 
Manual.
10.
STATISTICAL CONSIDERATIONS
This study is designed to estimate the effect of GSK2798745 relative to placebo on day-
time cough count totals following seven days of dosing. Day-time cough count totals 
will be derived from the total number of coughs during the first 10 hours following 
dosing, during which time the participant is expected to be awake. 
The inference to be carried out will be with respect to the following hypothesis:

Treatment with GSK2798745 leads to an improvement in day-time 10-hour cough 
count totals compared with placebo.
The above hypothesis will be investigated in this study by means of a Bayesian approach, 
which will assume a non-informative prior distribution.  It is anticipated that the day-time
10-hour cough count totals will be log-transformed before statistical analysis, and hence 
the treatment effect will be evaluated in terms of a ratio of day-time cough count totals 
(GSK2798745 / placebo).  A day-time cough count total of at least 30% less for 
GSK2798745 than for placebo is of interest.  The posterior probability that the true ratio 
of the mean effect size of the test treatment and the mean effect size of the reference 
treatment (test) / (reference), is less than 0.7, and corresponding 90% credible 
intervals, will be obtained.  The posterior probability that the true ratio is less than 0.7 
will be referred to as PP (ratio<0.7).
10.1.
Sample Size Determination
A simulation approach has been employed to investigate the chance of correctly 
determining a positive study with the planned number of participants. An estimate of 
0.28 for the within subject variability in cough count totals was obtained from previous 
studies and this estimate was used in the simulations. 
A treatment ratio (active:placebo) of 0.7 is considered to indicate an effective treatment.  
A treatment ratio of 0.5 is considered to represent a very effective treatment.
A positive study will be declared if the posterior probability that the true treatment ratio 
is less than 0.7 is more than 70% (PP(ratio <0.7) >70%). Given the planned sample size
of 24 participants, if our variability assumptions are correct, then if the true treatment 
ratio is 0.5, there is a 95.3% probability of correctly declaring success. Conversely, if the 
true treatment ratio is 1, there is a 0.2% probability of declaring success at the end of the 
study. 
An unblinded sample size re-estimation is planned in addition to the final analysis.  This 
will be performed when at least 12 participants have completed both dosing periods and 
key assessment data is available.  Cleaned efficacy data will be provided by Data 
Management to the unblinded study statistician. 
 
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Estimated treatment ratio of day-time cough counts between GSK2798745 and placebo 
will be calculated together with 90% credible intervals assuming a non-informative prior.  
This analysis will be supplemented by deriving predictive and/or conditional power in 
order to support sample size re-estimation. As a result of the sample size re-estimation, 
the sample size could be revised either upwards or downwards from the planned sample 
size of 24 evaluable participants, but the target number of evaluable participants will not 
exceed 40 participants.
Full details of the plan for the sample size re-estimation will be described in the 
Reporting and Analysis Plan (RAP).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database.
All Subjects
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Pharmacokinetic
All randomised participants who take at least 1 dose of study 
treatment and for whom a pharmacokinetic sample was obtained 
and analysed.
 
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10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Day-time 10-hour cough counts following seven days’ dosing of 
GSK2798745 as compared with placebo will be analysed by first log 
transforming the day-time 10-hour cough counts recorded on day 7 of each 
dosing period. The difference between GSK2798745 and placebo in log-
transformed count rates will be investigated using a mixed effects model with 
fixed effects terms for treatment and period. Centre effects and the effect of 
whether or not the participant has participated in a cough clinical trial (which 
will be included as a stratification factor in the randomisation) in the previous 
12 months will also be investigated. Baseline cough counts may be included 
in the model as a covariate. Participant will be treated as a random effect in 
the model. The posterior probability and corresponding 90% credible
intervals that the ratio of the mean effect size of the test treatment and the 
mean effect size of the placebo treatment μ(test) - μ(placebo), is less than 1 
will be constructed. In addition, the posterior probability true effect size 
distribution will be used to obtain estimates for the probabilities that the true 
effect size falls below thresholds of interest (e.g. what is the probability the 
true ratio is less than 0.7 and less than 0.5).
The presence of carryover effects or treatment by period interaction will also 
be investigated and, if deemed appropriate, an analysis by period will be 
undertaken. 
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 are being tested and no statistical 
analyses will be performed.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards.
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram 
(ECG) will be summarized by treatment and time-point.
 
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10.3.3.
Interim Analyses
At least one interim analysis will be conducted during the course of the study.  The 
treatment level results will be made available to the GSK study team who will review the 
available cough count data before making a decision on whether to:
i) stop the study on the grounds of futility
ii) adjust the sample size, in the event that futility criteria have not been met. 
The interim analysis will also include a preliminary assessment of whether there is any 
evidence for the presence of carryover effects or treatment by period interaction.
Following the interim analysis, any adjustment to the sample size will be communicated 
to the sites.
The interim analysis will be conducted after at least 12 participants have completed both 
dosing periods and will look at day-time 10-hour cough count data only. 
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statisticians (including QC statistician) and programmers will have access to 
individual participant data.  However, the findings of the interim analysis will be shared 
with the entire GSK study team. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.3.4.
Exploratory Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics
Modelling & Simulation Department within GlaxoSmithKline. Calculations will be 
based on the actual sampling times recorded during the study. The systemic 
concentrations of GSK2798745, any metabolites, and atorvastatin will be summarised, as 
data permit. The details of the PK analysis will be listed in the RAP. 
 
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11.
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Basoglu OK, A. Pelleg, S. Essilfie-Quaye, et al.,. Effects of Aerosolized Adenosine 5′-
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Baxter M, S. Eltom, B. Dekkak, et al. Role of transient receptor potential and pannexin 
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Ford AP, B.J. Undem. The therapeutic promise of ATP antagonism at P2X3 receptors in 
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GlaxoSmithKline Document Number 2013N162862_03. Investigator’s Brochure (IB) for 
GSK2798745. Version 04, 2016-Jun-03.
Idzko M, H. Hammad, M. van Nimwegen, et al. Extracellular ATP triggers and maintains 
asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-
919. 
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. 
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Schappert SM, C.W. Burt. Ambulatory care visits to physician offices, hospital outpatient 
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2006;159:1-66. 
Smith JA, A. Woodcock. Chronic Cough. N Engl J Med. 2017;376(2):183-184. 
Sumner H, Woodcock A, Kolsum U, Dockry R, Lazaar AL, Singh D, Vestbo J, Smith 
JA. Predictors of objective cough frequency in chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med. 2013;187(9):943-9. 
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. 
 
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Toft-Bertelsen TL, D. Krízaj, and N. MacAulay. When size matters: transient receptor 
potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor. The Journal 
of Physiology. 2017:doi: 10.1113/JP274135. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
ATP
Adenosine Triphosphate
AUC
Area under concentration-time curve
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 Disease
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicidality Severity Rating Scale
CT
Computed tomography
CXR
Chest X-ray
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IC50
50% maximal inhibitory concentration
ICF
Informed consent form
 
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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IVIVT
In Vitro/In Vivo Translations
IWRS
Interactive Web Response System
kg
kilogram
KO
Knockout
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
mSV
MilliSievert
NOAEL
No observed adverse effect level
nM
Nano Molar
P2X3
P2X purinoceptor 3
P-gp
p-glycoprotein
PK
Pharmacokinetic
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TPR
Third Party Resourcing
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Vitalograph
VitaloJAK
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)
Total Protein
Glucose 
(Fasting not 
required)
Calcium
Alkaline phosphatase
Creatinine 
phosphokinase 
(CPK)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin
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 hepatitis C 
virus antibody)
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 8.1.2 and Appendix 7.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
 
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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 International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 

Any 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 authorised 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 authorised 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 centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised 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 
authorised 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 authorised 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 multi-centre 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 (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

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 authorised 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 each 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
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 
 
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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 
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 (eg, 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, diarrhea, influenza, 
and accidental trauma (eg, 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
 
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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 
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
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 
 
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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.
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 
 
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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, 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.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g. check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in the SRM.
 
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SAE Reporting to GSK via Paper CRF (only necessary when electronic data collection tool 
is not available)

The SAE paper CRF should be emailed to the medical monitor (who is also the SAE 
coordinator).

In rare circumstances, if email is not possible, 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.
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.
2.
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) and estradiol 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 and estradiol 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 5 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 Section 6.1.

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 5
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 2 weeks 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 fetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2798745 or chronic cough and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2798745 (or study treatments of this drug class), and chronic 
cough. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome.

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2798745 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2798745 (or study treatments of 
this class) or chronic cough continues, but no longer than 15 years after the last 
participant last visit or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

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 chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(defined as Day -1; Treatment Period 1) (see 
MONITORING below)

Do not restart/rechallenge participant with 
study treatment (not allowed under this 
protocol)  

Permanently discontinue study treatment 
and continue any protocol specified follow up 
assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis, 
within 24 hours after last dose5

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 
 
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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 h

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) page 
For bilirubin or INR criteria:

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 et al, 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 pages.
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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.8.
Appendix 8: 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  09-OCT-2017
Overall Rationale for the Amendment:  The primary reason for amending the protocol 
is the removal of the Simplified Nutritional Appetite Questionnaire (SNAQ).  The 
original protocol included the SNAQ, because of the preclinical finding of reduced food 
consumption in dogs (30 mg/kg/day) and rats (300 mg/kg/day).  Since the publication of 
the original protocol, data has been reviewed from a study of GSK2798745 in heart 
failure patients.  Participants took 2.4 mg GSK2798745 (n=10) or placebo (n=12) for 
7 days.  As shown in the table below, there was no observable difference in weight and 
appetite in participants receiving GSK2798745 and placebo.  Therefore, the GSK Global 
Safety Board agreed to the removal of the SNAQ from future protocols.  Weight will be 
measured at screening, follow-up, and the beginning and end of each Treatment Period, 
and adverse events that may be associated with low food consumption will be reviewed.
Baseline (mean ± SD)
Day 7 (mean ± SD)
Change from Baseline
Weight (kg)
2.4 mg 
87.44 ± 18.54
87.67± 17.50
0.23
Placebo
83.58 ± 10.46
83.33 ± 10.56
-0.25
SNAQ Score (Maximum = 20)
2.4 mg
16.2 ± 1.69
16.7 ± 1.95
0.5 ± 1.18
Placebo
15.3 ± 1.83
16.2 ± 1.53
0.8 ± 1.11
 
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Section # and Name
Description of Change
Brief Rationale
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Removal of the SNAQ at the 
follow-up visit.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
The option for a CT scan at screening was 
included in the original protocol, in error.  If 
chest imaging (chest x-ray or CT scan) has 
not been conducted within 12 months of 
screening, a chest x-ray will be conducted.
Section 2.2 
(Treatment Period 1 
and 2 Schedule of 
Activities)
Removal of the SNAQ at 
Day -1 and Day 8, in each 
Treatment Period.
Rationale for removal of the SNAQ 
described above.
Section 3.3.1 (Risk 
Assessment)
Removal of the SNAQ.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
Rationale for removal of CT scan at 
screening described above.
Section 7.7.1 
(Permitted 
Medications)
The following change was 
made:  Stable use of some 
medications may be 
permitted if the dose is 
stable for at least 28 days
3 months prior to Day 1.
Time period of stable dose changed from 
28 days to 3 months, because 28 days 
might not be sufficient to achieve stable 
dosing of some permitted medications.
Section 8.1.3.2
(Symptoms of 
Cardiac Ischemia 
and Cardiac 
Troponin Stopping 
Criteria: 
Asymptomatic 
Participant)
The following change was 
made:  If any cardiac 
troponin assessment is 
>ULN or >2 times the 
participant’s baseline value 
(Screening Day -1, 
Treatment Period 1), the 
participant should be 
assessed for symptoms of 
cardiac ischemia (as above).
Definition of baseline changed from 
Screening to Treatment Period 1, Day -1 to 
be consistent with the baseline used for 
other laboratory tests.
Section 9.4.5 
(Simplified Nutritional 
Appetite 
Questionnaire)
Removal of complete 
section.
Rationale for removal of the SNAQ 
described above.
Section 9.4.6 (Chest 
Imaging)
Removal of the option for a 
CT scan at screening.
Rationale for removal of CT scan at 
screening described above.
 
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Section # and Name
Description of Change
Brief Rationale
Section 9.4.9 
(Columbia Suicidality 
Severity Rating 
Scale (CSSRS)
Addition of text stating that 
families of participants 
should be alerted about 
monitoring for emergence of 
suicidal ideation and 
behaviour.
New text added to ensure compliance with 
GSK’s Global Safety Board-Approved 
Recommendations for Prospective 
Assessment of Suicidal Ideation and 
Behaviour in Relevant Clinical Studies.
Section 9.5
(Pharmacokinetics)
Blood sample volume 
removed.
Blood volume of sample removed, as this is 
still to be confirmed.  Sample collection 
instructions to be provided in the laboratory 
manual. 
 
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207702
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TITLE PAGE
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised,
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in 
participants with chronic cough
Protocol Number: 207702 /Amendment 03
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Compound Number:
GSK2798745
Development Phase:
2
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): 2017-002265-21
Approval Date: 25-JUN-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
Version
Document
Date
Protocol Amendment 3
2017N319286_03
25-JUN-2018
Protocol Amendment 2
2017N319286_02
22-NOV-2017
Protocol Amendment 1
2017N319286_01
09-OCT-2017
Original Protocol
2017N319286_00
31-MAY-2017
The original protocol (31-May-2017) was published internally only, it was not reviewed 
by the competent authority or the research ethics committee.
Protocol Amendment 1 (09-OCT-2017) was submitted to both the competent authority 
and the research ethics committee.  The Summary of Changes table for Amendment 1 is 
in Section 12.8 (Appendix 8).
Protocol Amendment 2 (22-NOV-2017) was made in response to comments from the 
Medicines and Healthcare Products Regulatory Agency (MHRA), and was submitted to 
both the MHRA and the research ethics committee.  The Summary of Changes table for 
Amendment 2 is in Section 12.8 (Appendix 8).
Protocol Amendment 3 (25-JUN-2018):
Overall Rationale for the Amendment:  The protocol was amended after discussion 
with the study Principal Investigators.  Two minor changes have been made to the
inclusion criteria (described in the table below), because the original criteria were
considered unnecessarily restrictive.  The amendment is considered by the sponsor to be 
non-substantial, because the minor changes to the inclusion criteria (described in the table 
below) will not have a significant impact on the safety or scientific value of the clinical 
trial, and will not significantly alter the population recruited for the trial.
Other minor, administrative corrections have been made (described in the table below).  
Note:  Text added is denoted in bold font and deletion of text denoted in strikethrough in 
the summary of changes table below.
 
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Section # and Name
Description of Change
Brief Rationale
Sponsor Signatory
James L. Kreindler, MD
Director Clinical Development, 
Respiratory R&D
Joanna Marks-Konczalik, MD PhD
Project Physician Lead, Respiratory 
Therapy Area Unit
Change in project physician 
lead.
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Note for Forced Expiratory Volume in 
One Second (FEV1):  
Not required if documented evidence of FEV1 
≥ 80% and 120% within the 6 months before 
screening.
Removal of the upper limit for 
FEV1 from the eligibility criteria.  
An upper limit for FEV1 is not 
required to ensure participant 
safety.
Section 2.2 
(Treatment Period 1 
and 2 Schedule of 
Activities)
Note for Faecal Occult Blood Test 
(FOBT):
FOBT cards will be provided on Day 1 7 and 
returned on Day 7 or 8, if possible (or returned 
by post).
For logistical reasons, FOBT 
cards will be given to 
participants on Day 1 of each 
Treatment Period, and returned 
on Day 7 or Day 8.
Section 6.1 
(Inclusion Criteria)
4. FEV1 ≥80% and 120% of the 
predicted normal value (at screening), 
or documented evidence of FEV1 ≥80% 
and 120% within the 6 months before 
screening.
Removal of the upper limit for 
FEV1 from the eligibility criteria.  
An upper limit for FEV1 is not 
required to ensure participant 
safety.
Section 6.1 
(Inclusion Criteria)
6. Body weight ≥50 kg and body mass 
index (BMI) within the range 18 to 32 
40 kg/m2 (inclusive) at screening
The original BMI range included 
in the protocol is considered 
unnecessarily restrictive.  
Increasing the upper limit from 
32 to 40 kg/m2 is predicted not 
to impact GSK2798745 
pharmacokinetics (PK).
 
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Section # and Name
Description of Change
Brief Rationale
Section 9.4.6 (FEV1)
FEV1 will be measured to assess 
eligibility.  It does not need to be 
repeated if there is documented 
evidence of FEV1 ≥80% and 120%
within the 6 months before screening.
Spirometry assessments will be 
performed whilst the subject is in a 
seated position (if the assessment is 
done on a bed, the subject’s legs 
should be over the edge).
Spirometry assessments will be 
repeated until 3 technically acceptable 
measurements have been made.  To 
confirm eligibility, 1 or more of the 3 
measurements is required to be 
≥80%.
Removal of the upper limit for 
FEV1 from the eligibility criteria. 
An upper limit for FEV1 is not 
required to ensure participant 
safety.
Clarification of the FEV1
assessment used to confirm 
eligibility.
Section 10.3.3
The interim analysis will be conducted 
after at least 12 participants have 
completed both dosing periods and will 
look at day-time 10-hour cough count 
data only, as well as supporting PK 
data, if required.
Inclusion of PK data in the 
interim analysis data review, if
required to understand the 
cough count data.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
Screening and Follow-up Schedule of Activities..........................................11
2.2.
Treatment Period 1 and 2 Schedule of Activities.........................................13
3.
INTRODUCTION....................................................................................................16
3.1.
Study Rationale ..........................................................................................16
3.2.
Background ................................................................................................17
3.3.
Benefit/Risk Assessment ............................................................................17
3.3.1.
Risk Assessment .........................................................................18
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 ...............................................................................25
5.3.
Participant and Study Completion...............................................................26
5.4.
Scientific Rationale for Study Design ..........................................................26
5.5.
Dose Justification........................................................................................26
6.
STUDY POPULATION...........................................................................................29
6.1.
Inclusion Criteria.........................................................................................29
6.2.
Exclusion Criteria........................................................................................30
6.3.
Lifestyle Restrictions...................................................................................32
6.3.1.
Meals and Dietary Restrictions ....................................................32
6.3.2.
Alcohol and Tobacco ...................................................................32
6.3.3.
Activity .........................................................................................32
6.4.
Screen Failures...........................................................................................32
7.
TREATMENTS.......................................................................................................33
7.1.
Treatments Administered............................................................................33
7.1.1.
Medical Devices...........................................................................33
7.2.
Dose Modification .......................................................................................34
7.3.
Method of Treatment Assignment ...............................................................34
7.4.
Blinding.......................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability..............................................35
7.6.
Treatment Compliance................................................................................35
7.7.
Concomitant Therapy..................................................................................36
7.7.1.
Permitted Medications .................................................................36
7.7.2.
Prohibited Medications.................................................................36
7.8.
Treatment after the End of the Study ..........................................................37
8.
DISCONTINUATION CRITERIA.............................................................................38
8.1.
Discontinuation of Study Treatment ............................................................38
 
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8.1.1.
Adverse Event Stopping Criteria..................................................38
8.1.2.
Liver Chemistry Stopping Criteria ................................................38
8.1.2.1.
Rechallenge ...............................................................39
8.1.3.
QTc Stopping Criteria ..................................................................39
8.1.4.
Symptoms of Cardiac Ischemia and Cardiac Troponin 
Stopping Criteria..........................................................................39
8.1.4.1.
Symptomatic Participant:............................................39
8.1.4.2.
Asymptomatic Participant: ..........................................40
8.2.
Withdrawal from the Study..........................................................................40
8.3.
Lost to Follow Up........................................................................................40
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
9.1.
Efficacy Assessments.................................................................................41
9.1.1.
Cough Counting...........................................................................41
9.1.2.
Cough Visual Analogue Scale (VAS) ...........................................42
9.1.2.1.
Cough Severity VAS...................................................42
9.1.2.2.
Urge to Cough VAS....................................................42
9.1.3.
Leicester Cough Questionnaire (LCQ).........................................42
9.2.
Adverse Events...........................................................................................42
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................43
9.2.2.
Method of Detecting AEs and SAEs.............................................43
9.2.3.
Follow-up of AEs and SAEs.........................................................43
9.2.4.
Regulatory Reporting Requirements for SAEs .............................43
9.2.5.
Cardiovascular and Death Events................................................44
9.2.6.
Pregnancy ...................................................................................44
9.3.
Treatment of Overdose...............................................................................44
9.4.
Safety Assessments ...................................................................................45
9.4.1.
Physical Examinations.................................................................45
9.4.2.
Vital Signs....................................................................................45
9.4.3.
Electrocardiograms......................................................................45
9.4.4.
Audiometry ..................................................................................46
9.4.5.
Chest X-ray..................................................................................46
9.4.6.
FEV1 ............................................................................................46
9.4.7.
Clinical Safety Laboratory Assessments ......................................46
9.4.8.
Faecal Occult Blood Test.............................................................47
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS) ..................47
9.4.10.
Diary card ....................................................................................47
9.5.
Pharmacokinetics .......................................................................................48
9.6.
Pharmacodynamics ....................................................................................48
9.7.
Genetics .....................................................................................................48
10. STATISTICAL CONSIDERATIONS........................................................................49
10.1.
Sample Size Determination ........................................................................49
10.2.
Populations for Analyses ............................................................................50
10.3.
Statistical Analyses.....................................................................................51
10.3.1.
Efficacy Analyses.........................................................................51
10.3.2.
Safety Analyses...........................................................................51
10.3.3.
Interim Analyses ..........................................................................52
10.3.4.
Exploratory Analyses ...................................................................52
11. REFERENCES.......................................................................................................53
 
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12. APPENDICES........................................................................................................55
12.1.
Appendix 1: Abbreviations and Trademarks................................................55
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................58
12.3.
Appendix 3: Study Governance Considerations..........................................59
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................63
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................69
12.6.
Appendix 6: Genetics..................................................................................72
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................73
12.8.
Appendix 8: Protocol Amendment History...................................................75
 
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1.
SYNOPSIS
Protocol Title: A placebo-controlled, double-blind (sponsor open), randomised,
crossover study to assess the efficacy, safety, and tolerability of GSK2798745 in
participants with chronic cough
Short Title: A study to assess the effectiveness and side effects of GSK2798745 in 
participants with chronic cough
Rationale: Chronic cough is a disease with high unmet medical need. It is hypothesised 
that chronic cough reflects a state of neuronal hypersensitivity involving exaggerated 
spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) through P2X purinoceptor 3 (P2X3) receptors.  
Transient receptor potential vanilloid 4 (TRPV4) activation has been shown to cause ATP 
release from airway macrophages and airway epithelial cells, and studies have established 
a role for TRPV4-mediated ATP release and the P2X3 receptor in TRPV4-mediated 
activation of airway afferents.  ATP-stimulated cough is of particular interest as there are 
data to suggest that ATP levels are increased in the airways of patients with asthma and 
chronic obstructive pulmonary disease (COPD) – diseases in which cough is a prevalent 
symptom.  It is hypothesised, therefore, that a TRPV4-ATP-P2X3 axis contributes to the 
evolution and persistence of chronic cough. 
GSK2798745 is a potent and selective TRPV4 channel blocker being investigated for the 
treatment of chronic cough. The aim of this study is to evaluate whether blockade of 
TRPV4 channels is effective in reducing cough in participants with idiopathic or 
treatment-resistant chronic cough.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment-
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Overall Design:
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
 
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Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Study Design Overview
Number of Participants:
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. However, following a sample-size re-
estimation when approximately 50% of the target sample size has completed the study, 
the sample size may be revised upwards or downwards.  Following the sample size re-
estimation, the target number of evaluable participants will not exceed 40 and the number 
of participants randomised will not exceed 48. 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
2.1.
Screening and Follow-up Schedule of Activities
Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage, and 
family history of premature cardiovascular (CV) 
disease
X
Substances: Drugs, Alcohol, tobacco
Full physical exam, including height and weight
X
X
Height to be measured at screening only.  
Chest x-ray [CXR]
X
Not required if chest imaging has been conducted within 
12 months of screening with no significant findings.
Columbia Suicidality Severity Rating Scale (CSSRS)
X
X
Use ‘Baseline’ CSSRS at Screening.  Use the ‘Since Last 
Visit’ CSSRS at Follow-up.
Human immunodeficiency virus (HIV), hepatitis B 
(Hep B) and Hepatitis C (Hep C) screen
X
Clinical chemistry, haematology and urinalysis
(including cardiac troponin)
X
X
Non Fasting 
Follicle-stimulating hormone and estradiol 
X
As needed in women of non-childbearing potential only
Faecal Occult Blood Test (FOBT)
X
FOBT cards will be provided at screening and must be 
returned to the laboratory and analysed before Day -1.
Vital signs (blood pressure, heart rate and 
temperature)
X
X
Triplicate vital signs required at screening. 
12-lead ECG
X
X
Triplicate ECG required at screening.
Forced Expiratory Volume in One Second (FEV1)
X
Not required if documented evidence of FEV1 ≥ 80% 
within the 6 months before screening.
 
 
 
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Procedure 
Screening1
(up to 28 days before
Treatment Period 1, Day -1)
Follow up/Early Withdrawal
(7-10 days post last dose)
Notes
Cough Severity & Urge to Cough Visual Analogue 
Scale (VAS)
X (Severity only)
X (Severity & Urge)
Urge to cough VAS will not be completed at screening.
Audiometry
X
Audiometry to be done anytime between end of Treatment 
Period 2 and Follow-up.
Concomitant Medication review 
X
X
Adverse event (AE)/serious adverse event (SAE) 
review
X
X
SAEs collected from the time of consent.  AEs collected 
from the time of first dose (see Section 9.2.1).
1.
Screening assessments may be conducted at multiple visits, if required, but all samples for laboratory safety tests to be collected at one visit (unless repeats).
 
 
 
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2.2.
Treatment Period 1 and 2 Schedule of Activities
Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Study Treatment
Randomisation
X (TP1 only)
Can be done on Day –1 or Pre-dose Day 1.  
Participants will be stratified based on inclusion in a 
cough study within the last 12 months (defined as 
taking an investigational product in a cough study 
within the last 12 months).
Study Treatment dispensed
X
Study Treatment dosing
X
X
X
Home dosing on Days 2-6.  Dosing to be at about the 
same time each day (2 hours relative to dosing on 
Day 1).
Diary Card dispensed
X
X (TP1 only)
Diary card used to collect dosing information, AEs 
and concomitant medications.  Diary card dispensed 
on Day 7 in Treatment Period 1 only (to collect AEs 
and concomitant medications during washout period).
Efficacy Assessments
24- hour Cough Counting Starts
X
X
On Day 7, the cough counter must be attached 
immediately after dosing.  
Participant to be advised to avoid noisy environments 
whilst wearing the counter, and to stay awake for 10 h 
after attachment of the monitor.
24- hour Cough Counting Ends
X
X
On Day 1, the cough counter must be removed before 
dosing.
Cough Severity & Urge to Cough VAS
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.2).
Leicester Cough Questionnaire (LCQ)
X
X (pre-dose)
To be completed before other assessments (see 
Section 9.1.3).
Safety Assessments
Brief physical exam 
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
Weight
X
X
Baseline can be done on Day –1 or Pre-dose Day 1
 
 
 
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Procedure
Treatment Period 1 and 2 (Washout 14-21 days)
Notes
Day –1
Day 1
Day 2–6
Day 7
Day 8
Vital signs (blood pressure, heart rate and 
temperature)
X (pre-dose)
X
Single measurements
12-lead ECG
X (pre-dose)
X
Single measurements
Clinical chemistry, haematology and urinalysis 
(including cardiac troponin)
X (pre-dose)
X
Non-fasting.
FOBT
X
FOBT cards will be provided on Day 1 and returned 
on Day 7 or 8, if possible (or returned by post).
CSSRS
X
X
Use the ‘Since Last Visit’ CSSRS questionnaire.
The pre-dose CSSRS in each Treatment Period can 
be done on Day –1 or Pre-dose Day 1.
Audiometry
X
Pre-Treatment Period 1 audiometry can be done 
anytime between Screening and Treatment Period 1, 
Day 1, pre-dose. 
Pre-Treatment Period 2 audiometry can be done any 
time during the washout period (up to Treatment 
Period 2, Day 1 pre-dose).
Concomitant Medication review 
X
X
X
X
X
Concomitant medications collected in Diary Card 
during washout period.
SAE/AE review
X
X
X
X
X
AEs collected in Diary Card during washout period.
Other Assessments
PK blood samples 
X
X
X
Day 1 and Day 7:  predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 
3, 3.5 h post dose
Day 8:  24 h post dose
For participants taking atorvastatin, an extra sample 
will be taken at each time-point.
Optional Genetic Sample
X
Can be taken any time after consent has been signed 
and the participant has been randomised.
 
 
 
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
The Cough Severity & Urge to Cough VAS should be completed before the LCQ, and both questionnaires should be completed 
before any other assessments.  

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned study assessments, including:  safety and pharmacokinetic 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 ICF.
 
 
 
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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 chronic cough.
GSK2798745 is a potent in vitro blocker of recombinant human TRPV4 channels, with:

agonist-evoked Ca2+ influx 50% maximal inhibitory concentration (IC50) value of 
1.6 to 2.0 nM; 

hypotonicity-evoked Ca2+ influx IC50 value of 1.6 to 2.0 nM; and 

blocks native human endothelial TRPV4 channels (agonist-evoked impedance 
reduction in the presence of human whole blood IC50=6.5nM).  
GSK2798745 is a potent in vivo blocker of rat TRPV4 channels where full block of 
TRPV4-induced pulmonary edema was observed at a 38 nM total plasma concentration.  
Further information regarding the pre-clinical and clinical studies performed with 
GSK2798745 is available in the investigator brochure (IB) (GSK Document Number 
2013N162862_03). 
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 a repeat dose for 7 days in participants
with heart failure.
Review of data in healthy participants indicates that there were no clinically significant 
safety concerns with single or repeat administration of GSK2798745.  Review of data in 
participants with heart failure indicates that there are no clinically significant safety 
concerns with repeat administration up to 7 days. 
TRPV4 is widely expressed in the respiratory tract and is activated by a wide range of 
stimuli including temperature, pH and osmolarity [Toft-Bertelsen, 2017].  It is 
hypothesized that chronic cough reflects a state of neuronal hypersensitivity involving 
exaggerated spinal and cortical responses to afferent sensory signals originating from 
mechanosensitive and chemosensitive neurons. It is thought that cough reflexes are 
triggered by adenosine triphosphate (ATP) [Basoglu, 2005] through P2X purinoceptor 3 
(P2X3) receptors [Ford, 2013].  TRPV4 activation causes ATP release from airway
epithelial cells [Baxter, 2014], and studies have established a role for TRPV4-mediated 
ATP release and P2X3 receptor in activation of airway afferents.  ATP-stimulated cough 
is of particular interest as there are data to suggest that ATP levels are increased in the 
airways of patients with asthma [Idzko, 2007] and chronic obstructive pulmonary disease 
(COPD) [Baxter, 2014], diseases in which cough is a prevalent symptom. It is 
hypothesized, therefore, that a TRPV4-ATP-P2X3 axis contributes to the evolution and 
persistence of chronic cough [Bonvini, 2016].
3.1.
Study Rationale
The aim of this study is to evaluate whether blockade of TRPV4 channels is effective in 
reducing cough in participants with idiopathic or treatment refractory chronic cough.  
 
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TRPV4 and P2X3 antagonists have been shown to reduce cough effectively in a pre-
clinical cough model in guinea pigs [Bonvini, 2016].  Moreover, clinical data suggest that 
pharmacological inhibition of P2X3 receptors reduces cough frequency and improves 
patient reported outcomes and quality of life in a subset of patients with chronic cough
[Abdulqawi, 2015]. 
Therefore, blocking TRPV4 channels may be a viable therapeutic strategy for treating 
chronic idiopathic or treatment-resistant cough.
3.2.
Background
Chronic cough is defined in clinical practice as cough lasting greater than 8 weeks. It is 
highly prevalent worldwide and is a leading cause of unplanned visits to the doctor’s 
office [Schappert, 2006]. Chronic cough patients can be broadly divided into 3 groups:  
those with idiopathic cough, those with treatment refractory cough secondary to 
otherwise controlled triggers such as allergic rhinitis or mild asthma, and those with 
cough associated with underlying chronic lung diseases, such as COPD or Idiopathic 
Pulmonary Fibrosis (IPF) [Smith, 2017].  
Large epidemiological studies that include all 3 patient groups suggest that the prevalence 
of chronic cough is as high as 10% worldwide. The epidemiology of idiopathic and 
treatment refractory chronic cough is more difficult to determine precisely, though it is 
probable that these groups of patients represent a minority of the total compared with 
diseases such as COPD. However, the amount of coughing (coughs per hour) measured 
in patients with idiopathic or treatment refractory chronic cough tends to be much higher 
than in patients with COPD [Abdulqawi, 2015; Sumner, 2013]. Moreover, cough 
suppression in suppurative lung diseases such as COPD may carry additional risks that 
would require establishing a benefit risk ratio in a dedicated study. Therefore, 
demonstrating efficacy in idiopathic and treatment refractory chronic cough populations 
is a logical first step before exploring other populations.
Regardless of etiology, chronic cough is by nature difficult to treat and significantly 
diminishes quality of life. The commonly used therapies for cough are opioid-derived 
over-the-counter medicines, which tend to be relatively ineffective when compared with 
placebo. In addition, these medicines have significant side-effects and potential for abuse 
that limit their usability. Likewise, the opiate codeine is among the most commonly 
prescribed medicines for cough despite similar limitations to its clinical efficacy and even 
greater potential for abuse. Overall, there is a significant unmet medical need for safe 
and effective medicines to treat chronic cough.
3.3.
Benefit/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 IB.
 
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3.3.1.
Risk Assessment
All potential risks of GSK2798745 are based on pre-clinical data.  No risks have been identified in the clinical studies of GSK2798745 
conducted prior to the effective date of this protocol.
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*ug/mL and/or maximum observed 
plasma concentration (Cmax) of 0.050 ug/mL on 
an individual basis.
Myocardial toxicity
Dogs (4-week study):  at 30 mg/kg/day, myofiber 
degeneration/necrosis and inflammation (2 
animals)
Participant Selection: Participants with history 
of acute coronary syndromes (including unstable 
angina), coronary angioplasty, or stenting within 
the past 6 months will be excluded.
Participant Monitoring: Cardiac troponin levels 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
will be monitored throughout the study.
Participant Exposure: Exposure levels will be 
maintained below the threshold detailed in the 
Dose Justification Section (see Section 5.5).
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 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 gastrointestinal (GI) bleeding will 
be excluded.  
Participant Monitoring: Assessment of faecal
occult blood will be performed at screening and 
at the end of each study period.
Participants will be monitored for GI intolerance 
and sequential clinical chemistry analysis,
including liver enzymes.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 monitored 
throughout the study.
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 
Electroencephalography (EEG)/CV study.  In 
other compounds in the same series, 
convulsions have been observed.
Participant Selection: Participants with 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.  
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 pressure was observed in preclinical 
studies. 
Participant Monitoring: Blood pressure will be 
monitored throughout the study.
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 
Participant Monitoring: Despite the very low 
risk that hearing will be affected, audiometry will 
be conducted during the study at baseline in 
each Treatment Period and at the Follow Up 
Visit.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
However, these findings are academic, and have 
not been observed in any drug induced model. 
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].
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Risk associated with blood draws 
Fainting, mild pain, bruising, irritation or redness 
at a phlebotomy site may be associated with 
blood draws.
Experienced site staff will follow standard 
approaches for managing events related to blood 
draws.
Risk associated with cough monitoring
Mild contact dermatitis (skin irritation) or redness 
may be associated at the sites where a 
microphone is adhered.
Site staff will follow standard approaches for 
managing events related to application of self-
adherent pads.
Risks associated with CXR (if required for 
participant selection)
The approximate effective radiation dose for a 
chest X-ray is 0.1 milliSievert (mSv).
If a participant has had chest imaging within the 
12 months prior to starting the study, the 
procedure does not need to be repeated.
 
 
 
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3.3.2.
Benefit Assessment

Potential benefit of receiving GSK2798745 that may have clinical utility during 
study duration.

Medical evaluations and assessments associated with study procedures, e.g. physical 
examination, electrocardiogram, laboratory assessments, chest x-ray (CXR) (if 
applicable).

Contributing to the process of developing new therapies in idiopathic or treatment 
resistant chronic cough, an area of unmet medical need. 
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study 
(e.g. dose selection, careful participant selection and risk monitoring), the potential risks 
identified in association with GSK2798745 are justified by the anticipated benefits that 
may be afforded to participants with idiopathic or treatment resistant chronic cough.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts during day-time hours 
following 7 days of dosing
Secondary 

To compare the safety of GSK2798745 
with placebo in participants with idiopathic 
or treatment-resistant chronic cough

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and other safety biomarkers
Exploratory

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo in 
participants with idiopathic or treatment 
resistant chronic cough

Total cough counts over 24 hours following 
7 days of dosing

To compare the efficacy of 7 days dosing 
of GSK2798745 with placebo at improving 
patient reported outcomes in participants 
with idiopathic or treatment-resistant 
chronic cough

Change from baseline cough severity and 
urge to cough visual analogue scale (VAS)

Change from baseline Leicester Cough 
Questionnaire (LCQ) score

To evaluate the pharmacokinetics (PK) of 
GSK2798745 and its M1 metabolite in 
participants with idiopathic or treatment-
resistant chronic cough

Plasma concentrations of GSK2798745, 
and derived PK parameters, as data permit
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, randomised, placebo-controlled, double-blind, two-period 
crossover study, in participants with chronic cough.
Each participant will have 2 treatment periods, and be randomised to one of the following 
treatments in each period:

4.8 mg GSK2798745 on Day 1, followed by 2.4 mg GSK2798745 once daily for 
6 days

Matching placebo once daily for 7 days 
Each participant will:

be screened (screening may be conducted across more than 1 visit);

have 2 treatment periods (each 7 days) with a washout period of 14 to 21 days
between the treatment periods; and

have a follow-up visit (within 7 to 10 days after their last dose).
Each participant will be involved in the study for a maximum of 10½ weeks.
Coughs will be recorded using the VitaloJAK cough monitor for 24 hours before dosing 
in each treatment period (baseline) and for 24 hours after dosing on Day 7 of each 
treatment period.
A minimum of one interim analysis for futility and possible sample size adjustment will 
be conducted during the study.
Figure 1
Study Design Overview
5.2.
Number of Participants
This is a study in participants with idiopathic or treatment refractory chronic cough.  The 
target number of evaluable participants is 24. A participant will be considered evaluable 
if they have completed at least one Treatment Period and have evaluable cough counting 
Screening
Treatment 
Period 1
(7 days)
Treatment 
Period 2
(7 days)
Follow-up 
Up to 28
days
14-21 
days
7-10
days
Placebo
GSK2798745
Placebo
GSK2798745
    = 24-h cough recording
 
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data from at least one Treatment Period.  A sample-size re-estimation will be conducted 
when approximately 50% of the target sample size has completed the study.  The sample 
size may be revised upwards or downwards (see Section 10.3.3).  Following the sample 
size re-estimation, the target number of evaluable participants will not exceed 40 and the 
number of participants randomised will not exceed 48.
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

A multicentre, randomised, double-blind, placebo-controlled crossover trial is a well-
established strategy to evaluate efficacy and safety of investigational medicinal 
products, such as GSK2798745. 

A placebo arm is included to determine the absolute effect of GSK2798745. In 
addition, the placebo-controlled design is appropriate as there are no effective, 
currently approved prescription medicines for chronic cough, and over-the-counter 
cough medicines have generally not shown benefit over placebo.  

Cough will be measured using a VitaloJAK cough device which is a validated, 
dedicated high fidelity recording device that provides ambulatory objective 
monitoring of cough with post-recording signal processing and expert systems to 
analyse coughs. Coughs will be recorded for 24 hours prior to dosing of each 
treatment period (baseline) and for 24 hours following dosing on Day 7 of each 
treatment period. 

The crossover design will be employed to minimise, as much as possible, the 
potential for variability in randomisation in a relatively small sample size.  

As chronic cough can significantly impact physical and emotional wellbeing, patient 
reported outcomes are important factors in determining the impact of a cough 
treatment. The Leicester Cough Questionnaire (LCQ) will be utilised as it is an 
established self-completed health related quality of life measure of chronic cough. 
The LCQ is a valid, repeatable 19 item self-completed quality of life measure of 
chronic cough which is responsive to change [Birring, 2003].
5.5.
Dose Justification
In this study, participants will take a 4.8 mg starting dose on Day 1, followed by a 2.4 mg 
GSK2798745 (tablet) once daily for remaining 6 days.
In the first time in human study with GSK2798745 (GlaxoSmithKline [GSK] study 
TR4113787), single doses up to 12.5 mg, and repeat doses of 5 mg once daily for 
 
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14 days, were tested in healthy participants.  In addition, participants with heart failure 
were treated for 7 days with once daily doses of 2.4 mg GSK2798745 (as a capsule with 
food).  There were no serious adverse events (SAEs) in study TR4117387. In other 
studies, with GSK2798745, there has been only one SAE to date. A participant with 
heart failure (Study 201881) had orthostatic hypotension during the washout period 
between the 2 treatment periods. The Principal Investigator (PI) deemed it not related to 
study treatment.
Another healthy participant study was conducted to compare the pharmacokinetics (PK)
of different tablet formulations administered with or without food (GSK study 204725).  
A population PK (POP PK) approach was used to analyse all available clinical PK data 
(taking into consideration participant weight, formulation, impact of food, and other 
variables).  Trial simulations were performed with this POP PK model with different 
dosing regimen.
A rat study was conducted assessing the ability of different doses of GSK2798745 
infusion to reduce the increased lung-to-bodyweight ratio induced by the TRPV4 agonist, 
GSK1016790.  Based on this study, the estimated human IC50 is 2.1–3.2 ng/mL.  To 
evaluate drug activity/efficacy at the intended dosing regimen, TRPV4 blockade was 
estimated using the population model, and the potency values derived from the rat 
pulmonary study. 
Based on the simulations, the intended dosing scheme for this study with up to 40 
evaluable participants is a 4.8 mg dose on Day 1 followed by a 2.4 mg dose once daily 
for the following 6 days.  Table 1 lists the predicted average TRPV4 inhibition over the 
24-hour period on Day 7 based on this potency range.  The schematic in Figure 2 also 
depicts the range of GSK2798745 systemic exposure and the predicted percent inhibition 
of TRPV4 with the intended regimen.  With a loading dose of 4.8 mg, both GSK2798745 
exposure and TRPV4 inhibition reach steady state from the first dose, compared with 
after 4 to 6 days without the loading dose.
This dose regimen was selected to ensure that no participant intentionally exceeds the 
daily AUC of 513 ng*hr/mL and Cmax of 50 ng/mL while simultaneously providing 
sufficiently high channel blockade.  That is the exposure observed at the no observed 
adverse effect level (NOAEL) of 3 mg/kg in the 3-month dog safety study with a 30-fold 
safety margin.  The likelihood of one or more participants of the 40 participants to be 
dosed with this regimen, exceeding the threshold on Day 1 and Day 7 is listed in Table 1.
Food does not significantly impact the predicted exposures of GSK2798745 and the 
resulting TRPV4 inhibition as displayed in Table 1.  So, GSK2798745 can be 
administered with or without food. 
 
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Figure 2
GSK2798745 exposure and % TRPV4 inhibition
Table 1
Predicted exposure, probability of exceeding threshold and TRPV4 
percent inhibition
4.8 mg on 
Day 1 and 
2.4 mg 
OD 
Days 2–7
24 h
exposure
Median (95% PI)
% Probability that ≥ 
1 of 40 participants 
exceed threshold of
%TRPV4 
inhibition over 
24-hour period
Median (95% 
PI)
AUC24 
(ng*hr/mL)
Cmax (ug/mL)
AUC24
(513 
ng*hr/mL)
Cmax
(50 
ng/mL)
With food
Day 1
201.5 (127.5 –
302.8)
18.7 (11.2 –
29.8)
0
0
72.0 (56.5 –
82.6)
Day 7
147.6 (79.4 –
281.1)
13.1 (7.5 –
22.8)
2.0
0.2
67.3 (46.6 –
83.6)
Without 
food
Day 1
202.0 (128.3 –
303.5)
22.7 (15.3 –
34.2)
0
0.6
72.0 (55.3 –
83.4)
Day 7
141.5 (76.6 –
269.7)
14.9 (9.1 –
24.8)
1.8
0.4
65.7 (44.2 –
82.7)
 
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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 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Chronic idiopathic cough for ≥1 year (before screening), defined as:

a cough that is unresponsive to at least 8 weeks of targeted treatment, or

a cough for which no objective evidence of an underlying trigger has been 
determined, despite medical investigations.
3.
No significant findings on chest imaging (CXR or CT scan) within 12 months before 
screening (participants with an abnormal CXR within 12 months, from a temporary 
process, will be allowed to participate if a repeat CXR is normal). 
4.
FEV1 ≥80% of the predicted normal value (at screening), or documented evidence of 
FEV1 ≥80% within the 6 months before screening.
5.
Score of ≥40 mm on the Cough Severity VAS at Screening.
WEIGHT
6.
Body weight ≥50 kg and body mass index (BMI) within the range 18 to 40 kg/m2
(inclusive) at screening.
SEX
7.
Male or female
a.Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol from the time of first dose of study treatment until 2 weeks after last dose of 
study treatment, and refrain from donating sperm during this period.
b.Female participants: 
A female participant is eligible to participate if she is not of childbearing potential
as defined in Appendix 5.
 
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INFORMED CONSENT
8.
Capable of giving signed informed consent as described in Appendix 3, 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:
MEDICAL CONDITIONS
1.
History or current evidence of any serious or clinically significant gastrointestinal, 
renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on 
permitted therapies or that would, in the opinion of the investigator or the medical 
monitor, make the participant unsuitable for inclusion in this study.
2.
History or current evidence of chronic productive cough.
3.
History of acute coronary syndromes (including unstable angina), coronary 
angioplasty, or stenting within the 6 months before screening.
4.
Active ulcer disease or gastrointestinal bleeding at the time of screening (positive 
fecal occult blood test [FOBT] at screening).
5.
History of stroke or seizure disorder within 5 years of screening.
6.
Respiratory tract infection within 6 weeks of screening.
7.
Participant who, in the investigator’s opinion, 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 Suicidality Severity Rating Scale (C-SSRS) in the last 6 months (assessed 
at screening).
8.
Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
9.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at screening.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
11. QTc >450 msec or QTc >480 msec in participants with bundle branch block at 
screening.
NOTE: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method.  It is either 
machine-read or manually over-read.
 
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PRIOR/CONCOMITANT THERAPY
12. Use of a listed prohibited medication (Section 7.7) within the restricted timeframe 
relative to the first dose of study treatment.
13. Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-
glycoprotein (Section 7.7).
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months of screening.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. Current enrollment or past participation within the 3 months before screening in any 
clinical study involving an investigational study treatment or any other type of 
medical research.
DIAGNOSTIC ASSESSMENTS 
17. Positive human immunodeficiency virus (HIV) antibody test at screening.
18. Presence of Hepatitis B surface antigen (HBsAg) at screening.
19. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
20. 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.
21. Cardiac troponin at screening > ULN for the assay.
OTHER EXCLUSIONS
22. History of alcohol abuse within 6 months of screening, in the opinion of the 
investigator.
23. Current smoker or history of smoking within the 6 months before screening, or a 
cumulative history of ≥ 20 pack years.
Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked)
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study.
 
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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 pummelos, exotic citrus fruits, grapefruit hybrids or fruit 
juices from 7 days before the start of study treatment until the end of study treatment 
(in both Treatment Periods).
6.3.2.
Alcohol and Tobacco

During each Treatment Period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample on Day 7.

Only non-smokers may be recruited into this study.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities (e.g. walking, watching television, reading).

Participants will be instructed to avoid noisy environments 24 hours before the 
audiometry assessments.

Participants will be asked to stay awake for 10 hours after attachment of the cough 
monitor, and to avoid noisy environments whilst wearing the cough monitor
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 SAEs.
Participants may be rescreened once.  If rescreening is performed, participants must be 
assigned a different unique subject identification number for the rescreening, and all 
screening procedures must be repeated.  See the study reference manual (SRM) for more 
details.  
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 
subject will be considered a screen failure.
 
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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
Dosage formulation:
White to almost white, round, 
film-coated tablet.  
Tablet A (micronized active 
pharmaceutical ingredient 
[API])
White to almost white, round, 
film-coated tablet
Unit dose strength:
2.4 mg
Not applicable
Route of Administration 
Oral
Oral
Dosing instructions:
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Two tablets to be taken on Day 
1. One tablet to be taken on 
Days 2 to 7.  All doses to be 
taken with a glass of water 
(~240 mL) at about the same 
time each day (2 hours 
relative to dosing on Day 1).
Packaging and Labelling
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
7.1.1.
Medical Devices

The VitaloJAK (Model 7100; manufactured by Vitalograph Ltd) will be used to 
sense and record coughs for up to 24 hours (baseline and Day 7 in each treatment 
period).  The VitaloJAK has a CE mark, indicating compliance to the Medical 
Devices Directive of the European Community (see Section 9.1.1).

Instructions for using the VitaloJAK will be provided in a study-specific manual 
provided by Vitalograph.
 
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7.2.
Dose Modification
No dose modifications are permitted without submission of a substantial amendment to 
the protocol.
7.3.
Method of Treatment Assignment
All participants will be centrally randomised 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 assignment to one of the 2 treatment sequences shown in Table 2, 
according to the randomisation schedule generated prior to the study by the Clinical 
Statistics Department at GSK.  In the randomisation, participants will be stratified based 
on inclusion in a cough study within the last 12 months (defined as taking an 
investigational product in a cough study within the last 12 months).  Each participant will 
be dispensed blinded study treatment, labelled with his/her unique randomisation number.
Table 2
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
AB
Placebo tablets for 7 days
GSK2798745 tablets for 7 days
BA
GSK2798745 tablets for 7 days
Placebo tablets for 7 days
Study treatment will be dispensed at the study visits summarized in the Schedule of 
Activities (SOA) (Section 2.2).  Returned study treatment should not be re-dispensed.
7.4.
Blinding
This will be a double blind (sponsor open) 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.  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;
however, only the statistician and programmer (and delegates) will have access to 
individual participant level data.  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 a participant’s treatment 
assignment is unblinded GSK must be notified within 24 hours after breaking the blind.  
 
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The date and reason that the blind was broken must be recorded in the source 
documentation and Case Report Form (CRF), as applicable.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
A participant whose treatment sequence 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 (i.e. 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
Participants will take the study treatment at home on Day 2 to 6.  Compliance will be 
assessed at the end of each Treatment Period by reviewing the participant diary card and 
questioning the participant.  A record of the number of tablets dispensed to and taken by 
each participant must be maintained and reconciled with study treatment and compliance 
 
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records.  Treatment start and stop dates will be recorded in the CRF for Day 1, 6 and 7 of 
each Treatment Period.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements), approved by the investigator, in consultation with 
the GSK Medical Monitor, that the participant is receiving at the time of enrolment, or 
receives during the study, must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications
Paracetamol at doses of ≤3 grams/day is permitted for use any time during the study.
Other concomitant medication will be considered on a case by case basis by the 
investigator in consultation with the GSK Medical Monitor.
Stable use of some medications may be permitted if the dose is stable for at least 3 
months prior to Day 1, and the medication was prescribed for an indication other than 
cough. The dose should remain constant throughout the study. Changes in dose are not 
permitted, unless required for safety or tolerability. These willl be considered on a case 
by case basis by the investigator in consultation with the GSK Medical Monitor.
7.7.2.
Prohibited Medications
Except for the permitted medication noted above and those approved by the investigator 
in consultation with the GSK Medical Monitor (Section 7.7.1), participants must abstain 
from taking prescription and 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) or 30 days for ACE inhibitors, before the first dose 
of study treatment until completion of the follow-up visit, unless in the opinion of the 
investigator and GSK Medical Monitor the medication will not interfere with the study.
During the study, participants should not use drugs that are strong inhibitors or inducers
of Cytochrome P450 (CYP) 3A4 or p-glycoprotein (P-gp), because they may alter 
GSK2798745 concentrations.  The list of background therapy/drugs may be modified 
based on emerging data. These include, but are not limited to, those listed in Table 3.
 
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Table 3
Strong inducers/inhibitors of CYP3A4 and P-gp
Antiretrovirals:
atazanavir, danoprevir, elvitegravir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir, 
boceprevir
Antibiotics:
clarithromycin, telithromycin, troleandomycin, rifampin
Oral antifungals:
ketoconazole, itraconazole, voriconazole
Antidepressant
nefazadone 
Immunosuppressant
cyclosporine
Anti-Epileptic
carbamazepine, phenytoin
GSK2798745 has weak CYP3A4 inhibition potential. It is possible that concentrations of 
drugs that are substrates of CYP3A4 may be increased. HMG-CoA reductase inhibitors, 
such as atorvastatin and simvastatin, are examples of CYP3A4 substrates that might be 
taken by the eligible participants. Participants being treated with simvastatin will be 
allowed to participate in the study, as long as their dose is 20 mg once daily.  
Participants being treated with >20 mg once daily simvastatin will be considered on a 
case basis by the investigator in consultation with the GSK Medical Monitor.  
Participants being treated with atorvastatin of any therapeutic dose are allowed to 
participate in the study.  The concentration of atorvastatin may be evaluated after the 
study.  The investigators may also consider substitutions of these medications.
It is strongly recommended that participants avoid using drugs that are sensitive 
substrates of Cytochrome P450 (CYP) 3A4 and/or P-gp or that have a low therapeutic 
index because concentrations of these substrates may be increased by GSK2798745. If 
co-administration of medications with interaction potential with GSK2798745 is 
necessary, investigators should monitor participants for loss of efficacy or consider 
substitutions of these medications.  
All concomitant medications may be reviewed by the Medical Monitor and it will be up 
to the discretion of the Investigator in consultation with the GSK Medical Monitor, 
whether the medication can be continued and/or the participant can participate in 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 the indication being studied is not life threatening or seriously debilitating.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who withdraw or who are withdrawn from study treatment will be withdrawn 
from the study.  See the SoA (Section 2.1) for assessments to be performed at early 
withdrawal.
Participants who start taking a prohibited medication during the study will be withdrawn, 
unless approved by the investigator in consultation with the GSK Medical Monitor.
8.1.1.
Adverse Event Stopping Criteria
Participants who experience an adverse event, which in the opinion of the investigator 
could jeopardise the participant’s safety, will be withdrawn from the study.
8.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm; or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.
Figure 3
Phase II Liver Chemistry Stopping and Increased Monitoring 
Algorithm
 
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Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7.
8.1.2.1.
Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.1.3.
QTc Stopping Criteria
If a participant meets either bulleted criterion below, two further ECG recordings should 
be done (obtained over a brief [e.g. 5 to 10 minute] recording period).  A participant who 
meets either bulleted criterion, based on the average of the triplicate ECG readings, will 
be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  
8.1.4.
Symptoms of Cardiac Ischemia and Cardiac Troponin Stopping 
Criteria
8.1.4.1.
Symptomatic Participant:
If a participant experiences symptoms of cardiac ischemia (e.g. chest pain, increased 
shortness of breath, and diaphoresis), cardiology consultation should be obtained 
immediately.  GSK2798745 should be discontinued permanently.  The participant should 
be evaluated by a cardiologist and undergo any clinically appropriate testing.  The 
participant should be followed up until symptoms are resolved.
 
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8.1.4.2.
Asymptomatic Participant:
Cardiac troponin will be measured pre-dose and at the end of dosing, in each Treatment 
Period.  If any cardiac troponin assessment is >ULN or >2 times the participant’s 
baseline value (Day -1, Treatment Period 1), the participant should be assessed for 
symptoms of cardiac ischemia (as above).  If the participant is asymptomatic, the 
participant can continue in the study after discussion with the Medical Monitor and close 
monitoring for symptoms.
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 for data to be collected at the time of withdrawal (early withdrawal 
visit).
8.3.
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.

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 summarised in the SoA. 

Protocol waivers or exemptions are not allowed 

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. 

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.
Efficacy Assessments
9.1.1.
Cough Counting
Cough monitoring will be conducted at the beginning and end of each treatment period, 
as shown in Section 2 (SOA).
The VitaloJAK cough monitor will be used.  The VitaloJAK cough monitor was 
developed by Prof 
 Dr 
 and Prof 
 at 
University Hospital of South Manchester NHS Foundation Trust (UHSM), and has been 
fully validated in clinical studies.  The VitaloJAK cough monitor has CE registration and 
Food and Drug Administration (FDA) 510K clearance.
The VitaloJAK Cough Monitor requires a disposable, single use chest sensor that is 
attached to the participant’s chest, and a ‘lapel microphone’ that is attached to the 
participant’s clothing. The monitor collects high fidelity recordings, recording all sound 
frequencies required for the semi-automated analysis of cough.  The recording 
automatically stops at 24 hours.  
Kits will be supplied by Vitalograph to the site containing all items required for each 24-
hour recording, including the monitor, memory card and battery packs. 
Recordings from the VitaloJAK Cough Monitor will be sent to Vitalograph for analysis 
via the Vitalograph Web Portal.  Recordings will be processed through the semi-
automated cough analysis system developed by UHSM. Vitalograph will QC check the 
recordings on receipt.  The recording will then be processed to remove non-cough sounds 
 
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and silences, leaving a set of segmented files for analysis by a Cough Analyst at 
Vitalograph. 
9.1.2.
Cough Visual Analogue Scale (VAS)
Participants will be asked to complete 2 VAS forms, one each to rate the severity of their 
cough, and their urge to cough (see SRM).
The VAS forms should be completed before other clinical assessments (and before the 
LCQ), and participants should be given instructions on how to complete the form.  The 
forms will be provided by GSK – the site should not make photocopies of the forms, or 
print from the PDF file.
9.1.2.1.
Cough Severity VAS
The participant will be asked:  ‘How severe was your cough today?’ 
The participant will place a mark on a 100 mm horizontal line, rating the severity of their 
cough from ‘Not at all’ to ‘Extremely’.
9.1.2.2.
Urge to Cough VAS
The participant will be asked:  ‘Please rate the intensity of your urge to cough today’ 
The participant will place a mark on a 100 mm horizontal line, rating their urge to cough 
from ‘No urge’ to ‘Severe urge’.
9.1.3.
Leicester Cough Questionnaire (LCQ)
The LCQ is a validated, self-completed, quality of life measure of chronic cough
[Birring, 2003].  The questionnaire is designed to assess the impact of cough on various 
aspects of the participant’s life.  
The LCQ should be completed after the Cough VAS, but before other clinical 
assessments, and participants should be given instructions on how to complete the 
questionnaire.  The participant will be asked to read 19 statements, and rate their answer 
on a 7 point Likert response scale (see SRM).  
9.2.
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). 
 
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9.2.1.
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 immediately and 
under no circumstance should this exceed 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.
9.2.2.
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. 
9.2.3.
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 8.3). Further information on follow-up procedures is given in
Appendix 4.
9.2.4.
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 
 
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investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g. summary or listing of 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.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
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 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
9.3.
Treatment of Overdose
For this study, any dose of GSK2798745 greater than the planned dose in the protocol, 
will be considered an 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.
 
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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 24 h 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 will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A full physical examination will include, at a minimum, measuring weight, and 
assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 

A brief physical examination will include, at a minimum, measuring weight, and 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).

Height will be measured at screening only.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
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 screening, three readings of blood pressure and pulse 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.
9.4.3.
Electrocardiograms

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 8.1.3 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

At screening, triplicate ECG are required:  3 individual ECG tracings should be 
obtained over a brief (e.g. 5 to 10 minute) recording period.
 
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9.4.4.
Audiometry
Audiometry will be performed by authorised, trained staff using standard audiometry 
techniques.  Participants will be instructed to avoid noisy environments 24 h prior to the 
audiometry assessments.  Only air conductance will be performed.  It will be at the 
discretion of the Investigator, Medical Monitor and/or the audiologist to determine if 
significant changes from baseline are seen and if a bone conductance test should be 
performed.  Details of the audiometry testing are in the SRM.
9.4.5.
Chest X-ray
CXR is only required if a participant has not had chest imaging within 12 months of 
screening. If a participant has had an abnormal CXR within 12 months, from a 
temporary process, the CXR may be repeated to determine eligibility.  
CXR will be performed by authorised, trained staff.  
9.4.6.
FEV1

FEV1 will be measured to assess eligibility.  It does not need to be repeated if there 
is documented evidence of FEV1 ≥80% within the 6 months before screening.

Spirometry assessments will be performed whilst the subject is in a seated position 
(if the assessment is done on a bed, the subject’s legs should be over the edge).

Spirometry assessments will be repeated until 3 technically acceptable measurements 
have been made.  To confirm eligibility, 1 or more of the 3 measurements is required 
to be ≥80%.
9.4.7.
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. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 to 10 days after the last dose of study treatment 
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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
 
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9.4.8.
Faecal Occult Blood Test
Based on the preclinical finding of gastric erosions (See Section 3.3.1), FOBT will be 
performed to determine eligibility and assess any possible study treatment-related GI 
blood loss. 
At each time-point, participants will be given 2 FOBT cards with instructions for 
completing (using 2 different bowel movements) and returning the tests (in person or by 
post).
9.4.9.
Columbia Suicidality Severity Rating Scale (CSSRS)
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.
Participants being treated with GSK2798745 should be assessed and monitored 
appropriately for suicidality and unusual changes in behaviour.  Consideration should be 
given to discontinuing GSK2798745 in participants who experience signs of suicidal 
ideation or behaviour.  Families of participants being treated with GSK2798745 should 
be alerted about the need to monitor subjects for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour, and to report such 
symptoms immediately to the study investigator. 
The CSSRS is a measure of suicidal ideation and behaviour, with demonstrated 
predictive validity and reliability.  Sections of the CSSRS include suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual suicide attempt(s).  The CSSRS 
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.
At screening, the ‘Baseline’ CSSRS questionnaire will be completed.  At all other time-
points, the ‘Since Last Visit’ CSSRS questionnaire will be used (see Section 2, SOA).
9.4.10.
Diary card
In each Treatment Period, a diary card will be used to collect:

dosing information for Days 2 to 6 (Date and Time of Dose); 

AEs; and 

concomitant medications.
 
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Between Treatment Periods 1 and 2 (the ‘Washout Period’), a diary card will be used to 
collect AEs and concomitant medications.
Paper diary cards will be used (see SRM).
9.5.
Pharmacokinetics

Blood samples for pharmacokinetic analysis of GSK2798745 will be collected at the 
timepoints indicated in the SOA (Section 2).

Blood will be collected in ethylenediaminetetraacetic acid (EDTA) tubes.  The actual 
date and time of each blood sample collection will be recorded.  

The timing and volume of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure adequate PK monitoring of GSK2798745 
and, if possible, any relevant GSK2798745 metabolites.  

Additional collection, processing, storage and shipping procedures are provided in 
the laboratory manual.

PK analysis will be performed under the control of Platform Technologies and
Science-In Vitro/In Vivo Translation (PTS-IVIVT)/ and Third Party Resourcing 
(TPR) GlaxoSmithKline.  Plasma 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 may be analyzed for the metabolite M1.  GSK may store the 
remaining plasma from the PK plasma samples for future possible additional 
metabolite analysis.  Additional analysis of compound-related metabolites may be 
reported under a separate protocol.

For participants taking atorvastatin, an extra sample will be taken at each PK time-
point for analysis of atorvastatin concentration, and possible analysis of atorvastatin 
metabolites.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
 
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See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Laboratory 
Manual.
10.
STATISTICAL CONSIDERATIONS
This study is designed to estimate the effect of GSK2798745 relative to placebo on day-
time cough count totals following seven days of dosing. Day-time cough count totals 
will be derived from the total number of coughs during the first 10 hours following 
dosing, during which time the participant is expected to be awake. 
The inference to be carried out will be with respect to the following hypothesis:

Treatment with GSK2798745 leads to an improvement in day-time 10-hour cough 
count totals compared with placebo.
The above hypothesis will be investigated in this study by means of a Bayesian approach, 
which will assume a non-informative prior distribution.  It is anticipated that the day-time
10-hour cough count totals will be log-transformed before statistical analysis, and hence 
the treatment effect will be evaluated in terms of a ratio of day-time cough count totals 
(GSK2798745 / placebo).  A day-time cough count total of at least 30% less for 
GSK2798745 than for placebo is of interest.  The posterior probability that the true ratio 
of the mean effect size of the test treatment and the mean effect size of the reference 
treatment (test) / (reference), is less than 0.7, and corresponding 90% credible 
intervals, will be obtained.  The posterior probability that the true ratio is less than 0.7 
will be referred to as PP (ratio<0.7).
10.1.
Sample Size Determination
A simulation approach has been employed to investigate the chance of correctly 
determining a positive study with the planned number of participants. An estimate of 
0.28 for the within subject variability in cough count totals was obtained from previous 
studies and this estimate was used in the simulations. 
A treatment ratio (active:placebo) of 0.7 is considered to indicate an effective treatment.  
A treatment ratio of 0.5 is considered to represent a very effective treatment.
A positive study will be declared if the posterior probability that the true treatment ratio 
is less than 0.7 is more than 70% (PP(ratio <0.7) >70%). Given the planned sample size 
of 24 participants, if our variability assumptions are correct, then if the true treatment 
ratio is 0.5, there is a 95.3% probability of correctly declaring success. Conversely, if the 
true treatment ratio is 1, there is a 0.2% probability of declaring success at the end of the 
study. 
An unblinded sample size re-estimation is planned in addition to the final analysis.  This 
will be performed when at least 12 participants have completed both dosing periods and 
key assessment data is available.  Cleaned efficacy data will be provided by Data 
Management to the unblinded study statistician. 
 
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Estimated treatment ratio of day-time cough counts between GSK2798745 and placebo 
will be calculated together with 90% credible intervals assuming a non-informative prior.  
This analysis will be supplemented by deriving predictive and/or conditional power in 
order to support sample size re-estimation. As a result of the sample size re-estimation, 
the sample size could be revised either upwards or downwards from the planned sample 
size of 24 evaluable participants, but the target number of evaluable participants will not 
exceed 40 participants.
Full details of the plan for the sample size re-estimation will be described in the 
Reporting and Analysis Plan (RAP).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database.
All Subjects
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received.
Pharmacokinetic
All randomised participants who take at least 1 dose of study 
treatment and for whom a pharmacokinetic sample was obtained 
and analysed.
 
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10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Day-time 10-hour cough counts following seven days’ dosing of 
GSK2798745 as compared with placebo will be analysed by first log 
transforming the day-time 10-hour cough counts recorded on day 7 of each 
dosing period. The difference between GSK2798745 and placebo in log-
transformed count rates will be investigated using a mixed effects model with 
fixed effects terms for treatment and period. Centre effects and the effect of 
whether or not the participant has participated in a cough clinical trial (which 
will be included as a stratification factor in the randomisation) in the previous 
12 months will also be investigated. Baseline cough counts may be included 
in the model as a covariate. Participant will be treated as a random effect in 
the model. The posterior probability and corresponding 90% credible
intervals that the ratio of the mean effect size of the test treatment and the 
mean effect size of the placebo treatment μ(test) - μ(placebo), is less than 1 
will be constructed. In addition, the posterior probability true effect size 
distribution will be used to obtain estimates for the probabilities that the true 
effect size falls below thresholds of interest (e.g. what is the probability the 
true ratio is less than 0.7 and less than 0.5).
The presence of carryover effects or treatment by period interaction will also 
be investigated and, if deemed appropriate, an analysis by period will be 
undertaken. 
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 are being tested and no statistical 
analyses will be performed.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards.
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram 
(ECG) will be summarized by treatment and time-point.
 
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10.3.3.
Interim Analyses
At least one interim analysis will be conducted during the course of the study.  The 
treatment level results will be made available to the GSK study team who will review the 
available cough count data before making a decision on whether to:
i) stop the study on the grounds of futility
ii) adjust the sample size, in the event that futility criteria have not been met. 
The interim analysis will also include a preliminary assessment of whether there is any 
evidence for the presence of carryover effects or treatment by period interaction.
Following the interim analysis, any adjustment to the sample size will be communicated 
to the sites.
The interim analysis will be conducted after at least 12 participants have completed both 
dosing periods and will look at day-time 10-hour cough count data, as well as supporting 
PK data, if required. 
The interim analysis will be performed by GSK Clinical Statistics and only the 
responsible statisticians (including QC statistician) and programmers will have access to 
individual participant data.  However, the findings of the interim analysis will be shared 
with the entire GSK study team. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.3.4.
Exploratory Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacokinetics
Modelling & Simulation Department within GlaxoSmithKline. Calculations will be 
based on the actual sampling times recorded during the study. The systemic 
concentrations of GSK2798745, any metabolites, and atorvastatin will be summarised, as 
data permit. The details of the PK analysis will be listed in the RAP. 
 
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11.
REFERENCES
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chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 
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Basoglu OK, A. Pelleg, S. Essilfie-Quaye, et al.,. Effects of Aerosolized Adenosine 5′-
Triphosphate vs Adenosine 5′-Monophosphate on Dyspnea and Airway Caliber in 
Healthy Nonsmokers and Patients With Asthma. Chest. 2005;128(4):1905-1909. 
Baxter M, S. Eltom, B. Dekkak, et al. Role of transient receptor potential and pannexin 
channels in cigarette smoke-triggered ATP release in the lung. Thorax. 
2014;69(12):1080-1089. 
Birring S, B Prudon, A J Carr, S J Singh, M D L Morgan, I D Pavord. Development of a 
symptom specific health status measure for patients with chronic cough:  Leicester Cough 
Questionnaire (LCQ). Thorax, 2003 58(4):339-343.
Bonvini SJ, M.A. Birrell, M.S. Grace, et al. Transient receptor potential cation channel, 
subfamily V, member 4 and airway sensory afferent activation: Role of adenosine 
triphosphate. J Allergy Clin Immunol. 2016;138(1):249-261 e12. 
Ford AP, B.J. Undem. The therapeutic promise of ATP antagonism at P2X3 receptors in 
respiratory and urological disorders. Front Cell Neurosci. 2013;7:267. 
GlaxoSmithKline Document Number 2013N162862_03. Investigator’s Brochure (IB) for 
GSK2798745. Version 04, 2016-Jun-03.
Idzko M, H. Hammad, M. van Nimwegen, et al. Extracellular ATP triggers and maintains 
asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-
919. 
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. 
Schappert SM, C.W. Burt. Ambulatory care visits to physician offices, hospital outpatient 
departments, and emergency departments: United States, 2001-02. Vital Health Stat 13. 
2006;159:1-66. 
Smith JA, A. Woodcock. Chronic Cough. N Engl J Med. 2017;376(2):183-184. 
Sumner H, Woodcock A, Kolsum U, Dockry R, Lazaar AL, Singh D, Vestbo J, Smith 
JA. Predictors of objective cough frequency in chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med. 2013;187(9):943-9. 
Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. 
Neurosci Lett. 2005;382(3):304-8. 
 
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Toft-Bertelsen TL, D. Krízaj, and N. MacAulay. When size matters: transient receptor 
potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor. The Journal 
of Physiology. 2017:doi: 10.1113/JP274135. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
ATP
Adenosine Triphosphate
AUC
Area under concentration-time curve
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 Disease
CPK
Creatinine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
CSSRS
Columbia Suicidality Severity Rating Scale
CT
Computed tomography
CXR
Chest X-ray
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FOBT
Faecal Occult Blood Test
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IC50
50% maximal inhibitory concentration
ICF
Informed consent form
 
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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IVIVT
In Vitro/In Vivo Translations
IWRS
Interactive Web Response System
kg
kilogram
KO
Knockout
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemogloin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
mSV
MilliSievert
NOAEL
No observed adverse effect level
nM
Nano Molar
P2X3
P2X purinoceptor 3
P-gp
p-glycoprotein
PK
Pharmacokinetic
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SOA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TPR
Third Party Resourcing
TRPV4
Transient receptor potential vanilloid 4 
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WBC
White blood cells
WOCBP
Women of Child Bearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Vitalograph
VitaloJAK
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)
Total Protein
Glucose 
(Fasting not 
required)
Calcium
Alkaline phosphatase
Creatinine 
phosphokinase 
(CPK)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Cardiac troponin
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 hepatitis C 
virus antibody)
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 8.1.2 and Appendix 7.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
 
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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 International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 

Any 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 authorised 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 authorised 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 centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised 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 
authorised 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 authorised 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 multi-centre 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 (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

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 authorised 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 each 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.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
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 
 
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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 
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 (eg, 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, diarrhea, influenza, 
and accidental trauma (eg, 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
 
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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 
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
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 
 
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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.
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 
 
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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, 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.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g. check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor (who is also the SAE coordinator) by 
telephone.

Contacts for SAE reporting can be found in the SRM.
 
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SAE Reporting to GSK via Paper CRF (only necessary when electronic data collection tool 
is not available)

The SAE paper CRF should be emailed to the medical monitor (who is also the SAE 
coordinator).

In rare circumstances, if email is not possible, 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.
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.
2.
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) and estradiol 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 and estradiol 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 5 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 Section 6.1.

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 5
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 2 weeks 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 fetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2798745 or chronic cough and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2798745 (or study treatments of this drug class), and chronic 
cough. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome.

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2798745 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2798745 (or study treatments of 
this class) or chronic cough continues, but no longer than 15 years after the last 
participant last visit or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

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 chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(defined as Day -1; Treatment Period 1) (see 
MONITORING below)

Do not restart/rechallenge participant with 
study treatment (not allowed under this 
protocol)  

Permanently discontinue study treatment 
and continue any protocol specified follow up 
assessments 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis, 
within 24 hours after last dose5

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 
 
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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 h

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) page 
For bilirubin or INR criteria:

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 pages.
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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.8.
Appendix 8: 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 2  (22-NOV-2017)
Overall Rationale for the Amendment:  The protocol was amended in response to 
comments from the Medicines and Healthcare Products Regulatory Agency (MHRA).
Section # and Name
Description of Change
Brief Rationale
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Addition of the Columbia Suicidality Severity 
Rating Scale (CSSRS) at Follow-up.
Requested by the MHRA.
Section 7.4 (Blinding)
The following change was made:  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.  
Requested by the MHRA.
Section 8.1.1
(Adverse Event 
Stopping Criteria)
Addition of the following section:
8.1.1 Adverse Event Stopping Criteria
Participants who experience an adverse 
event, which in the opinion of the 
investigator could jeopardise the
participant’s safety, will be withdrawn from 
the study.
Requested by the MHRA.
Protocol Amendment 1  09-OCT-2017
Overall Rationale for the Amendment:  The primary reason for amending the protocol 
is the removal of the Simplified Nutritional Appetite Questionnaire (SNAQ).  The 
 
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original protocol included the SNAQ, because of the preclinical finding of reduced food 
consumption in dogs (30 mg/kg/day) and rats (300 mg/kg/day).  Since the publication of 
the original protocol, data has been reviewed from a study of GSK2798745 in heart 
failure patients.  Participants took 2.4 mg GSK2798745 (n=10) or placebo (n=12) for 
7 days.  As shown in the table below, there was no observable difference in weight and 
appetite in participants receiving GSK2798745 and placebo.  Therefore, the GSK Global 
Safety Board agreed to the removal of the SNAQ from future protocols.  Weight will be 
measured at screening, follow-up, and the beginning and end of each Treatment Period, 
and adverse events that may be associated with low food consumption will be reviewed.
Baseline (mean ± SD)
Day 7 (mean ± SD)
Change from Baseline
Weight (kg)
2.4 mg 
87.44 ± 18.54
87.67± 17.50
0.23
Placebo
83.58 ± 10.46
83.33 ± 10.56
-0.25
SNAQ Score (Maximum = 20)
2.4 mg
16.2 ± 1.69
16.7 ± 1.95
0.5 ± 1.18
Placebo
15.3 ± 1.83
16.2 ± 1.53
0.8 ± 1.11
Section # and Name
Description of Change
Brief Rationale
Section 2.1 
(Screening and 
Follow-up Schedule 
of Activities)
Removal of the SNAQ at the 
follow-up visit.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
The option for a CT scan at screening was 
included in the original protocol, in error.  If 
chest imaging (chest x-ray or CT scan) has 
not been conducted within 12 months of 
screening, a chest x-ray will be conducted.
Section 2.2 
(Treatment Period 1 
and 2 Schedule of 
Activities)
Removal of the SNAQ at 
Day -1 and Day 8, in each 
Treatment Period.
Rationale for removal of the SNAQ 
described above.
Section 3.3.1 (Risk 
Assessment)
Removal of the SNAQ.
Removal of the option for a 
CT scan at screening.
Rationale for removal of the SNAQ 
described above.
Rationale for removal of CT scan at 
screening described above.
 
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Section # and Name
Description of Change
Brief Rationale
Section 7.7.1 
(Permitted 
Medications)
The following change was 
made:  Stable use of some 
medications may be 
permitted if the dose is 
stable for at least 28 days
3 months prior to Day 1.
Time period of stable dose changed from 
28 days to 3 months, because 28 days 
might not be sufficient to achieve stable 
dosing of some permitted medications.
Section 8.1.3.2
(Symptoms of 
Cardiac Ischemia 
and Cardiac 
Troponin Stopping 
Criteria: 
Asymptomatic 
Participant)
The following change was 
made:  If any cardiac 
troponin assessment is 
>ULN or >2 times the 
participant’s baseline value 
(Screening Day -1, 
Treatment Period 1), the 
participant should be 
assessed for symptoms of 
cardiac ischemia (as above).
Definition of baseline changed from 
Screening to Treatment Period 1, Day -1 to 
be consistent with the baseline used for 
other laboratory tests.
Section 9.4.5 
(Simplified Nutritional 
Appetite 
Questionnaire)
Removal of complete 
section.
Rationale for removal of the SNAQ 
described above.
Section 9.4.6 (Chest 
Imaging)
Removal of the option for a 
CT scan at screening.
Rationale for removal of CT scan at 
screening described above.
Section 9.4.9 
(Columbia Suicidality 
Severity Rating 
Scale (CSSRS)
Addition of text stating that 
families of participants 
should be alerted about 
monitoring for emergence of 
suicidal ideation and 
behaviour.
New text added to ensure compliance with 
GSK’s Global Safety Board-Approved 
Recommendations for Prospective 
Assessment of Suicidal Ideation and 
Behaviour in Relevant Clinical Studies.
Section 9.5
(Pharmacokinetics)
Blood sample volume 
removed.
Blood volume of sample removed, as this is 
still to be confirmed.  Sample collection 
instructions to be provided in the laboratory 
manual. 
 
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